BREAST CANCERTRIALS AND TRIBULATIONS

Vivien Bramwell, MBBS, PhD, FRCPCClinical Professor, Department of Oncology,

University of CalgaryHead of Medical Oncology, Tom Baker Cancer Centre

Cancer Care, Alberta Health Services

October 2009

Objectives

1. To review the development, conduct and results of selected Cooperative Group (NCIC CTG) randomized clinical trials of treatment for early breast cancer (EBC)

2. To illustrate opportunities that arose, during the conduct of these trials, to explore additional endpoints/outcomes

3. To share lessons learned

NCIC CTG trials reviewed

Trial Dates Accrual Outcomes

MA.5 1989 – 1993 710 (1) RFS(2) OS, toxicity, QOL

MA.12 1993 – 2000 672 (1) OS(2) DFS, toxicity, compliance

MA.14 1996 – 2000 667 (1) EFS(2) OS, toxicity, QOL

MA.21 2000 – 2005 2,104 (1) RFS(2) OS, toxicity, QOL

NCIC CTG TRIALS − correlative studiesMA.5 • prognostic impact of amenorrhea

• prognostic/predictive value of HER2 overexpression• prognostic/predictive value of TOPO IIα alteration• anthracyclines in basal breast cancer

MA.12 • compliance with oral hormone therapy*• relationship of sequential hormone levels to outcomes*• relationship of biological classification to outcome• differential expression of OPN in biological subtypes• estrogen receptor profiling to better predict response

to hormone therapy

MA.14 • metabolic markers of insulin resistance*• markers of bone resorption and outcomes• OPN as a tissue and blood prognostic marker

MA.21 • triple negative breast cancer and prognosis

*pre-planned analysis, integral to study

Translational studies of osteopontin (OPN)

OPN is a secreted integrin-binding protein that has been associated with cancer and other pathologies. It can be measured in blood and tissue using an ELISA developed by Dr. Ann Chambers

Clinical studies in breast cancer (London Regional Cancer Centre)

• assays in blood plasma of normal women 1994

• assays in different stages of breast cancer 1995-1996

• assays in primary tumor tissue 1997 onwards

• prospective study in metastatic breast cancer 1997-1999

OPN − experimental studies

• OPN is a secreted integrin-binding protein produced in avariety of tissues and cell types

• OPN is a tumor associated protein

• OPN contributes functionally to tumor progression/metastasis

• OPN is linked with angiogenesis, cell survival, resistance toto apoptosis

OPN − clinical studies (using OPN ELISA)

• OPN plasma levels in 35 healthy womenmedian 47 (22 – 122) ng/ml

• OPN plasma levels in 44 controls(completed treatment for early breast cancer)

median 60 (15 – 117) ng/ml

• OPN plasma levels in 70 metastatic breast cancersmedian 142 (38 – 1312) ng/ml

• OPN expression (IHC) in 154 primary breast cancerscorrelates with survival (p = 0.014)

• OPN expression is higher in 33 sentinel LN than in paired primary tumors (p <0.001)

• OPN is expressed in other human cancers

OPN − study population and treatment

Accrual July 1997 – November 1999

Total Population 158*Age (yrs) 61 (20-84)Postmenopausal 138 (87%)Stage localized → metastatic 123 (78%)

metastatic (initial) 35 (22%)

First systemic treatment for metastasishormone 111 (70%)chemotherapy 43 (27%)none 4 (3%)

Database closed July 2003 − median survival 20 mos− patients alive 26 (16.5%)

*one patient registered but withdrew before baseline OPN collected

OPN − sample collection

Number of samples:

total samples 1378median (range)/patient 9 (1-26)baseline level median 177* (1-2648) ng/ml# with elevated levels 99 (63%)

Time interval:

from first to last sample median 13 (1-61) mosfrom last sample to death median 2 (1-35) mos

*upper limit of normal 123 ng/ml

OPN - Survival according to baseline OPN levels

OPN − conclusions

• in univariate analysis, elevated baseline OPN was associated with decreased survival (p = 0.02)

• in a multivariate model incorporating standard prognostic factors, baseline OPN was significantly associated with survival duration

(RR = 1.001 ; p = 0.038)MFI, visceral metastases, low ECOG also significant

• in a multivariate model incorporating standard prognostic factors and changes in sequential OPN levels

