Table of Contents -...

Table of Contents

Original articles

diet, Physical activity, Marital Status and risk of Cancer: a Case Control Study of adults from riyadh, Saudi arabia .......................06Eyad Fawzi AlSaeed and Mutahir A. Tunio

Clinico-hematological Profile of 184 Patients with non-Hodgkin’s lymphoma: an experience from Southern Pakistan ...................11Sadia Sultan, Syed Mohammed Irfan, Anila Rashid, Saira Parveen and Neesha Nawaz

ambiguity of Whole Body PeT CT Scans in diagnosis of Co-existing Tuberculosis and Malignancy: is Histopathological Confirmation Mandatory? .........................................................................................................................................15Prekshi Chaudhary, Sweety Gupta, Nitin Leekha, Ravi S. Rajendra, Shiv S. Mishra, Vandana Arora, Sudarsan De and Sandeep Agarwal

epidemiology and Outcomes with Platinum-Based Chemotherapy in recurrent or Metastatic Carcinoma Cervix in a developing Country: experience from a Tertiary Oncology Centre in Southern india ......................................................................20K.C. Lakshmaiah, Aditi Harsh Thanky, D. Lokanatha, K. Govind Babu, Linu Jacob, Suresh Babu, A.H. Rudresha, K.N. Lokesh, L.K. Rajeev and Aparna Sridharmurthy

disclosure of adverse Cancer news: The Public’s Perspective in a Middle eastern Country .................................................................27Jamal Zekri, Mohamed E. El Sayed and Youssef Nauf

Second Primary Tumors associated with Breast Cancer: Kuwait Cancer Control Center experience ....................................................35Salah Fayaz, Gerges Attia Demian, Heba El-Sayed Eissa and Sadeq Abuzalouf

implications of Observer variation in Gleason Scoring of Prostate Cancer on Clinical Management: a Collaborative audit ...............41A. Harbias, E. Salmo and A. Crump

Squamous Cell Carcinoma of the Buccal Mucosa: a Single institute retrospective analysis of nodal involvement and Survival ...........................................................................................................................................................46Vivek Tiwari and Rakesh Mahawar

Clinical and Pathological Characteristics of Triple Positive Breast Cancer among iraqi Patients ..........................................................51Nada A.S. Alwan, Faisal H. Mualla, Munawar Al Naqash, Saad Kathum, Furat N. Tawfiq and Sana Nadhir

Pre-Treatment nutritional Status and radiotherapy Outcome in Patients with locally advanced Head and neck Cancers ...............61Amit Bahl, Arun Elangovan, Satinder Kaur, Roshan Verma, Arun Singh Oinam,Sushmita Ghoshal, Naresh K Panda

evaluation of BrCa1 large Genomic rearrangements in Group of egyptian female Breast Cancer Patients Using MlPa ...................................................................................................................................................................................64Ola M. Eid, Eman A. El Ghoroury, Maha M. Eid, Rana M. Mahrous, Mohamed I. Abdelhamid, Zahra I. Aboafya, Esmat A. Abdel Ghaffar and Amany H. Abdelrahman

Case reportsBrain Metastasis from Colorectal adenocarcinoma: a Case report ........................................................................................................70Jaroslav Nemec, Abdulsalam Alnajjar, Jasem Albarrak , Shaban A, Mariam Al Otaibi and Asit Mohanty

leiomyosarcoma of Penis: an aggressive and exceptionally rare entity ...............................................................................................73Vinita Trivedi, Muneer A, Rita Rani, Richa Chauhan, Usha Singh and Naveen Kuna

review articlesChemotherapy-induced febrile neutropenia in Solid Tumours ...............................................................................................................77Ayman Rasmy, Mohammed Al Mashiakhi and Amal Ameen

Conference Highlights/Scientific Contributions• NewsNotes ............................................................................................................................................................................................85

• Advertisements .....................................................................................................................................................................................88

• ScientificeventsintheGCCandtheArabWorldfor2017 ..................................................................................................................89

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Corresponding author: Prof. Dr. Nada A.S. Alwan (MD, PhD), Director, National Cancer Research Center/Program, IRAQ. Mobile Numbers: +964 7901343257,

