F AKHSHEENA ANJUM
Transcript of F AKHSHEENA ANJUM
ARMACOTHERAPEUTlC STUDIES AND ASSOCIATED
RISK FACTORS OF BREAST CARCINOMA IN LOCAL
POPULATION
F AKHSHEENA ANJUM 8.Pharm, M.Pharm (Pharmaceutics)
~ Thesis Submitted For Partial Fulfillment Of The Requirement For The Degree Of Doctor Of Philosophy In (Pharmaceutics)
Pharmacy
DEPARTMENT OF PHARMACEUTICS FACULTY OF PHARMACY UNIVERSITY OF KARACHI
KARACHI·75270 PAKISTAN
2014
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DEDICATION
DEDICATED TO THE HOLY PROPHET
(PEACE BE UPON HIM)
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ACKNOWLEDGEMENT
All the praises are for ALMIGHTY ALLAH, the most beneficent and the most merciful, who
gave me the courage and strength to complete this task. May ALLAH always shower His endless
blessings onto me and my family, in all the ways and in all times.
The completion of this doctoral dissertation was not possible without the support of several
people and it is a pleasure to convey my gratefulness to all in my humble acknowledgment. First
and foremost I offer my profound gratitude to my research supervisor Prof. Dr. Nighat Razvi
for her unreserved guidance, help and support. She is a person with kind and positive disposition
and always comes up with constructive advices. Her life time tireless service in the field of
pharmacy exceptionally inspired and enriched my growth as a student and researcher and also as
a human being. Without her valuable and patient guidance and encouragement it was not
possible to finish this work. Her support, help and guidance through this Ph.D. work has been
priceless.
I would like to express my sincerest appreciation and gratitude to Dr. M. Aslam, for his
guidance and scientific support and encouragement in the course of my research work. I am truly
thankful to Dr. M. Sualeh and Dr. Riaz Bhatti for their help to accomplish the research in the
hospital. I offer my sincere thanks to Dr. Mehwish Tehseen and Dr. Ahmad Mateen, KIRAN
hospital for all their attention, consideration and kind help.
I am especially grateful to Prof. Dr. Ghazala H. Rizwani, Dean (Faculty of Pharmacy),
University of Karachi for her constant moral support throughout my work. Some faculty
members had been very kind enough to extend their help at different phases of my research
work, whenever I approached them. I would like to convey many thanks to Prof. Dr. Harris
Shoaib and also to Dr. Rabia Ismail Yousuf for valuable suggestions and comments to make
my research experience stimulating and productive.
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I am blessed with an affable and cheerful group of friends who are not only a source of joy but
also are always there for sincere, good advice and collaboration as well. I am thankful all to my
beloved friends who have always cared for me, prayed for me and supported me throughout the
course of this study. I am also thankful to Naeem Bhai at the Department of Pharmaceutics,
Faculty of Pharmacy, University of Karachi, who work tirelessly at the department.
Last but not least, very special thanks and deepest gratitude to my parents and my family
members for their endless love and constant prayers, for their patience and support throughout
my research work, without whom, I was unable to complete my project. Finally, I would like to
thank everyone who had been important to the successful completion of this Dissertation.
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ABSTRACT
Breast cancer has emerged as a major devastating disease for females globally. Trends in the
incidence of breast cancer differ worldwide due to various factors like cultural, environmental,
life-style factors, etc., hence distinct study for every geographical zone is necessary. Many
researches have been done to probe information regarding its major risk factors so that
improvements can be made not only regarding its screening procedures but also for its
pharmacotherapy/ management. The objectives of this research were: to determine the
association of selected characteristics in the cases and controls regarding breast cancer; to
determine the risk of breast cancer incidence in females associated with various factors; to
evaluate the use and response of various therapies employed in breast cancer cases; to assess the
adverse effects occurring after the use of various therapies in breast cancer cases.
This thesis is a descriptive study that covers both epidemiological and medical features of breast
cancer in Pakistani females and is presented with application of statistical methods and
international assessment scales. The research work was conducted in KIRAN hospital recruiting
n=811 breast cancer cases and n=1965 controls were recruited from all over Karachi. Majority
respondents lied in the age group of 31-50 years (p<0.05) and were married. There were
significant variations in the education level of both the cases and controls (p<0.001). Many of the
life style and reproductive characteristics of the respondents were associated significantly
(p<0.001). A strong, positive family history of breast cancer was found only in a very few cases
and not in the control group. The results of logistic regression analyses, stratification by tumor
receptor status and menopausal status showed that the odds of attaining breast cancer in the cases
were likely to be associated with marriage within family, in housewives, low education level,
milk consumption, menarche age > 13 years, in menopausal women, no breast feeding, family
history of breast cancer and concomitant diseases like hypertension and diabetes mellitus.
Breast cancer stage 1 was found prevalent with cases of left side; most of the patients were
suffering from breast cancer belonged to the age group of 31-50 years. Fortunately, breast cancer
metastasis was seen in a very few cases (n=101) which mostly involved bones (38.46%) and
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lungs (33.33%). Among n=811 cases, mostly were ER +ve, PR –ve and HER 2 Neu –ve. The
joint receptor status showed that there were 39.4% E/P+H-, 25.70% E/P+H+, 13.70% E-P-H+
and 36.16% E-P-H- breast cancer cases.
Different treatment modalities were employed for breast cancer cases and various treatments
involved local therapy (surgery and radiation), chemotherapy and endocrine therapy. Among all
the cases, 95.68% underwent surgery, majority belonging to the age group of 31-50 years.
Radiation therapy was employed for 97.16% cases. The overall response for radiation therapy
was ‘good’ (complete) in >90% cases showing statistically significant association in the age
groups of 31-40 (p<0.05) and >51 (p<0.001) years. The adjuvant endocrine therapies were
prescribed to n=508 cases, in which Tamoxifen (20 mg tablets) were prescribed to 96.06% cases.
The cases receiving endocrine therapy were mainly ER +ve (47.24%), PR –ve (53.7%) and HER
2 Neu –ve (45.3%); general response perceived was ‘good’ (complete) in the cases.
Chemotherapy was prescribed to n=760 cases, majority belonging to the age group of 41-50
years. Its response was found ‘good’ (complete) significantly (p<0.001) in the age groups of 20-
30 years and 41-50 years.
The ADRs occurring due to breast cancer treatments were assessed and also analyzed by using 3
different international scales for causality, preventability and severity i.e. Naranjo’s algorithm,
modified Schumock and Thornton scale and modified Hartwig’s and Siegel scale respectively.
The most common adverse effects observed in breast cancer cases due to radiation therapy were
fatigue/ body aches (>75%) and skin hyperpigmentation (>70%). The most commonly found
ADRs related to adjuvant endocrine therapy were heat intolerance (50.98%) and myalgia
(40.55%). Most commonly occurring adverse events due to chemotherapy were vomiting/ nausea
(98.52%), anemia/ neutropenia (94.20%), alopecia (94.08%) and fatigue/anorexia (91.61%).
The present study supports for the association of many characteristics that are potential risk for
developing breast cancer in female population in Karachi, Pakistan. The receptor status, cancer
grade, environmental, reproductive and life style factors and family history of diseases in the
breast cancer cases provide a deep insight to the incidence of breast cancer. The results regarding
the use of common treatment modalities in breast cancer cases can aid in designing better and
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newer treatment regimens while considering association of individual’s specific characteristics.
This may also aid in patient education, awareness and counseling to improve compliance;
patients can be facilitated with age-appropriate support and care. It was noted that adjuvant
biologic therapy besides adjuvant endocrine therapy was not prescribed to patients, which would
have been helpful to eradicate the disease.
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CONTENTS
DEDICATION……………………………………………………………………………..i
ACKNOWLEDGEMENT………………………………………………………………...ii
ABSTRACT……………………………………………………………………………...iv
KHULASA………………………………………………………………………………vii
LIST OF TABLES………………………………………………………………………xv
LIST OF FIGURES…………………………………………………………………...xviii
ABBREVIATIONS……………………………………………………………………..xix
1. INTRODUCTION……………………………………………………………….1
1.1 BREAST CANCER EPIDEMIOLOGY……………………………………...1
1.2 RISK FACTORS FOR BREAST CANCER…………………………………2
1.2.1 AGE…………………………………………………………………...3
1.2.2 BMI/OBESITY………………………………………………………..3
1.2.3 EDUCATION LEVEL/ SOCIO-ECONOMIC STATUS………….….4
1.2.4 GENETIC FACTORS/ FAMILY HISTORY…………………………4
1.2.5 LIFE STYLE/ ENVIRONMENTAL CHARACTERISTICS…...……5
1.2.5.1 DIET………………………………………………………………5
1.2.5.2 ALCOHOL INTAKE………………………………………….….6
1.2.5.3 XENO-ESTROGENS……………………………………………..6
1.2.5.4 SMOKE…………………………………………………………...6
1.2.6 USE OF EXOGENOUS HORMONES (CONTRACEPTIVES &
HRT)……………………………………………………………….….7
1.2.7 ENDOGENOUS HORMONES……………………………………….8
1.2.8 REPRODUCTIVE FACTORS……………………………………….8
1.2.8.1 AGE OF MENARCHE AND MENOPAUSE……………………8
1.2.8.2 PARITY…………………………………………………...............9
1.2.8.3 AGE AT FIRST CHILD BIRTH……………………………..…10
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1.2.8.4 BREAST FEEDING………………………………………….…10
1.3 THE FEMALE BREAST……………………………………………………11
1.4 THE FEMALE SEX HORMONES AND RECEPTORS……………….….12
1.5 THE TUMOR MARKERS IN BREAST CANCER……………………….15
1.5.1 ER & PR STATUS……………………………………………….….15
1.5.2 HER2/neu STATUS……………………………………………..…..16
1.6 BREAST CANCER CLASSIFICATION………………………………..…17
1.6.1 BREAST CANCER METASTASIS……………………………..…18
1.6.1.1 AXILLARY LYMPH NODE METASTASIS……………..…..18
1.6.1.2 DISTANT METASTASIS…………………………………..….18
1.7 BREAST CANCER STAGING AND GENERAL TREATMENT
RECOMMENDATIONS……………………………………………………19
1.7.1 STAGE 0……………………………………………………..……...20
1.7.2 STAGE I AND II (a OR b)…………………………………………..20
1.7.3 STAGE III a AND (OPERABLE) III c……………………………..21
1.7.4 STAGES III b, (INOPERABLE) III c AND INFLAMMATORY BREAST
CANCER…………………………………………………21
1.7.5 STAGE IV…………………………………………………………..22
1.8 THE PROGNOSTIC FACTORS FOR BREAST CANCER……………….22
1.9 BREAST CANCER TREATMENT: THERAPEUTICS BY CLASS……..22
1.9.1 LOCAL THERAPY (SURGERY & RADIATION)………..…..…..24
1.9.2 ENDOCRINE THERAPY…………………………………….….…25
1.9.2.1 TAMOXIFEN………………………………………………..….25
1.9.2.2 AROMATASE INHIBITORS………………………….……….26
1.9.3 CHEMOTHERAPY…………………………………………………26
1.9.3.1 CYCLOPHOSPHAMIDE……………………………………….30
1.9.3.2 PLATINUM COMPOUNDS……………………………………31
1.9.3.3 TAXANES………………………………………………………31
1.9.3.4 ANTHRACYCLINES………………………………………….32
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1.9.3.5 CAPECITABINE………………………………………………..32
1.9.3.6 GEMCITABINE………………………………………………...32
1.9.3.7 VINORELBINE…………………………………………………33
1.9.4 MONOCLONAL ANTIBODIES: TRATUZUMAB……………….33
1.9.5 PROTEIN TYROSINE KINASE INHIBITOR: LAPATINIB………34
1.10 SUMMARY ACCOUNT FOR ADJUVANT BREAST CANCER
THERAPY…………………………………………………………………34
1.11 SUMMARY ACCOUNT FOR METASTATIC BREAST CANCER
THERAPY…………………………………………………………………35
1.12 ADVERSE DRUG REACTIONS……………………………………..35
1.12.1 ASSESSMENT OF ADVERSE DRUG REACTIONS……………36
2. STUDY OBJECTIVES…………………………………………………………….38
3. LITERATURE REVIEW………………………………………………………….39
3.1 BREAST CANCER………………………………………………………..39
3.2 RISK FACTORS OF BREAST CANCER ……………………………….49
3.3 PHARMACOTHERAPY AND ADRs OF BREAST CANCER…………74
3.3.1 LOCAL THERAPY (SURGERY & RADIATION) IN BREAST
CANCER………………………………………………………………………74
3.3.2 ENDOCRINE THERAPY IN BREAST CANCER…………………….79
3.3.3 CHEMOTHERAPY IN BREAST CANCER…………………………..84
3.3.4 MISCELLANEOUS…………………………………………………….91
4. METHODOLOGY………………………………………………………………..93
4.1 STUDY DESIGN…………………………………………………………………93
4.2 PLACE OF STUDY………………………………………………………………93
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4.3 APPROVAL FOR STUDY……………………………………………………….93
4.4 SUBJECTS SELECTION CRITERIA……………………………………………93
4.4.1 DEMOGRAPHIC INFORMATION……………………………………………93
4.4.2 INCLUSION CRITERIA……………………………………………………….93
4.4.3 EXCLUSION CRITERIA…………………………………………………..…….94
4.4.4 INFORMED CONSENT…………………………………………………………..94
4.5 FORMAT OF STUDY QUESTIONNAIRE………………………………..………94
4.6 DATA COLLECTI0ON……………………………………………………………..95
4.6.1 DATA CODING……………………………………………………………….…..96
4.7 PROCEDURE FOR THE STUDY…………………………………….……….…....97
4.8 DATA ANALYSIS……………………………………………………………….…97
4.8.1 STATISTICAL ANALYSIS………………………………………………………97
4.8.2 ADRs ANALYSIS………………………………………………………………..98
5. RESULTS…………………………………………………………………………….99
5.1 DESCRIPTIVE ANALYSIS OF RISK FACTORS IN CONTROLS
AND CASES…………………………………………………………………………….99
5.2 LOGISTIC REGRESSION ANALYSIS FOR VARIOUS RISK FACTORS ASSOCIATED
WITH BREAST CANCER……………………………………………..99
5.3 BASELINE CHARACTERISTICS OF BREAST CANCER CASES……………100
5.4 PHARMACOTHERAPY OF BREAST CARCINOMA………………………….100
5.4.1 LOCAL (SURGERY & RADIATION) THERAPY IN BREAST CANCER
CASES………………………………………………………………………………..100
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5.4.2 ENDOCRINE THERAPY USED BY BREAST CANCER CASES…………..101
5.4.3 CHEMOTHERAPY USED IN BREAST CANCER CASES…………………..101
5.5 ASSESSMENT OF ADRs USING VARIOUS SCALES………………………….101
5.5.1 ADVERSE EVENTS ACCORDING TO VARIOUS INTERNATIONAL SCALES
AFTER BREAST CANCER RADIATION THERAPY………………………………101
5.5.2 ADVERSE EVENTS ACCORDING TO VARIOUS INTERNATIONAL SCALES
AFTER BREAST CANCER ENDOCRINE THERAPY………………………………101
5.5.3 ADVERSE EVENTS ACCORDING TO VARIOUS INTERNATIONAL SCALES
AFTER BREAST CANCER CHEMOTHERAPY…………………………………….101
6. DISCUSSION……………………………………………………………………….137
6.1 BREAST CANCER………………………………………………….……………137
6.2 RISK FACTORS OF BREAST CANCER…………………………………………139
6.2.1 DESCRIPTIVE STUDIES………………………………………………………139
6.2.2 BINARY LOGISTIC REGRESSION ANALYSES……………………………142
6.2.3 MULTINOMIAL LOGISTIC REGRESSION ANALYSES……………………148
6.3 BREAST CANCER CASES OF THE STUDY…………………………………...151
6.4 BREAST CANCER TREATMENT MODALITIES AND THEIR EFFECTS……155
6.4.1 LOCAL THERAPY (SURGERY & RADIATION) USED IN BREAST CANCER
PATIENTS…………………………………………………………………………….156
6.4.2 ADJUVANT ENDOCRINE THERAPY USED IN BREAST CANCER
PATIENTS……………………………………………………………………………158
6.4.3 ADJUVANT CHEMOTHERAPY USED IN BREAST CANCER PATIENTS..162
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7. CONCLUSION…………………………………………………………………..170
8. REFERENCES……………………………………………………………………172
9. APPENDIX……………………………………………………………………….236
9.1 RESEARCH PUBLICATION
9.2 STUDY QUESTIONNAIRE
9.3 INFORMED CONSENT
9.4 APPROVAL OF STUDY
9.5 BREAST CANCER STAGING
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LIST OF TABLES
Table 1: General classification of breast cancer………………………………..…17
Table 2: Stages of breast cancer………………………………………………..….19
Table 3: Therapeutic agents for breast cancer……………………………………..23
Table 4: Dose/schedule of some chemotherapeutic agents for breast cancer……...27
Table 5: Toxicities related to some chemotherapeutic agents for breast cancer…..30
Table: 6 ADRs assessment scales…………………………………………………..37
Table 7: Demographic characteristics of study subjects…………………………..102
Table 8: Life style characteristics of study subjects……………………………….103
Table 9: Reproductive characteristics of study subjects…………………………..105
Table 10: Disease information about study participants…………………………...106
Table 11: Binary logistic regression analysis for various characteristics of cases and
controls………………………………………………………………………………107
Table 12: Binary logistic regression analysis for various life style characteristics of study
subjects………………………………………………………………………………108
Table 13: Binary logistic regression analysis for reproductive variables of study
subjects…………………………………………………………………………………109
Table 14: Bivariate (adjusted) logistic regression analysis of risk factors of breast
cancer……………………………………………………...............................................110
Table 15: Bivariate (adjusted) logistic regression analysis of life style factors of breast
cancer………………………………………………………………………………….111
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Table 16: Bivariate (adjusted) logistic regression analysis of reproductive risk factors of breast
cancer………………………………………………………………………….112
Table 17: Multivariate adjusted logistic regression analysis of established risk factors of breast
cancer…………………………………………………………………………..113
Table 18: Multivariate adjusted logistic regression analysis for established and suspected risk
factors of breast cancer……………………………………………………………114
Table 19: Multinomial logistic regression analysis of breast cancer risk factors by hormone
receptor status……………………………………………………………….116
Table 20: Multinomial logistic regression analysis of breast cancer risk factors by breast cancer
stage…………………………………………………………………………….118
Table 21: Breast cancer risk factors stratified by menopausal status………………….119
Table 22: Breast cancer site in different age groups………………………………….122
Table 23: Breast cancer site in various cancer stages………………………………….122
Table 24: Receptor status in various age groups of breast cancer cases………………123
Table 25: Receptor status and breast cancer stages in patients……………………….124
Table 26: Surgery in various age groups of breast cancer cases………………………127
Table 27: Radiation therapy in various age groups of breast cancer cases……………..128
Table 28: Response of radiation therapy in various age groups of breast cancer
cases…………………………………………………………………………………….128
Table 29: Adverse reactions due to radiation therapy in breast cancer cases…………..129
Table 30: Use of Endocrine therapy by breast cancer patients…………………………129
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Table 31: Types of endocrine drugs used by breast cancer patients……………………130
Table 32: Adverse reactions due to endocrine therapy and their treatment in breast cancer
cases…………………………………………………………………………………..130
Table 33: Cycles and response of Chemotherapy in different age groups of breast cancer
cases…………………………………………………………………………………..131
Table 34: Various chemotherapeutic agents used in breast cancer cases…………….132
Table 35: Adverse effects and their treatment due to chemotherapy in breast cancer
patients………………………………………………………………………………133
Table 36: Different scales used for assessment of ADRs due to radiation therapy for breast
cancer………………………………………………………………………….134
Table 37: Different scales used for assessment of ADRs due to hormonal therapy for breast
cancer………………………………………………………………………….135
Table 38: Different scales used for assessment of ADRs due to chemotherapy for breast
cancer…………………………………………………………………………………136
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LIST OF FIGURES
Fig. 1: Effect of estrogen on the growth of breast cells……………………………….....13
Fig. 2: Proliferative changes in the breast cells due to estrogen…………………….…..14
Fig. 3: Different stages of cancer cell variation…………………………………………20
Fig. 4: Inhibition of estrogen receptor by Tamoxifen………………………………...…25
Fig. 5: Working of chemotherapeutic agents……………………………………………27
Fig. 6: Age distribution among cases and controls…………………………………….104
Fig. 7: House wives and working controls and cases…………………………………..104
Fig. 8: Year of diagnosis of breast cancer……………………………………..……….120
Fig. 9: Year of registration of breast cancer cases in hospital………………………….120
Fig. 10: Overall stages of breast cancer in patients…………………………………….121
Fig. 11: Breast cancer site in patients…………………………………………………121
Fig. 12: Metastatic sites in breast cancer patients………………………………………125
Fig. 13: ER status in breast cancer cases……………………………………………..125
Fig. 14: PR status in breast cancer cases………………………………………………..126
Fig. 15: HER2/neu status in breast cancer cases………………………………………..126
Fig. 16: Joint receptor status of ER, PR and HER2/neu in breast cancer cases………..127
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ABBREVIATIONS
AIs Aromatse Inhibitors
AC Adriamycin (Doxorubicin), Cyclophosphamide
AC x T Adriamycin (Doxorubicin), Cyclophosphamide x Taxane (Paclitaxel)
ADRS Adverse Drug Reactions
BMI Body Mass Index
C.I Class Interval
CV Cardio Vascular
CEF Cyclophosphamide, Epirubicin, Fluorouracil
CMF Cyclophosphamide, Methotrexate, Fluorouracil
DM Diabetes mellitus
DNA Deoxyribonucleic Acid
EC Epirubicin, Cyclophosphamide
E or ER Estrogen receptor
FAC Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
FEC Fluorouracil, Epirubicin, Cyclophosphamide
G-CSF G Colony stimulating factors
H or HER 2/neu Human epidermal growth factor receptor
HR Hormone receptor
HRT Hormone Replacement Therapy
HTN Hypertension
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IRB Institutional Review Board
KIRAN Karachi Institute of Nuclear Medicine and Radiotherapy
MBC Metastatic Breast Cancer
OPD Out Patient Department
OR Odds Ratio
P or PR Progesterone Receptor
PAH Polycyclic Aromatic Hydrocarbons
RR Relative Risk
SES Socio-Economic Status
TAC Taxane (Paclitaxel), Adriamycin (Doxorubicin), Cyclophosphamide
US-FDA United States- Food and Drug Administration
5-FU 5-Fluorouracil
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1. INTRODUCTION
1.1 BREAST CANCER EPIDEMIOLOGY:
The occurrence of breast cancer has increased globally with time (Hortobagyi et al., 2005, Hery
et al., 2008) It is the most prevalent and second principal cause of mortality in females. It is
rated as the third fatal cancer among top five cancers in American people (Jemal et al., 2008).
Higher incidence of breast cancer, affecting one in eight women in the UK in their lifespan, has
been reported by the researchers (Lawn et al., 2013). Increase in the occurrence of breast cancer
has been found in developing areas of the world which may be due to the increased availability
of healthcare settings that aid in the diagnosis of the disease (Hery et al., 2008). In the Western
countries, age >50 years in females and a moderately high SES account for the rise in the disease
frequency (Danø et al., 2003, Clarke et al., 2002) which may be due to the presence of more and
better health facilities (Hery C et al., 2008). The increase in the cases of breast cancer may also
be due to the presence of varied risk factors like low parity, older age at first child birth, etc.
(McPherson et al., 2000a) especially in females from high SES and in the developing countries
where the reproductive ranges changed (Khan et al., 2010, Parsa and Parsa, 2009). The forms of
breast cancer are multifaceted and complex than its prevalence (Ferlay et al., 2007, Jemal et al.,
2007).
Breast cancer is also the most widespread cancer in Asian females and its occurrence has been
growing in Asia (Kim and Choi, 2013). The incidence of breast cancer in Pakistan is highest in
Asia after Israel and 2.5 times higher than that in some neighboring countries, accounting for
34.6% of female cancers (Shaukat et al., 2013). It is reported that the breast cancer prevalence
increased in the 1950s and started declining in 1980s in many countries specifically observed in
the females of age from 35 years to<50 years (Hery C et al., 2008). Deficient information
regarding breast cancer etiology and epidemiology in Pakistan requires knowledge and research
about its susceptibility factors in the natives so as to prevent or treat and reduce its prevalence.
The Western system of living is dissimilar from that of Pakistani communities; therefore all the
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established risk factors of breast cancer are not applicable here and need to be studied
statistically to understand its incidence. The current thesis aimed to determine breast cancer risk
factors, its pharmacotherapy and related effects in the local population.
1.2 RISK FACTORS FOR BREAST CANCER:
The risk factors related to breast cancer have been considered and recognized in many studies
(Crivellari et al., 2007, Lee et al., 2008, Thomsen and Kolesar, 2008). Incidence of breast cancer
varies according to genetic, reproductive as well as cultural, environmental and life-style factors;
it also varies due to miscellany of these factors amid diverse ethnicity and geographical zones.
This highlights the enormous need for such studies in all diverse populations (Shaukat et al.,
2013, Mordukhovich et al., 2010, Labrèche et al., 2010, Gammon and Santella, 2008).
It has been determined that only 5-10% risks of breast cancer are due to genetic factors and most
of them are caused by environmental factors as put forward in a study in which there is a rise of
breast cancer risk in postmenopausal women if they travel from a low to high prevalence state. A
number of these environmental factors are associated with reproductive factors i.e. age of
menarche, age of menopause, parity, use of HRT, etc., which define the introduction of females
to circulating estrogens. Other environmental factors include xeno-estrogens, alcohol intake,
higher education level and socio-economic status (Key et al., 2001).
Reports have shown that only 25-47% of breast cancer risk in the US is described by the known
risk factors (Madigan et al., 1995, Rockhill et al., 1998). Over 5% rise in risk of breast cancer has
been recorded every year in China which is comparable to several other areas in East Asia
(Parkin, 1998). These chronological variations in breast cancer prevalence may be due to
modifications in the known risk factors of breast cancer (Honig, 1998). It is somewhat probable
that these modifications may be because of virtual rise in industrialization and development and
exposure of female population to various environmental aspects.
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Various risk factors for breast cancer are as follows:
1.2.1 AGE:
Age is regarded as the strongest known risk factor for breast cancer in females. It is considered to
be the most important factor of breast cancer occurrence; its association with breast cancer is
reported to be lesser in the younger age but it then increases as the age is >40 years (McPherson
et al., 2000a). Also in a collaborative reanalysis of individual data from several epidemiological
studies (Cancer, 2002), it was found that as the age increases, the occurrence of breast cancer
also increased; women at younger, child bearing age have lower risk of breast cancer. The RR of
developing breast cancer was found to be increased by 3% for each year if parity was delayed.
Nulliparous women are found to be at 30% increased risk of developing breast cancer than
parous women.
1.2.2 BMI / OBESITY:
Body mass index (BMI) is a proxy mark for obesity which is expressed as an individual’s weight
in kilograms per the square of their height in meters (Keys et al., 1972). The circulating estrogen
levels are associated with body fat proportions Women having greater body fat proportions could
be extra susceptible to estrogen-mediated breast cancer because the metabolism of estrogen
causes oxidative stress impairment to DNA. (Lipworth et al., 1996). The biosynthesis of estrogen
is connected with the adipose tissues and is catalyzed by aromatase P450 enzyme (Thompson
and Siiteri, 1974). The rates of estrogen biosynthesis rates are greater in older females than in
younger ones which may be due to stimulation of aromatase expression in stromal cells by
flowing serum glucocorticoids (Bulun and Simpson, 1994, Grodin et al., 1973). Aromatase
expression arises in the stromal cells that frame adipocytes (Price et al., 1992) but is variable
with maximum values being in the buttock and thigh areas (Bulun and Simpson , 1994).
Body mass index has been related to increase breast cancer risk, largely amid postmenopausal
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females (Trentham-Dietz et al., 1997, Van den Brandt et al., 2000, Yoo et al., 2001, Yang et al.,
2007). Obesity in post menopausal females has been reported to augment both breast cancer risk
and death in post menopausal females (Soerjomataram et al., 2008, Vainio et al., 2002). A little
shielding effect for breast cancer due to exercise has been found in various researches (West-
Wright et al., 2009).
1.2.3 EDUCATION LEVEL/SOCIO-ECONOMIC STATUS:
The education level and SES have been described as important factors regarding the incidence of
breast cancer. It has been observed that lower education level and low SES contribute to patient
delay at the healthcare facilities to seek medical assistance (Sharma et al., 2012). Previous
studies have defined delayed patient presentations to be associated with illiteracy, fear and lack
of awareness (Robinson et al., 1986), Elzawawy A, 1999). An earlier study also showed that
increased education level and hence increased awareness about the disease resulted in earlier
breast cancer detection and significant therapeutic advancement with considerable improvement
in patient survival (Harris et al., 1997).
Women who are educated and belong to a comparatively higher SES have found to have more
access to and availability of healthcare facilities for medical assistance and hence are
documented to be associated with breast cancer (McPherson et al., 2000b, Matson et al., 2000,
Zackrisson et al., 2004). This has contributed in the decrease of mortality rates of breast cancer
because of early identification of the disease and early onset of the treatment (Bouchardy et al.,
2006, Vona-Davis and Rose, 2009).
1.2.4 GENETIC FACTORS/ FAMILY HISTORY:
It has been established that only 5-10% of breast cancer cases are due to genetic reasons and
family history of the disease has been documented as a strong risk factor (McPherson et al.,
2000a), Morrow and Gradishar, 2002). The two tumor suppressor genes (BRCA1 and BRCA2)
were
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recognized to be the cause of ovarian and breast cancer (Foulkes, 2008); Morrow and Gradishar,
2002). It was evaluated that the presence of these genes in women put them up to 30 times
greater risk of getting aggressive breast cancer as compared to those who did not possess these
genes (Foulkes, 2008).
Family history is a known and established risk factor for breast cancer and the risk increases
progressively with the number of affected relatives (Cancer, 2001). It was found in a recent study
that the odds ratio for first degree family history of breast cancer was found resilient for younger
women than older woman and also statistically significant (Trentham-Dietz et al., 2014).
1.2.5 LIFE STYLE/ENVIRONMENTAL CHARACTERISTICS:
Different lifestyle characteristics are found to be associated with breast cancer risk and death
(McPherson et al., 2000a).
1.2.5.1 DIET:
There are no established evidences of strong associations for diet and smoking with breast cancer
(McPherson et al., 2000a, Singletary, 2003). It was found from a meta-analysis regarding meat
intake that the RR of breast cancer was 1.17 while comparing highest and lowest levels of intake
(Boyd et al., 2003). (Mahoney et al., 2008) documented that the presence of antioxidants and
fibers in fruits and vegetables could not show any protective effects against breast cancer in
those who consumed them as part of their diet. The consumption of dairy products has been
found to have inconsistent patterns of association as risk for breast cancer. Milk and cheese have
been reported to be associated with breast cancer due to evidence of presence of pesticides and
insulin growth factor I that may induce breast cancer (Moorman and Terry, 2004).
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1.2.5.2 ALCOHOL INTAKE:
A high alcohol intake relates to a meek but high breast cancer risk (Singletary, 2003). It has been
determined and established via several studies that alcohol intake intensifies the risk of breast
cancer (Allen et al., 2009, Aronson, 2003, Cancer, 2002, Smith-Warner et al., 1998, Longnecker,
1994). It was also seen in a recent study that ER+ and PR+ breast cancers are more associated
with alcohol consumption than any other types of tumors (Lew et al., 2009).
1.2.5.3 XENO-ESTROGENS:
Exogenous estrogen or estrogen like compounds called xenoestrogens can be associated with
breast cancer when they come in contact with breast cancer cell lines (Soto et al., 1994, Zava et
al., 1997, Dees et al., 1997). A number of such xenoestrogens have been found to act through the
estrogen receptor (Rivas et al., 2002, Watson et al., 2005, Wozniak et al., 2005). There are a
number of chemicals that interfere with hormonal metabolism and the common chemicals
observed are dichlorodiphenyltrichloroethane (DDT), polyvinyl chloride (PVC) and
polychlorinated biphenyls (PCBs) that are prevalent in plastics, detergents, food containers,
electronic equipment, cosmetics and various pesticides, etc. (Gray et al., 2009).
1.2.5.4 SMOKE:
Polycyclic aromatic hydrocarbons (PAHs) are chemical cancer-causing agents that are formed
due to partial combustion of organic substances. There are many sources for PAHs in
environment like air pollution, tobacco smoke, wood- and coal-burning stoves, etc. (Samanta et
al., 2002). PAHs well-known cancer causing agents in human population and is also found in
tobacco smoke. All PAHs do not have the ability to cause similar grade of cancer which is due to
diversity in their structure and biological activity. Research has suggested that the metabolites of
PAH may be more intoxicating than their parent PAHs (Strickland and Kang, 1999). PAHs bind
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to DNA and are frequently deposited in adipose tissues and fatty tissues of the breasts (Obana et
al., 1981, Gammon and Santella, 2008).
In an in vitro research it was found that cigarette smoke caused neoplastic changes in the
epithelial cells of breast (Russo et al., 2002). Smoking is known to have an uncertain link with
breast cancer risk specifically for genetically susceptible persons (Terry and Rohan, 2002, Terry
and Goodman, 2006). Most of the studies have not found significant association of primary
smoking with breast cancer (Terry and Rohan, 2002, Terry and Goodman, 2006, Ambrosone et
al., 2008) but a meek affirmative and statistically significant relationship between passive
(second hand) smoking and breast cancer risk has been established (Braithwaite et al., 1999,
Conway et al., 2002, Shantakumar et al., 2005).
1.2.6 USE OF EXOGENOUS HORMONES (CONTRACEPTIVES & HRT):
The use of contraceptives has been enquired about in various studies as a risk factor of breast
cancer. The use of exogenous hormones (i.e. contraceptives and HRT) has also been established
to be associated with breast cancer (McPherson et al., 2000a). The risk is more associated with
the use of HRT (medication including both oestrogens and progesterone) in women using it for
≥15 years (Beral et al., 1997, Borgquist et al., 2007) than those women who use oral
contraceptives (McPherson et al., 2000a, Calle et al., 1996). It has been reported that the use of
contraceptives for ≥5 years is associated with breast cancer among younger females especially
with ER- and triple negative breast cancer though this requires further investigation for
confirmation (Beaber et al., 2014).
Several studies have shown that hormone replacement therapy, irrespective of whether it is
estrogen or estrogen plus progestin, is linked with an higher breast cancer risk (Adami and
Ingemar, 1995, (Stanford et al., 1995, Colditz, 1998, Chlebowski et al., 2009). The DNA damage
related to breast cancer carcinogenesis is found to be associated with catechol metabolites of
steroidal estrogens (Adlercreutz et al., 1994, Yager and Leihr, 1996).
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Regarding progestins, it has been demonstrated that it intensifies the breast cancer risk of
exogenous estrogen hence can proliferate breast epithelium (Pike et al., 1993). An increase of up
to 3% per year in risk of breast cancer was observed in females taking estrogen replacement
supplementation in the Million Women Study (Crosignani, 2003). It was found from a study
recruiting postmenopausal women that due to use of HRT (estrogen plus progestin) women had a
5-6% augmented risk of breast cancer (Chlebowski et al., 2009). An increased risk of breast
cancer has been reported in females with higher level of education due to increased use of these
exogenous hormones (Menvielle et al., 2010).
1.2.7 ENDOGENOUS HORMONES:
The male (e.g. testosterone testosterone and androstenedione) and female (e.g. oestradiol and
oestrone) sex hormones have demonstrated to be associated with breast cancer risk in a joint
analysis and large prospective investigations (Manjer et al., 2003, Key et al., 2002). Estrogen and
testosterone levels were also found associated with breast cancer in Asian postmenopausal
females in a couple of case-control studies conducted in China (Wang et al., 2009, Yu et al.,
2003).
1.2.8 REPRODUCTIVE FACTORS:
Various reproductive factors are as under:
1.2.8.1 AGE OF MENARCHE AND MENOPAUSE:
An augmented breast cancer risk has been related to early menarche and late menopause
(McPherson et al., 2000a). The deferring of menarche every year is associated with 9% lesser
risk of breast cancer in premenopausal females and 4% in post menopausal females. There is a
3% increased risk of breast cancer each year if menopause is delayed (Group, 2002). (Brinton et
al., 1988) stated that an early menarche age i.e. >12 years was associated with breast cancer with
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RR of 1.3 as compared to those with >15 years of age. (Clavel-Chapelon, 2002) reported that the
RR for premenopausal breast cancer cases decreased around 7% for each year menarche delayed and by
3% for post menopausal cases after 12 years of age. In a previous study, the RR of 1.22 for breast
cancer was found in those females who were not menopausal until the age of ≥ 55 years as
compared with those < 45 years (Brinton et al., 1988). It was suggested that this may happen due
to the number of ovulatory menstrual cycles in a woman’s lifetime (Vogel, 1998).
1.2.8.2 PARITY:
A converse association between parity and breast cancer risk has steadily been shown in several
epidemiological studies (Layde et al., 1989, Ewertz et al., 1990, Kvåle, 1992, Key et al., 2001,
Hinkula et al., 2001, Clavel-Chapelon, 2002, Huo et al., 2008, Hajian-Tilaki and Kaveh-
Ahangar, 2011). In a comparative study of uniparous and multiparous women, it was found that
multiparity was more associated with breast cancer and was stronger in females giving birth for
first time before 20 years of age than in those after 30 years of age (Albrektsen et al., 1994).
Many factors have been associated with parity like age at first live birth and breast feeding (Parsa
and Parsa, 2009) and it is documented that there is 7% fall in risk for breast cancer with each
child birth (Group, 2002) though the validity of this effect in pre- or post-menopausal women is
still discordant (Clavel-Chapelon, 2002, Vatten and Kvinnsland, 1992).