– OPN increase >250 ng/ml at any time wasmost prognostic for poor survival (RR = 3.26 ; P = 0.0003)

– low ECOG also significant

• sequential monitoring of OPN may have utility in making management decisions for women with metastatic breast cancer

V. Bramwell Clin Cancer Res 12:3337, 2006

NCIC CTG MA.5 − rationale (1988)

• trials of adjuvant chemotherapy (CMF or AC) in EBC showed improved RFS/OS compared with no chemotherapy

• benefit was greatest in premenopausal women

• dose intensity seemed to be important

• anthracyclines showed superior activity in metastatic BC

• 1985-1988 pilot dose escalation study (OCOG) performed to develop dose intense CEF* regimen

• plan to compare CEF vs CMF in premenopausal population with node positive BC

*Cyclophosphamide/Epirubicin/Fluorouracil

NCIC CTG MA.5 - outcomes

10 y DFS5 y OS10 y DFS5 y DFSCMF (100/40/600) 53% 45% 70% 58%

q4w x 6

CEF (75/60/500) 63% 52% 77% 62%q4w x 6 p=0.009 p=0.005 p=0.03 p=0.047

M. Levine J Clin Oncol 16:2651, 199823:5166, 2005

• 710 women; all premenopausal• Node +ve; approx 70% ER+ve, no Tam• HR recurrence 1.30; HR death 1.22 5 yr• HR recurrence 1.31; HR death 1.18 10 yr

LRCC highest accrual 125 pts

NCIC CTG MA.12 − rationale

• protocol developed in 1992

• data very limited on premenopausal women, ER +ve/unknown tumors<200 women entered trials CT ± T for 5 yrs

• adjuvant CT frequently causes premature menopause− benefits both cytotoxic and endocrine, especially if ER +ve

• effect T in ER poor/-ve tumors uncertain

• experimental data − CT less effective if given concurrent with T

• need for study in premenopausal women with EBC, evaluating efficacy of 5 yrs of T following completion adequate adjuvant CT

• placebo (P) control facilitated evaluation of toxicity and compliance

NCIC CTG MA.12 − schema

Biopsy RANDOMIZE

total/partial mastectomy + axillary nodedissection

Chemotherapy, last IV dose

Tamoxifen 20 mg/dayx 5 yrs

Surgery Start within 6 weeks(concurrent with XRT, if given)

Placebo 20 mg/dayx 5 yrs

Objectives − Premenopausal women with EBC

1. To compare duration of overall survival (OS) in premenopausal node positive* breast cancer patients given T vs P for 5 yrs after adjuvant CT

2. To compare disease-free survival (DFS) and toxicities between the two arms

*1995 – include high risk node negative (≤ 1 cm and high grade or LVI +ve)

REGISTRATION

NCIC CTG MA.12 − planned analysis

• planned sample size 800 pts accrued over 5 yrs (160/yr)detect 8% difference in overall survival

70% (P) 78% (T) HR 0.6980% power 2 sided p = 0.05

requires 242 deaths for final analysis• 2 planned interim analyses 80 and 160 deaths

• July 1993 – April 2000: 672 pts accrued (1999−2000 42 pts)

• April 2000: DSMC recommended closure, due to slow accrual,projected still possible to observe 242 deaths with further 5 yrs FU

• Sept. 2000: first interim analysis to DSMC – continue study

• April 2006: overall survival in study better than projected second interim analysis to DSMC

• Sept. 2006: futility analysis, DSMC agreed to release results,possibility of combining data with other similar studies in IPDMA

NCIC CTG MA.12 − compliance issues

• only 52% women (similar T/P) completed full 5 yrs study medication

• rate of discontinuation due to recurrence/death lower in T vs P (15% vs 23%)

• more women stopped T vs P (8.5% vs 5%) because of toxicity, − unlikely most of these took additional hormonal therapy

• rates of refusal T vs P (13% vs 11%) similar− probable that many went on to receive open-label T

• greater attrition occurred during first 24 mos therapy− when T most likely to be effective (EBCTCG analyses 1992)