+964 7705888997; Email: [email protected]

introductionBreast cancer is the most widespread cancer among

women worldwide (1). The latest Iraqi Cancer Registry (2) revealed that it is still the most common malignancy among the general population since 1986 and the leading

abstract

Background: Breast cancer is the most common malignancy affecting the Iraqi population and the leading cause of cancer related mortality among Iraqi women. It has been well documented that prognosis of patients depends largely upon the hormone receptor contents and HER-2 over expression of their neoplasm. Recent studies suggest that Triple Positive (TP) tumors, bearing the three markers, tend to exhibit a relatively favorable clinical behavior in which overtreatment is not recommended.

aim: To document the different frequencies of ER/PR/HER2 breast cancer molecular subtypes focusing on the Triple Positive pattern; correlating those with the corresponding clinico-pathological characteristics among a sample of Iraqi patients diagnosed with the disease.

Patients and Methods: This retrospective study involved 570 female patients diagnosed with breast cancer who visited the Main Referral Center for Early Detection of Breast Cancer and the National Cancer Research Center. The requested data was mainly extracted from an established information system database, developed by the principal author over a 4-years period from 2012 to 2016. The registered information comprised data related to clinical presentation, diagnostic and pathologic findings. ER, PR and HER2 status were analyzed immunohistochemically and the detected profiles were correlated with the corresponding clinico-pathological characteristics.

results: The rates of ER (+), PR (+) and HER-2 (+) tumors were 66.8%, 64% and 29.3% respectively. The tumor marker expression status was documented in eight subtypes; 83 cases (14.6%) of the examined breast carcinomas were categorized as ER+/PR+/HER2+ (Triple Positive/Luminal B), 89 cases (15.6%) were ER-/PR-/HER2- (Triple Negative), 241 (42.2%) were ER+/PR-/HER2- (Luminal A) while 67 (11.8%) showed ER-/PR-/HER2+ expression (HER-2 variant). No significant variations were noted when comparing age, menopausal status and tumor grade of Luminal B pattern to Luminal A and the rest of the studied subtypes. Although our data revealed a statistical difference with respect to the distribution of tumor types; where infiltrative ductal carcinoma constituted the major histology among patients with Triple Positive/Luminal B subtype (86.7% as compared to 67.6% in Luminal A), nevertheless, more than two third of those patients (67.4%) were diagnosed at earlier stages (I and II) compared to 55.2% of those in the remaining groups.

Conclusions and recommendations: Our findings support the hypothesis that the Triple Positive subtype might be driven primarily by the hormone receptor status. Further comprehensive surveys are recommended to focus on the intrinsic interactions and tumor cell heterogeneity of that pattern to avoid overtreatment and predict accurate response to therapy.

Keywords: Breast cancer, clinical, pathological, Triple Positive, Iraqi patients.

Original Article

Clinical and Pathological Characteristics of Triple Positive Breast Cancer among iraqi Patients

Nada A.S. Alwan1, Faisal H. Mualla2, Munawar Al Naqash3, Saad Kathum4, Furat N. Tawfiq5, Sana Nadhir6

1Director, National Cancer Research Center, Iraq; Professor, Baghdad University 2Public Health, Queen Mary Hospital, UK

3Lecturer of Oncology, Baghdad Medical College, Iraq 4Lecturer of Statistics, College of Administration and Economics, Baghdad University, Iraq

5Lecturer of Informatics, National Cancer Research Center, Iraq 6Oncology Teaching Hospital, Iraq

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Triple Positive Breast Cancer among Iraqi patients, Nada A.S. Alwan, et. al.Triple Positive Breast Cancer among Iraqi patients, Nada A.S. Alwan, et. al.

cause of death from female cancers in Iraq; accounting for 34% of the registered cancers among women and 23% of cancer related mortality. The peak frequency is often observed among middle-aged women where the disease is frequently diagnosed at relatively advanced stages (3,4), with a likely prevalence of aggressive forms (5).