In two other studies, comparing the parous status of women with 5 or more children, decrease in
risk of breast cancer was found for each added child birth (Albrektsen et al., 1994, Ewertz et al.,
1990). This was explained by the fact that during each pregnancy, the stem cells get more
invulnerable to oncogenic provocations (Russo et al., 2005). It has also been reported for parous
women that the risk for breast cancer increased with childbirth for little time period but
decreased in long duration (Lambe et al., 1994, Hsieh et al., 1994, Leon et al., 1995, Liu et al.,
2002, Albrektsen et al., 2004).
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Meager prognosis and greater deaths are associated with the diagnosis of breast cancer during or
just after pregnancy (Trivers et al., 2007, Rosenberg et al., 2004, Whiteman et al., 2004, Phillips
et al., 2004, Kroman and Mouridsen, 2003, Olson et al., 1998). This happens due to the changed
hormonal situation which potentiates growth of previously cancerous cells (Henderson and
Bernstein, 1991). On the contrary, some researches could not determine any prognostic
properties related to parity (Whiteman et al., 2004, Kroman and Mouridsen, 2003, Ewertz et al.,
1991) except for only in elderly women.
1.2.8.3 AGE AT FIRST CHILD BIRTH:
A self- determinant of breast cancer risk is the age at first child birth (Group on Hormonal
Factors in Breast Cancer, 2002). (Hinkula et al., 2001) reported that women who deferred their
first child birth from 20-30 years were at twice the risk for breast cancer. The risk is more
established in pre-menopausal women than in post-menopausal women (Clavel-Chapelon and
Gerber, 2002) who may also alter the decline in risk attained from parity. It was documented by
(Althuis et al., 2004) that ER+ breast cancer was more associated with late age of first child birth
than ER- cancer.
1.2.8.4 BREAST FEEDING:
Breast feeding has shown protection against breast cancer in some studies. It was found by the
analysis of 47 epidemiological studies conducted in various countries (Group, 2002) that the
breast cancer risk reduced by 4.3% for every added year of breastfeeding. However, the duration
of breast feeding was not found associated with breast cancer (Butt et al., 2014). (Yang and
Jacobsen, 2008) also could not find any protective effects of breast feeding in breast.
The overall petite duration of breast feeding may increase the occurrence of breast cancer in the
West (Group, 2002). No clear relationship of breast feeding with breast cancer could be
determined nor could any clear protective effect be established in some researches (Whiteman et
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al., 2004). Longer period of breast feeding was found to be related to reduce breast cancer by
some researchers (Ursin et al., 2005, Phipps et al., 2008).
1.3 THE FEMALE BREAST:
The female breast comprises of a system of ducts that are made of a basal layer of myo-epithelial
cells and the inner duct wall is lined by a luminal layer of epithelial cells. During puberty, the
female sex hormones (estrogen and progesterone) increase the process of ductal development
(Howard and Gusterson, 2000). Estrogen leads to propagation of cells and progesterone leads to
much greater variation than before (Potten et al., 1988). During the menstrual cycle, the breast
undergoes numerous phases of development and apoptosis (Thompson, 1995). Extreme
development of breast epithelial cells is realized during the latter half of the menstrual cycle
(Ferguson and Anderson, 1981, Longacre and Bartow, 1986) which is due to deferred effect of
estrogen during the first half or follicular phase of the menstrual cycle (Dahmoush et al., 1994,
Clarke, 2004). The ultimate distinction stage in the breast is attained during pregnancy and
lactation, when numerous milk secreting alveolar cells are formed via broad production followed
by terminal distinction of cells. Termination of lactation causes widespread apoptosis and tissue
remodeling and the breast regresses to its previous form (Strange et al., 2001). Estrogen also
possesses growth stimulatory effects and hence has been identified as a carcinogen in breast
cancer (Report on Carcinogens, 2005).
Progesterone is responsible for the distinction and development of the epithelial cells and has
found to be protective against breast cancer. The progesterone levels rise generally in the third
trimester of pregnancy for extreme distinction in provision for lactation (Russo and Russo, 2004,
Russo and Russo, 1995). The differences of breast cancer risk with gestation period (Innes and
Byers, 2004, Melbye et al., 1999) and with progesterone levels during pregnancy (Peck et al.,
2002) definitely validate the protective role of progesterone in breast cancer. Progesterone is
associated to enhance risk of breast cancer only when women use HRT with synthetic progestin
and estrogen (Campagnoli et al., 2005).
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1.4 THE FEMALE SEX HORMONES AND RECEPTORS:
The female sex hormones (estrogen and progesterone) act through their specific intracellular
receptors that belong to the nuclear hormone family. There are two receptor subtypes of
estrogen: estrogen receptor alpha (ERα) and ER beta (ERβ) (Khan et al., 2005, Cordera and
Jordan, 2006) while progesterone has three receptor subtypes: PRA, PRB and PRC (Cordera and
Jordan, 2006, Aupperlee et al., 2006, Mendelson and Hardy, 2006). These receptors act through
manipulating transcription of genes linked to propagation and variation. ERα controls the
expression of progesterone receptors.
At the molecular level, ERα is existent only in around 10% of luminal epithelial cells (Petersen
et al., 1987) whereas ERβ exists frequently in all types of cells in the normal breast (Speirs et al.,
2002). In proliferative lesions, in situ cancer and invasive disease, the number of ERβ
progressively declines and the ratio of ERα/ERβ is disturbed (Roger et al., 2001), Leygue E et
al., 1998). ERα expression has been found higher through international research in European
women, and also in healthy females hence increasing the risk of breast cancer (Fabian et al.,
1997, Ricketts et al., 1991). During a normal menstrual cycle, ERα levels change due to higher
estrogen levels in follicular phase (Battersby et al., 1992) but this configuration lacks among
females having breast cancer (Khan et al., 1998). The progesterone receptors PRA and PRB bind
with DNA and exist in more or less same numbers in the normal breast; PRC does not bind with
DNA and upturns the transcriptional stimulation of PRA and PRB and (Aupperlee et al., 2006).
Though the expression of PRs is controlled by ERs (Mendelson and Hardy, 2006, Ciocca et al.,
2006) but progesterone is protective for breast cancer due to grander distinction of cells (Innes
and Byers, 2004, Melbye et al., 1999, Peck et al., 2002).
ER+ and ER- cancers signify diverse subtypes of breast cancer with dissimilar risk factors,
clinical representations and results (Chen and Colditz, 2007). It is evident from researches
concerning the Surveillance Epidemiology and End Results (SEER) database that ER-/PR-
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cancers are more common in African American pre-menopausal women than the Caucasians
(Chlebowski et al., 2005), (Li et al., 2002, Anderson et al., 2001, Yasui and Potter, 1999). Based
on hormone receptor status with most reproductive factors, increased endogenous estrogens in
females tend to cause ER+ breast cancer (Althuis et al., 2004, Huang et al., 2000). Risk factors
like genetic and smoking tend to cause ER- breast cancers (Huang et al., 2000, Manjer et al.,
2001).
The figure (1) as follows shows the effect of estrogen on breast cells (Lanfranchi and Brind,
2007):
(Fig. 1) Effect of estrogen on the growth of breast cells:
The following figure (2) demonstrates the changes in breast cells due to estrogen proliferation
(Lanfranchi and Brind, 2007):
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(Fig. 2) Proliferative changes in the breast cells due to estrogen:
Her2/neu receptor, an oncogene, is also called Epidermal growth factor receptor family-2
(EGRF-2) (Cordera and Jordan, 2006, Ciocca et al., 2006, Robert and Favret, 2007). It does not
have a ligand of its own but it produces dimers or heteromers of the same family and influences
the transcription of several genes related to cell growth and apoptosis. It is observed to be
overexpressed in 20-25% of all breast tumors with maximum expression in those tumors that are
deficient in expression of hormone receptors (Robert and Favret, 2007). Her2/neu is evident to
be over expressed in advanced and aggressive types of breast cancers; the prognosis being very
poor (Robert and Favret, 2007, Cordera and Jordan, 2006). It has been determined that Her2
expression indicates intensification in sternness of breast carcinoma with loss of ER control,
diminished cell death and treatment resistance(Ciocca et al., 2006).
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1.5 THE TUMOR MARKERS IN BREAST CANCER:
The tumor markers estrogen, progesterone, or Her-2/neu receptors may be found in the
cytoplasm of the tumor cells. These three tumor markers are used to identify, conclude treatment,
and categorize various types of breast cancer (Albrektsen et al., 2010).
1.5.1 ER & PR STATUS:
Hormone receptor status can aid in differentiating breast cancer tumors (Colditz et al., 2004)
because breast cancer tumors are dependent on female sex hormones i.e. estrogen and
progesterone for development and growth (Clemons and Goss, 2001). The ductal growth is
speedy under the influence of these hormones during puberty (Howard and Gusterson, 2000).
Cell proliferation is mediated by estrogen whereas increased differentiation is due to
progesterone (Potten et al., 1988). Due to its growth stimulatory effects, estrogen has been
associated with breast cancer whereas the role of progesterone due to cell differentiation and
maturation has been found protective against breast cancer (Russo and Russo, 2004, Russo and
Russo, 1995). The use of synthetic progestin and not progesterone itself in hormone replacement
therapy may be associated with breast cancer as compared to those HRT having estrogen only
(Campagnoli et al., 2005).
It is important to report the ER/PR status for breast cancer for improved treatment
commendations. Anti-estrogen therapy has shown complete response in the treatment of positive
tumor receptor breast cancer (Andry et al., 1989) and generally improved prognosis has been
seen for ER+ breast cancer cases. A high percentage (66%) of tumors is found to be ER+/PR+,
followed by ER-/PR- (19%) through several researches whereas the percentage of ER-/PR+
tumors is minimum (almost only 2-3%) (Cordera and Jordan, 2006).
ER+ and PR+ breast cancer patients show improved survival rates with the use of adjuvant
hormonal therapy (Naeim et al., 2010). Up to 60% of patients with ER+ metastatic disease
respond to hormonal therapy (e.g., Tamoxifen, a selective estrogen receptor modulator) as
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compared to ER- tumors (< 5%). Up to 80% PR+ patients with metastasis respond well to
hormonal therapy (Hussain et al., 2004). A positive tumor receptor status does not always set up
a satisfactory prognosis or response to treatment. The tumor receptor status does not influence
the patient’s response to chemotherapy. In a study conducted by (Ma et al., 2006), ER- tumors
were reported to be more associated with breast cancer than ER+ tumors. There was no
association reported between various tumour types and parity (Ursin et al., 2005). It has been
reported that better prognosis has been associated with ER+ patients; relapse being seen with
ER- in visceral and soft tissues and with ER+ in bone. The likelihood of relapse for ER- cancers
is utmost within the first 5 years while ER+ cancers tend to recur later (Andry et al., 1989, Hess
et al., 2003). Trends of ER+ breast cancer increase with increase of endogenous estrogen
exposure in a woman’s reproductive life time (Huang et al., 2000, Althuis et al., 2004). ER-
cancers have found to be more associated with risk factors like genetic risks, radiation and
smoking (Huang et al., 2000, Manjer et al., 2001). It is therefore indicated that ER+ and ER-
status represent different subtypes of breast cancer associated with diverse risk factors and
consequences (Chen and Colditz, 2007).
1.5.2 HER 2/NEU STATUS:
The Her-2/neu receptor is an orphan epidermal growth factor receptor with unknown ligand
(Ross JS et al., 2003). It is also known as the Epidermal growth factor receptor family-2 (EGRF-
2), an oncogene that belongs to the epidermal growth factor receptor family (Cordera and Jordan,
2006; Ciocca et al., 2006; Robert and Favret, 2007). Its expression is either low or lacking in
normal breast. Her 2/neu has found to be overexpressed in 20-25% of all breast tumors with
maximum expression in those tumors that lack expression of hormone receptors (Robert and
Favret, 2007). Her2 over expression can cause an increase in severity of breast cancer with
uncontrollable ER, diminished cell death and drug resistance. Her-2/neu receptor-positive tumors
have a greater relapse rate and a poorer general prognosis. It has been established that specific
subtypes of tumor receptors occur in females with specific characteristics (Martínez et al., 2010,
Bosch et al., 2010, Cicin et al., 2009, Millikan et al., 2008, Ma et al., 2006, Colditz et al., 2004).
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For instance, basal-like tumors i.e. triple negative tumors (ER-, PR-, and HER2-) can more
possibly occur with more violent behavior as compared with tumors of the luminal subtype (ER+
and/or PR+ and HER2-) in breast cancer cases who are younger and/or of African origin (Bosch
et al., 2010, Cicin et al., 2009).
1.6 BREAST CANCER CLASSIFICATION:
A general grouping of breast cancer shows two types: invasive and in-situ (Table 1) (Carlson et
al., 2009, Lakhani et al., 2006, Elston and Ellis, 1991). The other forms of breast cancer are
Paget’s carcinoma and inflammatory carcinoma (Anderson et al., 2006).
Table 1: General classification of breast cancer
S.no Breast Cancer type
Features
1 Invasive cancer that annexed the extra-ductal or extra-lobular tissues
2 In-situ cancer that is confined within ducts or lobules; do not have the ability to spread except for 1-3% patients who are diagnosed having invasive tumors with metastasis to regional lymph nodes
Ductal carcinoma in-situ (DCIS)
a pre-cancerous lesion that may progress to invasive breast cancer in 40-60% patients if not treated.
Lobular carcinoma in-situ (LCIS)
a strong risk factor for breast cancer and is not considered to be a pre-cancerous malignant lesion; has 40% lifespan risk to become invasive in either breasts among which 70% are ductal in beginning.
3 Paget’s carcinoma
a rare type of ductal carcinoma in-situ (DCIS), in which the ducts of the nipple epithelium with marginal unrefined nipple changes
4 Inflammatory carcinoma
the greatest malicious form of breast cancer with only <3% of freshly diagnosed cancer patients. In the aggressive form of the disease, the covering skin develops as erythematous, edematous, warm and tender. At times, the inflammatory changes in the breast are painful and enlarge the entire breast which is due to the carcinomatous incursion of the subdermal lymphatics. As the metastasis is quick and extensive therefore, inflammatory carcinoma is seldom treatable
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Invasive or in-situ breast cancers are recognized to be of prognostic inference; the TNM stage at
diagnosis and receptor status is important for invasive cancers (Rosen, 2001). Bilateral breast
cancers are very infrequent (1% per year approx.) that may happen more often in females with
<50 years of age, having family history of breast cancer with the primary lobular breast tumor
(Hartman et al., 2007).
1.6.1 BREAST CANCER METASTASIS:
1.6.1.1 AXILLARY LYMPH NODE METASTASES:
Almost 75% of the lymphatic drainage from the breast goes to the lymphatic tissue in the axilla.
Axillary lymph nodes metastases have an affinity to follow in order from level I nodes
(inferolateral to the pectoralis minor muscle) to level II nodes (beneath the pectoralis minor and
inferior to the axillary vein) and then to level III nodes (medial to the pectoralis minor and
against the chest wall). There is a 30% lifetime risk of breast cancer relapse in node negative
females while node positive females have 75% lifetime risk of breast cancer relapse. Hence, at
the time of diagnosis, disease-free and overall survival rates in breast cancer can be predicted by
axillary lymph node position (Sabel, 2009).
1.6.1.2 DISTANT METASTASES
Due to breast tumor neovascularization, breast cancer cells may go directly into the systemic
venous blood supply. The tumor cells may foldaway into the pulmonary circulation through
axillary and intercostal veins or may go into Batson’s plexus. The most common sites of breast
cancer distant metastases are bone, lung, pleura, soft tissues, and liver (Borst and Ingold, 1993).
Breast cancer metastasis is the most common cause of mortality among breast cancer patients as
about 60% women may attain (Hellman and Lecture, 1994) distant metastases in two years of
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management (Page, 1991); 95% women die of breast cancer distant metastases (Borst and
Ingold, 1993).
1.7 BREAST CANCER STAGING AND GENERAL TREATMENT
RECOMMENDATIONS:
One of the most reliable prognostic indicators of breast cancer is its staging. It has been observed
that there are 5 and 10 year fall in survival with increase in the stage. Axillary lymph node status
is linked with prognosis at all sizes of tumor. More than 95% patients have a 5 year survival if
they have ER+ PR+, small (<2 cm) and node negative breast cancers (Utah, 1989). The
involvement of axillary nodes with tumor decreases the survival rate of patients to 50-70% at 5
years and 25-40% at 10 years. The staging of breast cancer comprises of tumor size (T 1-4),
involvement and presence of lymph nodes (N 1-3) and presence/absence of distant metastases
(M 0-1). These stages (Wells et al., 2000) can be represented as follows in Table 2:
Table 2: Stages of breast cancer
Breast cancer stage
Features
Early: Stage 0 In-situ disease or which has not involved basement membrane
Early: Stage I Primary, small tumor and no involvement of lymph nodes
Early: Stage II Local lymph nodes are involved
Locally advanced: Stage III
Tumor is large with involvement of nodes widely; tumor or node is fixed to chest wall. Includes inflammatory disease also
Advanced: Stage IV (metastatic)
Distant metastases in organs from primary tumor
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The following figure (3) illustrates the variations in cancer cells
(https://science.education.nih.gov) in different stages:
Fig. 3: Different stages of cancer cell variation:
Breast cancer staging delivers valuable evidence about the existing status of cancer identification
and management, and the accomplishment of employing new approaches for treatment.
1.7.1 STAGE 0:
Lumpectomy alone can manage DCIS which is < 0.5cm in diameter but lumpectomy with
adjuvant radiation therapy is employed for larger lesions. Mastectomy is done when DCIS is
extensive, involving two or more quadrants of the breast. LCIS is not surgically resected.
Adjuvant Tamoxifen is considered in all patients with DCIS and LCIS (Fisher et al., 1998).
1.7.2 STAGE I AND II (a OR b):
For patients with stage I or II breast cancer, lumpectomy and radiation therapy after assessing
status of axillary lymph node are employed in current practice. This standard of care has shown
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comparable results for total mastectomy and for lumpectomy followed by radiation therapy with
5 and 8 year disease-free and overall survival rates (Arriagada et al., 1996). The patients with
prior radiotherapy to the breast or chest wall should undergo mastectomy due to surgical margins
subsequent to removal of a breast mass and definite connective tissue ailments and multi-centric
illness (Singletary et al., 2004). Evident axillary lymphadenopathy must go through a complete
axillary segmentation. Sentinel lymph node biopsy is performed for those patients in whom
axillary lymph nodes are not involved and have a primary cancer (T1 or T2). Systemic
chemotherapy is also employed with radiation therapy in women with early breast cancer.
Chemotherapy is given to those who have large tumors (> 1 cm) and node positive breast cancer
(Singletary et al., 2004). Adjuvant endocrine therapy is prescribed after assessment of hormone
receptor status. AIs or Tamoxifen are prescribed for ER+ or PR+ tumors and Trastuzumab
(monoclonal antibody) is suggested for HER 2/neu+ tumors.
1.7.3 STAGE III a AND (OPERABLE) III c:
This is a locally advanced form of breast cancer. The stage IIIa and IIIc cancers can be further
classified as resectable and non resectable (Singletary et al., 2004). The resectable cancer is
managed by a modified radical mastectomy and adjuvant chemotherapy plus radiation therapy.
Some patients may require a neo-adjuvant chemotherapy to decrease the size of the primary
tumor (Chen et al., 2004). Same hormonal therapy and/or trastuzumab are suggested as described
for stage I and stage II cancers.
1.7.4 STAGES III b, (INOPERABLE) III c, AND INFLAMMATORY BREAST CANCER:
This stage represents a locally advanced disease and requires multimodal attitude to therapy to
attain cure. The patients are initially treated with neo-adjuvant chemotherapy; if the response is
achieved then a modified major mastectomy followed by radiotherapy to the chest wall and
regional lymphatics are considered (Singletary et al., 2004). A breast-conserving surgery
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following chemotherapy may be suggested in some cases (Chen et al., 2004). Same hormonal
therapy and/or trastuzumab are suggested as described for stage I and stage II cancers.
1.7.5 Stage IV:
This is the most advanced stage of breast cancer having no cure and the goals of treatment are
increased survival rates and improvement of quality of life. For women with ER+ or PR+
cancers, having only bone or soft tissue metastases, or with limited and asymptomatic visceral
metastases, endocrine therapies are frequently recommended as first line management
(Singletary et al., 2004). Systemic chemotherapy is the most suitable application to hormone-
refractory cancers, ER- or PR- cancers, or symptomatic visceral metastases (Carlson et al.,
2009). Palliation is required on individual basis to control symptoms. Bisphosphonates can be
used for bone metastasis to avoid bone fractures.
1.8 THE PROGNOSTIC FACTORS FOR BREAST CANCER:
These are the measurements that, at the time of diagnosis or surgery, are linked with relapse rate,
mortality rate or other clinical consequences, in the absence of adjuvant therapy. These include
age of patient, tumor size and grade, involvement of lymph node, hormone receptor status and
HER2/ neu expression (Chisholm-Burns et al., 2010).
1.9 BREAST CANCER TREATMENT: THERAPEUTICS BY CLASS
The cancer diagnosis and the treatments may have substantial influence on the patients' quality
of life. The significance of risk factors’ measurements (and other patient characteristics) to long-
term effects can be evaluated progressively consistently for breast cancer treatment. Rational
therapeutic decision making for breast cancer patients can aid in family physicians care for their
patients during and after therapy. The systematized screening and identification of breast cancer,
and its staging define the treatment plan for this disease (Geay, 2013). Over- or under-treatment
may happen due to imprecise risk estimation in breast cancer patients due to limits provided by
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customary parameters (Koka and Ioffe, 2013). The treatments’ selection for breast cancer must
outweigh benefits over risks in length of life (Maughan et al., 2010).
It is important to observe the response of breast cancer treatment in order to prevent the disease
from progression or relapse or if it has become metastatic, then to provide palliative care
accordingly. The dose, dosing schedule and response of the therapeutic agents employed for
treating breast cancer all cause impact on the health status of the patients. Monitoring of breast
cancer patients via regular follow ups especially for those who are at risk of developing severe
illness must be maintained. Anti–cancer drugs cause ADRs in extension of their therapeutic
effects and they are non-selective for both normal and cancerous cells (Jose and Rao, 2006).
Adverse reactions discourage patient compliance and increase their distress. Therefore, the pre-
and post-medications to manage such symptoms must be in line with the standard guidelines.
Breast cancer therapy consists of various treatment modalities which include local treatment
(surgery and radiation), chemotherapy and adjuvant endocrine therapy (Lukaszewicz et al.,
2010). It was reported in a study by (Supramaniam et al., 2014) that the survival rate of
Aboriginal women suffering from breast cancer increased after surgical treatments. Various
therapeutic agents employed for breast cancer, some are as follows (Table 3):
Table 3: Therapeutic agents for breast cancer
Type of agent Name Class
Alkylating Cyclophosphamide Nitrogen mustard
Anti-metabolite Methotrexate Folic acid analogue
5-fluorouracil Pyrimidine analogue
Capecitabine
Gemcitabine
Natural product Vinorelbine Vinca alkaloid
Paclitaxel Taxane
Docetaxel
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Doxorubicin Antibiotic
Hormone and antagonist Tamoxifen Anti-estrogen
Letrozole, anastrazole Aromatase inhibitors
Miscellaneous Trastuzumab Monoclonal antibody
Lapatinib Protein tyrosine kinase inhibitor
1.9.1 LOCAL THERAPY (SURGERY & RADIATION):
In early stage of breast cancer, modified radical mastectomy or lumpectomy (segmental/partial
mastectomy) with radiation therapy are established. The surgery may consist of a full axillary
lymph node dissection or lymph node mapping with sentinel lymph node biopsy. The axillary
lymph node dissection for stage I and II breast cancer is suggested for information concerning
staging and prognosis but it is associated with complications therefore lymph node mapping with
sentinel lymph node biopsy is recommended. Principal therapy for stage I and II breast cancer is
conservation of the breast but certain contra indications must be considered for breast
conservation like multiples cancer sites in breast, pregnancy, large tumor in small size of breast,
etc. (Chisholm-Burns et al., 2010). Regarding local therapy, it was found through research that
improved local control and overall survival in breast cancer patients was associated with
adjuvant radiotherapy thereby decreasing 70% recurrence rate proportionally and 9-12%
proportional reduction of mortality (Taylor et al., 2009, Buchholz, 2009).
The adverse effects on skin due to radiation therapy are common in breast cancer patients (Chen
et al., 2010) but unfortunately no standard treatment guidelines are available for the prevention
and treatment of such toxicities though studies have suggested the use of many types of topical
agents on the skin (Schmuth et al., 2002, Gozzo et al., 2010).
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1.9.2 ENDOCRINE THERAPY:
1.9.2.1 TAMOXIFEN:
In the era of 1950s and 60s, radiation induced ovarian ablation was generally used for
managing metastatic breast cancer which was progressively substituted by pharmacologic
treatments like tamoxifen which is a selective estrogen receptor modulator (SERM) (Chen et
al., 2007). Tamoxifen 20 mg tablets are considered as gold standard for the treatment of
breast cancer; it binds to ER and has mixed agonist and antagonist properties (Wood et al.,
2003) The figure (4) as follows illustrates the working of Tamoxifen
(https://www.riverpharmacy.ca) in breast cancer:
Fig. 4: Inhibition of estrogen receptor by Tamoxifen:
In post menopausal women, third generation aromatase inhibitors i.e. letrozole, anastrozole and
exemestane, are widely used as alternative to Tamoxifen especially in ER+ breast cancer due to
their better efficacy (Bonneterre et al., 2001). ER+ metastatic breast cancer patients have shown
50-60% response with Tamoxifen therapy (Fisher et al., 1996). The adverse reactions associated
with Tamoxifen are menstrual irregularities, hot flashes and vaginal discharge (Fisher et al.,
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1996). It has been reported that there is a 50% reduction in risk of ER+ breast cancer recurrence
and 28% reduction in morbidity with use of Tamoxifen irrespective of menopausal or lymph
node status (Group, 1998).
Besides, there are findings that endocrine therapies like Tamoxifen itself might escalate the
agonistic effects of xenoestrogens on transmuted ERs that are related to drug refractoriness and
resistance (Hess-Wilson et al., 2006).
1.9.2.2 AROMATASE INHIBITORS:
The third generation AIs (letrozole, anastrazole) are non steroidal agents that block aromatase
enzyme reversibly which converts androstenedione into esterone and testosterone to estrogen;
aromatase is the main source of estrogen in post menopausal women. The AIs have shown
better-quality results and improved toxicity profiles in the post menopausal women (Nabholtz et
al., 2003, Mouridsen et al., 2003). The AIs have a better tolerability than previous hormonal
therapies for breast cancer but are associated with ADRs like hot flashes, arthralgia, lipid profile
variation and BMD loss (Waldman and Terzic, 2009). Adjuvant endocrine therapy is also
associated with certain adverse effects like arthralgia, nyalgia and hot flashes (Hadji et al., 2012,
Su et al., 2010). To evade the patients of toxic effects of these endocrine drugs, therapy should
be prescribed to patients on individual basis (Ameen et al., 2012).
1.9.3 CHEMOTHERAPY:
Various chemotherapeutic agents are employed for treating breast cancer that target various cell
cycle processes. The following figure (5) shows the working of chemotherapeutic agents
(triplesteptowardthecure.org) in general in cancer patients:
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Fig. 5: Working of chemotherapeutic agents:
Some of the most common regimens employed in breast cancer (Chisholm-Burns et al, 2010) are
as follows (Table 4):
Table 4: Dose/schedule of some chemotherapeutic agents for breast cancer
Chemotherapy regimen Dose/schedule
AC Doxorubicin 60 mg/m2 IV, Day 1
Cyclophosphamide 600 mg/m2 IV, Day 1
Cycles repeated every 21 days (4 cycles)
FAC Fluorouracil 500 mg/m2 IV, Day 1 & 4
Doxorubicin 50 mg/m2 IV continuous infusion over 72 hr
Cyclophosphamide 500 mg/m2 IV, Day 1
Cycles repeated every 21-28 days (6 cycles)
CAF Cyclophosphamide 600 mg/m2 IV, Day 1
Doxorubicin 60 mg/m2 IV bolus, Day 1
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Fluorouracil 600 mg/m2 IV, Day 1 & 8
Cycles repeated every 28 days (6 cycles)
FEC Fluorouracil 500 mg/m2 IV, Day 1
Epirubicin 100 mg/m2 IV bolus, Day 1
Cyclophosphamide 500 mg/m2 IV, Day 1
Cycles repeated every 21 days (6 cycles)
AC→paclitaxel Doxorubicin 60 mg/m2 IV bolus, Day 1
Cyclophosphamide 600 mg/m2 IV, Day 1
Cycles repeated every 21 days (4 cycles)
Then:
Paclitaxel 175 mg/m2 IV over 3 hr
Cycles repeated every 21 days (4 cycles)
TAC Doxorubicin 50 mg/m2 IV bolus, Day 1
Docetaxel 75 mg/m2 IV, Day 1
Cyclophosphamide 500 mg/m2 IV, Day 1
Cycles repeated every 21-28 days (6 cycles)
Paclitaxel→FAC Paclitaxel 80 mg/m2 IV per week (12 weeks) over 1 hr
Then:
Fluorouracil 500 mg/m2 IV, Day 1 & 4
Doxorubicin 50 mg/m2 IV continuous infusion over 72 hr
Cyclophosphamide 500 mg/m2 IV, Day 1
Cycles repeated every 21-28 days (6 cycles)
For MBC
Paclitaxel
(monotherapy)
Paclitaxel 175 mg/m2 IV over 3 hr
Cycles repeated every 21 days
OR:
Paclitaxel 80 mg/m2 IV per week over 1 hr
Dose repeated every 7 days
Vinorelbine Vinorelbine 30 mg/m2 IV, Days 1 & 8
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(monotherapy) Cycles repeated every 21 days
OR:
Vinorelbine 25-30 mg/m2 IV per week, Days 1, 8 & 15
Cycle repeated every 7 days (absolute neutrophil count
considered for dose adjustment)
Gemcitabine
(monotherapy)
Gemcitabine 600-1000 mg/m2 IV per week, Days 1, 8 &
15
Cycles repeated every 28 days (hold dose for day 15 to
see blood counts)
Docetaxel
(monotherapy)
Docetaxel 60-100 mg/m2 IV, over 1 hr
Cycles repeated every 21 days
OR:
Docetaxel 30-35 mg/m2 IV per week, over 30 min
Dose repeated every 7 days
Capecitabine
(monotherapy)
Capecitabine 2000-2500 mg/m2 oral per day, twice daily
in divided dose (14 days)
Cycles repeated every 21 days
Docetaxel+capecitabine Docetaxel 75 mg/m2 IV over 1 hr, Day 1
Capecitabine 2000-2500 mg/m2 oral per day, twice daily
in divided dose (14 days)
Cycles repeated every 21 days
Doxorubicin+docetaxel Doxorubicin 50 mg/m2 IV bolus, Day 1
Then:
Docetaxel 75 mg/m2 IV over 1 hr, Day 1
Cycles repeated every 21 days
Following (Table 5) are listed some toxicities (Waldman and Terzik, 2009, (Trevor et al., 2009)
associated with chemotherapeutic agents:.
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Table 5: Toxicities related to some chemotherapeutic agents for breast cancer
Chemotherapeutic
agent
Major toxicities to
limit dose
Other toxicities
Doxorubicin,
epirubicin
Myelosuppression,
cardiomyopathy
Alopecia, nausea, vomiting, stomatitis,
ulceration, necrosis
Paclitaxel Neutropenia, peripheral
neuropathy
Alopecia, fluid retention, myalgia, skin
reactions, ulceration, necrosis, stomatitis,
hypersensitivity reactions, nausea, vomiting,
arrythmia
Cyclophosphamide Myelosuppression,
hemorrhagic cystitis
Alopecia, stomatitis, amenorrhea, nausea,
vomiting
Capecitabine Diarrhea, hand-foot
syndrome
Myelosuppression, nausea, vomiting,
stomatitis
Gemcitabine Myelosuppression Nausea, vomiting, diarrhea, fever, chills,
arthralgia, myalgia
Fluorouracil Myelosuppression Diarrhea, alopecia, nausea, stomatitis,
neurotoxicity
Vinorelbine Myelosuppression Nausea, vomiting, fatigue, ulceration, necrosis
Cisplatin Myelosuppression Delayed nausea, vomiting, alopecia,
nephrotoxicity, ototoxicity
Carboplatin Myelosuppression Nephrotoxicity, alopecia, ototoxicity,
neuropathy, nausea, vomiting
1.9.3.1 CYCLOPHOSPHAMIDE:
It has been used for the treatment of metastasis and as adjuvant therapy for breast cancer by
preventing replication of DNA and cell division. It is a pro drug which is transformed into active
form through hepatic intracellular enzymes to active metabolites namely 4 hydroxy
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cyclophosphamide, aldophosphamide, acrolein and phosphoramide mustard (Waldman and
Terzik A P, 2009). It has been used widely for treating breast cancer in combination regimen of
CMF or with an anthracycline (Mouridsen et al., 1976). This drug has many side effects that are
listed in the Table 5.
1.9.3.2 PLATINUM COMPOUNDS:
Carboplatin and cisplatin are the drugs which are used against many cancers including breast
cancer. They are used as monotherapy or in combination regimen to treat breast cancer
(Waldman and Terzik A P, 2009). There is evidence that 20-35% patients of MBC under single
agent treatment responded to carboplatin therapy (Martín et al., 1992, O'Brien et al., 1993).
Platinum compounds are usually used in combination regimens with gemcitabine and taxanes
(Decatris MP et al., 2004 ; Perez EA et al., 2005; Burch PA et al., 2005). These compounds are
associated with various side effects that are listed in the Table 5.
1.9.3.3 TAXANES:
The two commonly used agents in this class are paclitaxel and docetaxel that stabilize cellular
microtubule elements hence causing mitotic arrest. They can be used both as monotherapy or in
combination regimen. The responses from 20-60% have been seen when they are used as
monotherapy for metastatic breast cancer patients (Sparano, 2000). Though side effects of
docetaxel were found more than paclitaxel in a randomized trial, it was established to be better
than paclitaxel with improved survival rate and progression time (Jones et al., 2005). Instead of
every 3 weeks plan, weekly management of these taxanes was seen to be well tolerated with low
toxicity in breast cancer cases (Burstein et al., 2000; Eniu et al., 2005). As compared with
doxorubicin and cyclophosphamide, a higher response rate was seen with paclitaxel and
doxorubicin but with more toxicity (Nabholtz et al., 2003). The toxicities associated with taxanes
are given in the Table 5.
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1.9.3.4 ANTHRACYCLINES:
The commonly used anthracyclines for breast cancer are doxorubicin and epirubicin. These
agents are widely used in the combination regimen to treat breast cancer such as FAC, AC, TAC,
AT and FEC. The multi drug combinations have proved to be more effective for breast cancer
yet they have related toxicities (Table 5) (Waldman and Terzik, 2009).
1.9.3.5 CAPECITABINE:
It is an oral prodrug of fluoropyrimidine which is transformed into 5-FU by thymidine
phosphorylase enzyme and has same effects as those of infusional 5-FU. It is used for
progressing MBC after the use of taxanes. This was also confirmed in a phase II study in which
MBC patients were initially heavily treated with anthracycline and taxane and then with
capecitabine giving 20-25% RR and 43% maintained stable disease. 5-FU had also been given to
those patients previously (Blum et al., 2001). Capecitabine has also shown good results in terms
of RR and survival rate with docetaxel as compared to docetaxel alone (O'Shaughnessy J et al.,
2002; Miles et al., 2004). Although toxicities (Table 5) are seen with the combination regimen
but they are manageable.
1.9.3.6 GEMCITABINE:
Gemcitabine or difluoro deoxy cytidine is a pyrimidine nucleotide that inhibits RNA synthesis
and replication of DNA. It is applied in a wide range of cancers like that of lung, bladder, breast,
pancreas etc. A weekly IV injection of gemcitabine is well tolerated (Waldman and Terzik,
2009) but the drug is associated with certain toxicities (Table 5).
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1.9.3.7 VINORELBINE:
Vinorelbine binds to the tubulin and disrupts the metaphase of mitosis. In advanced breast cancer
disease, this drug has established promising RR (40-60%) (Garcia-Conde et al., 1994, Weber et
al., 1995, Terenziani et al., 1996) and also in combination with doxorubicin or docetaxel or
trastuzumab (Spielmann et al., 1994, Accuna et al., 1999, Burstein et al., 2001). The side effects
of the drug are shown in the Table 5.
1.9.4 MONOCLONAL ANTIBODIES: TRASTUZUMAB:
It is a humanized monoclonal antibody which is biologically active and has better survival rates
for the patients of HER2/neu positive breast cancer (Slamon et al., 2001, Romond et al., 2005).
This monoclonal antibody was approved in the US for weekly administration but clinically safe
and effective schedule is of every 3 weeks (Baselga et al., 2004). This drug is also effective in
combination with paclitaxel, vinorelbine, carboplatin or gemcitabine (Pegram et al., 2004,
Burstein et al., 2003; O'Shaughnessy et al., 2004). This drug is effective in breast cancer
treatment but the response rate is <50% with HER2/neu positive disease (Waldman and Terzik,
2009). The dose of trastuzumab for breast cancer is 4 mg/kb IV over 90 min , Day 1; then 2 mg/
kg over 90 min once a week for 30 min if no reaction occurs due to infusion OR 8 mg/ kg IV
over 90 min, Day 1; then 6 mg/ kg IV over 90 min every 3 weeks. The adverse effects related to
trastuzumab are chills, fever, rigors due to infusion reaction; nausea and vomiting; pain at tumor
sites; headache and dizziness, hypotension and cardiac failure (Chisholm-Burns et al, 2010).
