Third Annual Maria Ricci Lecture Queen’s University and the NCIC CTG Clinical Trials Group Kingston, Ontario Canada

The Oxford Overview: Is it Still Relevant in 2010 ? Presented by KATHLEEN I. PRITCHARD, MD, FRCPC Sunnybrook Odette Cancer Centre University of Toronto Toronto, Canada

The Oxford Overview Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)

EBCTCG OVERVIEW Steering Committee K. Albain, S. Anderson, R. Arriagada, W. Barlow, J. Bergh, J. Bliss, M. Buyse, D. Cameron, M. Clarke, A. Coates, R. Collins, J. Costantino, J. Cuzick, S. Darby, N. Davidson, C. Davies, A. Di Leo, M. Dowsett, M. Ewertz, R. Gelber, C. Geyer, J. Godwin, A. Goldhirsch, R. Gray, D. Hayes, C. Hill, J. Ingle, R. Jakesz, M. Kaufmann, P. McGale, L. Norton, Y. Ohashi, S. Paik, E. Perez, R. Peto, M. Piccart, L. Pierce, G. Pruneri, K. Pritchard, V. Raina, P. Ravdin, J. Robertson, E. Rutgers, Y. F. Shao, S. Swain, C. Taylor, P. Valagussa, G. Viale, T. Whelan, E. Winer, Y. Wang, W. Wood.

EBCTCG OVERVIEW Oxford Secretariat Richard Peto Sarah Darby Mike Clarke Christina Davies Paul McGale Richard Gray Rory Collins Jon Godwin

EBCTCG OVERVIEW Steering Committee - Executive Marc Buyse Mike Clarke Rory Collins Sarah Darby Christina Davies Marianne Ewertz Martine Piccart Kathy Pritchard Eric Winer William Wood

EBCTCG OVERVIEW Past Chairs I. Craig Henderson William Wood Current Co-Chairs Kathy Pritchard Martine Piccart

EBCTCG September Preliminary results

EBCTCG OVERVIEW 1984 First overview process data sought from all randomized trials of systemic adjuvant therapy meta-analysis concept collaboration sought built sustained Trialists Secretariat

EBCTCG OVERVIEW Methodology Individual patient data dates of randomization treatment allocation age menopausal status nodes ER, PgR

EBCTCG OVERVIEW Methodology Data checked for internal consistency Data amended and updated by correspondence

EBCTCG OVERVIEW Methodology Each trial analysed separately Women in one trial are compared directly with only the women in the same trial One log rank statistic per trial Stratified by age and nodal status Combined to give an overall estimate of the effect of different treatments

EBCTCG OVERVIEW Outcomes Recurrence first reappearance of breast cancer includes contralateral breast cancer

EBCTCG OVERVIEW Outcomes Deaths unknown causes included with deaths from breast cancer unless specifically stated otherwise problem of death without recurrence

EBCTCG OVERVIEW Outcomes Breast Cancer Related Deaths deaths of/with breast cancer

EBCTCG OVERVIEW Outcomes Other Deaths cardiac stroke other cancers

EBCTCG OVERVIEW 1984 Tamoxifen improved survival CMF chemotherapy improved survival Ovarian ablation improved survival

EBCTCG OVERVIEW 1990 longer tamoxifen seemed better tamoxifen effects greater in ER+ve women tamoxifen reduced rate of contralateral breast cancer chemo effective in older and younger women

EBCTCG OVERVIEW 1995 huge magnitude of effect of 5 years of tamoxifen 5 years of tamoxifen clearly better than 1 or 2 tamoxifen prevented contralateral breast cancer only in women with ER+ve disease anthracycline containing regimens better than CMF

EBCTCG OVERVIEW year effects of chemo sustained in older and younger women chemo effect appears greater in ER negative than in ER positive disease But is this really true?

EBCTCG OVERVIEW year effects of 5 years of tamoxifen sustained and of great magnitude door opened to question of 5 years versus longer tamoxifen ovarian suppression/ablation effective but not significantly so when added to chemotherapy

EBCTG OVERVIEW Overview: Lancet, 2005 Trialists meet: new Steering Committee formed Many new trials added More women-years of follow-up for all major questions But major trials still missing

EBCTCG OVERVIEW 2006 Trialists met: new questions type of anthracycline-based regimen taxane trial status aromatase inhibitors trastuzumab chemoendocrine therapy (only in ER+, pre- and postmenopausal subsets) Subcommittees of the SC formed

EBCTCG OVERVIEW 2010 Tamoxifen AI’s Chemotherapy Locoregional therapy

2010 EBCTCG OVERVIEW TAMOXIFEN TAMOXIFEN VS NOT LONGER VS SHORTER TAM No of women 1 yr vs not 2 yr vs not 5 yr vs not – 4 vs 1 – 2 y 5 vs y 10 vs 5 y Median follow-up = 15y 22% are ER- PR- Median follow-up = 5y 50% are ER ?

