breast and OVARIAN cancer

DR DAVID FENNELLY

CONSULTANT MEDICAL ONCOLOGIST

ST VINCENT’S UNIVERSITY HOSPITAL

DUBLIN

HOW RELEVANT IS ONCOLOGY IN MEDICINE TODAY?

• Cancer is the second leading cause of death worldwide

• Only cardiovascular diseases overcome cancer as cause of death

• Overall incidence of cancer is increasing as a result of improved life expectancy

• The psychological impact of cancer on patients and their relatives is a big part of the “cancer problem” in modern Medicine

TRENDS IN MORTALITY FROM CANCER IN UK (1975-2007)

0

50

100

150

200

250

300

350

400

450

197

5

197

7

197

9

198

1

198

3

198

5

198

7

198

9

199

1

199

3

199

5

199

7

199

9

200

1

20

03

200

5

200

7

Rate

per

100,0

00

Year of diagnosis/death

Persons Incidence Persons Mortality

Age-standardised incidence rates for all cancers and mortality rates for all

BREAST CANCER IN IRELAND: THE FACTS

• Breast cancer is the most common type of malignant cancer among women in Ireland

• Ireland is one of the countries with the highest breast cancer mortality worldwide

• Breast cancer mortality is different with age but represents a substantial cause of death for ages between 40-70

Age-standardised rate (W):

A rate is the number of new cases or deaths per 100 000 persons per year. An age-

standardised rate is the rate that a population would have if it had a standard age structure.

Standardization is necessary when comparing several populations that differ with respect to

age because age has a powerful influence on the risk of cancer.

WHAT HAPPENED OVER THE LAST 20 YEARS?

• Diagnosis at earlier stages (breast, colon, prostate cancer) Role of screening and education

• Improvements in surgical treatments (breast, colon lung cancer, soft tissue sarcoma)

• Improvements in medical treatments for the early stage malignancies (adjuvant therapies)

• Changes in life-style (gastric, lung, cervical cancer)

• But most important…

• BETTER UNDERSTANDING OF MOLECULAR BIOLOGY OF CANCER

An example from clinical practice…

In 1981

• Mastectomy specimen: invasive breast cancer

• 21 mm in size

• 20 axillary lymph nodes negative for metastatic carcinoma

In 2011• WLE specimen: invasive breast cancer

• 21 mm in size

• 2 axillary sentinel lymph nodes negative for metastatic carcinoma

• Grade II

• Lymphovascular invasion present

• Ki-67 (proliferation index)

• ER and PGR positive

• HER2 negative (by IHC and FISH)

• OncotypeDX Recurrence Score: 26

Breast anatomy

Progress of breast surgery(early 1900s to 2000s)

1894

1655

1940s 1970s 1990s

DEFINITIONS OF CANCER

• Clinical definition

• “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change.” (Robbins, 7th

edition)

• Molecular definition

• “Cancer results by the clonal expansion of a single precursor cell that has incurred genetic damage (or mutation) acquired by the action of environmental agents, such as chemicals, radiation, or viruses, or inherited in the germ line. This process, called carcinogenesis, is a multistep process at both the phenotypic and the genetic levels, resulting from the accumulation of multiple mutations.

TNM staging of breast cancer (I)

TNM staging of breast cancer (II)

Epithelial Ovarian Cancer

• The crude incidence of ovarian cancer in the European Union is 18/100.000 women per year, the mortality is 12/100.000 women per year

• The median age at diagnosis is 63 yrs. Incidence increases with age and peaks in the 8th decade. Between age of 70-74 years age-specific incidence is 57/100.000 women per year