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1.9.5 PROTEIN TYROSINE KINASE INHIBITOR: LAPATINIB
Lapatinib is an orally active, small molecule and a reversible inhibitor of the EGFR and HER2
tyrosine kinase but its activity seems to be due to HER2 inhibition principally (Rusnak et al.,
2001). As a monotherpay, it has shown to persuade HER2-positive breast cancer cells apoptosis,
(Xia et al., 2002) and re-established sensitivity of tamoxifen to the resistant breast cancer cells
(Chu et al., 2005; Burris, 2004). Zhou H et al (2004) reported that Lapatinib sensitized breast
cancer cells to radiation which were HER2-positive. When HER2-positive breast cancers
showed advancement over the use of trastuzumab, Lapatinib was accepted in combination with
capecitabine for use in 2007. This agent in combination with letrozole is also officially used as
first-line treatment for HER2-positive metastatic breast cancer. Lapatinib is recognized as
effective for treatment of HER2-positive metastatic breast cancer but innovative methodologies
to improve its response rates are indispensable. In combination with chemotherapy, lapatinib
was established to accomplish a total 22% response rate and a 27% clinical value rate (Geyer et
al., 2006). Lapatinib, when used as a sole therapeutic agent, has shown 12.4% to 25% clinical
value rates in patients that were previously given trastuzumab though partial resistance to
lapatinib has also been observed in some cases (Toi et al., 2009; Blackwell et al., 2010).
1.10 SUMMARY ACCOUNT FOR ADJUVANT BREAST CANCER THERAPY:
The adjuvant therapy should be administered in all breast cancer patients as it decreases
recurrence rate and enhances survival rate. In post menopausal females with hormone receptor
positive breast cancer, AIs must be considered as adjuvant therapy due to their effectiveness
instead of Tamoxifen. Chemotherapy (3-6 months) should be administered in premenopausal
females and also in those who have hormone receptor negative breast cancer. Anthracycline
regimens are effective chemotherapeutic agents for breast cancer and taxanes are employed
especially in high risk patients due to their known adverse reactions. In patients with HER2/neu
positive breast cancer or with lymph node negative disease but at high risk, trastuzumab is
suggested in combination with chemotherapy (Waldman and Terzik, 2009).
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1.11 SUMMARY ACCOUNT FOR METASTATIC BREAST CANCER THERAPY:
Palliation is the goal of treatment for MBC patients as it is incurable with negligible long term
survival rate. Endocrine therapy is recommended in the patients with hormone receptor positive
disease if there is no extensive visceral involvement. Anti-hormonal alternatives can be given in
case of failure of first line or second line therapies. Anthracyclines and taxanes can be
administered if breast cancer is hormone receptor negative, there is progression on anti-hormonal
treatment or extensive visceral involvement. Although combination regimen shows high RR and
better rates of survival, but the relative toxicities are also to be managed. It has been suggested
that monotherapy in order can be just as effective. If previous chemotherapies fail in MBC, then
many subsequent-line therapies can be availed keeping in mind risk:benefit ratio of the
treatments. Use of trastuzumab is established with first line chemotherapy in HER2/neu patients
of breast cancer and is unclear with subsequent-line therapies (Waldman and Terzik, 2009).
1.12 ADVERSE DRUG REACTIONS
The definition of an ADR proposed by World Health Organization (WHO) states that “Any
response to a drug which is noxious and unintended, and which occurs at doses normally used in
man for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological
function.” (Organization, 2002). According to US-FDA standards, serious adverse reactions are
those if they are life-threatening, cause death, require short or long term hospitalization, there is
hereditary or natal deficiency, debility or permanent injury, or necessitate intervention to avoid
enduring impairment to patient.
(http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm , 2012).
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Patient protection is the foremost matter at the international level. It was reported by the Centre
for Health Policy Research that in the US, >50% of the official medications were related to
certain form of adverse consequence which was not identified preceding approval to use (Rabbur
and Emmerton, 2005). At least one ADR has been reported to occur in 10 to 20% of hospitalized
patients (Rao et al., 2006). In a report of a meta-analysis conducted by Raschke, et al (1998), it
was found that the rate of an ADR was 6.7% between the hospitalized cases. Another
epidemiological study executed in the US demonstrated that the rate of ADRs was 10–20% of
total hospitalized cases (Pirmohamed et al., 1998). A general estimate of 6.5 % and 28% of
ADRs is found to be preventable (Silverman et al., 2003).
ADRs can be principal basis of causing substantial ill health, death and financial expenses. Those
ADRs that may be avoidable may have arise due to medication error (McDonnell and Jacobs,
2002). Earlier studies have revealed that there are about 60- 70% ADRs that are preventable
(Davies et al., 2007). In a previous study it was reported that in the US around 28% of the ADRs
were preventable in the hospitalized patients (Bates et al., 1995). Globally, several countries
have established mechanism for reporting adverse drug reactions nationwide. The ADR
databases can deliver valuable facts and figures regarding prospective complications in
prescription practice. Moreover, studying collective records from varied environmental,
communal and therapeutic populations augments the capacity to detect uncommon happenings
thereby producing innovative indicators.
1.12.1 ASSESSMENT OF ADVERSE DRUG REACTIONS:
Since ADRs have been recognized worldwide as a main source of ill health, hospitalization
admission and mortality therefore, it is necessary to identify them and institute an association
among the ADR and the medication. It is necessary that the ADRs should be accurately
measured through a suitable and standard scale and be accessible. ADR reconnaissance enable
ADR recording and offer a system for observing the safety of medication usage in patients with
high risk hence encouraging learning of health care professionals. Various approaches have been
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anticipated to evaluate the correlation between medications and ADRs with a collection from
short forms to wide-ranging algorithms.
Different scales available to assess the adverse reactions that occur due to the use of various
therapeutic drugs are largely accepted and most extensively used means in clinical settings due to
their simple procedure for use. Some of the scales are as under (Table 6):
Table: 6 ADRs assessment scales
S.No Assessment
scale used for
Name of scale Categories used for suspected
medication and ADR
1 Causality WHO
Assessment
Scalea
Certain, probable, possible,
unassessable/unclassifiable,
unlikely, conditional/unclassified
Naranjo's
Assessment
Scaleb
Definite, probable and possible
2
Severity
Hartwig and
Siegel Scalec
Mild, moderate and severe
3 Preventability Modified
Schumock and
Thornton scaled
Definitely preventable, probably
preventable and not preventable
(Where a= de Expertos, 1972; b= Naranjo et al., 1981; c= Hartwig et al., 1992; d= Lau et al.,
2003).
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2. STUDY OBJECTIVES:
1. To determine the association of various characteristics in controls and cases in relation to
breast cancer. Statistical analysis will be conducted to establish significant associations.
2. To determine the risk of breast cancer associated with different factors in controls and
cases recruited in Karachi, Pakistan. Statistical analysis will be performed to obtain
significant results. This will help to exhibit the pattern of occurrence of breast cancer in
local population.
3. To evaluate the use and response of various treatment modalities employed for breast
cancer cases. The response from different treatment modalities can provide better
approach for selection of certain medications and their doses for the breast cancer in local
population.
4. To assess the adverse effects occurring due to the use of different treatments in breast
cancer patients. This will provide platform for holistic approach for use of medications
and patient counseling in local population.
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3. LITERATURE REVIEW:
3.1 BREAST CANCER:
Hashmi et al (2014) examined 1104 subjects with initial stage of breast cancer retrospectively to
identify triple negative breast cancer patients and found that the mean age of such patients was
48.4±12.3 years. It was observed that triple negative breast cancer illustrated advanced breast
cancers with particularly atypical medullary and metaplastic histology. It was suggested that
BRCA 1 mutations be identified because the occurrence of the disease was specifically at young
age.
Jamal et al (2014) measured the forms of cancers from tumor registry data from 2002-2011 with
19191 males and 13527 females with age group of 50 to 70 years. The males were mainly
suffering from the tumors of urinary bladder, prostate and lymphoma/leukemia while the females
were suffering chiefly from breast cancer. The results suggested for widespread determinations
of awareness and preliminary diagnostic programs.
Narod (2014) explained that unilateral breast cancer are mostly treated with bilateral mastectomy
to avoid a second primary breast cancer and thus to stay away from the resultant therapy and
eliminate the risk of death from contralateral breast cancer. Women at high risk of contralateral
cancer got help from it, such as carriers of BRCA1 and BRCA2 mutations, but for women with
no such mutations, the choice to remove the contralateral breast is divisive. On an individual
basis risk of contralateral breast cancer, and to tailor surgical treatment must be analyzed. The
annual risk of contralateral breast cancer is about 0.5%, but increases to 3% in carriers of a
BRCA1 or BRCA2 mutation. The decline in death from breast cancer was not established with
contralateral mastectomy, but the benefit is not predictable to be obvious until the second decade
after treatment. Substitute to contralateral mastectomy is adjuvant hormonal therapy, but the
level of jeopardy decline is smaller.
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Fatima et al (2013) evaluated 384 breast cancer cases retrospectively to find the relationship of
the disease with size, tumor receptor status and bone metastasis in local inhabitants. Left- sided
breast carcinoma ratio was expressively greater overall but that of the right side was more and
aggressive in the younger patients with smaller tumor size but higher bone metastases.
Khurshid et al (2013) conducted a retrospective study to define the occurrence of breast tumors
in young females up to the age of 25 years. The descriptive and pathological data of cancerous
tumors included that of both male and female patients and it was found that there were 80%
benign, 16% inflammatory and 2.8% malignant tumors. It was recommended to get an early
examination of wounds to circumvent death from the cancers.
Radi (2013) evaluated the level of breast cancer awareness in Saudi females focus of the study
was access the knowledge of breast cancer warning signs, risk factors, screening programs and
breast self-examination (BSE). It was correlational analysis. Modified Arabic version of the
Breast Cancer Awareness Measure (Breast CAM) version 2 was used to measure awareness and
Descriptive statistical analysis; Pearson's Product Moment correlation coefficients and ANOVA
test were used to answer study questions. Around half of the study population was aware of
breast lump as a warning sign of breast cancer and claimed family history as risk factor, 20.5%
undergone breast screening, 79% heard about BSE, and 47.5% knew how to perform BSE. It
revealed that awareness of breast cancer among Saudi Females were not sufficient.
Shamsi et al (2013) evaluated probable factors for breast cancer in a matched case-control study
which was piloted in 2 tertiary care hospitals of Karachi, Pakistan. It was established that only
limited of the documented risk factors were present in Pakistani women which included family
history of disease, being single/unmarried and older age of menopausal women. The
characteristics of discrete risk factors for breast carcinoma among Pakistani females remained
debatable.
Shaukat et al (2013) wrote that breast carcinoma might happen due to cultural, genetic, life style
and environmental factors. Variations in these characteristics would require deep studies among
PHARMACOTHERAPEUTIC STUDIES AND ASSOCIATED RISK FACTORS OF BREAST CARCINOMA IN LOCAL POPULATION
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various races and ethnicities. It was stated that highest frequency of this cancer was in Jews and
then in Pakistani inhabitants as compared to countries like Iran and India. Although there was
lacking regarding the complete knowledge of the disease in Pakistani population but
consanguinity was considered as one of the major causes for mutations and results emphasized
the point for identification of further breast cancer susceptibility genes.
Yalcin (2013) summarizes the risk factors for developing breast cancer, methods for risk
assessment and the accepted screening guidelines. It was found that in the western countries
breast cancer is widespread female malignant disease where hazard of emergent the disease is
more than 10%. Risk factors includes nulliparity or use of hormonal replacement therapy, family
history, or a history of therapeutic thoracic radiation. These days more novel efficient therapeutic
agents have been developed for the intrusion of the breast cancer, but prediction is still remained
deprived in the metastatic disease. For identification of early-stage breast cancer screening
mammography in women older than 40-45 years revealed successful in lessening the death rate.
Faheem et al (2012) reported the similarity between the incidence of hormonal receptors
expression in breast cancer cases from Northern Pakistan and published literature while Her 2
Neu overexpression was somewhat greater in Pakistani population. It was seen that there was a
converse association between hormonal receptors expression and Her 2 Neu expression. There
was greater frequency of HER-, ER+ and PR + cancers whereas HER+, ER- and PR – were
related with more progressive ailment and poor consequences.
Khokher et al (2012) statistically analyzed the data of 10 years in a Pakistani hospital to assess
the clinic-pathologic outline of breast cancer patients.Among breast cancer patients, female to
male ratio was 100:2 and breast cancer contributed for 23% of all and 41% of female cancers.It
was found that most of the cases of breast cancer were at Stage II and III with majority having
invasive ductal carcinoma. The earlier peak age and advanced breast cancer stage at appearance
was comparable to that in the developing regions. The male breast cancer accounted for greater
part in the local population. It was proposed that population based cancer registry should be
PHARMACOTHERAPEUTIC STUDIES AND ASSOCIATED RISK FACTORS OF BREAST CARCINOMA IN LOCAL POPULATION
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established and awareness regarding the breast cancer must be promoted in addition to setting up
of better healthcare system so as to reduce disease burden.
Qureshi et al (2012) stated that bony metastases was common in cancer patients and it was
considered as main prognosticator in progressive cancers. In the research, the patterns and
dissemination of bone metastases were presented with 146 cases among which 79 were males
and 67 were females with age from 25 to 82 years. The vertebrae were the main bones involved
with cancer in male cases while hip bones were the most common ones in the females. It was
found that the cancers of prostate and breast were frequently occurring in both the genders. It
was stated that the results of this study were consistent with the results of other published studies
regarding the site and dissemination of the metastatic disease.
Talpur et al (2012) examined the reasons for delayed exhibition of breast cancer in Nawabshah,
Pakistan in a descriptive study which was done in both private and public sectors 2004 to 2008.
An advanced stage of the disease was confirmed in majority of the cases perhaps due to low
SES, illiteracy and carelessness by physicians or patients themselves or their family members.
Christiansen P et al (2011) analyzed a population-based cohort of systemically untreated breast
cancer cases from the registry of the Danish Breast Cancer Cooperative Group. The patients
were node negative and ER+ and/or PR+ cancers. The relationship between standardized death
ratio and risk factors were examined in Poisson regression analyses. It was found that The
mortality rate was associated with larger tumor size and age except for a small subclass of breast
cancer cases aged≥ 60 years that had hormone-responsive early-stage tumors (up to 10 mm), and
had no systemic adjuvant therapy; they were not at enhanced risk of mortality when compared
with cases in this age-group in the overall population.
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Jemal et al (2011) stated that cancer continued to augment worldwide due to increase in age and
enhanced smoking in the developing countries. It was observed from GLOBOCAN 2008
assessments that 12.7 million cancer cases and 7.6 million cancer demises happened in 2008 with
most of them in the developing countries. Breast carcinoma was reported to be the most
frequently occurring cancer and major cause of death in the women while lung cancer followed
for males. Breast cancer was evident as main cause of mortalities in females in the developing
countries prior to which was cervical cancer; deaths due to lung cancer in females was
comparable with that of cervical cancer in the developing countries. Generally cancer death rates
were seen akin in the developed and the developing countries but the overall cancer frequency in
the developing countries was half to those as observed in the developed countries. Cancer
survival rates were poor in developing countries due to late presentations and access to therapies.
It was suggested that cancer control information and programs for tobacco control, vaccination,
early diagnosis and management and public health promotions for physical activity and an
improved diet should be implemented. Healthcare professionals and policy makers could be
involved in such activities.
Lari and Kuerer (2011) carried out a broad methodical review to recognize studies available in
the past 10 years that examined biological markers in ductal carcinoma in situ (DCIS).
Biological markers assessed in 6,252 cases comprised of hormone receptors, proliferation
indicators, cell cycle regulation and apoptotic indicators, angiogenesis-related proteins,
epidermal growth factor receptor family receptors, extracellular matrix-related proteins, and
COX-2. The studies included in this review delivered important initial evidence regarding the
expression and prognostic implication of biomarkers in DCIS but they were limited to small case
cohorts where the degree of surgery and procedure of radiotherapy or endocrine therapy and also
means of defining biomarker expression differed from patient to patient. These limitations made
explanation of total consequence of expression of various biomarkers on risk of local relapse
challenging. Basic important prognostic and predictive indicators linked with invasive breast
cancer were not sufficiently calculated in DCIS.
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Kotsopoulos et al (2010) examined prospectively hormonal and non-hormonal experiences and
risks according to the histologic sub-types in 4,655 ductal and 659 lobular cases of breast cancer
in postmenopausal women from the Nurses’ Health Study. After using Multivariate Cox
proportional hazards regression stratified by histologic subtype and time period, it was found that
breast carcinoma was a diverse disease and the variance in association with several risk factors
was indicative of etiologically discrete tumors. It was stated that the epidemiological studies
would be carried out to consider and understand the changing role of histology.
Philippe et al (2010) performed a Retrospective analysis from WHO mortality database from
1989 to 2006 to assess variations in chronological drifts in breast malignancy death in females in
30 European states. It was seen that the variations in breast cancer death after 1988 were diverse
between the European countries with UK having the leading declines. Women with age <50
years presented the utmost drops in death. The growing mortality in particular central European
countries revealed preventable death rates.
Weigelt et al (2010) described that breast cancer was a diverse ailment, with multiple entities
linked with characteristic histological and biological characteristics, clinical demonstrations and
responses to treatment. Numerous characteristics of breast cancer had been discovered through
micro-array procedures which included metastatic inclination and histological grade. It also led
to the recognition of prognostic and predictive gene expression markers. Additionally, a
molecular taxonomy of breast cancer established on transcriptomic investigation was suggested.
Histological sub types of breast carcinoma accounted for approximately 25% of all invasive
breast cancers. A straight proof of the presence of genotypic-phenotypic associations was
observed. Also, histopathological and molecular examination of tumors from conditional rodent
models had delivered straight confirmation for the relevant role of particular genes in the
tumorgenesis of specific histological types.
Hanif et al (2009) revealed that the cancer registry program at the national level in Pakistan is
non existent and data regarding cancers are available from healthcare facilities. They performed
a retrospective study of the cancer patients at Karachi Institute of Radiotherapy and Nuclear
Medicine (KIRAN) from 2000 to 2008. Among 16,351 cancer patients, 48.1% were males (mean
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age 50-/+9.6 years) and 51.8% were females (mean age 47-/+7.4 years) whereas only 3.4% were
children. The most frequent cancers in males were those of head and neck (32.6%) and lung
(15%) while in females breast cancer was the most frequent one (38.2%) and then head and neck
(15.1%) cancer at tolls more or less maximum in Asia.
Moore1 et al (2010) stated that even though there is enormous miscellany across the area, there
are adequate resemblances for a mutual line to control various ailments including cancer. Oral
and lung cancers were found to be on the top in the region with reasonably high numbers of
pharyngeal and/or laryngeal and prostate cancers in the urban areas. Breast and cervical cancer
stood first and second but in Pakistan, breast cancer is followed by oral cancer in general.
Evidently cumulative rates for breast cancer and dissemination modifications in other cancers
submit that the total affliction would be heftier in excess of time, particularly with increasing
obesity and aging. It was suggested that the organization of activities within South Asia must be
prioritized to control cancer in this zone.
Agarwal et al (2007) made a comparison of demographic, clinical, pathological and outcomes
data in breast cancer patients at breast cancer centers in India, Malaysia and Hong Kong. The
occurrence of breast cancer is lesser, yet the cause-specific mortality is significantly higher in
developing Asian countries compared with developed countries in Asia and the rest of the world.
As compared to developed nations patients were found to be decade younger in developing
countries. Poorer prognosis was carried with proportions of young patients differ from about
10% in developed to up to 25% in developing Asian countries. Greater part of breast cancer
patients diagnosed at a comparatively late stage. In the developing countries where as
distribution of the disease stage-wise is constructive in developed Asian countries. In young
Asian women pathology and the clinical picture of breast cancers found to be dissimilar from
those of average patients managed elsewhere in the world. Due to need of consciousness,
deficient in funding, be short of infrastructure, and low priority in public health schemes, breast
cancer screening and early detection have not fixed in these under-privileged societies.
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Clarke (2007) investigated the steroidal regulation of proliferation and differentiation in the
human mammary gland by ovarian hormones. The athymic nude mouse model was developed
with subcutaneous grafting of intact normal human breast tissue and treatment with estrogen
and/or progesterone at human physiological serum levels. It was revealed that estrogen was the
main epithelial cell mitogen in the grown-up normal breast and it induced progesterone receptor
expression maximally at low estrogen concentrations although this induction required higher
quantity of estrogen. After using double-label immunofluorescence it was established that steroid
receptor expression and cell proliferation followed in discrete cells in normal human breast
epithelium, and estrogen expressing cells invariably had the PR. The division between steroid
receptor expression and cell proliferation in normal epithelium was upset at an initial stage in
breast tumor development.
Polyak (2007) documented that breast cancer was not a solitary ailment and was composed of
discrete subtypes linked with dissimilar medical consequences. This elucidation would help to
develop targeted cancer-preventative and -therapeutic managements. Tumor commencement and
development are suggested to be principally due to attained genetic changes, but a role of micro-
environmental and epigenetic variations had been documented as well.
Cordera and Jordan (2006) reported that the ER and PR hormone receptors show a serious role in
breast cancer development. The ER and/or PR expression by tumor cells deliver significant
evidence that is critical for the treatment selection. Novel visions into the pathogenesis of breast
malignancy and resistance mechanisms to anti-hormonal therapy were provided by some new
studies. Improved considerations regarding steroid receptors and their ligands, and the
mechanisms through which they affect would permit the precise management to target to
receptive cancers.
Jamal et al (2006) surveyed the data from pathology based tumor registry of Rawalpindi,
Pakistan.All cancerous tumors from 1992 to 2001 were examined and a contrast evaluation with
the earlier publications, both national and international, was also completed.There were 21,168
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tumors overall out of which 59.5% were in males and 40.5% were in females whereas 4.4% were
in the pediatrics. Tumors of the prostate were the most common in males unlike previous study
that indicated lymphomas and leukemia to be the most frequent cancers. In females, breast
carcinoma persisted to be the most common and differing to the Indian and Western studies,
ovarian tumors were more frequent than cervical cancers.
Sant (2006) examined survival drifts in association to death and occurrence of breast cancer to
realize interrelations between occurrence, death and survival tendencies and their outcomes.
They assessed breast cancer incidence trends from 1970 to 2005 in 10 European countries
beginning with detected persistence from EUROCARE adn transience from WHO, by using the
MIAMOD technique. The survival trends were supposed to be comparable to those perceived by
EUROCARE (1983–1994). It was observed in Sweden, Finland that there was growing survival
with growing occurrence and diminishing or steady mortality; Denmark, the Netherlands and
France exhibited minor survival surge, noticeable surge in incidence and slender mortality
reduction; growing survival, striking reduction in mortality and affinity to frequency balance
was seen in UK; in Spain, Italy there was a clear survival surge, stable or declining mortality and
modest increase in occurrence; in Estonia, there was steady survival, growing occurrence and
death rate.
Dontu et al (2004) documented that significant development was made in the identification and
classification of stem and progenitor cells in the rodent and human breasts. There was accruing
indication that such cells would be objectives for alteration during breast carcinogenesis. A
model was proposed on the basis of this stem cell idea in which the alteration of diverse
subgroups of stem and progenitor cells resulted in the variety of breast cancer phenotypes, with
expression of the ER in breast cancers categories. Moreover, the idea of breast malignancy as a
ailment of breast stem and progenitor cells had intense inferences for the advancement of new
approaches for breast cancer deterrence and treatment.
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Cianfrocca and Goldstein (2004) noted that due to increased screening facilities, the majority of
patients were presented with primary stage of breast cancer. It was reported through the Oxford
Overview Analysis that adjuvant hormonal therapy and multiple regimen chemotherapy
decreased the risk of relapse and deaths caused by the breast cancer, however there were certain
associated risks. The use of established predictive and prognostic factors of breast cancer was
considered to be beneficial in the selection of optimal treatments for the patients suffering from
the disease. The Prognostic factor was defined as “any measurement accessible at surgery that
associated with disease-free or overall survival in the deficiency of systemic adjuvant treatment
and therefore was able to relate with the natural history of the disease.” The predictive factor was
defined as “any measurement related with response to a specified treatment.” Some factors, such
as hormone receptors and HER2/neu over expression were considered to be both prognostic and
predictive.
Aziz et al (2003) analyzed retrospectively a data base of 5100 patients to realize the incidences
of diverse cancers in Punjab. After coding the cancers according to international classification of
Disease-oncology-10, it was established that there were 47.7% male and 52.2% female cancers
overall. The most common cancers among the males were hematological cancers, colorectal and
lung cancer whereas in females, breast cancer (38.5%) and ovarian cancers were the most
common ones.
Malik (2002) prospectively investigated breast cancer in Karachi, Pakistan and compared the
information with that in the USA. The mean age of the patients was 47.7 ± 11.8 years and only
18% patients had a family history of breast cancer. Most of the patient opted for unconventional
treatments before attaining the standard medical care. Few patients had advanced disease and
17% were found to be suffering from metastasis upon diagnosis. Pakistanis were far lagging
behind as compared to the USA regarding the management of breast cancer and there was a
pronounced requirement for public edification to enhance cognizance about cancer and life style
characteristics.
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Reya T et al (2001) discussed that unambiguous evidence that stem cells present in the
haematopoietic system gave way to the probable isolation of numerous tissue-specific stem and
progenitor cells, the preliminary definition of their features and articulated genetic programs, and
the commencements of their usefulness in re-forming medicine. Through the property of self-
renewal of stem cells, remarkable parallels could be established between stem cells and cancer
cells.
Siddiqui et al (2001) analyzed the overall survival of breast cancer with metastasis in Pakistan
through retrospective analysis. They notified that the patients had a median survival of 2.83 years
which was similar to the figures that were available in the literature.
Borst and Ingold (1993) evaluated the metastatic locations of invasive lobular and invasive
ductal breast cancer patients from January 1973 to December 1990 by using of tumor registry.
There were 2605 patients of invasive lobular and invasive ductal breast malignancy. The
metastatic forms of lobular and ductal breast cancer were diverse revealing prominent metastases
of gastrointestinal system, gynecologic organs and peritoneum-retroperitoneum in lobular
cancer.
3.2 RISK FACTORS OF BREAST CANCER:
Berman (2014) examined the association of breast cancer risk with cardiovascular disease in
geriatrics (≥65 years) in a case control study. It was summarized that extended prediction in
breast cancer cases was influenced by managing comorbidities hence the evaluation and
management of diabetes and hypertension in geriatrics would enhance the overall survival rates
of such patients.
Butt et al (2014) investigated the association of breast feeding duration with breast cancer risk
for which numerous parous females were included. The results showed that no strong association
was revealed for duration of breast feeding and breast cancer risk and the risk was akin in breast
feeding quartiles.
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Farvid et al (2014) inspected the link between fat intake and breast cancer occurrence in the
Nurses' Health Study II. Multivariable-adjusted Cox proportional hazards analyses was
employed to evaluate dietary fat in relation to total, premenopausal, and postmenopausal breast
malignancies. The results showed that the total fat consumption was not related with breast
cancer risk on the whole. After adjustment for various factors, an affirmative relationship was
observed between animal fat intake and breast cancer on the whole. Likewise, an affirmative
relation for animal fat ingestion was also realized among premenopausal females only. Higher
ingestions of both saturated and monounsaturated fat was linked with discreetly greater breast
cancer risk among all women; greater cholesterol consumption was found to be related with
greater premenopausal risk of breast cancer. The findings revealed that there was an affirmative
relationship between initial adult consumption of animal fat and risk of breast cancer.
Gold et al (2014) discussed that management of breast cancer in diabetic patients was very
complex and required special care regarding the management of the coexisting diseases. It was
revealed that chemotherapy was given to lesser number of patients and there was a statistically
significant surge of death among diabetic patients. Disease relapse and metastases were varying
in such patients. Negative associations between diabetes and optimum management or death
among women with breast cancer were observed in several studies. It was suggested to have
overall management of these comorbidities to avoid surplus ill health and death.
Pranjic et al (2014) investigated the association between individual, social, occupational and
environmental factors of breast cancer in a case control study using an ambulatory based survey
in Zenica - Doboj Canton. Among new breast cancer patients, 52% were housewives and
physical activity diminished the risk of invasive breast cancer in majority of the females.
Converse significant associations between breast cancer and poverty, menopausal age and family
history in distant cousin were found.
Trentham-Dietz et al (2014) analyzed population based case control studies to assess various risk
factors of breast cancer according to age or menopausal status including 23959 cases and 28304
controls. Strong association of family history was found with breast cancer risk and also of
obesity in post menopausal women which was negative in premenopausal females. There was
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also positive association of alcohol consumption with breast cancer risk. Many of the menstrual
and lifestyle factors were linked with risk of breast cancer irrespective of age or menopausal
status.
Work et al (2014) stated that poorer prognosis was associated for ER- PR- breast cancers which
may occur due to high parity in the women but the risk would decrease by breast feeding. A case
control study consisting of 4011 cases and 2997 controls was carried out to confirm this
relationship in the women. The results showed that there were adaptable aspects for ER-PR-
breast malignancy and breastfeeding specifically may diminish the augmented risk of ER-PR-
cancers that were perceived from high parity.
Zsuzsanna (2014) stated that various studies intensely support that triple-negative breast cancers
might be diverse categories and that the etiologic aspects, medical features and therapeutic
options might differ by molecular categories. Several studies suggested that reproductive
characteristics and exogenous use of hormone influence the risk of triple-negative breast cancers
and ER+ cancers in a different way or rather contrariwise. It has been proposed through several
studies that the biological mechanisms that start both triple-negative breast cancers and non-
triple-negative breast cancers are completely ambiguous. It was established that the cancers are
multi-faceted but the disruption of appropriate estrogen signaling appeared to be a critical risk
factor for the attainment of breast carcinomas. The defect status in metabolic and hormonal
stability had been described to be directly related with the lifetime risk of triple-negative breast
cancers for women. Exogenous or parity-associated disproportionate estrogen source is said to be
suppressive against breast cancer. It was recommended for females for strict regulation and
conservation of hormonal stability from initial puberty to prevent all types of breast cancers.
Babu et al (2013) stated that India was undergoing epidemiologic evolution and breast cancer
surge was faster than before due to disparities in factors like reproductive, genetic, diet and age.
After a systematic review, it was revealed that surge in breast cancer occurrence was related to
many modifiable risk factors specifically in females aged >40 years who had delayed disease
presentations, were ignorant about the disease diagnostics, due to associated cost and social
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stigma. It was concluded that women would be educated regarding breast cancer to improve their
life styles in order to help prevent or decrease disease incidence.
Bahadoran et al (2013) investigated the association of dairy products intake with risk of breast
cancer by a case control study comprising of 175 controls and 100 cases. It was revealed that
increased consumption of total dairy products decreased breast cancer risk; lower consumption
of high fat dairy products was linked with decreased breast cancer risk, demonstrating protective
effects of the dairy products in general.
Jung et al (2013) conducted a case control study to investigate the effects of different medical
conditions in Korean population with breast cancer. Multiple logistic regressions adjusted for
different variables were applied to calculate the odds ratio for each disease. It was established
that hypertension, diabetes, thyroid and ovarian diseases were related with greater risk of breast
cancer. Ovarian diseases and hypertension were also found related more to breast cancer risk
after analysis by stratified menopausal status.
Link et al (2013) assessed breast cancer risk associated with the dietary patterns in a large cohort
of females by analyzing 5 different diets. The results concluded that vegetable source diets were
linked with a decreased risk of breast cancer especially in females with ER- PR- cancers.
Nazir et al (2013) stated that breast cancer was augmented in Kashmiri population and the
investigators studied prospectively different histo-pathological categories, the hormone receptor
status and their association with a number of clinic-morphological characteristics. There was
higher ER/PR expression in breast cancer in Kashmiris as compared to the researches that were
done in India or Asia but lower than those done in Western countries. The evidently inferior
receptor expression in the Indian or Asian investigations was probably due to pre-analytic
variables, inception for positivity and elucidation principles relative to genetic alterations. Hence
it was recommended that such variables should be additionally recognized and actions should be
taken to resolve them for progressive calculation of the receptor status.
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Parameshwari et al (2013) conducted a case control study to evaluate the association of breast
cancer risk with different factors in India. The subjects had a mean age of 49.7 + 10.39 years. It
was revealed that menarche < 13 years, being unmarried or single, a positive family history of
breast cancer, former history of benign breast tumors and breast feeding < 2 years were
positively associated with risk of breast cancer. There was lack of knowledge regarding the
disease and also about self examination among the inhabitants.
Bao et al (2012) studied the relationship of diet with breast cancer risk and also according to
hormone receptor status in Chinese women in a case-control study, enrolling 3,443 cases and
3,474 controls in two phases i.e. (1996–1998) phase I and (2002–2004) phase II, among which
the ER and PR data was available for 2,676 cases. The data was analyzed using multivariate,
polychotomous, unconditional logistic regression models. The findings showed that that more
consumption of overall vegetables, some fruits, milk, and eggs might decrease the risk of breast
cancer, whereas high intake of all kinds of fish and meat diets might enhance the risk. The
dietary links did not seem to contrast by the ER or PR status in the subjects.
Khokher et al (2012) examined ten years data from of a cancer hospital in Pakistan to assess the
clinic-pathological outline of local patients with breast cancer. The female to male ratio for the
cancers was 100:2 and there were overall 23% breast cancer patients; 41% of female cancers but
rate of male breast cancer were higher in the population. Almost 46% patients were inhabitants
of Lahore, with a mean age of 47±12 years. Majority patients had Stage II and III disease with
91% invasive ductal carcinoma. The patients with known tumor grades had 11% tumor grade 1,
55% grade 2 and 34% grade 3 tumors. As like other developing countries Pakistan also had
profile of breast cancer with earlier age and advanced stage of disease at presentation. It was
suggested to establish population based cancer registry and also use of hospital information
systems to acquire correct and comprehensive local records. A better healthcare system and
education of patients regarding breast cancer was highly emphasized.
PHARMACOTHERAPEUTIC STUDIES AND ASSOCIATED RISK FACTORS OF BREAST CARCINOMA IN LOCAL POPULATION
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Sobani et al (2012) statistically assessed the awareness and approaches of Pakistani urban
females about breast cancer and its existing screening facilities in a cross-sectional study. There
were 78.6% married women among which 69% were housewives and education level was
noticeably high with 57.4% graduate women. It was concluded that extensive health education
platforms were required in Pakistan concentrating on breast cancer education.
Conroy et al (2011) inspected all-cause and breast cancer-specific survival by BMI in the
Multiethnic Cohort (MEC) study for African American, Native Hawaiian, Japanese American,
Latino, and Caucasian females aged ≥50 years at cohort entry. Cox proportional hazards
regression was used for estimations. Breast cancer survival was found to be inferior in obese
women, though rare studies assessed that it was due to ethnic disparities; no evidence of ethnic
dissimilarities was seen in the study. It was proposed that sustaining sensible weight lifetime
would be helpful for breast cancer survival and in all ethnicities.
Liao et al (2011) investigated the association of diabetes with breast cancer risk through a meta-
analysis comprising of 16 publications between 2000 and 2010. This meta-analysis indicated that
23% augmented risk of diabetes was present particularly in post menopausal females and
furthermore, menstruation status along with geographical variation could influence the
association. The association was the most apparent in Europe (RR=1.88, 95%CI:1.56-2.25),
followed by America (RR=1.16, 95%CI:1.12-1.20) but insignificant in Asia (RR=1.01,
95%CI=0.84-1.21) as estimated using random-effects model.
Phipps et al (2011) emphasized that triple-negative breast cancer arose inexplicably among
African American women as compared with white women. It was found to be related with a
poorer prognosis than ER+ breast cancer. Hormonally mediated risk elements might be
differentially associated to risk of triple-negative and ER+ breast cancers.
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Albrektsen et al (2010) investigated histological category and tumor grade variations by parity or
age at first child birth among 22,867 Norwegian breast cancer cases aged 20 to 74 years.
Associations were estimated using chi-square statistics, polytomous and binary logistic
regression models. The findings of the study were in agreement with the earlier observations that
reproductive characteristics influenced the risk of various categories of breast cancer in a
different way. Paget disease, sarcomas, medullary cancers might be principally vulnerable to
pregnancy-related revelation.
Brown and Simpson (2010) reported the link between obesity and breast cancer risk. They
described that AMP-activated protein kinase (AMPK) is a master regulator of energy
homeostasis and it also phosphorylates and stops the actions of cAMP-responsive element
binding protein (CREB)-regulated transcription coactivator 2 (CRTC2). The CREB-dependent
regulation of aromatase is a critical element of breast tumor development through local estrogen
production in postmenopausal women.
Cannata et al (2010) stated that relationship between type II diabetes and cancer were
demonstrated through epidemiological research and Type 2 diabetes has been described due to
insulin resistance and hyperinsulinemia. The effect of insulin on its related receptor and the
insulin-like growth factor system might cause various cancers like breast cancer which had been
confirmed in animal and human studies. Medications used to treat type 2 diabetes may affect
cancer cells directly or indirectly. The serum insulin levels are affected by the use of anti diabetic
drugs that would affect the cancerous cells also.
Kabat et al (2010) evaluated the relationship of consumptions of dietary iron and heme iron with
risk of breast cancer in post menopausal women. The data was collected from the National
Institutes of Health–AARP Diet and Health Study with 116,674 postmenopausal women and
3396 cases of invasive breast cancer were recognized during 6.5 y of follow-up. Cox
proportional hazards models were used after adjustment for variables which revealed that no
associations were observed between iron or heme-iron intakes and breast cancer in post
menopausal females.