2010 EBCTCG OVERVIEW Tamoxifen for 5y vs same management but No Tam Benefits (ER+) Risks (all) Proportional risk reductions Recurrence 38% (2p< ) BC mortality 30% (2p< ) All deaths 22% (2p< ) Contralateral BC 39% (2p< ) Death w/o recurrence * RR 1.05 (+ 0.07) 2p>0.1 Endometrial incidence RR 2.33 (+ 0.25) 2p< * Numerical excess of deaths due to stroke, pulmonary embolus, uterine cancer (15 vs 13 ; 6 vs 0; 8 vs 1) Absolute gain at 15y 13% 9%

2010 EBCTCG OVERVIEW Tamoxifen for 5y vs same management but no Tam Learning more about Tam benefits On types of B.C. events… In subgroups In relation to chemotherapy administration Over time…

2010 EBCTCG OVERVIEW Tamoxifen for 5y : Impact on BC events

2010 EBCTCG OVERVIEW Tamoxifen for 5y: Benefits in subgroups

2010 EBCTCG OVERVIEW Tamoxifen for 5y vs same management but no Tam

TAM for 5y : BENEFITS for whom ? AGE Nodal status Tumor grade Tumor diameter 2010 EBCTCG OVERVIEW Tamoxifen for 5y : Benefits in subgroups All do benefit !!

2010 EBCTCG OVERVIEW

2010 EBCTCG OVERVIEW

2010 EBCTCG OVERVIEW Tamoxifen for 5y: Benefits in subgroups TAM for 5y : BENEFITS for whom ? ER levels (fmol/mg prot) ER- PR- ER- PR+ ER+ PR+ ER+ PR- No Uncertain Yes

2010 EBCTCG OVERVIEW Tamoxifen for 5y : Benefit over time

2010 EBCTCG OVERVIEW Duration of adjuvant Tam and outcome

2010 EBCTCG OVERVIEW Impact of TAM duration Even 1y only provides significant benefit 10y provide small benefit which could ↑ over time

2010 EBCTCG OVERVIEW Tamoxifen for 10y : Benefits vs risks at 10 y Mean follow-up only 5y Benefits Risks Proportional risk reductions Recurrence 8% (2p=0.03) BC mortality 3% (2p>0.1) Contralateral BC Death w/o recurrence * + 1,5% (2p=0.59) Endometrial cancers + 0.7% (2p= ) *Numerical excess of deaths due to cerebrovascular events (42 vs 38 in y0-4; 27 vs 24 in y5-10), thrombo-embolic events (10 vs 56 in y0-4), end. cancers (8 vs 6 in y0-4, 4 vs 2 in y5-10) Absolute gain 1% (2p 0.03) 2,9% (2p 0.55) 1.3% (2p 0.03) Absolute Xcess

2010 EBCTCG OVERVIEW TAMOXIFEN 5y in ER+ disease reduces recurrence by 38%, BC death by 30% all deaths by 22% contralateral BC by 40% benefits all women with ER+ disease unclear benefits in ER-PgR+ disease benefits women with ER very rich tumors more increases endometrial cancer by 2.3 fold

2010 EBCTCG OVERVIEW TAMOXIFEN 10 yrs vs 5 yrs of adjuvant TAMOXIFEN in ER+/? Disease absolute reduction in recurrence by 1% (2p=0.03) reduces contralateral BC by 1.3% (2p=0.03) increases endometrial cancer by 0.7% (2p= ) reduces BC mortality by 3% (2p=0.55) increases death without recurrence by 1.5% (2p=0.59)

2010 EBCTCG OVERVIEW TAMOXIFEN Messages for clinical practice in 2010 PgR does not predict for benefit of adjuvant TAM For ER-PgR+ patients, the tumor should be retested and if doubt remains, TAM could be offered There is presently little incentive to prescribe more than 5y of TAM, especially in women with an uterus

EBCTCG SEPTEMBER 2010 Aromatase inhibitors

Data from 1 st analysis No unplanned cross-over Cut-off 30 Sept 2006 Cohort 1: 5yrs AI vs 5yrs tam Cohort 2: 2-3 yrs of AI vs 2-3 yrs of tam after 2-3 yrs tam