* ESMO minimum Clinical Recommendations

Ann Oncol 19 (suppl 2): ii14-ii16, 2008

Five-year Survival in Ovarian Cancer30 years of experience

Vol. Year Cases Ia IV Overall

(n) %

16 1963-68 4588 66.7 5.0 27.3

19 1976-78 6724 72.3 4.5 29.8

21 1982-86 10912 82.3 8.0 35.0

23 1990-92 7059 83.5 11.1 41.6

25 1996-98 4116 89.3 13.4 46.4

26* 1999-01 4911 89.3 18.6 49.7

Int. J Gynecol Obstet 2006 (Suppl 1)

Epithelial Ovarian CancerMilestones

• Surgery according to FIGO guidelines

• At least LNS and peritoneal staging in early ovarian cancer

• Upfront maximal surgical debulking in advanced ovarian cancer

• Chemotherapy evolution

• Introduction of platinum compounds

• Introduction of taxanes

• The set-up of the GCIG in 1997

ARE THERE ANY NEW DEVELOPMENTS IN EARLY OVARIAN CANCER?FIGO I-IIA

• Grade and complete staging are strongest prognostic factors

• Low risk patients do not need chemotherapy as an adjuvant treatment (5-yr survival ≥ 95%)

• High-risk patients do need adjuvant platinum-based chemotherapy: combined analysis of ICON-1 and ACTION trial* showed 5-yr OS 82%vs 74%, p=.008 no significant difference in outcome, but recurrence rate with 6 cycles was 24% lower than with 3 cycles, and significantly more toxicity

*Trimbos et al, JNCI 2003Bell et al, Gynecol Oncol 2006

NEW DATA FOR ADVANCED OVARIAN CANCER

• NACT an alternative for not optimal resectable FIGO IIIc (Vergote et al, NEJM 2010)

• No benefit from adding a third drug to TC

• No role for consolidation/maintenance cytotoxic CT?1 study positive for PFS (12 vs 3 cycles paclitaxel PFS 28 vs 21 months, p<.005): Markman et al, JCO 2003)

• Dose dense TC superior (JGOG study)Confirmatory studies ongoing

• IP therapy finally recognized

MRC CHORUS

24.5 months

76% 1yr

survival

70% 1yr

survival

22.5 months

Primary sx

Adjuvant chemo

NACT

IDS

Bulky disease

Median age = 65

Treatment

35% OptDebulk

92% home 14/7

StgIII/IV

Surgery outcome OS

N= 550 randomised

25% % Stg IV Same chemo delivery

15% OptDebulk

78% home 14/7

MITO-7 TRIAL DESIGN

Phase I/II trial of weekly taxol MSKCC (fennelly D et al : J Clin Oncol 1996)

Aim of the trial is to compare the quality of life and PFS

1st -line advanced ovarian, tubal and peritoneal cancer

RANDOMISE

Carboplatin AUC 2

Paclitaxel 60 mg/m2

day 1,8 15 - every 21days

Carboplatin AUC 6

Paclitaxel 175 mg/m2

day 1 - every 21days

MITO – 7 PFS

MITO-7 QOL BETTER

MITO-7 OVERALL SURVIVAL

CLASSICAL ANTI-CANCER DRUGS VS NEW TARGETED AGENTS

• The new targeted anticancer agents are designed to target specific molecules which are considered crucial in specific pathways (e.g. growth regulation, DNA-repair, angiogenesis, invasion and metastasis)

Mechanism of action defined before their design

Highly selective therapeutic target

Patients selected for the target

Molecular rationale for associations of different agents

Targeted Therapies in Ovarian Cancer

Target Drug(s)

ErbB kinases Gefitinib, erlotinib, lapatinib, canertinib, cetuximab,

pertuzumab, matuzumab, trastuzumab

MUC1 / PEM Pemtumomab

MUC16 (CA 125) Oregovomab

mTOR / AKT Temsirolimus, everolimus, deforolimus

Apoptosis pathway AEG35156, OGX-011

Angiogenesis Bevacizumab, sunitinib, sorafenib, pazopanib, cediranib, vatalanib

Endothelial cells Combretastatin, Oxi4503

Matrix metalloproteinases BAY 12-9566, marimastat

FIRST-LINE TRIAL OF BEVACIZUMAB IN OVARIAN CANCER (GOG#218)