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Dey et al (2010) described that breast cancer occurrence was greater in developed countries with
advanced rates of ER+ tumors that were caused by estrogenic revelations. Xenoestrogens were
the risk factors that were estrogenic and development-related but hard to investigate because the
developed countries lacked unexposed inhabitants. The developing countries comprise of both
urban and rural inhabitants with exposure to xenoestrogens variably. The urban-rural breast
cancer occurrence was evaluated through classification by hormone receptor status using records
from Gharbiah population-based cancer registry from 2001 to 2006 in Egypt. The urban ER+
incidence rate was found to be greater than rural incidence rate; ER− frequency was 2-3 times
more in urban areas indicating that probably urban women had a higher contact to
xenoestrogens.
Novosyadlyy et al (2010) investigated the molecular mechanisms with the MKR mouse model of
T2D that link T2D to the development and advancement of breast cancer. MKR mice dock a
transgene encrypting human insulin-like growth factor-I receptor that is expressed entirely in
skeletal muscle, where it inactivates endogenous insulin receptor and insulin-like growth factor-I
receptor. The lean female MKR mice are glucose intolerant and insulin resistant, exhibiting
enhanced mammary gland growth and greater phosphorylation of IR/IGF-IR and Akt in
mammary tissue. Any of these metabolic abnormalities would speed up the expansion of
hyperplastic precancerous lesions. The mammary tissue isolated from these mice displayed
amplified phosphorylation of IR/IGF-IR and Akt. Tumor-promoting properties of T2D in these
models were inverted by pharmacological obstruction of IR/IGF-IR signaling by tyrosine kinase
inhibitor BMS-536924. The results were evident that T2D accelerated mammary gland growth
and carcinogenesis for which the IR and/or the IGF-IR were mainly responsible.
Owens (2010) investigated data from the National Longitudinal Study of Adolescent Health to
see association of SES with education. It was reported that when a student joined school with
more white and high-SES peers, low odds of educational achievement among students from
lower-SES vicinities were more lowered. Contrariwise, by attending school with more white and
high-SES peers, the high odds of educational achievement in students from higher-SES vicinities
were more improved. It was suggested that the policy makers should define a system of
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integration of students to be successful from various vicinities into a school’s organization and
culture.
Huang et al (2009) studied the distance between houses of females identified with breast
malignancy and the nearby mammography centre, as a risk factor for advanced stage analysis in
rural inhabitants. A total of 12,322 women (aged ≥40 years) diagnosed with identified cancer
stage were involved; 1999-2003 Kentucky Cancer Registry statistics were used for this
investigation. It was concluded that extensive travel distance also unfavorably affected timely
recognition of the disease apart from factors like socioeconomic status and age.
Parsa and Parsa (2009) reviewed effects of reproductive aspects on risk of breast cancer and
stated that by knowing risk factors of breast cancer it could be considerably prevented. It was
further added that substantial geographical variations existed regarding breast cancer with high
proportions in North America and North Europe and somewhat low proportions in Africa and
Asia.
Stead et al (2009)investigated clinico-pathologic types of breast cancer patients with triple-
negative tumours using likelihood tables and multivariate logistic regression model. Patients
were ethnically dissimilar and approximately 50% were obese. The tumors were 72% ER+
and/or PR+, 13% were HER2+ and 20% were triple-negative with 3 times higher odds of having
a triple-negative tumor in black females as compared with white females. Triple-negative tumors
were common in black women irrespective of age and BMI; allowing for all patients, triple-
negative tumors reduced as the BMI increased.
Ozmen et al (2009) did a prospective nested case-control survey among the Turkish women,
between the years 2000 to 2006, enrolling n=1492 breast cancer cases and n=2167 controls who
were admitted to hospital for non-cancerous, non-hormone connected diseases. The results
demonstrated that age ≥ 50 years, BMI ≥ 25, positive family history, age at first birth ≥ 35 years
and induced abortion were significantly linked with greater breast cancer risk while ≥13 years of
education, smoking, breast feeding, the use of oral contraceptive and hormone replacement
therapy were related with reduced risk of breast cancer among Turkish women. The results of
multivariable logistic regression models suggested that age ≥ 50 years, induced abortion and oral
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contraceptive use were statistically significantly associated with breast cancer risk as self-
determining factors.
Hulka and Moorman (2008) discussed that breast cancer frequency rose in the early reproductive
years and continued to progress in late ages in North America and Northern Europe unlike Japan
and less developed zones. Female gender, age, country of birth, family history and mutations in
the BRCA genes were considered as the solidest factors of breast cancer risk. Invasive carcinoma
was caused by atypical hyperplasia and molecular alterations in benign breast wounds. Greater
breast density in postmenopausal women demonstrated an increase in breast cancer risk. Bone
density and breast cancer were established to be associated due to the mechanism of endogenous
estrogen levels; serum estrogen levels were greater in breast cancer cases as compared to
controls. The use of exogenous hormones and alcohol intake were reported to increase breast
cancer risk reasonably. SERM modulators like Tamoxifen would probably diminish the risk of
breast cancer in prone females.
Wang et al (2008) conducted a case-control study (1,703 breast cancer cases 2,045 controls) and
in the San Francisco Bay area to evaluate the risk of breast cancer with dietary fat consumption
and cooking fat practice. By application of unconditional logistic regression it was seen that high
fat consumption was related with greater risk of breast cancer with an association for oleic acid
only. The risk was augmented for hydrogenated fats or vegetable/corn oil used in cooking as
compared to olive/canola oil. It was concluded that a low-fat food might be helpful in breast
cancer prevention.
Chen and Colditz (2007) wrote that breast cancer represented a heterogeneous disease and the
hormone-receptor status defined significant scientific and etiologic dissimilarities. The
epidemiologic data was reviewed regarding changes in risk-factor relations by hormone-receptor
status and focused chief drifts in the literature. The development and assessment of breast cancer
risk models were discussed, focusing the Rosner and Colditz model, which could distinctly
evaluate the risk of breast cancers according to the hormone status. The medical inferences of
accounting for hormone-receptor status in breast malignancy risk- estimation models were also
discussed.
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Gail et al (2007) stated that the Breast Cancer Risk Assessment Tool of the National
Cancer Institute is widely used for counseling and defining entitlement for breast cancer
prevention trials. They established a model for estimating absolute risk of invasive breast cancer
in African American women and compared its estimates with those from the Breast Cancer Risk
Assessment Tool after collecting the data from 1607 African
American women with invasive breast cancer and 1647 African American controls in the
Women’s Contraceptive and Reproductive Experiences Study. Absolute risks were attained by
joining data on invasive breast cancer occurrence in African American women from the
National Cancer Institute’s Surveillance, Epidemiology and End Results Program and with
national mortality records. Eligibility screening information from the Study of Tamoxifen and
Raloxifene trial were used to define the effects of the new model on eligibility; separate statistics
from the Women’s Health Initiative were used to measure the agreement between statistics of
invasive breast cancers projected by the new model and detected cancers. The findings suggested
that the Women’s Contraceptive and Reproductive Experiences model generally provided greater
risk assessments for African American females than the Breast Cancer Risk Assessment Tool;
hence was acclaimed for advising African American women regarding their risk of breast cancer.
Kerkeni et al (2007) studied the relationship between SES, occurrence of consanguineous
marriages and its effects on reproductive performance and death in Tunisia. Consanguineous
marriages signified 24.81% of the total marriages and most of them were between first cousins.
It was found that consanguineous unions contracted at a junior age with a greater fertility index
but higher rates of neonatal and post-neonatal expiries, and demises of children < 5 years were
observed.
Larsson et al (2007) evaluated the relationship between diabetes and risk of breast cancer
through a meta-analysis of case-control and cohort studies by searching MEDLINE from 1996 to
2007. Twenty studies i.e. 15 cohort studies and 5 case-control reported relative risk with 95%
confidence intervals for the association between diabetes mellitus and breast cancer occurrence
showing that women with diabetes had a 20% statistically significant augmented risk of breast
cancer as compared to the control group.
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Barlow et al (2006) prospectively studied risk factors of breast cancer in a cohort of 1 million
females who underwent mammography through stratified logistic regressions for premenopausal
and postmenopausal women. The models were created with 75% of the data and then with 25%
validation. The concordance (c) statistic subsequent to logistic regression model was used to
assess predicted vs. observed outcomes. In premenopausal women, statistically significant risk
factors for breast cancer common in both strata comprised age, family history, breast density and
past breast procedure whereas for postmenopausal women only, additional statistically
significant factors were BMI, race, ethnicity, natural menopause, hormone therapy, and a prior
false-positive mammogram; It was indefinite whether decrease in breast density would decrease
breast cancer risk although it was found to be a strong risk factor. For premenopausal females the
c statistics were (0.631; 95% CI = 0.618 to 0.644) and for postmenopausal women it was (0.624;
95% CI = 0.619 to 0.630). the model was claimed to be better than the Gail model for high risk
patient though it had moderate accuracy.
Fenton (2006) discussed that the risk of breast cancer was markedly affecetd by genetics, but
more than 70% women had non-inherited cancer. The environmental and life style features could
modify the risk of breast cancer. Contacts to some chemicals and hormone-mimicking or
endocrine-disrupting compounds (EDCs) were assumed to increase breast cancer occurrence and
also advanced adolescence in the US. Investigations of effects of endocrine-disrupting
compounds in rodents showed that numerous toxicants could amend breast gland development
depending on dose and exposure parameters. The atypical developmental forms included the
existence of carcinogen-sensitive structures either in larger numbers or for extended times in the
gland; they repressed functional differentiation causing malnourishment or augmented death of
their children. Progressive toxicants of the breasts could escalate the occurrence of breast cancers
by altering circulating or tissue-localized hormone levels, patterns of receptor expression,
hormone transport, or metabolism that caused changed response to endogenous hormones or
growth factors.
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Gorin et al (2006) explained the in the early diagnosis and management of primary breast cancer
across miscellaneous cultural groups after examining the data from the Surveillance,
Epidemiology, and End Results-Medicare database. The diverse groups were related in their
diagnostic, management, and medical deferment. It was noted that African American females
mostly had delays in early diagnosis and commencement of breast cancer management as
compared to those belonging to other ethnicities. Despite certain restrictions, the results are
steady athwart study, signifying the grave significance of decreasing these deferrals.
Kahlenborn et al (2006) carried out a meta-analysis of case-control studies to investigate the
association of oral contraceptive use with breast cancer in premenopausal women. DerSimonian-
Laird method was used to calculate joint odds ratios and confidence intervals and Mantel-
Haenszel test was used to measure link between oral contraceptive use and breast cancer from 34
studies. It was revealed that oral contraceptive use was related with enhanced risk of breast
cancer in premenopausal women in general and particularly before first full-term pregnancy in
parous females
Largent et al (2006) conducted a case-control study among women (aged 50-75 years) to
examine the association of breast cancer risk with hypertension and anti hypertensive drugs.
n=523 breast cancer cases were determined through a population-based cancer registry whereas
n=131 controls were determined through random-digit-dialing. Through unconditional logistic
regression analyses, adjusted for variables, it was found that the history of treated hypertension
was linked with significantly enhanced breast cancer risk but only in the females with BMI ≥25
kg/m2. The use of diuretics was also related with high risk of breast cancer which elevated with
time period of its use while the use of other antihypertensive drugs was not established to be
related with breast cancer risk.
Li et al (2006) stated that it is biologically probable that women with a migraine history might
have a diminished risk of breast cancer but this was evaluated in only one small study in which
the effect of migraine triggers could not be assessed that are well-recognized breast cancer risk
factors. Unconditional logistic regression model was used to measure the risk of breast cancer
with migraine history in a multicenter population-based case-control study in the USA. The data
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obtained supported that migraine history might be related with a diminished risk of breast cancer
in women and was not dependent on the exposure to common migraine activators.
Malone et al (2006) investigated white and black American women with breast cancer (aged 35
to 64 years) in a multi centered case control study for the occurrence and predictors of BRCA1
and BRCA2 mutations. BRCA1 mutations were expressively more enhanced in White versus
Black and in Jewish versus non-Jewish cases while BRCA2 mutations were to some extent more
common in Black versus White cases. Several family and demographic characteristics were
found to be significantly more related with BRCA1 than BRCA2 carries of ovarian cancer upon
individual assessment. The Jewish lineage persisted as predictive and intense BRCA1 carrier
chiefly.
Kuhl (2005) wrote that approximately 40% females could have occult breast tumors in the
climacteric and the tumor growth could have stimulated by the hormones. Several reproductive,
genetic and lifestyle features might have impact on the occurrence of breast cancer.
Epidemiological studies proposed that the increase in the RR of breast cancer induced by HRT
could enhance the RR of breast cancer and this risk augmented because of obesity but the risk
was not additionally increased by HRT use in obese postmenopausal women. It was found in the
WHI study that most of the females were obese; this experiment was inappropriate for the study
of breast cancer risk. A selection bias was observed in the study because upon treatment with an
estrogen/progestin combination, the RR of breast cancer increased only in those who were being
treated with hormones preceding the study. A stable decline in the RR of breast cancer (during
6.8 years of estrogen treatment) was detected in the estrogen-only arm of the WHI study which
was unanticipated because estrogens have been recognized to enhance the development and
growth of breast cancers, and the consequence becomes greater by adding progestins. The
metabolic syndrome with insulin resistance and hyperinsulinemia could be developed by obese
females. Raised insulin levels were related with an amplified risk for cardiovascular disease and
breast cancer in postmenopausal women. This could be explained by the effects witnessed in
mutual arms of the WHI study: low dose estrogens in HRT might progress insulin resistance and,
later, decrease risk of breast cancer in obese patients, while the favorable effect of estrogen
might be estranged by progestins. It was stated that the primary choices for the lessening breast
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cancer risk in postmenopausal women were the deterrence of obesity to circumvent the
development of hyperinsulinemia, the therapeutic management of insulin resistance, the
consumption of small doses of estrogens and the decrease in contact to progestins.
Lindgren et al (2005) found that greater incidence of some cancers among hypertensive patients
appeared to be somewhat explicated by obesity and the use of antihypertensive agents after
conducting a record related study of Hypertension Register of the North Karelia Project and the
Finnish Cancer Registry. There were 20,529 hypertensive patients with mean follow-up time of
16 years. The standardized incidence ratios and hazard ratios were measured and it was revealed
that in general cancer occurrence was near to that of the overall population for both males and
females.
Ursin et al (2005) documented that reproductive characteristics were related with decreased
breast cancer risk, but it was almost unknown whether there was differential protection against
categories of breast cancer. The effect of reproductive characteristics on types of tumours by
hormone receptor status and histology were evaluated via data from case control NIHCD
Women's Contraceptive and Reproductive Experiences (CARE) Study. Multivariate
unconditional logistic regression was employed to find the RR of breast cancer which suggested
that multiparity and early age at first birth were related with low RR of ER + PR + cancers only
while lactation duration was linked with reduced RR of both receptor-positive and receptor-
negative cancers proposing that parity and lactation act through diverse mechanisms. The
findings were steady across subdivisions based on age and ethnicity.
Braatan et al (2004) investigated the relationship between the education level and breast cancer
risk from a prospective cohort study containing 102,860 females from Norway and Sweden.
More than a thousand primary invasive breast cancer incidences were exposed during follow-up.
The RR was estimated by age adjusted Cox Proportional Hazards Model which revealed that the
females with greater than 16 years of education had a 36% enhanced risk of breast cancer as
compared to the lowermost educated females with 7 to 9 years of education. The association was
somewhat sturdier among postmenopausal than among premenopausal females however this
association came close in both the groups by adjustment for more variables. Even the results of
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multivariate model clearly indicated positive association of risk for breast cancer with level of
education.
Moorman et al (2004) observed that the risk of breast cancer might be affected due to variations
in dietary constituents and eating habits. Certain dairy foodstuffs, like whole milk and several
kinds of cheese might enhance the risk due to the presence of fairly high saturated fats.
Additionally, milk items might have toxins like pesticides and insulin-like growth factor I, which
would potentiate breast cancer cell development. On the contrary, calcium and vitamin D in
dairy stuffs have demonstrated to decrease the risk of breast cancer. Upon review of
epidemiologic texts of cohort and case-control studies it was seen that there were inconsistent
patterns of augmented or diminished breast cancer risk due to a high intake of dairy foodstuffs
and hence did not provide a robust link between breast cancer risk and the intake of milk or
further dairy foodstuffs.
Braaten et al (2004) described the positive association of education level with breast cancer risk
through a prospective cohort study in women from Norway and Sweden. To estimate relative
risks, Cox Proportional Hazards were used and it revealed that higher level of education was
more associated with the risk of breast cancer as compared to the lowest level and it was little
greater in the post menopausal women as compared to premenopausal women.
Tyrer et al (2004) stated that numerous risk factors like genetic, reproductive, medical and also
related to family history but it is important to relate these risk factors with a comprehensive
genetic investigation. BRCA1 and BRCA2 genes only do not elucidate all of the familial
accretion of breast cancer. A model was developed by incorporating BRCA gene with a less
penetrating gene and individual risk factors into a computer program that provided individual
risk estimation for breast cancer.
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Amir et al (2003) stated that precise personal breast cancer risk calculation was important to
deliver risk–benefit investigation before introducing interventions intended to reduce breast
cancer risk. Despite of existence of several models, not a single included hormonal factors,
family history and benign breast disease together completely. A new model by Tyrer and Cuzick
has addressed these deficiencies. In this study, Tyrer–Cuzick model was assessed against
recognized Gail, Claus, and Ford models. The goodness of fit and discriminatory precision of the
models was measured via records from 1933 women present at the Family History Evaluation
and Screening Programme, among which 52 established cancers. The precision of the models for
separate cases was estimated using ROC curves. The Tyrer–Cuzick model was found to be the
most steadily precise model for estimation of breast cancer while the other models considerably
undervalued risk, though the correctness of Claus model might be enhanced by modifications for
other risk aspects.
Chobanian et al (2003) presented "The Seventh Report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" in which they wrote
that hypertension is an important cardiovascular disease risk factor and such patients require
health-promoting lifestyle adjustments; thiazide-type diuretics alone or in combination used for
treatment of uncomplicated hypertension and some high-risk conditions are persuasive signs for
the preliminary use of other antihypertensive drugs. It was suggested that hypertension in the
patients would be controlled if they are motivated and the treatment prescribed is efficacious.
Group (2003) examined the relationship of obesity and breast cancer risk in postmenopausal
women from eight prospective case control studies. The data on BMI and pre-diagnostic
estradiol levels existed for 624 cases and 1669 controls and the relative risks of breast cancer
were assessed by applying conditional logistic regression models matched for age and enrolment
date and adjusted for parity. It was concluded that the rise in breast cancer risk with increasing
BMI among postmenopausal women was principally due to the accompanying escalation in
estrogens, principally bioavailable estradiol.
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Clavel-Chapelon (2002) studied the role of hormonal factors in breast cancer risk and also the
variation in reproductive characteristics according to age at diagnosis. The data was acquired for
1718 French breast cancer cases in the E3N cohort study. The findings suggested that generally
risk of breast cancer rose with declining age at menarche, inclining age at first pregnancy and
low parity which varied according to menopausal status; in premenopausal women, menarche
age reduced risk with inclining age of 7% per year. Age at first full-term pregnancy revealed
significantly growing risk per year of inclining age in all women, particularly at the age <30
years. A protective effect of more parity was detected associated only for postmenopausal
women with breast cancer risk. It was summarized that reproductive characteristics had
composite effects on breast cancer risk.
Cui et al (2002) investigated the relationship between body mass and stage of breast cancer stage
at diagnosis using hospital medical data from 1991 to 1997 in the Baltimore city. It was found
from multivariate adjusted analysis that obese females were more expected to be at an advanced
breast cancer stage at identification as compared to those with < 27.3 of BMI and this
relationship was stronger among women < 50 years (OR 2.34, 95% CI 1.34-4.08) as compared
with women > 50 years (OR 1.30, 95% CI 0.89-1.91). This result was quite alarming due to
prevailing obesity in the females in the United States and the poor prognosis related with late-
stage cancers.
Denic and Al-Gazali (2002) discussed that the outcomes of homozygosis of BRCA1/2 mutation
in human beings are undetermined and the children due to consanguineous family with
BRCA1/2 gene mutations are more probable to be BRCA1/2 homozygous. Human BRCA1/2
homozygotes are expected to be biologically non-viable and are unidentified to be present
because tumor suppressor genes are more preserved and less species-specific. It had been
observed that there had been excess perinatal and early-childhood mortalities and decreased risk
of breast cancer, especially in younger women due to consanguineous marriages. It was proposed
that this might be due to BRCA1/2 and homozygotes of some other unidentified tumor gene. The
researchers replicated via computer the breeding of non-consanguineous and consanguineous
people over 40 generations in order to evaluate the effect of consanguineous marriage on the
occurrence of cancer genes. The joint incidence of BRCA1/2 mutation of 1% was used as an
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initial reference point and non existence of unstructured mutations and gene flow were
presumed. It was concluded that the BRCA1/2 and perhaps other unidentified tumor gene carrier
proportions are considerably inferior in consanguineous populations. The rate of inbreeding and
extent of consanguineous marriages in a population defines the occurrence of specific gene and
might enlighten to some extent the variation of breast cancer occurrence globally.
Group (2002) collected epidemiological data from 30 countries comprising of 50302 invasive
breast cancer cases and 96973 controls to calculate RR for breast cancer related with
breastfeeding in parous women after stratification by various factors. The findings revealed that
small number of cases breast fed than the controls with relatively shorter breast feeding duration.
It was observed that women were protected against breast cancer if they breast fed for longer
time period but no considerable difference was seen upon stratification by various
characteristics. It was assessed that the cumulative occurrence of breast cancer in developed
countries would be lessened by more than half, from 6.3 to 2.7 /100 women by age 70, if they
had the average number of births and lifespan duration of breastfeeding that had been widespread
in developing countries until lately.
Liu et al (2002) conducted a case-control study nested within the Swedish Fertility Register
which comprised of 34,018 breast cancer cases from the Swedish Cancer Register and 170,001
controls from the Fertility Register. After using logistic regression analysis, it was concluded that
maternal breast cancer risk was at the peak at time window of 5 years postpartum. Instituting
timing of highest transient surge in postpartum breast cancer risk might express the latent age
necessary for pregnancy hormones in stimulating development of breast cells that underwent
early phases of cancer conversion.
Malik (2002) compared prospectively the clinic-pathological characteristics of Pakistani females
having breast cancer with the females having breast in the United States to find the variances.
Among 566 patients, there were 18% with a positive family history particularly in first degree
relatives. The mean age of the participants of the study was 47.7 ± 11.8 years among whom the
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average size of the lump was 5.7±2.3 cm. The use of unconventional treatments before getting
any health information was prevalent. The patients mostly underwent modified radical
mastectomy and few had locally-advanced disease; only 17% with metastases were diagnosed.
The results enlightened the need of public awareness regarding health issues in Pakistani
population as compared to the US population where substantial developments were made in
cancer care.
Petrelli et al (2002) investigated the association between BMI, height and postmenopausal breast
cancer mortality in the prospective American Cancer Society's Cancer Prevention Study II of US
adults who joined in 1982. There were 2852 breast cancer demises detected among 424,168
postmenopausal women after 14 years of follow up who were cancer-free. It was observed
through Cox proportional hazards analyses that deaths due to increasing BMI were continually
occurring in post menopausal women; height up to 66 inches was also associated with
augmented demises as compared to those with <60 inches. The findings highlighted the
significance of sustaining sensible weight all through life.
Solomon and Weiss (2002) reviewed the data on the levels of organochlorine pesticides,
polychlorinated biphenyls (PCBs), polychlorinated dibenzodioxins (PCDDs), polybrominated
diphenyl ethers (PBDEs), metals, and solvents in the breast milk. It was revealed that levels of
the organochlorine pesticides, PCBs, and dioxins dropped in breast milk in those countries where
these chemicals were banned or regulated while the levels of PBDEs were mounting. Local
variances in levels of xenobiotics in breast milk were associated with their use patterns. Diet was
a key factor that influenced breast milk levels of insistent organic pollutants. It was suggested
that better worldwide breast milk monitoring programs could permit more reliable data on drifts
over time, finding of novel xenobiotics in breast milk, and recognition of unreasonably exposed
inhabitants.
Stoll BA (2002) assessed that atypical insulin signaling might be the cause of promotion of
breast carcinogenesis and also investigated about etiology of abdominal visceral obesity which
was proposed to be related with enhanced risk of breast cancer. It was found that obesity badly
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affected breast cancer risk chiefly by more contact of breast epithelial tissue to endogenous
estrogen. The obesity of upper abdominal region seemed to include an added influence
connected to the existence of insulin resistance. It was concluded that etiological factors like diet
and insulin resistance were likely to be related to high risk of breast cancer in western
postmenopausal women.
Bergstrom et al (2001) studied the link between obesity and the risk of increasing cancer at a
number of sitesby meta-analysis, comprising colon, prostate, gallbladder, kidney, endometrium
and breast in post-menopausal women. It was found that the highest attributable rates for obesity
were attained for 39% cancers of the endometrium, 25% for kidney and almost 25% for
gallbladder. The leading figure of attributable cases was for colon cancer, then endometrium and
breast cancers respectively.
Denic and Bener (2001) stated that marriages between third-degree and more distant relatives are
common in many parts of the world. Offspring of consanguineous parents have increased
morbidity and mortality related to recessive gene disorders. In a population with a high
frequency of consanguinity, we studied prospectively the occurrence of breast cancer (related in
part to tumour genes) and cervical cancers (related to virus infection) among descendants of
consanguineous and non-consanguineous parents in UAE. In the married females, aged 40-65
years, tumour diagnosis was established by appraisal of medical records. Among 40% of
consanguineous and 60% of non-consanguineous parents there were 24 and 54 females with
breast cancer, respectively; family history of breast cancer in consanguineous and non-
consanguineous group was 21 and 23, respectively. The risk of breast cancer decreased in
younger females with consanguineous parents whereas the risk of cervical cancer was
unaffected.
Hinkula et al (2001) demonstrated from a cohort of women with minimum five births that early
age at first child birth and multiparity were self-determining and potent protective elements from
the fifth child forwards, though birth intermission was feeble in this respect. Standardized
incidence ratios (SIRs) were estimated and the findings revealed that breast cancer occurrence
was low in the cohorts and RR declined significantly from 5 to 8 parts. The rise in the age at first
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child birth from < 20 to 30+ years almost doubled up the risk; parity was a noteworthy hazard
factor only in ductal cancer, while restricting the birth intermission was protective only in lobular
malignancy. The occurrence of progressive breast malignancy among women surpassed the
population frequency in premenopausal females and also in those with first child birth at the age
≥30 years.
Manjer et al (2001) stated that female smokers had not as much of favorable prognosis after the
diagnosis of breast-cancer which might be due to late presentations. It was evaluatedon 268 cases
in a cohort of 10,902 women who were followed for an average of 12.4 years whether smoking
was related with further prognostic markers like hormone receptor status, histopathology and
tumor differentiation. IHC methodology was employed to evaluate HR status. It was found that
smoking was related with an amplified incidence of HR-negative tumors.
Manjer J et al (2001) stated that hypertension, obesity, dyslipidaemia and impaired glucose
tolerance had been linked with insulin resistance which might be a risk factor for breast cancer,
probably via elevated levels of oestrogens or insulin-like growth factor I. Breast cancer risk
association with these aspects was analyzed by the researchers in a prospective cohort study of
9738 females. Cox's proportional hazards analysis was employed for variables which revealed
that for age adjusted estimations, peri and postmenopausal women had a significantly elevated
risk of breast cancer linked with height and the RR was amplified over quartiles of cholesterol
levels; other significant relationships were not established even after adjustments for
confounders and stratification of pre or postmenopausal women.
Sowers et al (2001) reported that hypertension adds to the high occurrence of cardiovascular
diseases which are the main reasons of death in individuals with diabetes. Hypertension is found
to be almost twice as common in patients with diabetes and fresh data proposed that hypertensive
people are more liable to diabetes progression than normotensive people. More forceful therapy
is required for the patients with concurrent diabetes and hypertension. In these patients, other
significant risk factors for CVD include atherosclerosis, obesity, dyslipidemia, endothelial
dysfunction, microalbuminuria, coagulation abnormalities, platelet hyper-aggregability, and
"diabetic cardiomyopathy."
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Woolcott et al (2001) estimated the relationship between organo-chlorines and breast cancer
categories by various tumor characteristics i.e. ER/PR status, tumor size, and grade in a case-
control study in Kingston and Toronto, Canada. It was observed that the link between breast
cancer risk and the organo-chlorines did not considerably vary by category and the organo-
chlorines were more powerfully related with tumors of poor prognosis.
Enger et al (2000) assessed the differences in the earlier studies regarding the elevated
postmenopausal breast cancer risk with greater BMI or of decreased breast cancer risk with
greater physical activity ranks according to the tumor's ER and PR status. For the case control
studies, the subjects were premenopausal women (aged ≤ 40 years) and postmenopausal women
(aged 55-64 years) who were matched for age, race, parity (premenopausal women only) and
residential area. The joint ER/PR status was available for 424 premenopausal and 760
postmenopausal women. It was seen that obesity was associated with increased breast cancer risk
in postmenopausal women and BMI was not related with any of tumor subgroups in
premenopausal females. Greater levels of physical activities were found to be associated with
decreased risk of almost all tumor sub groups with marginal significance statistically.
Knize et al (1999) documented that heterocyclic aromatic amines and polycyclic aromatic
hydrocarbons were formed at times while food processing and heating and they were
carcinogenic in nature. It was observed through chemical examination of foods that both
heterocyclic aromatic amines and polycyclic aromatic hydrocarbons were made due to grilled
food. In commercial food stuffs, the detection limits ranged from 0.1 to 14 ng/g for heterocyclic
aromatic amines and up to 1 ng/g for polycyclic aromatic hydrocarbons for a liquescent smoke
seasoning. Procedures to reduce the formation of such carcinogens was advised during
processing or heating of food stuffs.
Soler et al (1999) investigated case control studies in Italy during 1983–1996 to assess the
association between hypertension and the risk of certain hormone-related tumors in women. The
cases were females (<75 years of age) with carcinoma of the breast (n=3406), ovary (n=970),
endometrium (n=745) and thyroid (n=145). There were n=3054 controls in the same
environmental zone admitted for acute, non–hormone-related, non-cancerous diseases.
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Unconditional logistic regression was applied after adjusting for variables and the results showed
higher odds for breast cancer, endometrial cancer, and also for hypertension even after ≥5 years
of diagnosis. It was found that the relationship for breast cancer was seemingly sturdier at age
≥55 years and subsequently after menopause. The odds of breast cancer risk were higher in
postmenopausal hypertensive women with BMI ≥30 kg/m2 as compared with normotensive
women.
Dees et al (1997) described that estrogens contribute critically in the etiology of established
breast cancer and estradiol stimulated the development of breast cancer both in vivo and in vitro.
The presence of exogenous estrogens in the diet and also in the environment promoted in vitro
development of breast cancer. The effects of DDT (1,1,1-trichloro-2,2- bis(chlorophenyl)ethane)
on ER positive MCF-7 and T-47D human breast cancer cells as well as on ER negative HS
578Bst breast cancer cells and rat liver cells were investigated which showed that estradiol and
DDT escalated the growth of MCF-7 cells with insulin existence. Cyclin-dependent kinase
(Cdk)2 activity enhanced in growth-arrested T-47D and MCF-7 cells that were treated with β-
estradiol or DDT. The anti-estrogen ICI 182,780 prohibited both growth and Cdk2 instigation
brought by DDT or estradiol. It was documented that breast cancer cells were stimulated to move
into the cell cycle by DDT by upsetting main regulatory components and the relative potency of
DDT in persuading cell-cycle development was only 100–300 times less than that of estradiol
upon measurement in the presence of insulin.
Zava et al (1997) examined the estrogenic activity of several environmental contaminants
(xenobiotics), especially xenoestrogen DDT, and matched their properties with those of
endogenous estrogens, phytoestrogens, and mycoestrogens on estrogen receptor binding
capability, introduction of estrogen end products, and stimulation of cell proliferation in
estrogen-sensitive human breast cancer cells in monolayer culture. The levels of phytoestrogens
in extracts of certain common diets, herbs/spices and in human saliva after eating high
phytoestrogen nutrition were calculated to match phytoestrogen bioavailability comparative to
the stated xenoestrogen load in humans. It was demonstrated that all categories of estrogens
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initiated cell proliferation at concentrations that half-saturated ER, but only specific categories
could initiate estrogen-regulated end products. Furthermore, it was reported that various foods,
herbs/ spices and soy milk also generally comprise of substantial quantities of phytoestrogens
that evidently surged phytoestrogens levels in saliva; hence a diet with more phytoestrogens
would considerably decrease the binding of weak xenoestrogens in vivo to ER.
Bittles et al (1993) determined six categories of consanguineous marriage and evaluated the
effects on reproductive activities and death through survey based studies in Punjab, Pakistan,
between 1979 and 1985. The data was collected from 9520 women and it was concluded that
there were 50.3% consanguineous marriages overall between second cousins or closer; generally
they showed better fertility than non-consanguineous pairs but antenatal and postnatal deaths
were steadily greater.
Cold et al (1990) stated that breast cancer risk was related to the build of a woman and a greater
BMI appeared to be protective in the premenopausal women. The results from the review of
articles from MEDLINE revealed that height and breast cancer risk were positively associated.
BMI and body shape were also related to breast cancer risk in post menopausal women only. It
was concluded that obesity reduction or prevention in post menopausal females would alter signs
of breast cancer risk in a more positive direction.
Stalsberg et al (1989) conducted a study in 2,728 patients regarding the relationship between
breast cancer risk factors and histologic categories of invasive breast carcinoma. Lobular and
tubular cancers arose with augmented occurrence in majority of high-risk patients; the
percentage of these cancers inclined with age from 45 to 49 years and then declined in the
subsequent decade. Significantly elevated risk of lobular and tubular cancers was also linked
with various factors. The frequency of other histologic categories of breast cancer also amplified
with increased breast cancer risk but relatively to a lesser grade as compared to lobular/tubular
cancers. It was proposed that all hormone-related, geographic and socio-economic risk factors
influenced by selectively increasing the amount of lobular cells at risk. Family history of breast
cancer and age over 49 years might function via other mechanisms.
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Robison et al (1985) explained that DDT supported the development of an estrogen-responsive
cancer. A clonal cell line of MTW9/PL cells called MT2 cells first attained from a mammary
adenocarcinoma produced estrogen-responsive growths in Wistar-Furth rats. DDT promoted
MT2 tumor growth at a proportion parallel to 17β-estradiol and it was precise and dose
dependent.
3.3 PHARMACOTHERAPY AND ADRs OF BREAST CANCER:
3.3.1 LOCAL THERAPY IN BREAST CANCER:
Group EBCTCG (2014) did a meta analysis for 8135 females individually who received
radiation therapy after mastectomy and axillary surgery and compared it with the similar surgery
but with no radiation therapy. Follow ups were conducted for both relapses and deaths in the
patients. It was reported that radiotherapy diminished both breast cancer relapse and death in the
women with 1 to 3 positive lymph nodes even though systemic treatment was specified.
Pan et al (2014) discussed that radiation was beneficial particularly for younger patients after
breast-conserving surgery but those who had young offspring were resistant to the therapy. From
MarketScan Database, women aged 20 to 64 years were selected for the study and it was
revealed that due to baby sitting or baby care, the younger patients (20 to 50 years) were
hindered from getting complete breast cancer treatment.
Supramaniam (2014) analyzed the NSW registry data of breast cancer to estimate the survival of
Aboriginal and non-Aboriginal women related with surgery. it was seen that due to greater
number of surgical procedure, the survival rates for NSW Aboriginal women increased.
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Krotneva et al (2013) stated that radiation therapy done after breast conserving surgery was very
beneficial in the breast cancer patients. In this prospective cohort study, this objective was
studied among 27483 breast cancer patients and the results revealed that majority received
radiation therapy particularly in the age group of 50 to 69 years. The females with local
incidence receiving chemotherapy were more prone for the radiation therapy and the co existing
diseases, longer distance to healthcare facilities and social segregation deprived the patients from
getting the therapy.
Kiderlen et al (2012) analyzed an international contrast of surgical and radiation management for
ageing women (≥ 65 years) with early stage breast cancer including numerous European
countries and the US. Statistics were acquired from population-based registries in the European
countries and from the Surveillance, Epidemiology, and End Results (SEER) database of USA. It
was seen that a greater proportion of women did not undergo any surgery with increasing age in
several countries though there were disparities between the countries. In many countries, more
than half of the cases received breast conserving; highest percentage was observed in
Switzerland. The proportion of patients that had radiotherapy after breast conserving surgery
reduced with age in all states. There were no big dissimilarities recorded in survival between
countries.
Van Parjis et al (2012) investigated conventional radiotherapy versus hypofractionated
tomotherapy to assess the difference in related toxicities in a trial from 2007 to 2011. It was a
randomized trial with breast cancer stage I who underwent tumorectomy or mastectomy. Among
69 evaluated cases, no unanticipated severe toxicities were found and short course radiotherapy
of the breast with concurrent integrated boost over 3 weeks evidenced to be reasonable.
Pulmonary tests presented a slight favor to Tomotherapy that would require validation with
extended follow-up of the patients.
Ravo et al (2011) retrospectively assessed the most effective topical hydrating management to
prevent cutaneous radiotherapy associated acute effects in 100 female breast cancer patients aged
47 years on average. cutaneous toxicities were observed in the patients receiving radiation
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therapy despite of using various topicals. Chemotherapy with taxanes and/or anthracyclines or
use of hormonal therapy did not amplify the cutaneous toxicity made by radiotherapy.
Williams et al (2011) evaluated the rationalization of exclusion of post-operative radiotherapy
after breast-conserving surgery and endocrine therapy in a randomized controlled trial setting in
breast cancer patients with age ≥ 65 years. The quality of life of the patients was not improved
due to the radiation exclusion and radiation was found to be well tolerated by the patients with
no detrimental effects on the quality of life.