It is believed that breast cancer represents a heterogonous disease which comprises various biologic subtypes with diverse history, clinical, pathological and molecular features thus yielding different prognosis and predictive outcomes. The routine management of these patents depends upon the findings of their molecular tumor marker assays that include Estrogen receptor (ER), Progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) expressions (6). Retrospective evaluation from epidemiological breast cancer adjuvant trials has clearly illustrated a more favorable prognosis among patients expressing both hormone receptors (HR) (7).

Although HR negative breast cancers are often less differentiated yet there has been a general consensus that HER2 expression is the dominant driver that determines its behavior regardless of HR status (8). In general, HR positive breast cancers are classified as luminal variants, which are in turn sub divided according to their HER2 status into ER/PR positive/ HER2 positive ‘‘Luminal B Triple Positive (TP)’’ and ER/PR positive / HER2 negative “Luminal A” subtypes (6,9). That categorization has become a perquisite in routine pathology reports (10). Recently, it has been claimed that TP tumors might represent a distinct entity with a more favorable prognosis in which over treatment should be avoided (11).

The main objective of this study is to document the different frequencies of ER/PR/HER2 breast cancer molecular subtypes among Iraqi patients diagnosed with the disease; correlating the clinical and pathological characteristics of Luminal B TP breast cancer with those demonstrated in patients exhibiting Luminal A and other subtypes. Up to our knowledge, this is the first comprehensive report on the distribution of the Luminal and other molecular subtypes of breast cancer among the Arab patients in Iraq.

Material and MethodsThe present comparative study involved 570 female

patients who were diagnosed with breast cancer at the Main Training Center for Early Detection of Breast Cancer / Oncology Teaching Hospital and the National Cancer Research Center.

The majority of the data was retrospectively extracted from an established information system database

developed by the principal author, under supervision of the International Agency for Research on Cancer over a 4-year period from July 2014 to June 2016 (12). That data-based system comprised all relevant information belonging to the registered patients including family history, clinical presentation, diagnostic (clinical and pathological) findings along with treatment outcomes. The study was reviewed and approved by the Ethical Committee of the National Cancer Research Center of Baghdad University and has been performed in accordance with the ethical standards laid down by 1964 Declaration of Helsinki.

The studied parameters in this study included age at the time of diagnosis, menopausal status, tumor histological type, its grade, size, lymph node status, stage of the disease at presentation, ER, PR, and HER2 contents of the primary breast cancer. Tumor characteristics were obtained from the diagnostic pathology reports. Breast cancer types were classified according to WHO, ductal carcinomas were graded following SBR categorization while the UICC TNM system was used in staging patients with the disease.

Histopathologically, all studied specimens were fixed in 10% formaldehyde, embedded in paraffin, sectioned and stained with Hematoxylin and Eosin. Formalin fixed paraffin-embedded blocks were used to evaluate HRs (ER, PR) and HER2 expressions through semi quantitative immunohistochemical (IHC) staining in a fashion depending on the staining intensity and the percentages of the positively stained tumor cells utilizing Dako kits ™ (Dako, Denmark). Regarding ER and PR, the staining should be reflected in at least 10% of the tumor cells to be regarded as positive and was graded as: +3 strong, +2 moderate, and +1 weak. For HER2 assessment in the current study, complete, dark membrane staining in 30% of the cells was scored as +3 and considered as positive. Cases with doubtful expressions exhibiting circumferential thin membrane staining and/or heterogeneity in staining distribution in less than 30% of cells (scored as equivocal +2) were considered as negative or positive according to the results of Fluorescence in situ hybridization (FISH) analysis carried out on sections obtained from the same tissue samples.

Based on that IHC staining, breast carcinomas were mainly classified into four molecular subtypes as follows (Table 1):

The main clinical variables of patients exhibiting the TP Luminal B subtype (Group I) and the pathological characteristics of the corresponding tumors were reviewed and correlated to those observed in Luminal A subtype (Group II) (Table 3) and all other subtypes (Table 4). In general, no significant variations were noted

Triple Positive Breast Cancer among Iraqi patients, Nada A.S. Alwan, et. al.