Stage III°

Optimal and

Suboptimal or

Stage IV

R

A

N

D

O

M

I

Z

E

Paclitaxel/Carbo (PC) + placebo x6

placebo x16

PC+bev* x6 placebo x16

PC+bev x6 bev x16

*Dose of bevacizumab 15 mg/kg q 3 weeks

°Total number of patients 2000

KEY RESULTSTHERE IS CLEAR CLINICAL EFFECT OF BEVACIZUMAB ON PFS

• Per protocol analysis:

• Significant improvement of PFS in Arm III only

• Per protocol analysis: 3.8 mo increase PFS (med)HR 0.717, p <0.0001

• ~ half of all progression events occurred on therapy

Pro

po

rtio

n s

urv

ivin

g p

rog

ressio

n f

ree

Months from randomization

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

+ BEV (Arm

II)

Chemo (Arm I)

+ BEV → BEV maintenance (Arm

III)

• CA 125 censored PFS (sensitivity analysis):

– Similar outcomes (HR 0.645), but 25% fewer events

GOG 218

FIRST-LINE TRIAL OF BEVACIZUMAB IN OVARIAN CANCER (ICON - 7)

Stage Ic - IV°

Excluding those scheduled for further surgery

R

A

N

D

O

M

I

Z

E

Paclitaxel/Carbo (PC)

PC+bev* x6 bev x12

*Dose of bevacizumab 7.5 mg/kg q 3 weeks

°Total number of patients 1500

ICON-7: PFS

http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf

Accessed 15 October 2010

Academic analysis

Number at riskControl 234 205 98 36 14 2Research 231 213 159 56 10 1

PFS: FIGO STAGE III SUBOPTIMAL AND FIGO STAGE IV WITH DEBULKING

1.00

0.75

0.50

0.25

0

Pro

porti

on

ali

ve w

ith

ou

t p

ro

gressio

n

Time (months)0 3 6 9 12 15 18 21 24 27 30

Control

(n=234)

Research

(n=231)

Events, n (%) 173 (74) 158 (68)

Median, months 10.5 15.9

Log-rank test p<0.001

Hazard ratio (95% CI) 0.68 (0.55–0.85)

Restricted mean 13.3 16.5

10.5 15.9

ControlResearch

http://www.ctu.mrc.ac.uk/icon7/content_pages/documents/ICON7_%20ESMO%20Presidential%20Presentation.pdf

Accessed 15 October 2010

Kristensen G. et al, ASCO 2011, abstract #LBA5006

RECURRENT OVARIAN CANCER: IMPORTANT ISSUES

• Presentation (asymptomatic 55-70%; TFI*)

• Realistic goals

• When to treat

• How to treat

• New combinations and compounds

*<6 months; 6-12 months; <12 months

REALISTIC GOALS OF SECOND-LINE THERAPY IN OVARIAN CANCER

• Improve cancer-related symptoms

• Optimize overall quality of life

• Delay time to symptomatic disease progression

• Prolong overall survival

• Achieve an “objective response”

Markman M, 2002

Harries and Gore, 2002

WHEN TO TREAT?

Ovarian Ca…Conclusions

• Upfront surgery followed by 6 cycles of Pt-Tax-based CT is still standard

• Paclitaxel + carboplatin (TC) generally agreed standard arm for trials

• NACT followed by surgery in stages IIIc-IV OC showed the same OS and PFS as PDS with less morbidity in one large randomized GCIG trial.

• A dose-dense therapy approach may be of benefit

• Intraperitoneal chemotherapy suitable for selected patients

• Targeted therapy is promising, in particular anti-angiogenic approaches, however cost effectiveness questions remain.

The Physician’s Dilemma

To standardize? To individualize ?

This is the question!