Bastiaannet et al (2010) described breast cancer stage at diagnosis, management and relative
survival of aged breast cancer patients compared to younger patients in the Netherlands. There
were almost 41% elderly cases who underwent surgery, >45 % took hormonal monotherapy and
upto 55% received adjuvant systemic therapy. It was concluded that the relative survival for the
elderly patients was lower as compared to younger females while the mortality percentages due
to other reasons increased with age. This would point towards poor patient selection and fit
patients would have "under treatment". It was suggested to have precise screening tools for
geriatrics to recognize fit patients who would obtain more "aggressive" management whereas
finest supportive care would be given to weak elderly patients.
Miao-Fen et al (2010) evaluated the occurrence of dermatitis due to adjuvant 3 D conformal
radiation therapy in breast cancer patients who underwent surgery. Moist desquamation and
dermatitis were observed as adverse effects and significantly increased skin forbearance was
observed after prophylactic topical management for irradiated skin.
Kaufmann et al (2010) wrote that strategies for the loco-regional treatment of primary breast
carcinoma were most recently issued by the US National Institutes of Health in 1991 after which
innovative surgical and radiation procedures were developed that would emphasize the revision
of the published strategies. A group of opinion leaders from different countries collectively set
and officially recognized the defined set of endorsements for the practice of surgery and
radiotherapy in primary breast cancer apart from clinical trials.
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Schonberg et al (2010) examined tumor features, managements (mastectomy, breast-conserving
surgery with radiation therapy or alone, or no surgery), and consequences in females with age ≥
80 years with stage I or II breast cancer, paralleled with females aged 67 to 79 years using
adjusted Cox proportional hazard models from the linked Surveillance, Epidemiology and End
Results-Medicare data set. It was concluded that females aged ≥80 years had breast cancer
features akin to those aged 67 to 79 years yet received not as much of aggressive therapy and
experienced greater mortality from early-stage breast carcinoma.
Gorey et al (2009) investigated the impact of SES on delays for surgical and adjuvant radiation
therapy of breast carcinoma in Canada and California. Significant links between lower SES and
extended surgical waits, lesser access to adjuvant radiation therapy and to extended radiation
therapy waits were observed only in California. No basic difference on access to surgery or on
surgical waits was seen in the two states.
HT et al (2008) studied Surveillance, Epidemiology, and End Results (SEER)-Medicare database
consisting of females with stage I breast cancer or ductal carcinoma in situ. The patients had
undergone surgery and radiation therapy within a year of diagnosis. Delayed and partial
radiations were reported by some patients which would augment breast cancer events.
Gebski et al (2006) examined whether the post-mastectomy radiation diminished loco-regional
relapse of operable breast cancer in females and whether it enhanced survival rates among the
patients. It was found that radiation therapy was associated with statistically significant
improved survival rates up to 10 years.
Boér (2005) delivered a summary regarding different treatment modalities of breast cancer in
the geriatrics. The assessment of geriatric patients through various angles provided an improved
and beneficial choice of the individualized therapeutic options that would produced enhanced
survival rates and better quality of life. It was documented tat surgery would be applied to breast
cancer patients in any age and also radiation therapy provided good results in the elderly. In case
endocrine therapy had failed then chemotherapy would be employed in such patients.
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Vinh-Hung and Verschraegen (2004) inspected the consequences of radiotherapy or its exclusion
after breast-conserving surgery on confined tumor development and patient existence. It was
concluded from the analyses that exclusion of radiotherapy was related with a great surge in
ipsilateral breast tumor relapse risk and minor rise in the death risk of patients.
L’opez et al (2002) discussed that the outcome of radiotherapy should be with the therapy-
associated side effects. They evaluated and reported the incidence and the severity of skin
reactions in breast cancer patients who received adjuvant radiotherapy after surgery. Different
scales were used to analyze normal tissue impairment and the most common adverse effects
found were erythema and desquamation. It was stated that the RTOG system was better for
assessing the acute effects due to radiotherapy in women with breast cancer.
Fisher et al (2002) conducted a trial to ascertain the requirement of breast irradiation after
lumpectomy in node-negative invasive breast cancers, alongwith Tamoxifen that would appear to
be more effective to diminish relapse of ipsilateral breast tumor in such females. It was
concluded that radiation therapy and Tamoxifen combination were suitable for ER+ breast
cancers.
Schmuth et al (2002) examined the use of topical 0.1% methylprednisolone corticosteroid versus
0.5% dexpanthenol emollient in breast cancer patients that underwent fractionated radiation.
Therapy was started at the initiation of radiation and sustained fortnightly after radiation
cessation. The outcomes showed that the use of the topical drugs improved dermatitis due to
radiation but could not prevent it.
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Van de Steene et al (2000) stated that the effects of surgical adjuvant radiotherapy on overall
survival of patients were contentious. A prospective analysis was conducted on 36 trials of the
Early Breast Cancer Trialists', Collaborative Group, 1995. It was concluded that surgical
adjuvant radiotherapy with standard fractionation significantly increased overall survival of
breast cancer patients and there was decrease in mortality rates of > 20%. Also it was
emphasized to reduce the toxicities like CV events in the patients receiving radiation therapy.
3.3.2 ENDOCRINE THERAPY IN BREAST CANCER:
Nazarali and Narod (2014) stated that the use of Tamoxifen had been very much beneficial for
breast cancer prevention since decades despite of its adverse effects that included enhanced risk
of endometrial cancer and pulmonary embolism; though these adverse were not very much
common. The use of Tamoxifen was recommended to be individualized for every patient in
order to have proper beneficial effects rather than the side effects.
Seruga et al (2014) compared Tamoxifen with AIs in a small observational study and found that
adjuvant therapy with AIs increased the hazard for coronary artery disease and the patients had
to undergo cardiac angiography after receiving the therapy angiography.
Gambacciani (2013) reported that Tamoxifen which is a SERM, had been used since years for
the treatment and prevention of breast cancer. Tamoxifen employs positive estrogenic effect on
bone mineral density but it acts as agonist on the endometrium, and may cause a greater risk of
endometrial hyperplasia and cancer. Moreover, tamoxifen is related to considerably higher risks
of hot flushes, stroke and venous thromboembolism due to which it is not used for the prevention
of osteoporosis. Hence, more SERM generations like Raloxifene and bazedoxifene were
developed for the prevention and treatment of osteoporosis in postmenopausal women.
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Jankowitz and Davidson (2013) stated that an insistent risk of setback was present even in the
patients with HR+ preliminary stage breast cancer regardless of using adjuvant treatment. The
use of prolonged endocrine treatment with either tamoxifen or an aromatase inhibitor after 5
years of primary adjuvant tamoxifen had been proved to be effective to diminish the relapse and
deaths due to breast cancer. But, the optimum total period and frequency of AI therapy, and the
best scheduling from tamoxifen to an AI was uncertain. Potential approaches contrasts that were
liable to a woman's menopausal status at preliminary diagnosis.
Hadji et al (2012) retrospectively examined overall and disease free survival through German
cohort of the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial in 1502 patients
receiving adjuvant endocrine therapy with and without arthralgia or myalgia and/or menopausal
indications. It was reported that incidence of arthralgia or myalgia or menopausal signs while
receiving endocrine management was related with innocently enhanced overall survival rates.
Jin et al (2012) stated that it was observed from the analysis of the National Cancer Institute of
Canada Clinical Trials Group MA.17 trial that letrozole was proved to be a beneficial drug for
HR+ post menopausal females regarding disease free survival following Tamoxifen therapy. In
this cross over study with letrozole versus placebo, it was found that letrozole had greater
beneficial effects for the long-term prevention of breast cancer in the patients.
Cohen et al (2011) reported that Letrozole was completely approved by the US-FDA for
adjuvant and long term treatment of HR+ postmenopausal women who had initial stage of breast
cancer. This approval was based on double blind multicenter trials in which it was further found
that bone fractures, osteoporosis, myocardial infarctions were more related with letrozole than
Tamoxifen and Tamoxifen was more linked with thromboembolic events, endometrial
proliferation and its cancer. Both the drugs required co-medications with lipid lowering drugs in
the patients.
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James et al (2011) documented that an association between Her-2/neu over-expression and
Tamoxifen resistance in ER+, primary and metastatic breast malignancy was submitted. HR+ /
Her-2/neu+ cases had a meager response to endocrine therapy. It was found from the study that
Her-2/neu overexpression contributed to Tamoxifen resistance; Trastuzumab type drugs could be
used in combination with Tamoxifen as monotherapy was inadequate in HR+ / Her-2/neu+
tumors. The patients who had surgery, chemotherapy, and radiotherapy exhibited considerably
diminished serum Her-2/neu levels, presenting good response to management.
Burstein et al (2010) reviewed randomized trials from various databases to develop evidence-
based recommendations for endocrine therapy for HR+ postmenopausal women with breast
cancer. It was stated that instead of Tamoxifen mono-therapy, adjuvant therapy comprising of
primary AI, consecutive AI and Tamoxifen or extended AI after 5 years of Tamoxifen would be
helpful. The optimum frequency and length of endocrine therapy was unsettled.
Gozzo et al (2010) examined the skin toxicity due to the neo-adjuvant and adjuvant
chemotherapy among breast cancer women. Skin toxicities and extravasations were reported
mainly due to these therapies. It was advised to keep records for adverse events and venous
puncture sites during the chemotherapy management of the patients.
Huang et al (2010) examined the incidence and severity of fatigue using 11-point scale and
Visual Analog Scale among female breast cancer patients with stage I to III (A) receiving
endocrine therapy in an urban region. The factors BMI, clinical stage, menopausal status,
duration of endocrine therapy, physical activity, and diet were found to be related to cancer-
related fatigue via logistic regression analyses and a trend test method.
Ashraf et al (2009) studied Indian 3000 cases who received Tamoxifen. The adverse effects
reported by the patients were hot flashes, mild vaginal dryness, discharge and bleeding. Some
asymptomatic patients were diagnosed of thickened endometrium on ultrasound examination for
which curettage executed. Fatty liver was observed in nearly half of the Indian women. It was
concluded that Indian women could tolerate tamoxifen better than Western women.
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Johansson et al (2009) compared the medical consequences of breast cancer patients with stage I
after giving adjuvant Tamoxifen alone and in combination of hormonal or cytotoxic therapy in
HR+ cases. It was observed that high risk patients could not be benefited from enhanced use of
systemic treatment and the decline in metastatic disease was found in HR- patients.
Mao et al (2009) evaluated the use of adjuvant AIs in a cross-sectional survey of postmenopausal
female breast cancer patients. Arthralgia was recognized to be caused by AI by (47%) women;
onset of arthralgia was reported by 74% females within 3 months of therapy initiation and joint
pain was moderate to severe in 67% patients in preceding week. It was seen from adjusting for
covariates in multivariate logistic regression analyses that 73% women who had their last
menstrual period within 5 years had the highest probability of reporting arthralgia as compared to
those who had their last menstrual period ≥ 10 years. It was suggested that arthralgia was caused
due to estrogen withdrawal and wrists/hands, ankles/feet, elbows, and knees seemed to be more
related with arthralgia.
Robert and Favret (2007) stated that it was important to confirm the biologic features of the
tumor when handling a patient with advanced breast carcinoma. The human epidermal receptor 2
should also be assessed along with the hormone receptor status which is important to optimize
the systemic therapy. The researchers reviewed the biology and analysis of HER-2, scientific
researches assessing HER2-based treatments, adverse effects and approaches for HER2-based
treatments.
Ciocca et al (2006) described that response of breast cancer cases to endocrine treatment was
directed by the expression of ER alpha and/or progesterone receptors. Their expression is studied
by immunohistochemistry in the breast tumor biopsy sections. The expression/amplification of
Her-2/neu marker predicted the response to anti-Her-2/neu immunotherapy. There had been
certain contradictory reports regarding medical inferences for response to endocrine therapy in
the cases with HR and Her-2/neu co-expression. The associations between their expression, and
the follow-up of the patients that used tamoxifen, with or without chemotherapy were studied. It
was evident that the co-expression of HR with Her-2/neu was not frequent, with patients
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presenting a squatter disease free and overall survival. It was found that ER was less related with
invasion/metastasis while ER- induced gene expression was involved with metastasis.
Colleoni et al (2006) investigated premenopausal women with axillary node–positive, operable
breast cancer who were administered chemotherapy i.e. AC or EC for 4 courses followed by
CMF for 3 courses. The chemotherapeutic regimen was followed by Tamoxifen therapy for 5
years or no more therapy. Disease free survival was significantly improved in ER+
premenopausal patients receiving Tamoxifen unlike ER- cases among which Tamoxifen was not
suggested.
Howell et al (2005) described Tamoxifen as the typical adjuvant endocrine therapy for HR+
postmenopausal women but its use was limited due to the adverse effects and relapse cases. The
AI anastrozole was compared with tamoxifen in 9366 postmenopausal women for 5 years with
confined breast carcinoma. It was reported that anastrozole significantly extended disease-free
survival and time to relapse with decline in distant metastases. Anastrozole was found to be
related with lesser adverse effects as comaperd to tamoxifen i.e gynaecological and vascular
problems but there was an increase shown in arthralgia and fractures.
Bonneterre et al (2001) prospectively examined 1021 post menopausal females receiving 20 mg
Tamoxifen daily or 1 mg anastrozole as first choice medications. Anastrozole was found to be
superior to Tamoxifen therapy with fewer adverse effects; both were well tolerated.
Barakat et al (2000) conducted a study prospectively enrolling 159 patients of breast cancer who
were prescribed Tamoxifen. Office endometrial biopsies were used to observe the endometrium
in the patients but the effectiveness of repetitive office endometrial biopsies for screening in
tamoxifen-receiving patients appeared to be restricted. Few patients had to undergo dilation and
curettage for atypical endometrial biopsies, insistent blood loss, or for estimation of adnexal
masses at laparoscopy time.
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3.3.3 CHEMOTHERAPY IN BREAST CANCER:
Ketkaew et al (2014) analyzed commonly prescribed chemotherapeutic agents in OPDs of
different cancer centers that included 36.15% FAC regimen, 16.15% CMF regimen, 14.84% AC
regimen, 12.63% Paclitaxel, 7.49% Capecitabine and 4.88% Docetaxel. They reported
significant difference in the pattern of use of the treatments due to different cancer types, hospital
formularies and policies.
Naeim et al (2013) retrospectively analyzed the data of patients who were given chemotherapy
for breast, lung, ovarian, non-Hodgkin's lymphoma or colorectal cancers and were treated with
filgrastim and pegfilgrastim prophylactically. It was known that chemotherapy caused
myelosuppression and led to dose-limiting febrile neutropenia. It was observed that pegfilgrastim
prophylaxis was related with a lower risk of neutropenia or hospitalizations due to various
factors as compared to filgrastim.
Kluger et al (2012) examined clinic-histological aspects of alopecia after receiving adjuvant FEC
and docetaxel treatment for breast cancer in 21 white Caucasian women. It was evident from the
biopsy specimen alopecia pattern was androgenetic-like. Laboratory investigations confirmed the
deficiency of iron or zinc and thyroid syndromes and also established hormonal menopause
without hyper-androgenism.
Pallis et al (2012) reported that a phase III trial of capecitabine monotherapy versus vinorelbine
or gemcitabine doublet was conducted in metastatic breast carcinoma patients by the The Breast
Cancer Study Group of the Hellenic Oncology Research Group. It was established that
capacitabine monotherapy was better than the combination therapy in terms of adverse effects
and ease of oral management.
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Schmitz et al (2012) documented that postmenopausal females had more breast cancer frequency
with greater CV disease risk due to the adjuvant systemic therapies; such risks might be as much
as >30%. It was reported that previously established morbidities like hypertension or left
ventricular dysfunction would add to the severity of treatment related cardio-toxicities for which
there were no medical practice guidelines that would address cardiac surveillance after breast
cancer and even the existing ones for observing and supporting CV health in geriatrics were not
followed regularly.
Albert et al (2011) analyzed loco-regional control and overall survival rate with paclitaxel
addition to anthracycline based regimen in patients receiving 8 cycles of the regimen. In this
randomized trial, patients received FAC (8 cycles), FAC (4 cycles) + Paclitaxel (4 cycles) and no
influence was seen by the researchers in ten years overall survival or loco-regional control of the
disease in various treatment groups of breast cancer.
Palappallil et al (2011) stated that FAC and AC-P were two most commonly used therapies to
treat breast cancer. They studied prospectively the adverse effects related to these two treatment
combinations in 50 patients according to WHO toxicity grading. The high risk patients had been
given AC-P treatment whereas the others were on FAC schedule. It was seen that FAC therapy
was associated with anemia, hyperpigmentation, stomatitis, and diarrhea while AC-P regimen
was associated with myalgia, arthralgia, leukopenia, and peripheral neuropathy. Due to AC-P
regimen, the Karnofsky performance status was greater in the patients. It was concluded that
despite of several adverse effects, AC-P therapy displayed better profile in the patients.
Amiri and Rafiei (2010) assessed 15 patients with mean age 43.4 ± 10.6 years after receiving
chemotherapy for breast cancer with joint indications. The patients were administered typical
chemotherapy comprising of cyclophosphamide and tamoxifen according to stage of breast
cancer. In about 6 months, joint symptoms initiated in the patients to whom various medications
were prescribed such as, disease modifying anti-rheumatic drugs, non-steroidal anti-
inflammatory drugs, venlafaxine and corticosteroids. Satisfactory responses were reported by 13
patients after a mean of 3 months' treatment with more than 50% decline in morning stiffness,
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pain, and tender joint counts and 9 patients showed thorough resolution of indications and
terminated the use of all medicines.
Burnell et al (2010) reported that adjuvant CEF and AC x T were commonly used adjuvant
chemotherapies for early breast cancer. It was found that in locally advanced breast cancer, 3
months of dose-dense EC was equivalent to 6 months CEF therapy. 2,104 females (≤60 years)
with axillary node-positive or high-risk node-negative breast carcinoma were given CEF, EC/T,
or AC/T randomly for 6 months after lumpectomy or mastectomy. Relapse free survival of 3
years for CEF, EC/T, and AC/T were 90.1%, 89.5%, and 85.0%, respectively. There was more
association of febrile neutropenia with CEF and EC x T and more neuropathy with EC x T and
AC x T. it was concluded that AC x T was not superior to CEF and EC x T for relapse free
survival.
Montemurro (2010) et al analyzed data of breast cancer patients from various institutional
settings to whom atleast one trastuzumab-based regimen for HER-2(+) metastatic breast cancer
was administered. The patients were entitled for anthracyclines for metastatic cancer who were
never exposed or had been formerly exposed to an anthracycline and had reverted after 12
months from the last dosage. Then anthracycline-based therapy after failure with the first
trastuzumab-based course of therapy in entitled patients was evaluated. An anthracycline was
given as first rescue therapy in 14 never exposed and two formerly exposed patients. Another 15
never exposed and nine formerly exposed patients received an additional anthracycline for
management. Out of 119 entitled patients who expired due to breast cancer it was found that only
30 were administered an anthracycline for metastatic stage. Anthracyclines were being used
irregularly to manage trastuzumab-refractory malady although two thirds of the patients were
entitlted to receive them with trastuzumab-based therapy for HER-2 metastatic breast cancer.
Roscoe et al (2010) identified risk factors for nausea in 1,696 patients from 3 multicenter studies
starting a chemotherapy treatment containing carboplatin, cisplatin or doxorubicin. It was found
that average nausea for breast cancer patients receiving doxorubicin was significantly larger than
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for other patients receiving the prescribed chemotherapy. Mean nausea was decreased with age
and also in those patients who assessed themselves to be less vulnerable to nausea. These
findings would help the physicians to timely identify the patients with more susceptibility to
chemotherapy associated nausea.
Smith et al (2010) conducted a systematic review and meta-analysis of randomized controlled
trials to elucidate the risk of clinical and sub clinical cardiotoxicity of anthracyclines in patients
treated for various cancers including breast cancer. A considerably higher risk of both clinical
and sub clinical cardiotoxicity was observed with anthracycline compared with non-
anthracycline treatments, anthracycline vs. mitoxantrone, and bolus vs. continuous anthracycline
infusions. The risk of cardiotoxicity was expressively inferior with epirubicin vs. doxorubicin,
liposomal vs. non-liposomal doxorubicin and with a simultaneous cardioprotective drug.
Temperate to great statistical heterogeneity for 4 of 5 combined analyses was seen for any
cardiotoxicity concluding that there was not enough substantiation to strongly back for clear
validation on the anthracycline therapies or for regular use of cardiac protective drugs or
liposomal preparations; though cardiac monitoring is required in oncology trials.
Su (2010) et al emphasized through a cross-sectional research of postmenopausal breast cancer
survivors who received adjuvant AIs receiving adjuvant that increase in weight was a risk factor
for occurrence of hot flashes. After an average AI experience of 23 months, 32% breast cancer
survivors stated moderate to severe hot flashes whereas 25% stated substantial deterioration of
hot flashes since beginning of adjuvant AI treatment. Only 27% gained 10 lb or more weight and
11% reported 10 pounds or more weight loss. After adjusting for confounding, weight gain was
seen to be independently linked with hot flashes manifestation in multivariable analysis. Hot
flashes were more significantly associated with those women who gained at least 10 pounds than
those who lost or maintained their weight.
Barrett-Lee et al (2009) stated that the anthracyclines were the most potent chemotherapeutic
drugs to treat breast carcinoma but they were restricted due to their cumulative, dose-related
cardiotoxicity which caused progressive decline in cardiac function after each succeeding dose.
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It was suggested that the oncologist be aware of the toxicities and manage them timely by early
detection.
Burnell et al (2009) performed interim analysis for recurrence-free survival for AC/T versus
CEF, AC/T versus EC/T and EC/T versus CEF and reported highest rate for CEF then EC/T and
AC/T respectively. Febrile neutropenia was found to be more associated with CEF and EC/T
whereas neuropathy was associated more with EC/T and AC/T.
Du et al (2009) investigated 19,478 women with breast cancer with age >65 years from 16 areas
in the Surveillance, Epidemiology, and End Results program to evaluate the risk of
chemotherapy-related cardiac toxicity. The excess cumulative incidence of congestive heart
failure was found to be 4.7% among patients getting anthracycline-based chemotherapy when
compared with patients without receiving chemotherapy. Upon adjustment for patient and tumor
features, congestive heart failure was 25% more likely to be in the patients receiving
anthracyclines as compared with those deprived of chemotherapy. When compared with those
not receiving chemotherapy, it was observed that the adjusted risk of cardiomyopathy was 2-fold
greater in females who were administered anthracyclines and was 16% more in those getting
other agents. The augmented risk for attaining congestive heart failure, cardiomyopathy, and
cardiac dysrhythmias in relationship with chemotherapy were alike after adjusting for
hypertension and diabetes but not considerably linked with ischemic heart disease or conduction
illnesses.
Kawaguchi et al (2009) explained that the use of chemotherapeutic agents was rare in patients
under palliative care for the management of symptoms as these agents would show adverse
effects as well. It was seen in 43 years old female, with metastatic breast carcinoma that the
administration of low-dose capecitabine (60 mg per day) as sole therapy improved the quality of
life without serious adverse events.
Muss et al (2009) randomly assigned breast cancer patients with stage I, II and III either CMF or
AC or capecitabine. Endocrine therapy was suggested after chemotherapy in hormone-receptor-
positive patients. Patients receiving capecitabine were two times expected to have a recurrence
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and almost two times expected to expire as patients who were given standard chemotherapy.
Standard adjuvant chemotherapy was found to be better than capecitabine in early-stage breast
cancer patients who were ≥65 years of age.
Robson and Verma (2009) stated that anthracyclines have been the basis of adjuvant care in
breast cancer since years but with undesirable rate of noteworthy cardiac and leukomogenic
toxicities. From the systematic review of the literature it was analyzed that anthracycline-based
regimens were more toxic than non –anthracycline containing regimens and were equally
successful. Due to the emergence of breast cancer predictors such as human epidermal growth
factor receptor 2 and topoisomerase II alpha, it is essential to re-assess the use of anthracycline-
containing chemotherapy in early-stage breast cancer.
Srokowski et al (2009) investigated the use of adjuvant chemotherapy-related adverse effects in
an observational study with diabetic and non diabetic patients of breast cancer. They found that
diabetic breast cancer patients were at a higher risk of developing adverse reactions due to
chemotherapy administration. A noteworthy relation between diabetes and chemotherapy use for
breast cancer-specific deaths was observed.
Vici et al (2009) studied the action and acceptability of docetaxel-gemcitabine regimen as first-
line therapy in metastatic breast cancer patients treated with adjuvant anthracyclines earlier. The
dose was gemcitabine 1000 mg/m2 (30-minute infusion) on days 1 and 8, and docetaxel 80
mg/m2 (1-hour infusion) on day 8, with cycles repeated every 3 weeks. Median time to
progression was 6 months and overall survival was 16 months. Common side effects were
neutropenia in almost 35% patients and fever, vomiting mucositis and peripheral neurotoxicity
were observed in only 3% cases.
Zauderer et al (2009) inspected the use and toxicity profile of adjuvant dose-dense AC-T
chemotherapy in 162 aged females (≥60 years) having breast cancer from the Memorial Sloan-
Kettering Cancer Center database. It was found that the risk of toxicity would have been
influenced due to comorbidities and baseline hemoglobin value rather than age in the patients.
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Berry et al (2006) compared differences in benefits from adjuvant chemotherapy, received by
patients with ER-negative versus ER-positive tumors from data of a randomized trial from the
Cancer and Leukemia Group B and US Breast Cancer Intergroup. The adjuvant chemotherapy
comprised of 3 schedules of cyclophosphamide, doxorubicin, and fluorouracil; 3 prescriptions of
doxorubicin simultaneous with cyclophosphamide, with or without following paclitaxel;
consecutive doxorubicin, paclitaxel, and cyclophosphamide with parallel doxorubicin and
cyclophosphamide followed by paclitaxel, and also 3-week versus 2-week cycles. Patient
outcomes were analyzed by ER status using hazards over time and multivariate models. The
results showed that doxorubicin/cyclophosphamide plus paclitaxel given twice a week dropped
the chances of relapse and demises by over 50% as compared to that with low-dose
cyclophosphamide, doxorubicin, and fluorouracil in the patients with node positive, ER negative
breast cancer.
Bergh et al (2001) wrote that a methodical review of chemotherapy trials in numerous tumour
forms was done by The Swedish Council of Technology Assessment in Health Care (SBU)
which was based on 233 randomized investigations, 9 meta-analyses, a population-based cohort
study and 18 retrospective studies comprising of 155,243 patients. It was concluded that
adjuvant multiple chemotherapy at 10 years would show an absolute death decline in patients <
50 years by 12% for node positive and 6% for node negative patients; it was 6% and 2%,
respectively for women aged 50 to 69 years. Anthracycline-based combinations showed an
absolute survival value at five years of 3%, compared with non-anthracycline containing
regimens. There was limited data that indicated more improved survival with the use of
paclitaxel as compared with anthracyclines. The addition of tamoxifen to chemotherapy
additionally enhanced the survival value for HR+ subcategories. The data presented with use of
more dose-intensive regimens, particularly with stem cell support were contradictory and did not
support high-dose treatment in general. It was documented that adjuvant chemotherapy had a
preliminary harmful effect which proved to be beneficial in the long run. Combination
chemotherapy in typical doses would be given to premenopausal node positive females,
postmenopausal women with a receptor-negative case and also to node negative cases with high
risk factors; it would be jointly given with tamoxifen to all receptor-positive breast cancer
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patients. It was stated that the treatment for locally advanced breast cancer would comprise of
neoadjuvant chemotherapy as it would statistically considerably surge the offer of breast-
conserving surgery to the patients. In metastatic breast cancer median survival for with
conventional chemotherapy regimens was upto 2 years. Retrospective cohort studies showed that
there might be a survival gain of 6 to 9 months after using non-anthracycline base regimen as
compared with no chemotherapy; combination therapy proved better than monotherapy. In
some studies, the second line regimen with vinorelbine or docetaxel was found to be statistically
significantly better than others.
3.3.4 MISCELLANEOUS:
Rita (2012) documented that HER2 tyrosine kinase was over expressed in almost 30% patients of
metastatic breast cancer for which Trastuzumab and Lapatinib had been recommended.
Resistance to trastuzumab was observed in preliminary clinical trials with median time to
advancement < 1 year. Likewise, majority of patients displayed resistance to lapatinib as well
which was used for trastuzumab-refractory cases. It was seen that trastuzumab reduced early-
stage HER2+ breast cancer relapses. The measurement of probable molecular prognosticators of
trastuzumab resistance would permit individualization of HER2-targeted therapeutic tactics.
Blackwell et al (2010) reported that metastatic breast cancer cases (ErbB2-positive) who
progressed on previous trastuzumab-based therapies were given lapatinib alone or in
combination with trastuzumab. It was established that lapatinib in combination with trastuzumab
was considerably better than either monotherapies with diarrhea, rash, nausea, and fatigue as the
major side effects.
Toi et al (2009) studied the relapse of breast carcinoma in Japanese patients after receiving
anthracyclines, taxanes and trastuzumab. Management with lapatinib monotherapy (1500 mg
once daily) was assessed in the metastatic disease. It was concluded that patients showed positive
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response to lapatinib therapy even in brain metastasis and lapatinib might had different
biomarkers profiles from that for trastuzumab.
Ross et al (2009) stated that HER-2 oncogene encoded a trans-membrane tyrosine kinase
receptor which would classify invasive breast cancer and treatment target. Prognostic implication
of HER-2 gene amplification and protein overexpression was conferred in 39,730 patients from
107 researches showing that there were >22% HER 2+ patients with RR of 2.74 for overall
survival. HER-2 status in initial and metastatic disease was considered. Several HER-2 testing
techniques were also discussed along with various biomarkers that were linked with trastuzumab
and lapatinib resistance. Furthermore, the anti-HER-2 combination therapies in addition to new
drugs like bevacizumab, tenespimycin, pertuzumab, HER-2 vaccines etc. were also included in
the discussion. Finally, HER-2 standing in the calculation of response to non-HER-2 directed
managements (hormonal therapy, anthracyclines, and taxanes) was reviewed.
Geyer et al (2006) stated that HER2-positive breast cancer patients were given combination
therapy of lapatinib and capecitabine after relapse from the therapy of an anthracycline, a taxane,
and trastuzumab. It was found that Lapatinib and capecitabine combination proved to be superior
to capecitabine monotherapy in HER2 + advanced breast carcinoma. The effect was attained
deprived of rise in adverse effects or cardiac events.
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4. METHODOLOGY:
4.1 STUDY DESIGN:
This research was conducted to study breast cancer epidemiology, pharmacotherapy and its
effects among Pakistani women. This research comprises of descriptive, non interventional,
observational and also case control study. The breast cancer cases were taken from KIRAN
hospital, Karachi and the control group was also population based from Karachi city. The study
was accomplished on researcher administered questionnaire and face to face interviews with the
study subjects.
4.2 PLACE OF STUDY:
The control group was recruited from Karachi city. KIRAN hospital, Karachi, was selected to
study breast cancer patients for this research because a large number of cancer patients approach
here for treatment and it is the only one of its kind in Karachi.
4.3 APPROVAL FOR STUDY:
Prior to initiation of this research, the study review and agreement was done between the
administrative representatives of Faculty of Pharmacy, University of Karachi and KIRAN
hospital, Karachi.
4.4 SUBJECTS SELECTION CRITERIA:
4.4.1 DEMOGRAPHIC INFORMATION:
The subjects recruited for this study were adult Pakistani females. The age group of the study
participants was from 20 to 80 years.
4.4.2 INCLUSION CRITERIA:
The controls were recruited from Karachi city.
The cases of breast cancer were being treated at KIRAN hospital, Karachi. This was
necessary for the ease of follow-up of the cases.
The controls did not have breast cancer and not even in their history.
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The cases of breast cancer were histologically confirmed of the disease. The physical
examination, mammography, ultrasound, chest x-ray and tissue biopsy were evident of
the cases having breast cancer.
The cases did not have evidence of any other type of cancer.
The age range of the study subjects was 20-80 years.
4.4.3 Exclusion criteria
Evidence of any cancer in the controls.
Evidence of any other cancer in breast cancer cases.
Any participant of the study was not willing to continue with the study.
4.4.4 INFORMED CONSENT:
The study participants were briefed well about the protocol and purpose of this research and their
written consents were obtained preceding the study. The informed consent was designed simply
and translated for the controls and cases if required.
4.5 FORMAT OF STUDY QUESTIONNAIRE:
The questionnaire comprised of Part A and Part B (i) and (ii). Part A was used for all the controls
and cases recruited for this study whereas Part B comprised of questions for cases of breast
cancer only. Basic information from the subjects collected in Part A included age of subjects,
marital status, education, place of birth, employment status, any disease history of subjects, any
disease history of parents and family history of breast cancer. Part A also included information
regarding life style characteristics like social habits and diet. Reproductive characteristics in Part
A included information about menstruation, contraceptive use, parity and lactation. Part B
comprised of basic information from the cases’ medical records, information regarding the
disease, various treatment modalities employed and their responses and the adverse effects due to
the treatments in cases.
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4.6 DATA COLLECTION:
The data of the study subjects was collected from April 2011 to September 2013. The
questionnaire was researcher administered; face to face interview was conducted with the
subjects and all the information was noted on the questionnaire. Face to face interview has been
described as a very strong way to understand individual experience and sound data collection.
(Seidman, 2012). Follow up data was collected regarding any adverse events observed among
the cases after treatment and in 3-6 months for newly initiated cases, which are common with
cancer treatment modalities.
After discussion with the oncologists, interviews with the patients (n=811) were conducted at
KIRAN hospital, Karachi, where a large number of cancer patients are being treated. The
patients were interviewed in the OPD area in a segregated place, where they were waiting to see
their physician. The data of breast cancer cases was also collected from their medical records
available in the hospital. All the filled questionnaires were marked with a code number by the
researcher and by registration number given by the hospital to the patients for record linkage.
Any missing data from the medical record were either enquired about from the patients or the
physicians treating them. The interviews were also conducted by researcher herself to ensure the
uniformity of data collection and minimizing chances of error. The data of those subjects were
excluded whose missing information as per structured questionnaire could not be retrieved.
However, regarding the data of hormone receptor status, all the available data was included and
the data not reported was mentioned since this is an important factor in breast cancer assessment
and its treatment. Data of the controls (n= 987) was collected from the visitors at the hospital
and also from people from the community at large in Karachi city. This case-control study had
population based control group. (Paul et al., 1990) reported that selection bias was unlikely to
affect the results when cases and controls were drawn from the same population and participation
rates are high among both cases and controls. All the information was entered into computer (MS
Office: Excel) after the questionnaires were filled.
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Women who were menstruating were considered as ‘pre-menopausal’. Since menstruation
became irregular in the breast cancer cases for 6 months to 2 years after treatment therefore those
who received chemotherapy near the age of menopause and/or stopped menstruating for more
than one calendar year were considered as ‘post-menopausal’. Informed consent was taken by
the researcher herself from the subjects prior to their interviews and data collection. The
questionnaire was pre-tested to validate the information required for this study and was modified
accordingly. The interview was conducted to determine information regarding marital status,
interfamily marriage, education, any concomitant disease, disease in subjects’ parents, family
history of breast cancer, some life style characteristics (i.e. eating betel nuts or betel leaves, milk
consumption, tea consumption and diet), reproductive characteristics like age of menarche,
regularity of menstruation, use of contraceptives, age at first child birth, parity and breastfeeding
(i.e. breastfeeding all children). There may be chances of recall bias regarding the menarche age,
menopause age and age at first child birth especially in older women which might have affected
the results. However, menarche age was confirmed in case of educated subjects by referring to
their school attending period. Since many subjects were illiterate, it took long time for the
researcher to interview them to satisfactorily complete the questionnaire. Some subjects were
very reluctant to give information regarding their reproductive characteristics, therefore, it took
much time to explain to them that the information would be kept confidential and was used for
the study purpose only. The ADRs were enquired through patients’ interviews after discussing
with the physicians. Three patients under 20 years of age were excluded from the study so as to
avoid any distortion in the data.
4.6.1 DATA CODING:
The coding of the data was necessary to maintain the confidentiality of the information of the
subjects. The initials of the names of the subjects were recorded and then coded in the form of
serial number. This serial number was used for the data entry in the computer with complete
information of the subjects.
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4.7 PROCEDURE FOR THE STUDY:
The interviews were conducted in the simple language that was understandable by the recruited
subjects. The data available from the medical records of breast cancer patients was verified by
the physicians prior to recording. The collected information about the ADRs was used to assess
their causality, preventability and severity. The ADRs recorded were also verified from the
literature available for the suspected drugs. After completing the questionnaires for both the
controls and the cases of breast cancer, the data collected was then coded and entered in the
computer system which was edited as and when required. Some data was based simply on
dichotomous replies (yes/no); however, certain questions were complex and their answers were
categorized and coded. Initially all the categorical and continuous variables were determined to
observe the general data pattern, starting with descriptive statistics. Then, regression was also
applied for further analysis. All the results of the statistical analysis were verified by an expert
statistician. The significance of receptor status and different age groups was further tested in
multinomial logistic regression analysis. For the analysis of data regarding breast cancer cases
only, descriptive statistics was employed again. Significant associations regarding the treatments
and their effects were mentioned.
4.8 DATA ANALYSIS:
4.8.1 STATISTICAL ANALYSIS:
Statistical analysis of the data was done by using SPSS version 16.0. The initial data generated
important statistics and information; the data of subjects showing extreme values were excluded
to avoid distortion in the analysis.