• around 50% of women developed amenorrhea after completion CT before starting T/P− menopausal symptoms attributed as toxicity of

study medications may have reduced compliance

NCIC CTG MA.12 − compliance comparison other studies

• 3 other studies of similar design also had similar compliance problems

• compliance rates were better in AI studies, with about 20% of patients stopping AI or T, but women were already menopausal

• in cohort of 2816 Irish women (pre & postmenopausal) receiving adjuvant T, many stopped medication early (22% by 1 yr, 35% by 3.5 yrs)

• in a cohort of 1633 Scottish women, longer duration of adjuvant Twas associated with improved OS

• 672 premenopausal women, after completion of adjuvant CT, were randomized to T vs P for 5 yrs

• at median FU 9.7 yrs, for T vs P at 5 yrs

OS 87% vs 82% HR 0.78 (95% CI 0.57-1.07),p = 0.12DFS 78% vs 71% HR 0.77 (95% CI 0.59-1.01),p = 0.055

• no evidence of greater benefit for hormone receptor +ve subgroup (75%)

• compliance with T vs P was suboptimal in both arms, only 52% completing 5 yrs of treatment

• poor compliance is likely to have influenced the efficacy of treatment in this trial, and other similar studies

• these findings have implications for use of oral anti-cancermedications in many settingsV. Bramwell Ann Oncol. Epub ahead of print, July 2009

NCIC CTG MA.12 − key findings

NCIC CTG MA.12 − serum collection − objectives

1. To determine if there is a difference in effect of T on OS, based on menopausal status (defined by FSH/LH, estradiol levels) at randomization (post-chemotherapy)

2. To determine if T increases the probability of becoming biochemically postmenopausal within 5 yrs of randomization

3. To determine if T causes higher estradiol levels in patients who are premenopausal at randomization

Objectives

Collection planPrechemotherapy (registration)Prerandomization T/PPostrandomization 3 mos, 6 mos year 1

every 6 mos years 2−5Relapse

NCIC CTG MA.12 − serum collection – status (2005)

Total # specimens* : approx 2800

Total patientsPre-chemo specimen : 225 (33%)During chemo : 262 (39%)Pre-chemo and/or : 325 (48%)

during chemoPre-randomization : 313 (46%)Multiple post TP : 320 (48%)

randomizationRelapse : unknown

*based on case report forms

DNA MICROARRAY GENE EXPRESSION PROFILING REVEALS SIGNATURES OF BREAST CANCER SUBTYPES WITH PROGNOSTIC VALUEPerou CM et al Nature 2000; 406:747. Sorlie T et al PNAS 2001; 98:10869.

BASAL HER2 LUMINAL ALUMINAL B

The Major Breast Cancer Intrinsic Biological Subtypes

Lum ALum A Lum BLum B HER2HER2 basalbasal

++ ++ -- --

-- ++ ++ ++

-- +/+/-- ++ --

-- -- -- ++

Estrogen Response genes:ESR1, PGR, GATA3, FOXA1

Proliferation genes:MKI67, CCNB1, CENPF, FOXA1, MYBL2, ORC6L

HER2-associated:ERBB2, GRB7

Basal markers: KRT5, KRT17, ERBB1,

TRIM29, CRYAB

BIOLOGICAL CLASSIFICATION Immunohistochemistry (IHC)

Luminal A ER+ or PR+ AND HER2– Ki67–

Luminal B ER+ or PR+ AND Ki67+ OR HER2+

HER2+ ER–/PR– AND HER2+

Basal ER–/PR– AND HER2– AND CK5/6+

NCIC CTG MA.12 − OPN study

Hypothesis : OPN expression by IHC, and its prognostic significance will differ across biological subtypes of BC – Luminal A, B, HER2+, basal

Analysis : TMA (492 patient samples)

(1) OPN expression (IHC) − scored by Dr. A. Tuck* (London)

(2) OPN expression (IHC) − automated (AQUA)analysis byDr. A. Magliocco (Calgary)

*comparison with 72 MA.12 specimens scored in whole sections

NCIC CTG MA.14 − outcomes

Tamoxifen (T) 20 mg/d x 5 yr

Tamoxifen (T) 20 mg/d x 5 yrOctreotide LAR (O) 90 mg IM/mos x 5 yr*

Serum collected for markers of insulin resistance at multiple time points over 5 yr