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Triple Positive Breast Cancer among Iraqi patients, Nada A.S. Alwan, et. al. G. J. O. Issue 25, 2017

Table 1: Molecular Tumor Subtypes according to the iHC Profile expressions of invasive Breast Carcinomas• HR Positive (Luminal A): ER/PR (+) and HER2 (-,) • HR Positive (Luminal B / Triple Positive) : ER/PR (+ ) and HER2 (+)• HR Negative (Non-luminal / HER-2 Negative): ER/PR (-) and HER2 (+)• HR Negative (Non-luminal / Triple Negative): ER/PR (-) and HER2 (-)

Table 2: distribution of the studied cases according to iHC Profile expressions

regarding age and menopausal status; where almost one third of patients within all studied groups were diagnosed in their fifth decade of life, while 51.8% of patients in Group I were premenopausal (vs. 45.6% and 46.6% in Luminal A and All Other subtypes respectively). On the other hand, a statistical difference was illustrated with respect to the distribution of tumor types in the TP Luminal B pattern where infiltrative ductal carcinoma constituted

the major type accounting for 86.7% as compared to 67.6% in Luminal A which displayed higher rates of carcinoma in situ components. Approximately 69% of breast carcinomas in the current study were graded as moderately differentiated; the observed slightly higher frequencies of grades I and II in Group II/Luminal A were not sufficient to express a significant difference.

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Table 3: descriptive clinico-pathological characteristics of the Triple Positive (luminal B) breast cancer subtype compared to luminal a.


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Table 4: Clinico-pathological characteristics of TP luminal B breast cancer compared to the other subtypes.

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Histological examinations of the excised tumor specimens revealed no significant differences regarding the distributions of tumor sizes and lymph node status in the three studied groups; where 57.8% of the breast cancer tissues in Group I measured between 2-5 cm in diameter (vs. 60.2% and 56.3% in Luminal A and All other subtypes respectively) and almost one third of the patients had no nodal involvement. Although 67.4% and 69.6% of patients showing Luminal B and Luminal A subtypes respectively were diagnosed at earlier stages I and II at the time of presentation compared to 55.2% of those in All Other subtypes, yet those differences were not proved to be statistically significant.

discussionHR positive breast cancers are clustered into a group

designated as ‘Luminal Class’ which is sub-divided into Luminal A and Luminal B depending on presence or absence of HER2 over expression (8, 9, 11). Considering the prognostic and predictive significance of HR tumor content in the survival of patients with breast cancer (7), it has been

emphasized that among HER2 positive tumors, HR status classifies two distinct subtypes with different clinical behavior and sensitivity to therapy; whereby patients with the Luminal B/TP breast cancer might derive less benefit from endocrine manipulation than those bearing the Luminal A pattern (8, 9, 13). Nevertheless, recent reports proposed that TP Luminal B breast cancer might be driven primarily by HR status and could thus behave biologically in a manner similar to HER2 negative/HR positive Luminal A subtype; indicating that co-expression of both HRs in the presence of HER2 positive influence might still identify a subset of breast cancer with a favorable prognosis (9, 11).

Approximately 15-25% of breast cancer over expresses HER2 and has an aggressive clinical behavior (8,9,11). Earlier studies from US demonstrated that about 50% of HER2 positive breast cancers actually bear HR positive content as well although often at lower levels compared with HR positive/ HER2 negative tumors (15, 16). Interestingly, very close figures were encountered in this data base study where the overall rate of HER2 positive tumors was 29.3% whereas the TP (E+/P+/H+) subtype

Table 5: reported breast cancer subtype profiles in the literature.

figure 1: Molecular subtypes of breast carcinomas according to the iHC staining results.

figure 2: distribution of the studied cases according to the molecular subtypes as determined by iHC staining.


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constituted 14.6%. Conversely, other investigators reported that approximately 10% of HR positive tumors are also HER2 positive (13). Findings from the California Cancer Registry trial revealed that the survival rates of patients exhibiting the TP subtype was superior to that of those bearing the (E+/P-/H+) variant (which constituted only 3.3% in the present study) emphasizing the significant role of PR in addition to ER on survival in HER2 positive tumors (17). Nevertheless, oncologists still prescribe chemotherapy with anti-HER2 agents to all patients showing the HER2 positive breast cancer subsets, regardless of HR status; given that molecular heterogeneity of HER2 positive tumors might yield different therapeutic implications.