Simple statistics using frequency, percentage and standard deviation estimation with chi square
statistics were used to compare breast cancer cases and controls. Strong and significant
associations were mentioned. Logistic regression analysis offers quantitative explanation of the
relationship between various risk factors and probability of development of disease. The odds
ratio were determined (with 95% C.I.) for various factors regarding breast cancer to test the
statistical significance of each characteristic under study. The established risk factors of interest
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included in this study were age, BMI, menarche age, age at first child birth, family history of
breast cancer and parity status; suspected risk factors included were profession of study subjects,
various life style characteristics and diet, use of contraceptives, breast feeding and the presence
of concurrent diseases. Although age is an established risk factor for breast cancer but it was
used as a confounder in this study along with education levels of the study subjects. Multivariate
analysis was done after assessment of biological or statistical significance of various
characteristics. Furthermore, multinomial regression analyses were applied for various risk
factors of breast cancer based on hormone receptor status, stage of breast cancer and stratified
menopausal status. Premenopausal and post menopausal statuses were stratified and were used as
a third variable in this study.
4.8.2 ADRs ANALYSIS:
The adverse events that occurred due to radiation therapy, adjuvant endocrine therapy and
adjuvant chemotherapy were categorized and estimated for frequency and percentage. The ADRs
due to the chemotherapeutic agents were also confirmed from British National Formulary
(Association and Britain, 2011). Furthermore, they were analyzed for causality, preventability
and severity according to the International scales i.e. Naranjo’s algorithm, modified Schumock
and Thornton scale and modified Hartwig’s and Siegel scale respectively.
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5. RESULTS:
The study population comprised of n= 811 breast cancer cases and n= 1154 controls (total=1965
subjects).
5.1 DESCRIPTIVE ANALYSIS OF RISK FACTORS IN CONTROLS AND CASES:
Mean age of the control group was 45.85±9.97 and that of the breast cancer cases was 47.02±
11.79. The socio-demographic characteristics using descriptive statistics for controls and cases of
breast cancer are shown in Tables 7 and 8 for frequency and percentages. Fig. 6 shows the age
distribution among the controls and cases of breast cancer. Fig. 7 shows the percentage of
working women and housewives in the controls and cases.
The mean age of menarche for controls was 13.53±1.01 and that for cases of breast cancer was
13.33±0.87. The mean age of menopause for controls was 46.34±3.19 and that for cases of breast
cancer was 44.51±4.70. Mean age of first child birth was 21.98±3.95 for control group and that
for breast cancer cases was 22.13±4.07. Various reproductive characteristics of controls and
cases of breast cancer, using descriptive statistics are shown in Tables 9 for frequency and
percentages.
Table 10 illustrates the information regarding the existing diseases in the controls and cases of
breast cancer. This table also shows the frequency of family history in the subjects by applying
descriptive statistics for frequency and percentages.
5.2 LOGISTIC REGRESSION ANALYSIS FOR VARIOUS RISK FACTORS
ASSOCIATED WITH BREAST CANCER:
Binary univariate logistic regression was applied to estimate the odds (with 95% C.I.) of various
risk factors of breast cancer in controls and cases as shown in Tables 11-13. The odds were
infinite for the history of breast cancer in the family among subjects, hence could not be
mentioned. A series of bivariate and multivariate logistic regression analyses models were then
applied including all variables of interest related to breast cancer risk. Odds were estimated and
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95% C.I. were reported (Tables14-18). Multinomial regression analyses of modifiable breast
cancer risk factors after adjustments for age and education are shown in Tables 19 and 20. Table
21 shows the analysis of modifiable risk factors of breast cancer stratified by menopausal status
adjusted for age and education.
5.3 BASELINE CHARACTERISTICS OF BREAST CANCER CASES:
The year of diagnosis and year of registration of breast cancer cases in KIRAN hospital are
shown in Fig. 8 and 9 respectively. Overall distribution of cases with respect to breast cancer
stages are shown in Fig. 10 and Fig. 11 shows the cancer involvement of the side of the breast
among the cases. The site of breast cancer with respect to age groups and stages are given in
Tables 22 and 23 respectively. Breast cancer metastases sites are given in Fig. 12. Receptor
status information for ER, PR and HER2/neu with respect to age distribution and breast cancer
stages are shown in Tables 24 and 25 for the cases. The overall available status of ER, PR and
HER2/neu are shown in Fig. 13-15. The joint status for ER, PR and HER2/neu are shown in Fig.
16.
5.4 PHARMACOTHERAPY OF BREAST CARCINOMA:
5.4.1 LOCAL (SURGERY AND RADIATION) THERAPY IN BREAST CANCER
CASES:
The frequency and percentages of breast cancer cases that underwent surgery are given in Table
26 with age distribution. Table 27 shows the application of radiation therapy in various age
groups of the cases of breast cancer. To obtain required outcomes from radiation therapy, it is
given to the patients for specific time periods in fractions as shown in Table 28. The adverse
effects observed due to radiation therapy and the treatment given to the patients were also
recorded (Table 29).
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5.4.2 ENDOCRINE THERAPY USED BY BREAST CANCER CASES:
The use of endocrine therapy and their types in breast cancer are given in Tables 30 and 31
respectively. The side effects of endocrine therapy and their treatments were also recorded
(Table 32).
5.4.3 CHEMOTHERAPY USED IN BREAST CANCER CASES:
The cases of breast cancer were treated with different cycles of chemotherapy of various types
and their response was recorded (Table 33 and 34). The adverse effects due to chemotherapy and
their treatment in patients of breast cancer are given in Table 35.
5.5 ASSESSMENT OF ADRS USING VARIOUS SCALES
5.5.1 ADVERSE EVENTS ACCORDING TO VARIOUS INTERNATIONAL SCALES
AFTER BREAST CANCER RADIATION THERAPY:
Table 36 shows the assessment of ADRs arising due to radiation therapy in the breast cancer
cases.
5.5.2 ADVERSE EVENTS ACCORDING TO VARIOUS INTERNATIONAL SCALES
AFTER BREAST CANCER ENDOCRINE THERAPY:
Table 37 shows the assessment of ADRs arising due to endocrine therapy in the breast cancer
patients.
5.5.3 ADVERSE EVENTS ACCORDING TO VARIOUS INTERNATIONAL SCALES
AFTER BREAST CANCER CHEMOTHERAPY:
The assessment of ADRs due to chemotherapy in the breast cancer patients are given in Table 38
using different assessment scales.
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Table 7: Demographic characteristics of study subjects
Characteristics Control (n=1154)
n (% within group)
Cases(n=811)
n (% within group)
p-value*
Age Groups (Years) 0.02
20 - 30 89 (7.7) 66 (8.1)
31 – 40 300 (26.0) 209 (25.7)
41 – 50 474 (41.0) 282 (34.7)
51 - 60 144(12.5) 101 (12.4)
> 60 147 (12.7) 154 (19)
Profession 0.002
House wife 979 (90.9) 767 (94.57)
Working 98 (9.1) 44 (5.5)
Married --
Yes 1083 (93.8) 760 (93.6)
No 71 (6.2) 51 (6.4)
Interfamily marriage <0.001
Yes 327 (30.2) 370 (45.6)
No 756 (69.8) 441 (54.4)
Education <0.001
Post-Graduate 70 (6.1) 7 (0.9)
Graduate 217 (18.8) 62 (7.6)
Intermediate 150 (13.0) 69 (8.5)
Secondary 184 (15.9) 119 (14.7)
Primary 323 (28.0) 223 (27.5)
Illiterate 210 (18.2) 331 (40.8)
BMI --
< 18.5 136 (11.8) 94 (11.6)
18.5-25 896 (77.6) 652 (80.3)
>25 122 (10.6) 66 (8.1)
p-value* < 0.05 = significant
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Table 8: Life style characteristics of study subjects
Characteristics Control (n=1154)
n (% within group)
Cases (n=811)
n (% within group)
p-value*
Social history 0.02
Betel nuts 89 (7.7) 75 (9.2)
Betel leaves 113 (9.8) 49 (6)
Others (smoking, naswar, gutka) 11 (1.0) 7 (0.9)
None 941 (81.5) 680 (83.9)
Regular use of milk <0.001
Yes 346 (30.0) 471 (58)
No 808 (70.0) 340 (42)
Milk type <0.001
Fresh 284 (24.6) 399 (49.19)
Pack 62 (5.4) 72 (8.87)
None 808 (70.0) 340 (41.92)
Regular use of tea 0.003
Yes 1064 (92.2) 718 (88.4)
No 90 (7.8) 93 (11.6)
Diet <0.001
Vegetable 632 (54.8) 441 (54.3)
Meat 231 (20.0) 73 (9.1)
Both 291 (25.2) 297 (36.6)
p-value* < 0.05 = significant
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Fig 6: Age distribution among cases and controls
Fig. 7: House wives and working controls and cases
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Table 9: Reproductive characteristics of study subjects
Characteristics Control (n=1154)
n (% within group)
Cases (n=811)
n (% within group) p-value*
Menarche age (years) <0.001
11-12 150 (13.0) 67 (8.3)
13-14 826 (71.6) 675 (83.1)
>14 178 (15.4) 69 (8.6)
Regular menstruation <0.001
Yes 1013 (87.8) 801 (98.6)
No 141 (12.2) 10 (1.4)
Menopause status <0.001
Post-menopausal 433 (37.5) 514 (63.3)
Pre-menopausal 721 (62.5) 297 (36.7)
Menopause age (years) <0.001
40-45 112 (25.3) 255 (45.1)
46-50 321 (72.6) 293 (51.9)
>50 9 (2.0) 17 (3.0)
Contraceptive use <0.001
Yes 282 (24.4) 43 (5.3)
No 872 (75.6) 768 (94.7)
Age at first child birth (years) <0.001
<16 63 (6.6) 23 (3.6)
16-20 370 (38.9) 243 (38.5)
21-25 360 (37.9) 292 (46.3)
>25 157 (16.5) 73 (11.6)
Parity (no. of children) <0.001
Nulliparous 204 (17.7) 171 (21.1)
1 66 (5.7) 38 (4.7)
2-3 333 (28.9) 236 (29.1)
4-5 403 (34.9) 188 (23.2)
>5 148 (12.8) 178 (22)
Breast feeding 0.01
Yes 1013 (87.8) 683 (84.1)
No 141 (12.2) 128 (15.9)
p-value* < 0.05 = significant
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Table 10: Disease information about study participants
Characteristics Control (n=1154)
n (% within
group)
Cases (n=811)
n (% within
group)
p-value*
Family history of breast
cancer
<0.001
Yes 0 (0) 127 (15.65)
No 1154 (100) 684 (84.34)
Which member has breast cancer <0.001
None 1154 (100) 684 (84.34)
Brother 0 (0) 7 (0.9)
Cousin 0 (0) 14 (1.7)
Daughter 0 (0) 5 (0.6)
Son 0 (0) 0 (0)
Father 0 (0) 11 (1.4)
Husband 0 (0) 7 (0.9)
Maternal relative 0 (0) 15 (1.8)
Mother 0 (0) 14 (1.7)
Sister 0 (0) 31 (3.8)
Paternal relative 0 (0) 23 (2.8)
Concomitant disease in subjects 0.001
No 748 (64.8) 493 (60.8)
HTN 191 (16.6) 133 (16.4)
DM 49 (4.2) 35 (4.3)
HTN+DM 46 (4.0) 69 (8.5)
Multiple (HTN+DM+Others) 120 (10.4) 81 (10.0)
Disease in subjects’ parents <0.001
Arthritis 17 (1.5) 4 (0.5)
Asthma 13 (1.1) 1 (0.1)
Any other cancer (except
Breast)
15 (1.3) 3 (0.4)
CVD 12 (1.0) 13 (1.6)
DM 50 (5.1) 51 (6.3)
DM+HTN 23 (4.3) 38 (4.7)
HTN 58 (5.0) 122 (15.0)
HTN+Angina 42 (3.6) 0 (0)
Ulcer 9 (0.8) 1 (0.1)
TB 6 (0.5) 3 (4)
Others 16 (1.4) 13 (1.6)
None 893 (77.4) 562 (69.3)
p-value* < 0.05 = significant
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Table 11: Binary logistic regression analysis for various characteristics of cases and
controls
Risk Factors Frequency (n) p-value* Odds Ratio (95%) C.I
Age Groups (Years)
20 - 30 155 ----- Reference -----
31 – 40 509 0.73 0.93 (0.65,1.35)
41 – 50 756 0.21 0.80 (0.56,1.13)
51 – 60 245 0.78 0.94 (0.62,1.42)
More than 60 301 0.08 1.41 (0.95,2.08)
Married
-----
NO 122 ----- Reference -----
Yes 1843 0.82 0.95 (0.66,1.38)
Profession
House wife 1740 0.003 1.73 (1.19,2.50)
Working 140 ----- Reference -----
Interfamily marriage
No 1197 ----- Reference -----
Yes 697 <0.001 1.94 (1.60,2.34)
Education level
Post graduation 77 ----- Reference -----
Graduation 279 0.13 2.85 (1.25,6.53)
Intermediate 219 <0.001 4.60 (2.01,10.52)
Secondary 303 <0.001 6.46 (2.87,14.54)
Primary 546 <0.001 6.90 (3.11,15.29)
Illiterate 541 <0.001 15.76 (7.11,34.93)
BMI
18.5-25 1548 ----- Reference -----
< 18 230 0.72 0.95 (0.71,1.25)
>25 188 0.06 0.74 (0.54,1.02)
Concomitant disease in subjects
No 1241 ------- Reference ----------
HTN 324 0.66 1.05 (0.82,1.35)
DM 84 0.72 1.08 (0.69,1.69)
HTN+DM 115 <0.001 2.27 (1.54,3.36)
Multiple
(HTN+DM+others)
201 0.87 1.02 (0.75,1.38)
p-value* < 0.05 = significant
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Table 12: Binary logistic regression analysis for various life style characteristics of study
subjects
Risk Factors Frequency (n) p-value* Odds Ratio (95%) C.I
Social history
No 1622 ---- Reference ----
Betel nuts 164 0.35 1.16 (0.84,1.60)
Betel leaves 162 0.04 0.59 (0.42,0.85)
Others
(smoking,naswar,gutka)
18 0.79 0.87 (0.33,2.28)
Regular use of milk
No 1149 ---- Reference --
Yes 817 <0.001 3.22 (2.67,3.89)
Milk type used
Fresh 683 <0.001 3.49 (2.86,4.26)
Pack 128 <0.001 2.64 (1.82,3.83)
No 1133 ---- Reference ----
Regular use of tea
Yes 1782 0.005 0.64 (0.47,0.87)
No 183 ---- Reference ----
Diet
Vegetables 1073 <0.001 0.68 (0.55,0.83)
Meat 305 <0.001 0.31 (0.23,0.42)
Both 588 ---- Reference ----
p-value* < 0.05 = significant
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Table 13: Binary logistic regression analysis for reproductive variables of study subjects
Factors Frequency (n) p-value* Odds Ratio (95%) C.I
Menarche age (years)
11-12 217 ------- Reference -------
13-14 1501 <0.001 1.83 (1.34, 2.48)
>14 248 0.53 0.88 (0.59,1.31)
Regular menstruation
Yes 1814 ------- Reference -------
No 152 <0.001 0.09 (0.05,0.18)
Menopause status
Post-menopausal 947 <0.001 2.87 (2.38,3.45)
Pre-menopausal 1019 ------- Reference -------
Menopause age (years)
38-45 367 0.66 1.20 (0.52,2.78)
46-50 614 0.08 0.48 (0.21,1.10)
>50 26 ------- Reference -------
Number of children
Nulliparous 375 0.01 0.69 (0.51,0.93)
1 104 0.001 0.47 (0.30,0.75)
2-3 569 <0.001 0.58 (0.44,0.77)
4-5 591 <0.001 0.38 (0.29,0.50)
>5 327 ------- Reference ----
Use of contraceptives
Yes 325 <0.001 0.17 (0.12,0.24)
No 1641 ------- Reference ----
Age at first child birth (years)
<16 86 0.002 0.45 (.027,0.74)
16-20 613 0.064 0.81 (0.64,1.01)
21-25 652 ------- Reference ----
>25 230 0.001 0.57 (0.41,0.78)
Breast feeding
Yes 1696 ------- Reference ----
No 270 0.02 1.35 (1.04,1.75)
p-value* < 0.05 = significant
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Table 14: Bivariate (adjusted) regression analysis of risk factors of breast cancer
Characteristics Adjusted
OR (95% C.I)a
Adjusted
OR (95% C.I)b
Profession
House wife 1.77 (1.20,2.61) 0.94 (0.61,1.47)
Working Reference Reference
Married
Yes 0.90 (0.62,1.32) 0.98 (0.66,1.45)
No Reference Reference
Interfamily marriage
Yes 2.06 (1.69,2.50) 1.82 (1.48,2.23)
No Reference Reference
Education
Post-Graduate Reference
(Adjusted) Graduate 2.95 (1.27,6.83)
Intermediate 4.45 (1.94,10.21)
Secondary 6.73 (2.97,15.26)
Primary 7.23 (3.24,16.13)
Illiterate 16.10 (7.21,35.94)
BMI
< 18.5 0.96 (0.72,1.27) 1.01 (0.75,1.37)
18.5-25 Reference Reference
>25 0.74 (0.54,1.02) 0.67 (0.48,0.94)
Concomitant disease in subjects
No Reference Reference
HTN 0.94 (0.71,1.23) 0.75 (0.56,1.00)
DM 1.07 (0.67,1.68) 1.12 (0.69,1.82)
HTN+DM 1.84 (1.20,2.82) 1.56 (0.99,2.45)
Multiple (HTN+DM+Others) 0.92 (0.66,1.27) 0.97 (0.68,1.36)
a- Adjusted for age
b- Adjusted for age and education
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Table 15: Bivariate (adjusted) regression analysis of life style risk factors of breast cancer
Characteristics Adjusted
OR (95% C.I)a
Adjusted
OR (95% C.I)b
Social history
Betel nuts 1.18 (0.85,1.63) 1.19 (0.85,1.66)
Betel leaves 0.56 (0.39,0.80) 0.60 (0.41,0.87)
Others (smoking, naswar, gutka) 0.88 (0.34,2.31) 0.61 (0.22,1.65)
None Reference Reference
Regular use of milk
Yes 3.17 (2.62,3.83) 3.36 (2.75,4.11)
No Reference Reference
Milk type
Fresh 3.42 (2.80,4.19) 3.64 (2.94,4.51)
Pack 2.65 (1.83,3.85) 2.76 (1.87,4.08)
None Reference Reference
Regular use of tea
Yes 0.61 (0.45,0.83) 0.60 (0.44,0.84)
No Reference Reference
Diet
Vegetable 0.67 (0.54,0.82) 0.65 (0.52,0.80)
Meat 0.28 (0.20,0.38) 0.25 (0.18,0.35)
Both Reference Reference
a- Adjusted for age
b- Adjusted for age and education
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Table 16: Bivariate (adjusted) reproductive risk factors of breast cancer
Characteristics Adjusted
OR (95% C.I)a
Adjusted
OR (95% C.I)b
Menarche age (years)
11-12 Reference Reference
13-14 1.91 (1.40,2.61) 1.63 (1.17,2.25)
>14 0.92 (0.61,1.37) 0.79 (0.52,1.21)
Regular menstruation
Yes Reference Reference
No 0.06 (0.03,0.13) 0.06 (0.03,0.12)
Menopause status
Post-menopausal 3.33 (2.70,4.12) 3.48 (2.78,4.35)
Pre-menopausal Reference Reference
Menopause age (years)
40-45 1.39 (0.51,3.79) 0.73 (0.22,2.40)
46-50 0.55 (0.20,1.48) 0.28 (0.08,0.93)
>50 Reference Reference
Contraceptive use
Yes 0.15 (0.10,0.21) 0.13 (0.09,0.19)
No Reference Reference
Age at first child birth (years)
<16 0.43 (0.26,0.72) 0.29 (0.17,0.50)
16-20 0.77 (0.61,0.97) 0.63 (0.50,0.81)
21-25 Reference Reference
>25 0.48 (0.35,0.68) 0.64 (0.45,0.92)
Parity (no. of children)
Nulliparous 0.70 (0.51,0.95) 0.73 (0.53,1.01)
1 0.43 (0.27,0.69) 0.60 (0.36,0.99)
2-3 0.57 (0.43,0.76) 0.68 (0.51,0.92)
4-5 0.37 (0.28,0.49) 0.38 (0.28,0.51)
>5 Reference Reference
Breast feeding
Yes Reference Reference
No 1.45 (1.11,1.88) 1.73 (1.30,2.29)
a- Adjusted for age
b- Adjusted for age and education
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Table 17: Multivariate adjusted logistic regression analysis of established risk factors of
breast cancer
Characteristics Adjusted
OR (95% C.I)
Age Groups (Years)
20 - 30 Reference
31 – 40 0.15 (0.07,0.32)
41 – 50 0.11 (0.05,0.22)
51 - 60 0.14 (0.06,0.31)
> 60 0.11 (0.05,0.24)
BMI
< 18.5 1.12 (0.77,1.63)
18.5-25 Reference
>25 0.75 (0.51,1.10)
Menarche age (years)
11-12 Reference
13-14 1.46 (0.98,2.17)
>14 0.36 (0.21,0.61)
Age at first child birth (years)
<16 0.26 (0.14,0.46)
16-20 0.63 (0.49,0.80)
21-25 Reference
>25 0.66 (0.45,0.96)
Adjusted for education
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Table 18: Multivariate adjusted logistic regression analysis for established and
suspected risk factors of breast cancer
Characteristics Adjusted OR (95% C.I)
Age Groups (Years)
20 - 30 Reference
31 – 40 0.10 (0.04,0.24)
41 – 50 0.06 (0.02,0.14)
51 - 60 0.09 (0.04,0.23)
> 60 0.07 (0.03,0.18)
BMI
< 18.5 1.32 (0.88,1.97)
18.5-25 Reference
>25 0.91 (0.60,1.39)
Menarche age (years)
11-12 Reference
13-14 0.43 (0.24,0.76)
>14 1.73 (1.10,2.71)
Age at first child birth (years)
<16 0.34 (0.19,0.63)
16-20 0.52 (0.39,0.69)
21-25 Reference
>25 0.49 (0.31,0.77)
Interfamily marriage
Yes 2.14 (1.64,2.79)
No Reference
Social history
No Reference
Betel nuts 1.10 (0.66,1.85)
Betel leaves 0.45 (0.28,0.70)
Others (smoking,naswar,gutka) 0.30 (0.08,1.05)
Regular use of milk
No Reference
Yes 6.02 (4.57,7.92)
Regular use of tea
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Yes 1.01 (0.64,1.59)
No Reference
Diet
Vegetables 0.78 (0.59,1.04)
Meat 0.22 (0.14,0.33)
Both Reference
Profession
House wife 0.22 (0.11,0.44)
Working Reference
Breast feeding
Yes Reference
No 1.12 (0.76,1.65)
Adjusted for education
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Table 19: Multinomial regression analysis of breast cancer risk factors by hormone
receptor status
Characteristics ER and/or
PR+ H-
(n=165)
OR (95%
C.I.)
ER and/or
PR+ H+
(n=118)
OR (95%
C.I.)
ER- PR- H+
(n=60)
OR (95%
C.I.)
ER- PR- H-
(n=166)
OR (95%
C.I.)
BMI
< 18.5 0.77
(0.43,1.38)
1.12
(0.63,1.99)
1.79
(0.89,3.61)
0.86
(0.49,1.50)
18.5-25 ---- Reference ----- -----
>25 0.55
(0.29,1.03)
0.43
(0.18,1.01)
0.88
(0.36,2.14)
1.02
(0.60,1.74)
Interfamily marriage
Yes 1.57
(1.10,2.23)
1.74
(1.15,2.61)
1.55
(0.89,2.70)
2.60
(1.82,3.71)
No ---- Reference ----- -----
Social history
No ---- Reference ----- -----
Betel nuts 0.93
(0.48,1.83)
1.69
(0.90,3.16)
0.82
(0.28,2.40)
1.15
(0.62,2.13)
Betel leaves 0.54
(0.27,1.09)
0.35
(0.12,1.01)
0.69
(0.26,1.83)
0.38
(0.16,0.90)
Others
(smoking,naswar,gutka)
0.46
(0.05,3.69)
1.21
(0.25,5.79)
N/A 0.82
(0.17,3.89)
Regular use of milk
No ---- Reference ----- -----
Yes 3.84
(2.70,5.45)
2.45
(1.65,3.64)
4.30
(2.47,7.47)
4.20
(2.95,5.98)
Regular use of tea
Yes 0.50 1.31 0.91 0.50
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(0.29,0.86) (0.55,3.13) (0.34,2.39) (0.30,0.86)
No ---- Reference ----- -----
Diet
Vegetables 0.74
(0.50,1.78)
0.41
(0.26,0.63)
1.43
(0.75,2.74)
0.70
(0.48,1.02)
Meat 0.32
(0.17,0.57)
0.34
(0.18,0.61)
0.34
(0.10,1.08)
0.20
(0.10,0.39)
Both ---- Reference ----- -----
Use of contraceptives
Yes 0.07
(0.03,0.19)
0.25
(0.13,0.49)
0.19
(0.06,0.54)
0.12
(0.05,0.28)
No ---- Reference ----- -----
Profession
House wife 0.89
(0.32,2.49)
0.76
(0.31,1.88)
1.89
(0.39,9.14)
1.97
(0.70,5.52)
Working ---- Reference ----- -----
Adjusted for age and education
PHARMACOTHERAPEUTIC STUDIES AND ASSOCIATED RISK FACTORS OF BREAST CARCINOMA IN LOCAL POPULATION
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Table 20: Multinomial regression analysis of breast cancer risk factors by breast cancer
stage
Characteristics Stage I
(n=392)
OR (95% C.I.)
Stage II
(n=270)
OR (95% C.I.)
Stage III
(n=80)
OR (95% C.I.)
Stage IV
(n=69)
OR (95% C.I.)
BMI
< 18.5 0.70 (0.46,1.06) 0.97 (0.62,1.50) 1.99 (1.11,3.56) 2.08 (1.12,3.86)
18.5-25 ---- Reference ----- -----
>25 0.61 (0.39,0.94) 0.98 (0.64,1.52) 0.21 (0.05,0.91) 0.38 (0.11,1.27)
Interfamily marriage
Yes 1.73 (1.35,2.23) 2.02 (1.52,2.70) 2.38 (1.48,3.84) 1.09 (0.64,1.86)
No ---- Reference ----- -----
Social history
No ---- Reference ----- -----
Betel nuts 1.17 (0.77,1.79) 1.07 (0.65,1.75) 0.78 (0.30,2.02) 2.38 (1.17,4.80)
Betel leaves 0.51 (0.30,0.86) 0.72 (0.43,1.22) 0.45 (0.15,1.28) 0.83 (0.31,2.17)
Others
(smoking,naswar,gutka)
0.69 (0.21,2.26) 0.52 (0.11,2.45) 1.11 (0.13,9.04) N/A
Regular use of milk
No ---- Reference ----- -----
Yes 3.35 (2.61,4.29) 3.52 (2.66,4.67) 3.55 (2.21,5.71) 2.66 (1.62,4.38)
Regular use of tea
Yes 0.55 (0.37,0.82) 0.70 (0.44,1.12) 0.70 (0.31,1.61) 0.47 (0.22,1.01)
No ---- Reference ----- -----
Diet
Vegetables 0.71 (0.55,0.93) 0.67 (0.50,0.91) 0.55 (0.33,0.92) 0.36 (0.20,0.62)
Meat 0.19 (0.12,0.31) 0.30 (0.19,0.49) 0.30 (0.14,0.64) 0.34 (0.16,0.70)
Both ---- Reference ----- -----
Use of contraceptives
Yes 0.12 (0.07,0.20) 0.13 (0.07,0.23) 0.14 (0.05,0.35) 0.17 (0.07,0.45)
No ---- Reference ----- -----
Profession
House wife 1.11 (0.62,2.00) 0.93 (0.49,1.77) 0.89 (0.32,2.51) 0.52 (0.19,1.38)
Working ---- Reference ----- -----
Adjusted for age and education
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Table 21: Breast cancer risk factors stratified by menopausal status
Characteristics Pre-menopausal
(n=1019)
OR (95% C.I.)
Post-menopausal
(n=947)
OR (95% C.I.)
BMI
< 18.5 1.09 (0.79,1.50) 0.91 (0.66,1.25)
18.5-25 Reference Reference
>25 1.06 (0.75,1.49) 0.94 (0.67,1.32)
Interfamily marriage
Yes 1.05 (0.85,1.31) 0.94 (0.76,1.17)
No Reference Reference
Social history
No Reference Reference
Betel nuts 1.06 (0.74,1.53) 0.93 (0.65,1.34)
Betel leaves 0.48 (0.33,0.71) 2.06 (1.40,3.02)
Others (smoking,naswar,gutka) 6.64 (1.39,31.55) 0.15 (0.03,0.71)
Regular use of milk
No Reference Reference
Yes 0.50 (0.41,0.62) 1.96 (1.59,2.42)
Regular use of tea
Yes 0.76 (0.54,1.09) 1.30 (0.91,1.85)
No Reference Reference
Diet
Vegetables 1.33 (1.06,1.67) 0.75 (0.59,0.94)
Meat 0.50 (0.36,0.70) 1.97 (1.41,2.75)
Both Reference Reference
Use of contraceptives
Yes 2.19 (1.64,2.94) 0.45 (0.34,0.60)
No Reference Reference
Profession
House wife 0.41 (0.25,0.65) 2.43 (1.53,3.86)
Working Reference Reference
Adjusted for age and education
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Fig. 8: Year of diagnosis of breast cancer
Fig. 9: Year of registration of breast cancer cases in hospital
0
5
10
15
20
25
30
35
2001 2002 2004 2005 2006 2007 2008 2009 2010 2011
(%)
YEAR OF DIAGNOSIS
0
5
10
15
20
25
30
35
40
2000 2001 2002 2004 2005 2006 2007 2008 2009 2010 2011
(%)
YEAR OF REGISTRATION
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Fig. 10: Overall stages of breast cancer in patients
Fig. 11: Breast cancer site in patients
Table 22: Breast cancer site in different age groups
48%
33%
10%9%
STAGE 1 STAGE 2 STAGE 3 STAGE 4
53%46%
1%
Left Right Both
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Breast site
Age group (years) Left Right Both Total (%)
20-30 32 34 0 66 (8.1)
31-40 108 101 0 209 (25.77)
41-50 142 136 4 282 (34.77)
51-60 63 36 2 101 (12.4)
>60 81 69 3 152 (18.74)
Total 426 376 9 811
Table 23: Breast cancer site in various cancer stages
Cancer stage
Breast cancer site 1 2 3 4 Total (%)
Left 212 138 38 37 425 (52.4)
Right 175 129 41 31 376 (46.36)
Both 5 3 1 1 10 (1.23)
Total 392 270 80 69 811
Table 24: Receptor status in various age groups of breast cancer cases
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Age group (years)
Negative (%
within group)
Positive (%
within group)
Not known (%
within group)
Total (%
within group)
ER (p=<0.05)
20-30 35 (10.3) 24 (6.4) 7 (7.5) 66 (8.1)
31-40 101 (29.6) 90 (23.9) 17 (18.3) 208 (25.6)
41-50 118 (34.6) 120 (31.8) 44 (47.3) 282 (34.8)
51-60 39 (11.4) 55 (14.6) 7 (7.5) 101 (12.5)
>60 48 (14.1) 88 (23.3) 18 (19.4) 154 (19)
Total 341 377 93 811
-- PR
20-30 41 (9.6) 17 (5.8) 8 (8.4) 66 (8.1)
31-40 111 (26.1) 80 (27.5) 17 (17.9) 208 (25.6)
41-50 146 (34.4) 91 (31.3) 45 (47.4) 282 (34.8)
51-60 57 (13.4) 37 (12.7) 7 (7.4) 101 (12.5)
>60 70 (16.5) 66 (22.7) 18 (18.9) 154 (19)
Total 425 291 95 811
-- HER 2 NEU
20-30 23 (6.9) 17 (9) 26 (9) 66 (8.1)
31-40 83 (24.9) 52 (27.7) 73 (25.2) 208 (25.6)
41-50 114 (34.2) 63 (33.5) 105 (36.2) 282 (34.8)
51-60 54 (16.2) 17 (9) 30 (10.3) 101 (12.5)
>60 59 (17.7) 39 (20.7) 56 (19.3) 154 (19)
Total 333 188 290 811
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Table 25: Receptor status and breast cancer stages in patients
Receptor Breast cancer stage Cases
ER (p=<0.001) I II III IV Total (%)
Negative 198 114 20 9 341 (42.04)
Positive 164 130 49 34 377 (46.48)
Not known 30 26 11 26 93 (11.46)
Total 392 270 80 69 811
PR (p=<0.001)
Negative 239 143 29 14 425 (52.40)
Positive 120 106 39 26 291 (35.88)
Not known 33 21 12 29 95(11.71)
Total 392 270 80 69 811
HER 2 NEU (p=<0.001)
Negative 193 105 24 11 333 (41.06)
Positive 53 84 35 16 188 (23.18)
Not known 146 81 21 42 290 (3.57)
Total 392 270 80 69 811
Fig. 12: Metastatic sites in breast cancer patients
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Fig. 13: ER status in breast cancer cases
0
5
10
15
20
25
30
35
40
Lung Bone Liver Brain Mutiple
(%)
42%
46%
12%
Negative Positive Not known
PHARMACOTHERAPEUTIC STUDIES AND ASSOCIATED RISK FACTORS OF BREAST CARCINOMA IN LOCAL POPULATION
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Fig. 14: PR status in breast cancer cases
Fig 15: HER2/neu status in breast cancer cases
52%36%
12%
Negative Positive Not known
41%
23%
36%
Negative Positive Not known
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Fig. 16: Joint receptor status of ER, PR and HER2/neu in breast cancer cases
Table 26: Surgery in various age groups of breast cancer cases
-- Surgery --
Age group (years) Yes No Total (% within group)
20-30 61 5 66 (8.13)
31-40 198 11 209 (25.77)
41-50 269 12 282 (34.77)
51-60 100 1 101 (12.45)
>60 148 4 153 (18.86)
Total 776 33 811
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Table 27: Radiation therapy in various age groups of breast cancer cases
Age group (years) Radiation therapy Total (% within group)
20-30 Yes 53 (91.4)
-- No 5 (8.6)
Total 58
31-40 Yes 181 (95.3)
-- No 9 (4.7)
Total 190
41-50 Yes 249 (98.8)
-- No 3 (1.2)
Total 252
51-60 Yes 81 (96.4)
-- No 3 (3.6)
Total 84
>60 Yes 124 (99.2)
-- No 1 (0.8)
Total 125
Table 28: Response of radiation therapy in various age groups of breast cancer cases
Number of days (n=no. of patients)
Age group (years) Radiation response 18 (n) 21 (n) 25 (n) 30 (n) Total (%)
20-30 Good 18 19 2 4 43
Partial 2 3 0 1 6
Total 20 22 2 5 49 (6.21)
31-40
(p= <0.05)
Good 80 71 7 11 169
Partial 5 5 0 2 12
Total 85 76 7 13 181 (22.96)
41-50 Good 87 105 18 7 217
Partial 11 10 0 0 21
Total 98 115 18 7 238 (30.2)
51-60
(p= <0.001)
Good 38 31 4 3 76
Partial 3 2 0 1 6
Total 41 33 4 4 82 (10.4)
>60
(p= <0.05)
Good 41 51 1 2 95
Partial 12 2 1 0 15
Total 53 53 2 2 110 (13.95)
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Table 29: Adverse reactions due to radiation therapy in breast cancer cases
S.No Tissue Side effects Treatment given
1 Skin/nail Hyperpigmentation
(n= 568, 72.08%)
ABX/ Fusidic acid cream or iodine
solution
2 Skin Erythema/
Scars/marks
(n= 549, 69.67%)
Steroid cream
(1% hydrocortisone)
Ulcers
(n= 202, 25.63%)
Analgesics, antibiotics
3 Overall
body
Fatigue/body aches
(n= 598, 75.88%)
Rest, balanced diet
Where ABX= bacitracin, neomycin, polymyxin B
Table 30: Use of Endocrine therapy by breast cancer patients
Endocrine therapy used
Age group
(years)
Yes (% within
group)
No (% within
group)
Total (% within
group)
20-30 38 (7.5) 28 (9.24) 66 (8.13)
31-40 131 (25.78) 77 (25.41) 208 (25.6)
41-50 186 (36.61) 96 (31.68) 282 (34.8)
51-60 60 (11.81) 41 (13.53) 101 (12.5)
>60 93 (18.30) 61 (20.13) 154 (19)
Total 508 306 811
Table 31: Types of endocrine drugs used by breast cancer patients
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Table 32: Adverse reactions due to endocrine therapy and their treatment in breast cancer
cases
S.No Tissue Side effects Treatment given
1 Musculoskeletal Arthralgia
(n= 53, 10.43%)
Acetaminophen, exercise, NSAIDs
Myalgia
(n= 206, 40.55%)
2 Vasomotor symptoms Hot flashes
(n= 173, 34.05%)
Antidepressants
Night sweats
(n= 113, 22.24%)
Heat intolerance
(n= 259, 50.98%)
3 Genitourinary tract Vaginal dryness
(n= 47, 9.25%)
Lubricants/moisturizers
4 Cardiovascular (CV events) (n= 283, 55.70%)
at risk*
Optimize cardiac risk factors
Where NSAID= non steroidal anti-inflammatory drug
*patients at risk of CV events due to existing comorbidities i.e. hypertension, diabetes mellitus
and others
Table 33: Cycles and response of Chemotherapy in different age groups of breast cancer
cases:
Age Group
(years)
Endocrine therapy
Tamoxifen Letrozole Total (%)
20 - 30 38 0 38 (7.48)
31 - 40 129 2 131 (25.78)
41 - 50 175 11 186 (36.61)
51 - 60 57 3 60 (11.8)
>60 89 4 93 (18.30)
Total 488 20 508 (100)
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Chemotherapy Chemotherapy response
Age group (years) No. of cycles Good Partial Total (%)
20-30
(p=<0.001)
4 5 1 5
6 52 3 55
8 2 0 2
-- -- -- 62 (8.15)
31-40 4 5 0 5
6 175 5 180
8 11 0 11
-- -- -- 196 (25.78)
41-50
(p=<0.001)
4 7 2 9
6 244 5 249
8 3 0 3
-- -- -- 261 (34.34)
51-60 4 4 0 4
6 91 0 91
8 2 0 2
-- -- -- 97 (12.7)
>60 4 4 0 4
6 133 6 139
8 1 0 1
-- -- -- 144 (18.94)
760 (100)
Table 34: Various chemotherapeutic agents used in breast cancer cases
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Chemotherapy used
Age
group
(years)
Chemotherapy
cycles
Capecitabin
e
FAC TA
C
AC x
T
5-FU/Vinorelbine or
Carboplatin/Gemcitabin
e
Total
(%)
20-30 4 -- 5 -- -- -- 5
6 -- 47 4 -- 5 56
8 -- 2 6 -- -- 8
-- -- 54 10 -- 5 69
31-40 4 1 6 -- -- -- 7
6 1 181 5 2 6 195
8 -- 11 -- -- -- 11
-- 2 198 5 2 6 213
41-50 4 -- 10 1 -- -- 11
6 3 247 4 7 5 266
8 -- 3 -- -- -- 3
-- 3 260 5 7 5 280
51-60 4 -- 3 -- -- -- 3
6 -- 96 -- 3 3 102
8 -- 2 -- -- -- 2
-- -- 101 -- 3 3 107
>60 4 -- 3 -- -- -- 3
6 -- 132 1 3 2 138
8 -- 1 -- -- -- 1
-- -- 136 1 3 2 142
Total 5 749 21 15 21 811
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Table 35: Adverse effects and their treatment due to chemotherapy in breast cancer
patients
S.No Side effects due to
chemotherapy (Frequency n,
%)
Treatment prescribed
1 Anemia/Neutropenia (n=764,
94.20)
Blood transfusion, Filgrastim, Iron complex,
Vit. B 12, Antibiotic
2 Vomiting/ nausea (n=799, 98.52) Metoclopramide, Dimenhydrinate
3 Diarrhea/constipation (n=35,
4.31)
Normal saline/ Ringer’s lactate, Antibiotic,
Loperamide Hydrochloride, Dicotahedral
smectite
4 Alopecia (n=763, 94.08) Sulphur and Zinc containing multi-vitamins
5 Skin/nail discoloration (n=59,
7.27)
Prednisolone and dexamethasone
preparations. Wait and watch
6 Fatigue/anorexia (n=743, 91.61) Rest, balanced diet, multi-vitamins
7 Mucositis/mouth ulcers (n=743,
91.61)
Mouth wash, Nystatin, Fluconazole
8 Fever/chills (n=56, 6.90) Acetaminophen, Ibuprofen
9 Headache/pain (n=57, 7.02) Diclofenac sodium, Mefenamic acid,
Acetaminophen
10 Anxiety (n=41, 5.05) Alprazolam
11 Other toxicities (n=36, 4.43) As per diagnosis
Table 36: Different scales used for assessment of ADRs due to radiation therapy for breast
cancer
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S.No
ADRs
Naranjo’s algorithm
Hartwig’s and
Siegel scale
Schumock and
Thornton scale
DE PR PO DO MI MO SE DP PP NP
1 Skin/ nail hyper-
pigmentation
568 220 -- -- 788 -- -- -- -- √
2 Skin/ nail
erythema/scar/marks
31 33 192 105 99 256 -- -- √ --
3 Fatigue/body aches 299 192 158 110 743 35 -- -- -- √
Where:
DP= definitely preventable, PP= probably preventable, NP= not preventable
MI= mild, MO= moderate, S= severe
DE= definite, PR= probable, P= possible, DO= doubtful
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Table 37: Different scales used for assessment of ADRs due to hormonal therapy for breast
cancer
Naranjo’s algorithm Hartwig’s and
Siegel scale
Schumock and
Thornton
scale
S.No System
involved
ADRs DE PR PO DO MI MO SE DP PP NP
1 Musculo-
skeletal
Arthralgia 20 35 -- 60 44 20 -- -- √ --
Myalgia 60 153 186 -- 190 65 -- -- √ --
2 Vaso-
motor
Night
sweats
-- 93 20 317 131 -- -- -- -- √
Heat
intolerance
-- 169 90 60 186 38 -- -- -- √
Hot flashes -- 131 186 93 224 -- -- -- -- √
3 Genito-
urinary
tract
Vaginal
dryness
38 131 186 38 -- -- -- √ --
4 CVS CV
events*
-- 93 60 186 190 -- 93 -- √ --
Where:
CVS events*= for patients at risk; due to any concomitant disease
DP= definitely preventable, PP= probably preventable, NP= not preventable
MI= mild, MO= moderate, S= severe
DE= definite, PR= probable, P= possible, DO= doubtful
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Table 38: Different scales used for assessment of ADRs due to chemotherapy for breast
cancer
S.No
ADRs
Naranjo’s algorithm
Hartwig’s and
Siegel scale
Schumock and
Thornton scale
DE PR PO DO MI MO SE DP PP NP
1 Anemia/Neutropenia 764 20 -- -- -- -- 764 -- -- √
2 Vomiting/ nausea 779 20 -- -- -- 779 -- √ -- --
3 Diarrhea/constipation -- 35 -- 764 743 35 -- -- √ --
4 Alopecia 763 36 -- -- 21 763 -- -- -- √
5 Skin/nail
discoloration
-- 15 42 742 36 -- -- -- -- √
6 Fatigue/anorexia 56 -- 743 -- 742 36 -- -- -- √
7 Mucositis/mouth
ulcers
15 743 21 -- -- 758 -- -- √ --
8 Fever/chills -- 56 722 -- 742 36 -- -- √ --
9 Headache/pain -- 21 36 742 21 -- -- √ -- --
10 Anxiety -- -- 41 -- 41 -- -- √ -- --
11 Other toxicities 15 21 742 -- 20 36 -- -- √ --
Where:
DP= definitely preventable, PP= probably preventable, NP= not preventable
MI= mild, MO= moderate, S= severe
DE= definite, PR= probable, P= possible, DO= doubtful
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6. DISCUSSIONS
6.1 BREAST CANCER
Breast cancer has been affecting more than a million women annually. It is the most common
cancer of females globally contributing to almost one quarter of all types of female cancers
(Ferley et al., 2010). Several etiological factors have been associated with breast cancer in
various geographical zones (Stewart and Kleihues, 2003); the trends in the occurrence of this
disease differ worldwide and the estimation of its risk factors has become important to have
control over this multi factorial disease. This is observed that not only the occurrence, medical
staging and survival rates of breast cancer cases differ in diverse geographic zones but also
among dissimilar ethnicities within the same geographic area (Merkin et al., 2002, Gorin et al .,
2006, Stead, 2009). There have been reports of greater occurrence but lesser death rates due to
breast cancer from developed countries, whereas overall 45% of cases and 55% of mortality is
found to be happening in the developing countries. Also aggressive cancer with late staging in
comparatively younger people is characteristically found in these developing countries (Igene,
2008) which may be due to variations in economic, genetic and life style features.