M. Pollak J Clin Oncol 26:145 A532, 2008

• 667 women : all postmenopausal, receptor +ve

• median FU 7.9 yrs, 220 events

• no difference in EFS HR 0.93, p = 0.62

• unacceptable level of cholelithiasis, therefore duration O reduced to 2 yrs in July 2000*

NCIC CTG MA.14 − OPN study objectives

Objectives:

1. To evaluate whether baseline plasma OPN levels are prognostic for RFS and/or OS

2. To explore changes in plasma OPN levels over time in relationship to RFS, or bone-only RFS

3. To explore differences in plasma OPN levels from baseline to recurrence

4. To evaluate whether baseline primary tumor OPN IHC levels are prognostic for RFS and/or OS

5. To explore whether baseline tumor OPN levels are associated with plasma OPN levels

NCIC CTG MA.14 − OPN study collection (started Nov 1998)

Plasma collectionTime period # plasma samples

Baseline 3314 mos 3478 mos 38712 mos 40524 mos 20936-48 mos 541End treatment/60 mos 271Recurrence 35Total samples 2526# with samples 656 (98% of 667)

Tumor collectionTime period # tumor samples

Baseline 419 (63% of 667)

NCIC CTG MA.21 − rationale

• AC is equivalent to CMF (NSABP B15, B23)

• CEF is better than CMF (NCIC MA.5)

• AC → Paclitaxel (P) is better than AC (CALGB 9344)

• CEF is standard adjuvant regimen in Canada

• AC → P is standard adjuvant regimen in US

• by indirect comparison CEF and AC → P regimens may have similar efficacy

• for locally advanced breast cancer EC and CEF have similar efficacy and toxicity

• EC → P may be more effective than CEF or AC → P

NCIC CTG MA.21 − outcomes

3 y DFSCEF q4w x 6 90.1%

EC q2w x 6 → P q3w x 4 89.5%(120/830)

AC q3w x 4 → P q3w x 4 85%

M. Burnell J Clin Oncol In Press, October 2009• 2104 women*; pre/post menopausal age ≤60 y : median FU 30 m• 82% node +ve; 60% receptor +ve → sequential T; 16% HER2 +ve• 3 y DFS

AC → P vs CEF RR 1.49 p = 0.005AC → P vs EC/P RR 1.68 p = 0.0006EC → P vs CEF RR 0.89 p = 0.46

*V. Bramwell in London/Calgary contributed 118 pts

NCIC CTG MA.21 − correlative science studies

M. Burnell J Clin Oncol 26:18S A550, 2008

• 1623/2104 (77%) primary tumors had assays performed for ER, PR and HER2 (local institutions)

• 551 (34%) were triple negative

• compared with all other groups, triple negative had worse3 yr RFS 80.5% vs 86.5%, p<0.0002

• too early to evaluate whether triple negative group benefit more from one of the 3 types of chemotherapy

MA.21 Tumor bank status October 2009Tissue 1370/2104 (65%)Blocks 1120/2104 (53%)Slides 914/2104 (43%)

Lessons learned

• there are many excellent reasons to participate in Cooperative Group activities (vs Industry)

• make active contributions – these will be noticed and recognized

• if invited to be a Principal Investigator – make your mark!

• incorporate a tumor specimen bank into the clinical trial protocol

• tumor banks need to be well-organized and adequately funded

• be open/search for opportunities for trial-relatedtranslational research studies

• cultivate collaborations with scientists in your own institution, but also establish networks across the country

AcknowledgementsNCIC CTG Breast Chair Kathy Pritchard

Disease Site Committee Trial PIs Mark Levine (MA.5)Michael Pollak (MA.14)Margot Burnell (MA.21)

Statisticians Dongsheng TuJudy-Anne Chapman

Pathologist Lois Shepherd

OPN Team Leader/Scientist Ann ChambersPathologist Alan TuckScientist Allison AllanStatisticians Gordon Doig

Larry Stitt

Other Collaborators Pathologist Tony MaglioccoClinician Marc Webster

Pathologist/Scientist Torsten NielsenClinician Stephen Chia

London, ON

Calgary, AB

Vancouver BC

WOMEN WHO PARTICIPATED IN OUR BREAST CANCER STUDIES