In the current study, overall, ER and PR positive breast cancers were observed in 66.8% and 64% respectively. The registered rates for the (E+/P+/H+), (E-/P-/H-), (E+/P+/H-) and (E-/P-/H+) subtypes were equivalent to 4.6%, 15.6%, 42.2% and 11.8% respectively. The corresponding figures recorded within the SEER data registry (18) were 10.3%, 12.2%, 72.7% and 4.6%; reflecting higher frequencies of ER and PR positive breast cancers among American female patents. Focusing on the Arab World, the reported distribution rates of those subtypes reveal significant variations. In agreement with previous reports from the Eastern Mediterranean Region (10, 18-23) the most common illustrated IHC pattern (42.2%) in our study was the (E+/P+/H-), i.e., (HR+/HER2 –) /Luminal A subtype. A very close figure was reported in a comprehensive survey on the IHC subtypes of breast cancer in Saudi Arabia (10); which displayed a higher rate for ER positive tumors approaching 75% while the (E-/P-/H-) / Triple Negative (TN) subtype was lower (9%).It has been declared by the researchers of that study that two IHC patterns, not reported previously in the Arabic literature, were discovered namely the (E+/P-/H+) and (E+/P-/H-) subtypes which constituted 5% and 11.1% respectively (as compared to 3.3% and 5.4% in the present study).

ER positive breast cancers were more frequently encountered (78%) in an earlier study from Kurdistan (19) which documented an identical rate for PR positive tumors (64%) to that noted in our findings. That study which was carried out in Sulaimaniya, Northern Iraq, on the ethnically distinct Kurdish population, demonstrated Luminal A, TP and TN IHC subtypes in 54.7%. 5.7% and 12.4% of their examined cases respectively; HER2 positive tumors being registered in 20.4%. On the other hand, another study conducted on Tunisian patients diagnosed with breast cancer (24) concluded that ER+, PR+ and HER2+ tumors were encountered in 61.2%, 51%, and 29.6% respectively. While the rate of HER2 positive cancers in Tunis was identical to that observed in our study, the

percentage of TN subtype was slightly higher (17.3%). In the United Arab Emirates (20), the documented rate of Luminal B pattern was in accordance to that reported in this study; on the other hand, the incidence rate of the Luminal A variant was higher (65.8%) thus yielding lower TN expression (10.4%).

The American University of Beirut (25) illustrated slightly higher rates for ER and PR positive breast cancers (74.4% and 69% respectively), nevertheless, the rates of HER2 positive tumors and the TN subtype were lower (23.8% and 12.3% respectively). Recently, a large population-based survey on molecular breast cancer subtypes and their clinic-pathological characteristics among 2260 Moroccan patients (21) displayed that ER, PR, HER2 positive rates and the TP subtype were detected in 64.2%, 66.5%, 28.6% and 16.1% respectively. Likewise, a study on the molecular distribution of breast carcinomas among Jordanian patients (22) showed that 60%, 13%, 15% and 12% of the tumors were classified as Luminal A, Luminal B, TN and HER2 respectively.

Focusing on the Luminal B pattern, within the literature of developed countries in general 10-20 percent of breast cancers are classified as TP (18, 26-29). As displayed above, the reported rate in the present study for that subtype (14.6%) was in accordance with those highlighted in previous surveys from the region (10, 20-22). Nevertheless, it was higher than what was documented by other investigators (18, 19) and, on the other hand, still lower than that observed in other studies (23). In fact, variations in the expressions of these tumor markers were noted as well in relevant studies reported from the same country. A review on the IHC subtypes of breast carcinoma among Egyptian patients (23) in Cairo recorded higher frequencies for HER2 and TP expressions (73%, 63%, 37% and 23% for ER, PR, HER2 and TP respectively), while another study performed during the same year in Sohag University (26) demonstrated that ER, PR and HER2 were expressed in 78.7%, 76.4%, and 13.2% of their reviewed cases respectively. Such variations in the expressions of IHC patterns among breast cancer might be attributed to various racial backgrounds, patients’ characteristics or tumor cell heterogeneity. Nevertheless, the technical variations in the results of IHC staining as consequences of utilizing different manufactured kits should be considered.