Hospital or institution based records are significant basis of data for cancers in the developing
countries because population based cancer registries are not present there including Pakistan.
Most of the existing statistics from these regions are evaluations that are based on records from
small units of inhabitants (Velsecchi and Steliarova-Foucher, 2008). The population based
cancer registry statistics from South Asia indicates that Pakistan has the peak Age Standardized
Rate (ASR) at 69 per 100,000, of breast cancer in this area (Moore et al., 2009). Some studies
from Pakistan have steadily revealed breast cancer to be the most common female cancer (Aziz
et al .,2003, Bhurgri et al., 2006, Jamal et al., 2006, Hanif et al., 2009). It has been reported that
most of the cancer patients live in developing countries where means to combat this ailment are
inadequate (Parkin DM et al., 1993). Monetary constraints, overall illiteracy, paucity, insufficient
sanitary environments and pollution, shortage of well-resourced oncology institutes, skilled and
proficient health experts and deficiency of continuous government efforts and common people,
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all have produced an enormously alarming condition. Public edification and better cognizance
have given rise to timely recognition of this disease in the United States, and hence substantial
therapeutic developments have been made improving survival rates (Harris J et al 1993).
This thesis presents research on the risk factors and pharmacotherapy of breast cancer in the
local population of Karachi. As mentioned earlier, this thesis is a descriptive study for which
data was collected via interviews and patients’ medical records. A printed questionnaire form
was used for taking the interviews of both case and control groups after taking their consent to
participate in the study. The subjects were confirmed for keeping the confidentiality and the
cases were assured of not having any consequences on ensuing medical care due to the
information they gave. Due to low literacy rate, social stigma and keeping in view the condition
of the patients, it was very difficult to fully enquire and assess responses for various questions
especially historical assessments like information about contraceptive use or any other procedure
adopted for birth control in the past; detailed habits about breast feeding; economic conditions
etc. Although the patients were repeatedly assured and explained by the researcher and the
attending doctors that their medical treatment would not be altered by providing the enquired
information but still some patients were very shy or reluctant to respond and some had a strong
perception that treatment could be refused if they respond to such questions. It is also important
to note that there is a substantial trend in Pakistan on part of the family to ‘shield’ the patient and
not disclose the finding of any life threatening disease. They feel that cognizance of diagnosis
will badly affect mental and physical well being of the patient. In these situations, patients define
their cancers as tumor, infection, germs, etc; the doctors every so often go along with the wish of
the families which creates communication breach between the patients and the doctors and
hence, proper knowledge and discussions regarding the disease between them could not be done
which ultimately affects the condition of the patients (El Ghazali S 1997, Solanke 1997, Burn G
1997). Some of the females in control group were also difficult to enquire and they felt as if they
were being accused of hiding the disease or were being put at risk by making them aware about
different aspects of breast cancer while interviewing them.
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6.2 RISK FACTORS OF BREAST CANCER
All cases had a diagnosis of breast cancer prior to enrollment in the study and the controls
signified a heterogeneous group of women from Karachi city which were not having breast
cancer. It has been previously mentioned that the range of age of controls and cases was 20-80
years for overall 1154 controls and 811 cases.
6.2.1 DESCRIPTIVE STUDIES:
The statistics and frequencies for various breast cancer risk factors across case and control
groups are illustrated in Tables 7-10.
The controls and cases were frequency matched based on age (Fig. 6) in this study so age is
considered as a confounder and is included in the regression models for analysis. The mean age
of control group was 45.85±9.97 years and that of breast cancer cases was 47.02±11.79 years.
Similar age group of breast cancer patients has been reported in two other studies from Pakistan
(Malik 2002, Khokher et al 2012). Two largest age blocks comprised of 41-50 years (41%
controls and 34.7% cases) and 31-40 years (26% controls and 25.7% cases) respectively. The
smallest block comprised of 20-30 years with 7.7% controls and 8.1% cases (Table 7). Few of
the subjects were working women by profession in this study and majority was housewives and
married (Fig. 7). Consanguineous marriages are communal in Pakistan (Bittles et al 1993, Wahab
and Ahmed, 1996) and can be seen from our study that almost 50% of cases had interfamily
marriage which is significantly different from that of controls. Consanguineous marriages in
Pakistan have been reported previously to be more common in illiterate or low level education
females or whose parents were also married within their families (Hussain and Bittles, 1998).
Educational level is generally regarded as the solidest distinct interpreter of SES and it also
associates very deeply with complete measures of SES (Owens, 2010, Croll et al 2008). In a
study conducted by Hulka et al (2001), education was considered as a proxy for SES of the
subjects and in this study also it has been used as a proxy measure of SES in this study. A
significant variance (p<0.001) between the controls and the cases in relation to the distribution of
education levels was identified (Table 7). No significant difference in the BMI was observed
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between the controls and cases and majority subjects had a normal BMI (18.5-25 kg/m2). BMI is
considered as an established risk factor of breast cancer.
Table 8 shows the life style characteristics of the controls and cases with significant differences
among the two groups. Habits like smoking and others were found to be very less in both the
groups but eating of betel leaves was more in the controls (9.8%) than the cases (6%). 58% cases
were habitual of drinking milk on regular basis as compared to controls (30%) and fresh milk
was consumed more (49.19%) than milk supplied in packs (8.87%) by the case group. The
controls were found to be habitual of taking tea more (92.3%) than the cases (88.4%). Regarding
the diet, meat intake was found more in the control group (20%) than the case group (9.1%) who
took both vegetarian and meat diet with more frequency (36.6%) than the control group (25.2%).
The menarche age and age at first child birth are established risk factors of breast cancer. The
mean age of menarche of control group was 13.53±1.01 years and that of cases was 13.33±0.87
years. Significant difference was observed for the age of menarche between controls and cases
when categorized in different age groups as shown in Table 9. 71.6% controls had menarche at
13-14 years whereas 83.1% cases had menarche in this age; 15.4% controls had age of menarche
at age >14 years and only 8.6% cases experienced menarche in this age. Majority subjects had
regular menstruation. Mean age at first child birth (full term birth) was 21.98±3.95 years for
controls and 22.13±4.07 years for cases. Statistically significant differences were found in the
different categories of age for first child birth among the study subjects (Table 9). Regarding
parity, a significant (<0.001) difference was observed among the study subjects (Table 9).
Almost 35% of control group and around 23% cases had 4-5 children whereas multi-parity i.e. >
5 children, was seen in cases (22%) more than that in controls (12.2%). Though most of the
study subjects did not use contraceptives but its use was found significantly more in control
group (24.4%) than in the cases (5.3%). Breast feeding was a common trend among all the
subjects and significantly more in controls (87.8%) than cases (84.1%). There were more than
60% cases who experienced menopause which was statistically significant (<0.001) as compared
with the controls (Table 9). Menopausal status has been used as a third variable in this study to
observe effect modification in the population under study. The third variable is considered to be
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an “effect modifier” when the association between an exposure and an outcome in the core
population varies over diverse levels of a third variable (Rosner B 2006).
Disease information about the study participants is illustrated in Table 10 from which it can be
seen that only few cases had a family history of breast cancer (15.65%) and none was found in
the control group which is a statistically significant difference among the study subjects.
Moreover, the family history was related more to sisters, first cousins and other paternal relatives
of the cases.
Concomitant diseases found in the cases and controls were mainly hypertension (16.4% and
16.6% respectively) and multiple diseases (10% and 10.4% respectively). Diabetes mellitus and
hypertension have appeared as chief health concerns internationally. Approximately 285 million
people suffering from diabetes globally were reported in 2010 representing a frequency of
6.4% (Sicree et al, 2003). WHO has reported that the occurrence of DM in grown-ups globally is
expected to increase to 5.4% i.e up to 300 million by the year 2025 (King et al.,
1998). Furthermore, HTN affects about one billion people worldwide and by 2025,
approximately up to 1.56 billion grown-ups will be hypertensive universally (Chobanian, et al.,
2003, Kearney, et al., 2005). DM and HTN are also identified to co-occur in approximately 40%
to 60% patients with type 2 DM (Lago, et al, 2007, Sowers, et al., 2001, Arauz-Pacheco, et al.,
2002). The subjects were also enquired about disease information in their parents as well and it
was found that the parents of 15% cases and 5% controls were suffering from hypertension; any
other type of cancer except breast cancer was identified in the parents of 1.3% controls and 0.4%
cases. It was necessary to enquire about the disease history of parents as well so as to have
knowledge of the hereditary patterns of certain diseases.
6.2.2 BINARY LOGISTIC REGRESSION ANALYSES:
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A series of logistic regression analyses for various risk factors of breast cancer is illustrated in
Tables 11-18.
The initial results of this study (Table 11) showed that interfamily marriage was significantly
associated with breast cancer risk (OR 1.94; 95% C.I= 1.60, 2.34). The association was
consistently shown in the bivariate and multivariate analysis (Tables 14 and 18) revealing that
the odds increased in bivariate analysis adjusted for age (OR 2.06; 95% C.I= 1.69, 2.50) and then
somewhat decreased when adjusted for both age and education (OR 1.82; 95% C.I=1.48, 2.23)
whereas in multivariate analysis adjusted for education, it increased again (OR 2.14; 95%
C.I=1.64, 2.79). There are variations globally for the occurrence of breast cancer in developed
and developing states due to variations in environmental and genetic aspects. It has been
observed that occurrence of breast cancer decreased with an increase in consanguineous
marriages. The rich Gulf States have an extraordinary standard of living, similar to that in
developed countries and a low incidence of breast cancer. In these states, incidence of breast
cancer is reported to be the lowest (between 16 and 32 per 100,000 woman-years) although
matrimony between relatives is very much common (Denic and Bener, 2001, Anonymous,
2000). A low incidence of breast cancer and antiquity of consanguinity is also linked with a
developed country like Japan (Imaizumi, 1996.). In Pakistan, the probable reasons for its high
breast cancer occurrence in spite of much of consanguineous matrimonies could be a diminutive
account of consanguinity and gene implications. The information about social and population
immigration accounts may expand data elucidation. Nevertheless, consanguinity should be
considered as a likely risk factor for breast cancer which may also explain universal
dissimilarities in breast cancer incidence (Denic and Al-Gazali, 2002).
House wives by profession were found to have significant odds of 1.73 (95% C.I= 1.19, 2.50) in
uni-variate analysis (Table 11) in this study which declined in the adjusted bivariate analysis
(Table 14) and became insignificant; it was not further analyzed in multivariate adjusted model.
In a recent study also, the incidence of breast cancer was found to be common in the housewives
(Pranjic and Gledo, 1857). Although the women at home are engaged in household chores but
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working women are more physically active. It has been reported that women who are not
habitual of physical activities have a prognosticator of increasing breast cancer (Group, 2003,
Bergstrom, et al., 2001). Though variations are found regarding the physical activities to be
‘protector’ of breast cancer but some studies have found them to decrease about 30-40% risk for
breast cancer (Sprague, et al., 2007, Berglund, 2002, Vainio et al., 2002, Cantor, et al., 1995).
This is of prime importance that several toxic pesticides and herbicides are being sold in the
developing countries like Pakistan that are carcinogenic, found existing not only in the water
supplies but also in the air and dust in homes. Pakistani media has been bursting advertisements
regarding farmers using cheap pesticides to enhance crop productivity that unfortunately remains
in the harvests even after washing and cooking. Such environmental carcinogens are
xenoestrogens which act like estrogens when in contact with breast cancer cell lines (Zava et al.,
1997, Dees et al., 1997, Steinmetz et al., 1996). The most significant xenoestrogens which are
used in plastics are bisphenol-A and polyvinyl chloride, pesticides and insecticides include
DDTs, PCBs, parabens and placental extracts in the makeups (Gray et al, 2006). Two other
studies have also confirmed that the development of ER+ breast tumors augmented due to DDT
(Robison et al., 1985, Scribner and Mottet, 1981). Thus, xenoestrogens might be causative of
breast cancer significantly, especially ER+ breast cancer.
Regarding the education levels of the subjects of this study, significantly high odds were
observed (Table 11) in uni-variate analysis that were consistent in the age adjusted bivariate
model for the cases with low education level (Table 14). Factors like ignorance, patient and
treatment arrangements delays and non-accessibility to health care system are attributing to
higher breast cancer incidence. In contrast, higher level of education was found to be associated
with more risk of breast cancer in previous studies which might be related to variation in their
life style i.e. use of hormonal therapy, use of contraceptives, etc. (Heck and Pamuk, 1997,
Braaten et al., 2004). As mentioned earlier, education level was used as a proxy for SES in this
study and a potential confounder so it was used further for adjustment in models.
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The normal range for BMI is 18.50 to 24.99 kg/m2 (WHO, 2004) and the majority of the
subjects enrolled in this study were found having normal BMI. BMI was not found to be
associated with breast cancer risk in the univariate analysis (Table 11) though the results showed
strengthened odds for adjusted bivariate (Table 14) and multivariate (Table 17,18) models for
BMI < 18.5 kg/m2 but insignificant statistically. This may be due to the inclusion of covariates in
these models. Studies have shown that higher BMI is linked to higher breast cancer risk
especially in post menopausal females and it has been also found related to hyperinsulinemia and
insulin resistance which result in increasing the risk of developing breast cancer (Kuhl, 2005, Cui
et al., 2002, Cold et al., 1988).
In this study, hypertension and diabetes mellitus showed significant association (OR 2.27; 95%
C.I=1.54, 3.36) with breast cancer risk in the uni-variate model (Table 11) but it was inconsistent
in the bivariate adjusted models (Table 14). The relationship between diabetes and breast cancer
risk has been studied previously (Wolf et al, 2005, Larsson et al, 2007, Liao et al, 2011).
Hyperinsulinaemia, an indicator of insulin resistance in obesity and type 2 DM, has been
supported as possible cause in attaining breast cancer (Plymate et al., 1990, Rosner,
1990, Singh et al, 1990, Kaaks, 1996). Moreover, obesity itself is related to type 2 DM which
elevates endogenous oestrogen levels in the body. Insulin prevents the making of sex hormone-
binding globulin, resulting in elevated free steroid hormones, especially free oestrogens
(Barker et al, 1964; Van der Burg et al, 1988; Conover et al, 1992). Hyperinsulinaemia may also
have combined effects with the insulin growth factor I that could elaborate breast cancer-causing
progressions (Novosyadlyy et al, 2010). Insulin is also documented as a growth- supporting
hormone in-vitro with mitogenic effects in both normal and malignant breast tissues (Lippman
and Bolan, 1975, Cannata et al, 2010). It is also reported that chronic hyperglycaemia might rise
the breast cancer risk through Warburg effect, in which cancerous cells principally yield energy
by a high level of glycolysis in the cytosol (WARBURG and Dickens, 1931, Brown and
Simpson, 2010). On the contrary, no decline in the risk of breast cancer was seen in randomised
trials with much more glycaemic control of type 2 DM (Johnson and Bowker, 2011). In a meta-
analysis, association of DM with breast cancer risk was supported with a statistically significant
23% greater risk especially in postmenopausal women. The association was the most noticeable
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in Europe followed by America but the result was not significant in Asia (Liao S et al., 2011).
Evidently, hypertension without diabetes has been reported to escalate the risk of breast cancer
considerably which might be due to the genetic mutations in lymphocytes in hypertensive
females (Nordén, et al., 1975); this has also been observed in the hypertensive rats having an
atypical cell cycle (Hamet, 1997). Hyperinsulinemia is described as a risk factor for both
diabetes and hypertension since hypertension is associated with insulin resistance (Kaaks, 1996,
Soler et al, 1999). The link between breast cancer and hypertension has been reported in several
studies (Largent et al, 2006, Soler et al., 1999, Land et al., 1994) whereas some were
unsuccessful to catch any relationship (Peeters et al., 2000, Manjer et al., 2001, Lindgren et al
2005).
Former studies have shown relationship of various reproductive and life style features with
breast cancer (Kelsey et al., 1993, Bernstein, 2002, Wang et al., 2008). Regarding the life style
characteristics, uni-variate analysis (Table 12) revealed that regular consumption of milk whether
fresh or pack, was significantly associated with breast cancer risk (OR 3.22; 95% C.I=2.67, 3.89)
which consistently increased in the adjusted bivariate and multivariate models (Tables 15 and 18
respectively). Our findings are in support with the investigation in which breast cancer has been
found related to dairy goods like milk and cheese due to existing fats, growth factors like insulin
growth factor I and manifestation of certain pesticides having oncogenic prospective (Moorman
PG and Terry PD, 2004). Organochlorines are the substances that are used as pesticides and also
in industrial products. DDE, which is a metabolite of DDT, and PCB are the commonly found
organochlorine residues in human tissues (Coyle, 2004). Other life style characteristics showed
negative associations with breast cancer risk in all the binary logistic regression models. Bao et
al (2012) also reported a converse relation of vegetable and fruit intake with breast cancer risk
but a positive relation of increased meat consumption with breast cancer.
The risk factors like early menarche, nulliparity, increased age at first child birth, late menopause
and hormonal factors have been established potentially to be related to breast cancer. Factors like
obesity, diet, alcohol intake and inactive life style have been reported to be mediated via
hormonal pathway and contributed to the development of breast cancer in females (Chan, 2000,
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International, 1997). In this research, age at menarche (13-14 years) was associated significantly
with risk of breast cancer (Table 13) in uni-variate analysis (OR 1.83; 95% C.I=1.34, 2.48)
which was consistent in the adjusted bivariate models (Table 16). In multivariate analysis (Table
18), it showed negative association and instead odds of age at menarche (>14 years) showed
significant association with breast cancer risk (OR 1.70; 95% C.I=1.09, 2.66). Table 13 showed
increasing odds for postmenopausal women (OR 2.87; 95% C.I=2.38, 3.45) in relation to breast
cancer risk and the trend was consistently shown towards higher side in the adjusted bivariate
models (Table 16). It has been reported that menstruation at the age <12 years was associated
with the risk of breast cancer as compared to those who had after 15 years of age and those who
experienced menopause at or after 55 years of age were also positively at risk for attaining breast
cancer as compared to those who became menopausal at the age <45 years (Brinton et al., 1988).
This may be due to a modest role of the number of ovulatory menstrual cycles that a woman goes
through in her lifetime (Vogel, 1998). Another study showed a 9% lesser breast cancer risk in
premenopausal women for each year menarche was deferred and a 4% lesser risk in
postmenopausal women; a 3% rise in breast cancer risk was observed for each year menopause
was postponed (Group, 2002).
Parity has been considered as self determining for breast cancer risk and several features are
correlated to parity, such as age at first birth, breastfeeding, etc. (Parsa and Parsa, 2009). Parity
in the females was found to be negatively associated with breast cancer risk in this research.
Neither the uni-variate analyses (Table 13) nor did the bivariate analyses (Tables 16) showed a
connection between parity and breast cancer risk though it was found in a research that every
added childbirth convenes an almost 7% decline for breast cancer risk (Group, 2002) but it is still
debatable whether this influence is steady all over life regardless of hormonal status, or is related
to pre- or postmenopausal women (Clavel-Chapelon, 2002). In another study, high parity was
found to be negatively linked with breast cancer mortality in adult females (Phipps et al., 2011).
This reduced risk of breast cancer was ascribed to the diminished oscillation of endogenous
hormones during pregnancy against the nulliparity (Jerry et al., 2010, Ursin et al., 2005). In a
recent study, parity was detected with an interim greater risk for breast cancer after giving birth
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but a longstanding diminished risk (Albrektsen et al., 2005, Liu et al., 2002). Age at first
childbirth has been shown to be an individual risk factor of breast cancer risk (Group, 2002).
Age at first child birth was not found to be related to breast cancer risk in the study participants.
This was consistently true for all the binary logistic regression analyses models (Table 13, 16,
17). It has been mentioned earlier that several features are interrelated to parity, such as age at
first birth, breastfeeding, etc. (Parsa and Parsa, 2009). Hinkula et al (2001) detected a doubled up
threat for women deferring their first delivery from 20 to 30 years of age. Similarly, negative
association was found regarding the use of contraceptives in uni- and bi-variate models (Tables
13 and 16) and was not further analyzed in the multivariate model.
The uni-variate analysis in this study (Table 13) showed significant association of breast cancer
risk with those participants who never breast fed their children (OR 1.35; 95% C.I=1.04, 1.75).
The odds showed significant increase in the adjusted bivariate analyses (Table 16) and though
were consistent in multivariate analysis but became insignificant (Table 18). It has been
documented that ever having breast fed and/ or extended periods of breast feeding are related to
decrease in breast cancer risk (Shantakumar et al., 2007, Lee et al., 2003, Group 2002).
Similarly, Kuru et al (2002) reported that there was a significant association in Turkish women
with breast feeding and decreased risk of breast cancer.
Regarding the family history of breast cancer in the participants, infinite odds were found in all
the binary logistic regression analyses and hence they are not mentioned in the tables; this has
been confirmed through various studies that there is a connection between family history and
breast cancer risk (Pankratz et al., 2008, Gail et al., 2007, Tyrer, 2004, Amir et al., 2003,
McTiernan, 2001) which may be due to the interaction between genetic and environmental
aspects. The inherited effects on breast cancer can be “polygenic”, making it challenging to
identify a precise inheritance array for different types of breast cancer. Although BrCA1 and
BrCA2 are the well-known breast cancer risk genes but they are found to be causative of less
than 20% of familial breast cancers (Malone, et al., 2006, Offit, 2006).
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In conclusion, the established risk factors of breast cancer i.e. age, BMI and age at first birth
were not found to be associated with risk of breast cancer in this study through binary logistic
regression analyses except for age at menarche. The frequency matching of the age of study
subjects did not permit evaluation of the effect of age on the risk of breast cancer. Further, this
thesis study did not support a relationship between breast cancer risk and various life style
characteristics except for the regular consumption of milk.
6.2.3 MULTINOMIAL LOGISTIC REGRESSION ANALYSES:
Multinomial regression analyses were also performed to further assess the risk of breast cancer
by hormone receptor status, breast cancer stage and menopausal stratification among the study
subjects (Tables 19-21).
ER, PR and HER2/ neu are the 3 tumor indicators which are widely used to detect and categorize
breast cancer and then conclude its treatment (Albrektsen et al., 2010). These tumor indicators
have been also used to study and assess the risk factors and the perseverance of breast cancer
(Bernstein and Lacey, 2011). In order to calculate the tumor markers in women with breast
cancer precisely, it has been suggested to see the effect of various characteristics like SES, life
style and reproductive aspects in the females (Bernstein and Lacey, 2011, McGarvey et al., 2011,
Burris and Andrykowski, 2010). ER positive tumors are classified as Luminal A and B while
HER2-overexpressing tumors are hormone receptor-negative HER2 (i.e., ER−/PR−/HER2+).
Triple negative tumors are basal-like (70%) or uncategorized tumors (Bidard et al., 2007). For
the purpose of multinomial regression analysis, the hormone receptor status for estrogen,
progesterone and HER2/neu were measured in four different combinations as shown in the Table
19. There were 165 ER and/or PR+H– (luminal A) cases, 118 ER and/or PR+H+ cases (luminal
B), 60 ER-PR-H+ (HER2 overexpressing) cases and 166 ER-PR-H- (triple negative) cases that
were used in this multinomial analysis. The control group (n=1154) was used as the baseline in
this analysis. Variations were seen in the associations of various risk factors and breast cancer
risk by hormone receptor status among the participants. It was observed that though odds of BMI
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<18.5 kg/m2 were seen high in luminal B and overexpressing cancer subtypes but no statistical
significance was seen; for BMI >25 kg/m2, insignificant odds were observed for triple negative
breast cancer only. This may be due to small numbers of subjects present in these strata as
majority respondents of this study had a normal BMI. Unlike the results of this study, previous
studies have reported significant associations between BMI and risk of breast cancer especially
in ER positive breast cancer (Colditz et al., 2004, Enger et al., 2000). Conversely, it has been
documented that non-hormonal aspects like cytokine levels and genetic elements may also add to
risk of luminal, HER2-overexpressing, or triple-negative tumors (Newcomb et al., 1995,
Hankinson et al., 1998, Stoll, 2002). The odds for interfamily marriage were seen associated with
breast cancer risk in all hormone receptor sub groups except for over expressing sub group for
which it was found insignificant statistically. As mentioned earlier, this may be due to variations
in environmental and genetic aspects. Regarding life style characteristics, negative association
with breast cancer risk was found with all the subgroups except for regular consumption of milk
for which the odds were found higher consistently in all the 4 sub groups. This has been
attributed due to existing fats, growth factors like insulin growth factor I and presence of
insecticides/ pesticides having oncogenic potential (Moorman and Terry, 2004). Family history
of breast cancer among the participants was consistently showing infinite odds relating to breast
cancer risk significantly in this study. In two other studies also , family history was related to 2
fold augmented risk of breast cancer in all sub types of breast cancer except for mucinous tumors
and 2 to 3 fold risk was found related to increased breast cancer risk in all the subtypes except
for tubular cancers respectively (Li et al., 2006, Stalsberg H, 1989).
The results of multinomial regression analysis by cancer stage are illustrated in Table 20. The
odds of BMI <18.5 kg/m2 were found significantly associated with breast cancer risk for stage III
and IV whereas BMI >25 kg/m2 was found protective significantly for stages I and III.
Interfamily marriage was found to be significantly associated with breast cancer risk in stage I, II
and III whereas it became insignificant for stage IV. Significant increased risk only for stage IV
breast cancer due to eating betel nuts was observed in this analysis whereas tea consumption was
negatively associated for all breast cancer stages. Significantly increased risk of breast cancer in
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all stages was observed for those having regular consumption of milk whereas diet appeared to
be protective of breast cancer risk.
There are indications that etiology and risk factors of breast cancer may differ among pre- and
post-menopausal women (Barlow et al 2006, Chen et al 2006). Hence, this approach has been
used in various studies so as to determine any significant association of an exposure and an
outcome based on pre- and post- menopausal divisions. In the analysis using stratified
menopausal status (1019 pre-menopausal and 947 post-menopausal subjects), adjusted
multivariate logistic regression model was run once for each stratum and is illustrated in Table
21. By profession, housewives in post menopausal stage were at more risk for breast cancer than
in premenopausal stage (OR 2.43: 95% C.I=1.53, 3.86) which has already been defined due to
sedentary lifestyle and genetic predispositions. Habit of eating betel nuts was found to be
significantly associated with breast cancer risk in post-menopausal group (OR 2.06: 95%
C.I=1.40, 3.02). Similarly, consumption of milk (OR 1.96: 95% C.I=1.59, 2.42) and eating meat
in diet (OR 1.97: 95% C.I=1.41, 2.75) were found associated with breast cancer risk in post-
menopausal women only. Cho et al (2006) reported that red meat consumption was positively
associated with ER and PR positive pre-menopausal breast cancer risk. This may be due to
highly bioavailable iron in red meat and free iron is related to oxidative damage of DNA and
lipid peroxidation (Kabat et al., 2007). It was also suggested that meat prepared at a high
temperature may have carcinogens for breast cancer like heterocyclic amines and polycyclic
aromatic hydrocarbons (Knize et al., 1999, Balogh et al., 2000). Moreover, exogenous hormones
given to animals or hormones used in meat dispensation could be delivered on to meat eaters
(Linos and Willett, 2009, Zhong et al., 2010). The use of vegetable diet showed association with
breast cancer risk in pre-menopausal women only (OR 1.33: 95% C.I=1.06, 1.67) and was found
protected for post menopausal women. There is a possibility that variation or inadequacy of
modification for probable confounders may partly add to the debatable role of diet in breast
cancer risk. Upon stratification, it was found that the use of contraceptives was positively
associated with breast cancer risk in pre-menopausal women (OR 2.19: 95% C.I=1.64, 2.94).
Kahlenborn C et al (2006) also found that the use of oral contraceptives was significantly
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associated with breast cancer risk in premenopausal females particularly when used before first
full term pregnancy. BMI showed increased odds in premenopausal women only but did not
reach statistical significance; on the other hand, in various studies conducted for analysis by
menopausal stratification, it was found that BMI was related to post menopausal females as a
risk for breast cancer (Yoo et al., 2001, Friedenreich, 2001, Petrelli et al, 2002, Vainio and
Bianchini, 2002).
6.3 BREAST CANCER CASES OF THE STUDY:
Breast malignancy is the most commonly diagnosed cancer and the foremost reason of mortality
in females, contributing for 23% of overall new cancer cases and 14% of overall cancer demises
in 2008 universally (Jemal et al., 2011). It is a diverse ailment, with etiologically discrete tumors
due to the variance in relationship with different risk elements that require continual
epidemiological investigations to assess the varying role of histology (Kotsopoulos et al., 2010).
It was stated that there is a chance of 1 in 8 for a woman to get invasive breast cancer in her life
and that of dying from the disease is approximately 1 in 35 (Ries et al., 2008, Parkin et al.,
2002). McPherson et al (2000) found that among women aged 50 years, 2 of every 1000 women
would be diagnosed of breast cancer and before 50 years of age, almost 15 would be diagnosed
of the disease contributing to 2% breast cancer incidence. In this research, 811 cases of breast
cancer were identified in whom majority of were diagnosed of and registered for breast cancer in
the hospital in the years 2010 and 2011 (Figures 8, 9). It should be noted that extended diagnosis
of breast cancer leads to more destructive and invasive type of the disease with deleterious vital
status (Huang et al., 2009). It was found that (Figure 10) most of the patients had breast cancer
stage I (48.3%) and II (33.3%) and the cancer of left breast (Figure 11) was more prevalent
(52.5%) among the cases. Breast cancer was more common among the cases (Table 23) in the
age groups of 41-50 years (n=282, 34.77%) and 31-40 years (n=209, 25.77%). Autier et al
(2010) reported that breast cancer was rare in females younger than 20 years and among those of
80 years of age, with only 0.8% breast cancer attained in females younger than 30 years of age
and 6.5% occurring in the age range of 30 to 40 years. The cancer of both breasts was rarely
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found and was more associated with cancer stage I (Table 24). Breast cancer metastasis was
found in n=101 cases only (Figure 12) mainly with metastasis of bone (38.46%) and lung
(33.33%). Arranging from most to least often found, the common distant metastatic sites for
breast cancer have been reported to be bone, lung, pleura, soft tissues, and liver (Borst and
Ingold, 1993).
Breast cancer tumors are classified by stage and grade to categorize the physiognomies of these
malignant cells (Young et al., 2001). Breast cancer risk is usually estimated by the ER and PR
status of the tumors because of variations in the prevalence rates and the associated risk factors
(Colditz et al., 2004). Clemons and Goss (2001) documented that breast cancer is unlike other
tumors as it depends on female sex hormones for expansion and progression. Estrogen and
progesterone bind to their specific nuclear receptors and control the growth/ differentiation of the
breast tissues (Habel and Stanford, 1993, Pike et al., 1993). During adolescence, ductal
development is swift under the influence of these 2 female sex hormones (Howard and
Gusterson, 2000). Full development of mammary epithelial cells occurs during the latter half of
the menstrual cycle, because of the augmented progesterone levels in the luteal stage (Ferguson
and Anderson, 1981, Longacre and Bartow, 1986). On the contrary, this may also be due to late
effect of estrogen during the follicular stage of the menstrual cycle (Dahmoush et al., 1994,
Clarke, 2004). Estrogen has also been evidently concerned as a cancer-causing agent in breast
malignancy due to its growth stimulatory effects (NTP, 2004) whereas progesterone has been
implicated as defending against breast cancer as it causes differentiation and maturation of the
epithelial cells. It was reported that progesterone levels chiefly rise in pregnancy in the third
trimester when breast cells undergo maximum differentiation in preparation for lactation (Russo
and Russo, 2004, Russo and Russo, 1995). Apart from ER and PR, the Human epidermal
receptor2 (Her2/neu) receptor also identified as the Epidermal growth factor receptor family-2
(EGRF-2) is an oncogene that belongs to the epidermal growth factor receptor family (Cordera
and Jordan, 2006, Ciocca et al., 2006, Robert and Favret, 2007). In the normal breast, its
expression is small or lacking but is overexpressed in 20-25% of all breast tumors with extreme
in those tumors in which there is dearth of expression of hormone receptors (Robert and Favret,
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2007). Her2/neu is also expressed in advanced and severe phases of breast cancer with loss of
ER control, demonstrating a very poor prognosis (Cordera and Jordan, 2006, Robert and Favret,
2007).
It is important to know the status of hormone receptors and HER2/ neu overexpression because
they are used as both predictive and prognostic indicators in breast cancer (Cianfrocca and
Goldsteindoi, 2004). Among n=811 breast cancer cases in this study, mostly were ER+ve, PR-ve
and HER 2 Neu –ve (Figures 13, 14, 15). From the joint receptor status for ER and PR, it was
found that n=249 (35.07%) cases were ER+PR+, n=120 (16.9%) were ER+PR-, n=36 (5.07%)
were ER-PR+ and ER-PR- were n=305 (42.95%). Data for joint ER and PR receptor status was
missing for n=101 (12.45%) patients. The ER status in various age groups of breast cancer cases
(Table 25) showed significant association (p=<0.05). Diverse outlines for ER+ and ER- cancers
with variable clinical pictures and outcomes have been found in epidemiological investigations
(Chen and Colditz, 2007); reproductive aspects that escalate a woman’s lifespan introduction to
endogenous estrogens are accountable for ER+ breast cancer (Huang et al., 2000, Althuis et al.,
2004) and risk factors like radiation, smoking and genetic risks contribute to ER- breast cancers
(Huang et al., 2000, Manjer et al., 2001). The xenoestrogens , having estrogenic effects (Robison
et al., 1985, Dewailly et al., 1994, Woolcott et al., 2001), as risk factor for breast cancer may
contribute in growing ER+ breast cancer in metropolises because the women in urban areas use
more cosmetics, plastics, domestic pesticides, detergents, etc. They are also more visible to
vehicular and industrial air pollution, which contain PAHs (Gusten et al., 1994). Moreover, the
foodstuffs (both vegetarian and non-vegetarian) which reach in cities are more processed or have
greater amounts of additives such as pesticides (Barakat, 2004).
It has been suggested that the ER status of breast cancer is also associated to the era in women’s
life when they are visible to numerous risk factors. The breast stem cells are also considered as
the basis of breast cancer (Reya et al., 2001, Marx, 2003, Singh et al., 2003, Al-Hajj M , 2003). It
is known that there are 3 acute phases in the development of mammary glands: the intrauterine
phase particularly just before delivery, the peripubertal phase and the phase of gravidity and
lactation (Fenton, 2006). Investigation into mammary stem cells established that during the
intrauterine period all progenitor stem cells are ER- which differentiates into ER+ cells post -
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natally, later forming mammary glands in puberty, under estrogen effects (Bartow, 1998, Keeling
et al., 2000). Though it is recognized that genetic and non-estrogenic factors are the reason for
ER- breast cancer (Huang et al., 2000) but it may be likely that exposure during intrauterine
phase or near to delivery upset the predominantly ER- progenitor stem cells leading to ER-
breast cancer. However, it is known that progenitor stem cells are quite resilient to mutations and
ER- breast cancer might be greater than in unexposed people but still lesser than ER+ breast
cancer within the similar exposed people. ER+ breast cancer must be greater in exposed people
because ER+ stem cells are more frequent and less resistant to mutations in older ages (Dontu et
al., 2004). Hence, this also enlightens the greater incidence of breast cancer in exposed post
menopausal women. Exposure to xenoestrogens in initial lifetime is quite probable as there are
evidences which showed excretion of xenoestrogens in human milk (LaKind et al., 2001,
Solomon and Weiss, 2002, LaKind et al., 2004); women are exposed to greater xenoestrogens
levels in cities from fetal period due to which the possibility of ER- breast cancer in life later
might be increased. Later in life progenitor stem cells differentiate into numerous intermediate
ER+ stem cells that are less resistant to mutations (Dontu et al., 2004). The expression of PR has
been described under close regulation of ER expression (Mendelson and Hardy, 2006, Ciocca et
al., 2006) but it should be noted that not all ER+ tumors express PR, thus decreasing PR+
occurrence than ER+ cancer occurrence.
Many researches have shown a great percentage (66%) of ER+/PR+ tumors followed by (19%)
ER-/PR- whereas only (~2-3%) tumors are ER-/PR+ (Cordera and Jordan, 2006). This finding is
close to the results of this study showing (35.07%) cases were ER+PR+, (42.95%) were ER-PR-,
(16.9%) were ER+PR- and (5.07%) were ER-PR+. Progesterone receptor-negative tumors are
reported to be of very aggressive subtype and considered having a meager prognosis (Lari and
Kuerer, 2011, Phipps et al., 2011). It has been found that breast cancer in premenopausal women
is related with more belligerent tumor subtypes, bigger tumor sizes, greater lymphatic
association, and augmented recurrence as compared to that in postmenopausal women (Conroy
et al., 2011).
From the available data of this study, the joint receptor status for ER, PR and HER 2/neu showed
that there were n=165 (39.4%) ER and/ or PR+ H- cases, n=118 (25.70%) ER and / or PR + H+
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cases, n= 60 (13.70%) ER-PR-H+ cases and n=166 (36.16%) ER-PR-H- cases (Fig. 16). The
hormone receptor status in various breast cancer stages showed significant association (p<0.001)
with the disease (Table 26). HER 2/neu is reported to be overexpressed in about 30% of breast
tumors (Slamon et al., 1987) and is linked with amplified tumor aggressiveness, greater relapse
rates, and increased deaths in node-positive patients, whereas the effect in node-negative patients
is further variable (Borg et al., 1990, Paterson et al., 1991, Clark and McGuire, 1991). Analysis
of several HER 2/neu studies is restricted by inconsistency in the means of detection of its
overexpression and characterization of its positivity and hence its use in selection of adjuvant
therapy (Cianfrocca and Goldsteindoi, 2004).
6.4 BREAST CANCER TREATMENT MODALITIES AND THEIR EFFECTS:
Breast cancer is an extremely varied illness rather than solitary ailment (Polyak, 2007)
comprising of a number of indicators (Qadir and Malik, 2007) that are related to characteristic
features of tissues, therapeutic assessment and reaction to management (Weigelt et al., 2010).
Progresses in the diagnosis and management of breast cancer have been observed, accompanying
decline in frequency of mortality, but it differs extensively between different geographic zones
(Sant et al., 2006, Autier et al., 2010). The aim of therapy for early and locally advanced breast
cancer is cure whereas for metastasis, it is to improve signs and symptoms, quality of life and
extend life of the patients. The management of breast cancer is also related with considerable
toxicities which vary according to different agents, administration mode, and combination
treatment. Breast cancer is managed by different methodologies such as surgical excision,
radiation therapy, endocrine therapy and chemotherapy (Lukaszewicz et al., 2010).
6.4.1 LOCAL THERAPY (SURGERY AND RADIATION) USED IN BREAST CANCER
PATIENTS:
In this study it was found that out of n=811 breast cancer patients, mostly (n=776, 95.68%)
underwent surgical procedure as breast conservation therapy irrespective of the cancer stage and
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majority belonged to the age group of 31-50 years (Table 26). Kiderlen and co workers (2011)
found variations regarding surgery in different countries; several elderly patients never
underwent surgery and regardless of management variations, survival rate was not mainly
affected. In another study regarding breast cancer it was reported that there was a possibility of
increasing survival rate of NSW Aboriginal women if their comorbidities were prevented and
surgical excisions were increased (Supramaniam et al., 2014).
In current practice, standard of care for stage I, II and III breast cancer, surgery is followed by
adjuvant radiation or systemic treatment or both when required (McPhee et al., 2010). In this
study also it was found that after surgical healing, the patients were given adjuvant radiation and/
or systemic treatment. Neo-adjuvant therapy was not given to any patients in any of the cases.
Radiation damages DNA strand of cancer cells inhibiting further growth though radiation
damages normal cells as well but it has more effect on cancerous cells and they cannot repair the
damage easily (Nahta, 2012). Radiation therapy was given to the breast cancer patients by using
linear accelerator with cobalt 60 as the source. The dose given to the patients was 1.8 to 2 grays
per fraction using 3-D conformal radiation method. In various clinical trials also, improved
survival rates of breast cancer cases was observed with the conventional 1.8 to 2.5 Gy per
fraction dose of radiation for over 5 to 7 weeks (Van de Steene et al., 2000, Gebski et al., 2006,
Buchholz , 2009, Kaufmann et al., 2010). Accelerated partial breast irradiation, in which only the
part of the breast from which tumor is removed is irradiated for 1-2 weeks seems effective in
acquiring local control (McPhee et al., 2010). Only 3-D conformal breast irradiation was
employed to all the breast cancer patients in this research and upon enquiring the physicians
regarding any other method for radiotherapy, they replied that it was the only convenient one in
the public set up like ours due to resource constraints. Radiation therapy was given to n=709
(87.42%) cases of this study, majority belonging to the age group of 41-50 years (Table 27).
After giving half of the radiation therapy to the patients, investigations were done in order to
assess the response. Radiation therapy was employed mostly for 21 or 18 days giving
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significantly ‘good’ (complete) responses in the age groups of 31-40 years (p<0.05) and >51
years (p<0.001) (Table 28) rendering complete response in >90% cases. The survival gains after
radiation therapy have been established in other studies also (Vinh-Hung and Verschraegen,
2004, Clarke et al., 2005). Adjuvant radiation therapy has been demonstrated recently to reduce
almost 70% recurrence risk and 9 to 12% mortality risk proportionally due to breast cancer
(Vinh-Hung et al., 2004, Nielsen et al., 2006, Taylor et al., 2009, Buchholz, 2009). In spite of
this proven part of radiotherapy in breast cancer management, there are substantial differences in
the acceptance of radiotherapy in local people that are attributable to numerous issues like
inadequate availability of treatment facilities, distance to travel for attaining healthcare, lengthy
waiting hours, and expenses of the healthcare. These issues are found to be in consistency with
other studies also (Gold et al., 2008, Jones et al., 2008, Gorey et al., 2009).
The radiation therapy is associated with certain adverse effects that are tolerable but it is hard to
assess the occurrence and intensity of these effects. The most common adverse reactions
observed in breast cancer patients after radiation therapy (Table 29) were fatigue/ bodyaches
(>75%) and skin hyperpigmentation (>70%). The ADRs occurring in the patients of this study
due to breast cancer radiation therapy were assessed using 3 different scales as shown in Table
36 (Naranjo et al., 1981, Hartwig et al., 1992, Schumock and Thornton, 1992). These scales have
been employed for assessment of various types of ADRs in recent studies as well (Anovadiya et
al, 2011, Belhekar et al., 2014, Modi et al., 2014). It can be seen from the table that skin/ nail
hyper-pigmentation were definite but mild in the patients; skin/nail erythema/scar/marks were
doubtful chiefly and probably preventable whereas fatigue/bodyaches were mainly definite or
probable and not preventable in the patients. There were not any unanticipated intense toxicities
reported during the course of radiotherapy in the breast cancer cases. This is in line with another
study which also documented that short course breast radiotherapy with concurrent integrated
boost over 3 weeks was reasonable practically for the patients without additional toxicities (Van
Parjis et al., 2012). Skin toxicity is regarded as the major adverse effect of radiotherapy affecting
breast cancer patients (Chen et al., 2010). The treatments prescribed for the adverse effects to the
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patients in this study are illustrated in Table 29. The adverse effects were temporary and started
to vanish in time with use of advised treatments. Treatment and prevention guidelines for skin
toxicity due to radiotherapy in the cancer patients are varying and are subjective to clinical
assessment by the physicians that may prescribe different types of topical medicaments for use
on the skin (Ravo et al., 2011, GozzoTde et al., 2010, Schmuth et al., 2002).
6.4.2 ADJUVANT ENDOCRINE THERAPY USED IN BREAST CANCER PATIENTS:
The hormonal therapy is the fundamental part of the management of breast cancer in all stages
(Howell et al, 2005, Barakat et al., 2000). The assessment of ER/PR status for breast cancer is
important because of the associated implication of disease management. Both ER/PR positive
tumors respond greatest to anti-estrogen therapy unlike the negative hormone receptors. The
history of disease between ER+ and ER- tumors also differs with improved prognosis in general
realized for ER+ patients. Recurrence patterns also vary with the site of relapse which is found to
be more common in visceral and soft tissue for ER- patients and in bone for ER+ patients. The
ER+ cancers have a tendency to revert later than ER- cancers within the first 5 years (Andry et
al., 1989, Hess et al., 2003). Adjuvant endocrine therapy is very potential in diminishing relapse
and mortality of breast cancer by 25% for hormone receptor positive tumors in both pre- and
post-menopausal women. Palliation in metastatic breast cancer is also based on the ER status of
the tumor. ER – breast cancer patients should not be given endocrine therapy as only 5-10% of
them respond to the treatment except for in elderly who are not able to bear chemotherapy. The
advantages of endocrine therapy for hormone receptor positive cancers are not dependent on age.
The response rate for ER + tumors for endocrine therapy are higher in both pre- and post-
menopausal women (McPhee et al, 2010).
Adjuvant endocrine therapy comprising of Letrozole (2.5 mg) tablets and Tamoxifen (20 mg)
tablets was prescribed to n=508 (62.63%) breast cancer cases in this, majority belonging to 41-
50 years of age group study (Table 30). Tamoxifen was prescribed to majority of the cases
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(96.06%) cases (Table 31) as it has been used since years for management and prophylaxis of
ER+/PR+ breast cancer. Tamoxifen interrupts ER based signaling, which is the key oncogenic
cause in receptor positive tumors (Hoskins et al., 2009). It binds to estrogen receptors and has
diversified agonist and antagonist properties, liable to target cells (Wood et al., 2003). It does not
amend circulating estrogen levels in postmenopausal women unlike the aromatase inhibitors
which decrease them to very low levels by obstructing the conversion of androstenedione to
estradiol in the adipose tissue (Burstein et al., 2010). Use of tamoxifen has shown considerable
benefit in successful patient outcome and extended duration therapy due to which significant
reduction of breast cancer related patient losses have been observed. However, all patients do not
respond to tamoxifen and in this case patients would be better assisted by substitute therapies
like AIs (Brauch and Jordan, 2009).
As mentioned earlier, the joint receptor status of the patients in this study was (39.4%) E/ or P+
H-, (25.70%) E/ or P+ H+, (13.70%) E- P- H+ and (36.16%) E- P- H- (Fig. 11). It was found
that endocrine therapy was prescribed to all the patients (n=508) irrespective of their hormonal
receptor status and even in those patients who had Her2 neu overexpressed disease. Outcomes of
tamoxifen use in the adjuvant and metastatic settings have been described as contradictory from
retrospective assessments of the influence of HER2/neu in breast cancer. Assumed that ER
expression and HER2/neu are contrariwise linked, several endocrine therapy investigations have
limited numbers of HER2/neu-positive patients, thus restricting their elucidation (Cianfrocca and
Goldsteindoi, 2004). Though ER – breast cancer patients should not be given endocrine therapy
because only 5-10% of them respond to the treatment but it may be used for in elderly who
cannot tolerate chemotherapy (McPhee et al., 2010). Moreover, non- reporting of receptor status
of all the patients was observed which might be due to the financial restraints on the part of
patients or negligence on the part of the physicians due to SES of the patients. Only a very few
patients were prescribed letrozole as AI therapy although it is now widely known substitute to
tamoxifen as first-line therapy in ER+ postmenopausal women with advanced breast cancer,
because of its proven enhanced medical efficacy (Bonneterre et al., 2001). Though ER – breast
cancer patients should not be given endocrine therapy because only 5-10% of them respond to
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the treatment but it may be used for in elderly who cannot tolerate chemotherapy (McPhee et al.,
2010). This should also be considered that evidence from investigations have shown that most of
the breast cancers occurring in post menopausal women are ER and/or PR–positive, therefore,
the patients of this study were prescribed endocrine therapy without knowing their receptor
status since adjuvant endocrine therapy has a big part in the treatment plan of breast cancer. But
it is noteworthy that aromatase inhibitors are now the preferred endocrine therapy in post
menopausal women which was prescribed to only a very few of the study participants; hence the
physicians need to be aware in their practice about AIs profile (Files et al., 2010). Tamoxifen
therapy for 5 years remains the gold standard for premenopausal women whereas AIs have been
used for treating post menopausal women. It should be noted that patients not giving response to
tamoxifen or ovarian ablation can be treated with chemotherapy but this depends on the
metastatic sites of breast cancer. AIs are used for treating advanced breast cancer in post
menopausal women after Tamoxifen therapy (McPhee et al., 2010). Goss et al (2009) proposed
that women who were premenopausal at the commencement of tamoxifen treatment but became
postmenopausal after 5 years of treatment had progressed in disease-free survival due to
aromatase inhibition.
The patients receiving adjuvant endocrine therapy in this research were advised for follow up
every 3 months and then on annual basis by the physicians. The patients were followed up to 6
months only by the researcher. The general response perceived in the follow ups for adjuvant
endocrine therapy was ‘good’ (complete) in all the cases. The most common adverse reactions
detected in breast cancer patients due to adjuvant endocrine therapy (Table 32) were heat
intolerance (50.98%), myalgia (40.55%) and hot flashes (34.05%). The ADRs occurring in the
patients of this study due to breast cancer endocrine therapy were also assessed using 3 different
scales (Naranjo et al., 1981, Hartwig et al., 1992, Schumock and Thornton, 1992) as shown in
Table 37. It was found that musculo-skeletal adverse effects were mild to moderate and probably
preventable in the patients. Vasomotor effects like hot flashes and heat intolerance were also
chiefly probable, mild but not preventable; vaginal effects were possible but probably
preventable whereas CVS effects could be probable or doubtful with less or much severity
depending upon the comorbid condition of the patients. The most common side effect of
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Tamoxifen use has been reported in other studies as hot flashes experienced by 50% females
(Hoda et al., 2003, De Vita et al., 2008) which is in agreement to the findings in this study also.
Hadji et al (2012) described that though arthralgia, myalgia or menopausal symptoms are the
adverse effects related to endocrine treatment but the treatment is linked with considerably
improved overall survival rate. The adverse effects found by Ashraf et al (2009) due to endocrine
therapy in Indian women having breast cancer are also in line with the findings of this study. To
accomplish timely management over such effects, patients were advised for regular follow ups
and were prescribed treatment. Investigations on regular basis were also done since many
patients were also at risk of cardiovascular diseases due to various comorbidities like
hypertension, diabetes mellitus and other multiple complications (Table 10). The side effects due
to Tamoxifen were not severe enough in the patients to switch over to an alternate drug by the
treating doctor. All the cases responded to the support for reassurance only. During the follow
up, no significant evidence of cardiac or vascular events were observed by the researcher in the
patients although such events have been reported in the literature (De Vita et al., 2008). Despite
of various side effects, Tamoxifen has found to be well tolerated in Indian women as compared
to the Western women (Agarwal et al., 2007). It is the only USFDA approved drug that is being
used for treatment of ER + breast cancer (Fisher et al., 2002, Colleoni et al., 2006). In our study
also, Tamoxifen has appeared to be a largely safe drug for women under treatment for breast
cancer, with tolerable side effect outline. Tamoxifen appears as if to have an insignificant
probability to cause endometrial cancer or other uterine cancers. Though there are evidences of
endometrial cancers due to tamoxifen therapy (Barakat, 1995, Barakat et al., 2000) but none such
reports were observed during the follow up period in the study which may be due to the fact that
increased endometrial thickness remains asymptomatic and is revealed upon ultrasound.
Increased endometrial thickness has been documented in more than 1/3rd patients on ultrasound
examination in Indian women (Ashraf et al., 2009). Though the patients in this study were
continuously advised by their attending doctors for regular investigations and condition
monitoring during their treatment but lack of awareness, cost of medical assistance, fear of
illness and associated mortality deprived the patients of following their instructions completely.
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6.4.3 ADJUVANT CHEMOTHERAPY USED IN BREAST CANCER PATIENTS:
In addition to radiation therapy, women with early breast cancer generally receive systemic
adjuvant chemotherapy which is directed for all node-positive breast cancers and tumours >1cm
size (Singletary et al., 2004). Valuable effect of chemotherapy in early breast cancer has been
established and it can reduce the risk of relapse and mortality in females aged < 50 years.
Improved clinical outcomes have been seen in elderly with higher risk disease. Adjuvant
systemic treatment should not be given to women having small node negative breast cancers with
favorable histologic findings and tumor indicators (McPhee et al., 2010). The optimum extent of
adjuvant chemotherapy use is not established but it may be given from 12 to 24 weeks and it also
depends on the treatment/ combination being used. Chemotherapy is primarily given within 3
weeks of surgery and to achieve optimal results, dose intensity and dose density should be
considered. Dose intensity is defined as “the amount of drug administered per unit of time and is
expressed as mg per square meters of BSA per week.” Dose density can be increased by
increasing dose, decreasing time or both. Dose density is defined to be “achieved by increasing
dose intensity, by decreasing time between treatment cycles.” The dose for standard treatment
regimens should not be abridged until severe toxicity is faced by the patient. Similarly, the dose
for standard treatment regimen should not be increased because it does not assist the patient as
there is a threshold for chemotherapy dosing exceeding which more toxicity is observed without
improvement in patients (Chisholm-Burns et al., 2010).
Adjuvant chemotherapy in 4-8 cycles was given to the breast cancer patients in this research,
majority belonging to 41-50 years of age group (Table 33, 34). After giving 3 cycles of
chemotherapy, investigations were done to check the treatment response; the number of
chemotherapy cycles depended on the achievement of ‘complete’ response. The response ‘good’
was considered as ‘complete response’ with disappearance of almost all radiologic or biologic
abnormalities which were observed at the time of diagnosis and absence of any new ones. The
response of adjuvant chemotherapy (4-8 cycles) in the age groups of 20-30 years and 41-50 years
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was ‘good’ (complete) significantly (p<0.001) (Table 33). ‘Partial response’ was seen in only a
very few breast cancer cases which means that there were no new abnormalities and
disappearance of 50% of all radiologic or biologic abnormalities. As per protocol of hospital for
breast cancer treatment, the primary chemotherapy consisted of FAC therapy, then TAC or AC x
T therapy (6 cycles). In case of metastasis, Vinorelbine/ 5-FU (8 cycles) or Carboplatin/
Gemcitabine (6 cycles) were also prescribed to few patients; Capacitabine was prescribed to only
a very few patients with metastatic breast cancer.
Various chemotherapeutic drugs were used for the treatment of breast cancer cases among which
FAC therapy was the primary therapy (Table 34), given mostly to the patients. It has been stated
before that the therapies were being used without taking into account the hormone receptor status
of the patients and chemotherapeutic agents were substituted in very few cases. Patients ease for
tolerability of treatment; budgetary limitations, etc have previously been described as the factors
that deprived the patients of better therapeutic regimens. At present, the inadequate data
regarding HER2/neu-overexpressing tumors drifts toward selecting an adriamycin-based regimen
for treatment (Cianfrocca and Goldsteindoi, 2004). In a retrospective, multicenter, randomized
trial analysis, FAC therapy was found to offer same survival rates for both HER2-positive and
negative patients of breast cancer (Vera et al., 1999). Ketkaew and co workers (2014) evaluated
3,485 chemotherapy prescriptions of OPD and reported that the most commonly prescribed
chemotherapy combinations were FAC regimen (36.15%, 1,260 prescriptions), CMF regimen
(16.15%, 563 prescriptions), AC regimen (14.84%, 517 prescription), Paclitaxel (12.63%, 440
prescriptions), Capecitabine (7.49% 261 prescriptions) and Docetaxel (4.88%, 170
prescriptions); thie study shows quite close results regarding the use of therapeutic agents with
the current study. Other regimen combinations given to the patients to achieve response in this
study were TAC, AC x T, Vinorelbine/5FU or Carboplatin/ Gemcitabine; Capecitabine was
administered to only a very few patients (n=5) for palliation. Kawaguchi et al (2009) also
documented that low-dose capecitabine monotherapy may be administered in patients under
palliative care setting. Docetaxel/ capecitabine therapy has been established as an important
management choice for women with MBC pretreated with anthracyclines (O’Shaughnessy et al.,
2002). From research it was found that AC or EC as compared to CMF are more effective
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therapies for breast cancer. Anthracyclines are found to be effective in HER2 positive breast
cancer and in HER2 negative, node negative cancers, 4 cycles of AC or 6 cycles of CMF are
almost equally effective (McPhee et al., 2010). In this study also, anthracycline based therapies
were mainly employed in the patients as FAC, TAC or AC x T combinations. The overall
duration of adjuvant chemotherapy is still uncertain. In a recent study, Kadakia et al (2013)
found the use of Anthracycline-based Paclitaxel regimen to be more frequent in >75% breast
cancer patients. AC followed by paclitaxel T are evident as the commonly used adjuvant therapy
in women with early breast cancer (Burnell et al., 2010).
Triple negative breast cancers are treated with cytotoxic chemotherapeutic agents as such tumors
are aggressive and have poor prognosis. Cytotoxic drugs should be administered to treat
metastatic disease if visceral metastases are present, hormonal therapy is not successful or if
there are ER- tumors. Numerous drugs like vinorelbine, paclitaxel, gemcitabine, carboplatin,
cisplatin, capecitabine etc can be used as sole agents providing response rates 30 to 50%;
although combination regimens show significantly better response rates but not overall survival
rates (McPhee et al., 2010). As stated earlier, there were (36.16%) cases of triple negative breast
cancer in this study but conventional approach of using FAC therapy mainly was employed in
majority of the cases. Capecitabine regimen was employed in a very few of the cases in this
study after investigations in which the response was not achievable with prior therapy. For stage
III and IV breast cancer, combination chemotherapy, endocrine therapy or combination of both
shows only 10 to 20% complete response rates. It is evident that almost 50 to 60% patients with
metastasis respond to initial chemotherapy like anthracyclines, taxanes, navelbine, capecitabine,
gemcitabine, cisplatin, cyclophosphamide and methotrexate. Taxanes and anthracyclines remain
the most active classes of cytotoxic drugs and anthracyclines are considered as standard of care
in first line therapy. Partial remissions are obtained for about 10 months whereas complete
remissions persist for almost 15 months which are not durable (Katzung et al., 2004).
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Most of the patients with breast cancer in this study showed ‘good’ response to chemotherapy as
anthracycline based combination agents were employed for the treatment. HER2 + tumors are
relatively resistant to alkylating based therapy and anthracycline based therapy are effective in
such types of breast cancers; Capecitabine is an oral drug that is used in metastatic breast cancer
when anthracycline combinations and taxanes could not provide desired outcomes, producing
almost 25% response rates (Chisholm-Burns et al., 2010). In stage I node negative breast cancer,
surgery only can reduce overall reversion of the disease in the patients but adjuvant
chemotherapy for premenopausal women and adjuvant tamoxifen for post menopausal women
have proven to be effective. There is amplified risk of local and systemic recurrence of disease in
lymph node positive breast cancers for which post operative use of adjuvant systemic therapy
comprising of 6 cycles of CMF or FAC have been found effective to prolong survival rates.
Alternatively, 4 cycles of AC or 6 cycles of FEC may be used (Katzung et al., 2004). Similar
alternate therapies were used in this study also as described above but only in few cases in which
either FAC therapy could not meet outcomes or the patients required palliation.
Trastuzumab ia monoclonal antibody that binds to HER2/ neu receptors. It has been
recommended that the patients with HER 2/neu positive tumors should be treated with
trastuzumab containing chemotherapy regimens. Since 20% breast cancers are reported to be
HER 2 positive, trastuzumab is given in combination with chemotherapy to such patients. The
adjuvant chemotherapy AC x T is the most common combination for trastuzumab (McPhee et
al., 2010). Trastuzumab is usually given as i.v. perfusion after a loading dose depending upon
body weight, in weekly schedule as adjuvant, neoadjuvant, and metastatic therapy or every-3-
week schedules as adjuvant setting. Trastuzumab management is normally sustained for
metastatic breast cancer until the time of disease advancement (Ross et al., 2009). When HER2-
positive breast cancers showed progression over the use of trastuzumab, Lapatinib was
recognized in combination with capecitabine for use in 2007. Lapatinib in combination with
letrozole is also officially used as first-line treatment for HER2-positive metastatic breast cancer.
It is recognized as an effective treatment for HER2-positive metastatic breast cancer but
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innovative methodologies to improve its response rates are essential. In combination with
chemotherapy, lapatinib was proven to accomplish a total 22% response rate and a 27% clinical
value rate (Geyer et al., 2006). Lapatinib, when used as monotherapy, has shown 12.4% to 25%
clinical value rates in patients that were previously given trastuzumab, although partial resistance
to lapatinib has also been observed in some cases (Blackwell et al., 2012, Toi et al., 2009).
Unfortunately, no such combinations were found to be employed in this study for the patients
under treatment. It has been evaluated that patients significantly developed cardiomyopathy by
using trastuzumab combinations, hence cardiac function was required to be regularly monitored
throughout therapy and also anthracyclines were not given with trastuzumab concurrently that
might increase the risk of cardiac events (McPhee et al., 2010). It is possible that due to the
existence of such literature regarding the side effects of trastuzumab and lapatinib as well, the
doctors deprived the patients of this therapy as it would not only increase disease burden but also
economically it did not seem feasible to add in such drugs although it may provide better
outcomes.
Neo-adjuvant chemotherapy enhances the opportunity of breast conservation by shrinkage of
primary tumor in females who would then require mastectomy for local control of the disease
(McPhee et al., 2010); it was also not found to be employed in any of the breast cancer patients
in this study, although it might obtain complete pathologic response in patients with hormone
receptor negative tumors improving survival rates. Such findings from this study clearly indicate
the need of educating healthcare professionals in the management of breast carcinoma.
In cancer patients, the development and extent of adverse effects due to chemotherapeutic agents
depend on the hereditary polymorphism of enzymes that are responsible for biotransformation of
drug and signaling paths (Snozek et al., 2009). It is well established that the chemotherapeutic
agents are not selective in their action for only cancerous cells and they affect cell lines
expressing greater development and replication rates. Some of these adverse effects can be
prevented by the administration of various other compounds to the regimen. Myelosuppression
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may be avoided or palliated by using haemopoietic growth factors, blood transfusions, and bone
marrow transplants. To reduce nausea and vomiting, potent anti-emetics are administered
especially when successive cycles of chemotherapy are employed. Antalgic/analgesic therapies
are also of considerable importance in the management of breast cancer (González et al., 2000).
Due to chemotherapy induced ADRs, pre- and post-therapies were prescribed to manage
symptoms in breast cancer cases in this study; the treatments prescribed were in line with the
standard treatments (Table 35). Most common adverse effects found in the cases due to adjuvant
chemotherapy (Table 35) were Vomiting/ nausea (n=799, 98.52%), Anemia/Neutropenia (n=764,
94.20%), Alopecia (n=763, 94.08%) and Fatigue/anorexia (n=743, 91.61%). The ADRs
occurring in the patients of this study due to breast cancer chemotherapy were assessed using 3
different scales (Naranjo et al., 1981; Hartwig et al., 1992; Schumock and Thornton, 1992) as
shown in Table 38. It was evaluated that anemia/neutropenia, vomiting/nausea and alopecia were
the major definite effects encountered by the patients receiving chemotherapy which were quite
severe in nature and were not preventable. Mild to moderate diarrhea/constipation was doubtful
in the cases and probably preventable; skin/nail discoloration was doubtful in the patients but not
preventable; mucositis/mouth ulcers were moderately probable to occur whereas fever/chills
were possible in the patients. Headache/pain encountered by the patients was mild and definitely
preventable by the use of proper medication. Dose-limiting febrile neutropenia is caused by
myelosuppressive chemotherapy for reducing which prophylactic use of recombinant human G-
CSF (daily filgrastim /once-per-cycle pegfilgrastim) is recommended (Naeim et al., 2013).
Alopecia has been reported as one of the most deleterious effects of chemotherapy in breast
cancer female patients (Kim et al., 2012, Kluger et al., 2012).
The toxicities due to adjuvant chemotherapy are generally well tolerated but numerous adverse
effects are seen with chemotherapeutic administration like alopecia, fatigue and termination of
menses that may or may not recur (Chisholm-Burns et al., 2010). Although anthracyclines are
the most active agents for the treatment of breast cancer but their use is restricted due to dose-
related cardio-toxicity. It is imperative that the treating physicians are alert to these adverse
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effects in the patients and cope with them properly especially in the advanced breast cancer
(Barrett-Lee et al., 2009). The patients in this study were advised for regular monitoring and
investigations during breast cancer treatment but at present no printed medical practice
guidelines are available that provide discourse for continuing cardiac surveillance after breast
cancer; current strategies for monitoring and supporting cardiovascular health in elderly are
every so often not followed (Schmitz et al., 2012). Zauderer et al. (2008) analyzed that the risk of
chemotherapy related toxicity like fatigue, neutropenia, etc in elderly patients treated with
adjuvant dose-dense AC-T (with white blood cell growth factor maintenance) was more related
to comorbid health conditions. It was observed in a study with AC X T therapy given to high risk
patients and the rest given FAC therapy that leucopenia, myalgia, arthralgia and peripheral
neuropathy were significantly high in patients receiving the former combination while anemia,
hyperpigmentation, stomatitis, and diarrhea were significantly high in those receiving latter
therapy (Palappallil et al., 2011). The results of aforementioned researches are consistent with
the findings of this study. In a comparative study between vinorelbine/gemcitabine doublet over
single-agent capecitabine, both treatments were found to be mostly well tolerated and similar in
treatment outcomes. Neutropenia and fatigue were more common with vinorelbine/gemcitabine
and hand-foot syndrome with capecitabine. Given the favorable toxicity and convenience of oral
administration, single-agent capecitabine is recommended for compliant patients (Pallis et al.,
2012).
Unluckily, our capability to precisely conclude patients who are probable to progress to
metastatic disease without adjuvant therapy as well as our capability to individualize treatment
for a given patient established on recognized prognostic and predictive factors is imperfect at the
present time. Toxic treatments are still given to several patients who would have been meant to
do well deprive of therapy, and still there are numerous patients who successively progress to
metastatic disease in spite of receiving adjuvant therapy. Overall, it can be concluded that best
course of therapy for each patient on individual basis must be chosen to evade the patient by
toxic effect of drugs.
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7. CONCLUSIONS:
The conclusions of this research are as follows:
The risk factors significantly associated with breast cancer were found to be education,
interfamily marriage, no breastfeeding, milk consumption especially fresh milk,
menarche age, family history and hypertension and diabetes mellitus. Diet was found to
be protected through analyses.
Established risk factors like BMI, age at first child birth and contraceptive use were
found negatively associated with breast cancer.
Post menopausal women were at more risk of developing breast cancer.
Inter family marriage and milk consumption were consistently found to be associated
with the risk of breast cancer in multinomial analyses by receptor status and by cancer
stage, adjusted for education.
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Most of the breast cancer patients were presented with cancer stage I and then II, majority
belonging to the age group of 41-50 years and then 31-40 years.
The cancer of left breast was more prevalent among the patients.
Individual hormone receptor status revealed that most of the patients were ER+, PR- and
HER2/neu negative. The joint receptor status revealed that majority of the patients was
having either triple negative (E-P-H-) or ER and/or PR+ HER2- (luminal A) disease.
Most of the patients underwent surgery and radiation therapy also for 18 or 21 days.
The side effects due to radiation therapy encountered by the patients in general were
skin/nail hyper-pigmentation, skin erythema/marks and fatigue/body-aches.
Neo-adjuvant therapy was not given to any of the patients.
Adjuvant endocrine therapy prescribed to the patients was Tamoxifen for 5 years due to
which the side effects observed in the patients were myalgia, heat intolerance, hot flashes
and increased risk of CV events especially in the susceptible patients already having
comorbid conditions.
Chemotherapy i.e. FAC regimen (6 cycles) was administered to majority of the patients.
There was no prescription of trastuzumab or lapatinib in combination of chemotherapy
for any of the breast cancer patients.
Most common adverse effects due to chemotherapy were anemia, neutropenia, nausea,
vomiting, alopecia, mucositis and fatigue.
The pre- and post-medications prescribed for management of patients with
chemotherapeutic administration were in line with the standard treatment guidelines.
The medications for the management of adverse effects due to various treatment
modalities of breast cancer were prescribed rationally.
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9. APPENDIX