Clinically, it has been concluded that HR positive expressions are associated with older age, smaller tumors, lower grade and earlier stage at presentation of breast cancer, while HER2 impact on HR positive breast cancer is often reflected by younger age at diagnosis, higher tumor grades and advanced stages at the time of presentation (8,13,16). Compared to Luminal A, it has been reported in

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the literature that patients with Luminal B breast cancers are commonly diagnosed at younger ages, tend to present with larger and rather poorly differentiated tumors which are associated with lymph node involvement (18,,27-29,31) but may have fairly good survival rates (32).

On reviewing the characteristics of the examined population in our study and correlating the data base findings to those demonstrated in other studies from the region, comparable results were noted regarding the general clinicopathological features of patients diagnosed with breast cancer. The encountered younger age at presentation has already been emphasized in earlier studies from Iraq and other Arab countries (2-5, 12, 19, 21,

26) probably reflecting the age pyramid structure of the populations and/or genetic and environmental factors. No significant differences were observed in the current study with respect to age and menopausal status among the different examined IHC groups. However, our analyzed data illustrated that 52% of patients with the TP pattern were premenopausal and only 20% were under the age of 40 years. Interestingly, there was a statistical difference regarding the distribution of breast cancer types within the TP Luminal B group; infiltrative ductal carcinoma constituted the major histology accounting for 86.7% as compared to 67.6% in the Luminal A group which displayed higher rates of carcinoma in situ components. Approximately 70% of the tumors in our study were moderately differentiated with no significant variations among the studied subtypes. While no lymph nodes were involved in almost one third of the examined patients belonging to the TP group, 67.4% of them were diagnosed at earlier stages (I and II) as compared to 55.2% in the remaining groups.

In Saudi Arabia (10, 30) where the majority of their breast cancers are moderately differentiated infiltrative ductal carcinomas, most of their patients who exhibited the TP phenotype were diagnosed at younger age groups, 62% of the tumors were moderately differentiated while 29% were poorly differentiated. Jordan University Hospital (22) recorded in their cancer registry that at older age groups the most common detected subtype was Luminal A (72%) in which most of the cases were moderately differentiated. Likewise in Morocco (21) invasive mammary ductal carcinoma was the predominant type overall and specifically among the TP subtype, categorized as grade II in 70.4% and, in accordance to our findings, the lymph nodes were positively involved in almost two third of the patients. On the other hand, when correlating the breast cancer subtypes with lymph node status in a similar Egyptian study (26) it was displayed that the Luminal B

variant was more likely to have axillary node metastasis while the Luminal A was the most protected group.

ConclusionsThe reported data on IHC molecular subtypes of breast

cancer exhibit variations among the different populations. Our study displayed that Luminal A was the most common pattern followed by TN, Luminal B/TP and HER2. Since no significant variations were noted regarding the clinic-pathological presentation of Luminal B/TP subtype as compared to Luminal A and the other variants (apart from the observed differences in the histological types), our findings support the hypothesis that TP pattern might be driven primarily by HR status. Further comprehensive surveys are recommended to focus on investigating the intrinsic interactions of the biological tumor cell heterogeneity of that subtype in order to avoid overtreatment and predict accurate response to therapy.

Conflict of interestThe authors declare that they have no conflict of

interest that competes with any of the contents of the manuscript.

author contributionProf. Nada Alwan, Director of the National Cancer

Research Center, organized the information system data base under supervision of IARC, designed the study, wrote the manuscript and presented the final version. Other co-authors supported in providing relevant information, data entry and statistical analysis.

acknowledgementWe thank gratefully Dr. R. Sankaranarayanan, Mr. Eric

Lucas (from the Screening Unit of IARC, Lyon) and other members of the staff who worked at the Main Training Center for Early Detection of Breast Cancer and the Cancer Registry Section of the National Cancer Research Center in Baghdad.

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