JCO, 2010, 28, years AI vs tamoxifen: trial-specific recurrence data

JCO, 2010, 28, years AI vs tamoxifen: life table curve, recurrence

JCO, 2010, 28, years AI vs tamoxifen: subgroup analysis, recurrence

JCO, 2010, 28, years AI vs tamoxifen: trial specific mortality data

JCO, 2010, 28, years AI vs tamoxifen: life table curves, br ca mortality

JCO, 2010, 28, years AI vs tamoxifen: life table curves, mortality (C) without recurrence, (D) all cause

JCO, 2010, 28, yr AI vs tam after 2-3 yrs tam: trial-specific recurrence data

JCO, 2010, 28, yr AI vs tam after 2-3 yrs tam: trial-specific recurrence data

JCO, 2010, 28, yr AI vs tam after 2-3 yrs tam: life table curve, recurrence

JCO, 2010, 28, yr AI vs tam after 2-3 yrs tam: subgroup analysis, recurrence

JCO, 2010, 28, yr AI vs tam after 2-3 yrs tam: trial specific mortality data

JCO, 2010, 28, yr AI vs tam after 2-3 yrs tam: life table curve, br ca mortality

JCO, 2010, 28, yr AI vs tam after 2-3 yrs tam: life table curve, mortality (C) without recurrence, (D) all cause

2010 EBCTCG OVERVIEW Aromatase Inhibitors Message for Clinical Practice in 2010 AIs > tamoxifen recurrence survival good given early after 2 yrs

N ≈ N ≈ EBCTCG OVERVIEW CHEMOTHERAPY Polychemo vs NOTAnthracycline (A) vs CMFTaxane (+A) vs A N = N = N = N ≈ 9500 N ≈ N ≈ N ≈ CMF vs NOT (only 5000 st CMF) Anthrac vs NOT (only 3000 of Mas strenght) Anthrac vs st CMF Tax + A vs lots of A Tax + A vs more A Tax + A vs same A

2010 EBCTCG OVERVIEW Polychemotherapy versus No chemotherapy 10y results in women

2010 EBCTCG OVERVIEW Polychemotherapy vs NIL : 10y results ANTHRACYCLINEANTHRACYCLINE CMFCMF STANDARDSSTANDARDS

2010 EBCTCG OVERVIEW Polychemotherapy vs NO CTX : 10y results Anthracycline vs No CTX CMF vs No CTX RR RR Recurrence BC mortalityRecurrence BC mortality A≥60 E≥90 Lower doses All A≥60 E≥90 Lower doses All St CMF other CMF All St CMF other CMF All

2010 EBCTCG OVERVIEW Polychemotherapy vs NIL Learning more about benefits Over time... In subgroups

2010 EBCTCG OVERVIEW Polychemotherapy vs NO CTX : Impact over time Anthracycline vs No CTX CMF vs No CTX Strong, early effect... !

2010 EBCTCG OVERVIEW Polychemotherapy vs NO CTX : Impact on recurrence in subgroups Anthracycline vs NO CTX Standard CMF vs NO CTX No indication of reduced benefit ! No indication of reduced benefit !

Tumour diameter PolyCTX vs No CTX Who benefits ? Tumour Grade AGE ER poor, + or ? Concurrent endocrine therapy Nodal Status 2010 EBCTCG OVERVIEW Polychemotherapy vs NO CTX : Benefits in subgroups All do benefit !

2010 EBCTCG OVERVIEW Anthracycline regimens vs standard CMF 10y results in women

ACX4ACX4 ANTHRACYCLINEANTHRACYCLINE MOREMORE 2010 EBCTCG OVERVIEW

EBCTCG OVERVIEW Anthracycline vs standard CMF : 10 y results mortality with recurrence Ratio of annual death rates Any A regimen Cum dose A 360 E Cum dose A 300 E Cum dose A ≤ 360 Dose per cycle < A60, E90 Dose per cycle ≥ A60, E90

2010 EBCTCG OVERVIEW Taxane + Anthracycline regimens vs Anthracycline regimens 5y results in women

2010 EBCTCG OVERVIEW T + A Vs s a m e A T + A Vs m o r e A

EBCTCG OVERVIEW Taxane + Anthracycline vs A : 5 y results in women Recurrence Mortality w/ recurrence Ratio of annual event rates all T+A vs same A T+A vs more A T+A vs int A T+A vs int A T+A vs more A T+A vs same A all 2p< p= p< pNS 2p= p= p=0.0032pNS

2010 EBCTCG OVERVIEW: Polychemotherapy : Impact on recurrence over time Anthracycline vs st CMF Anthracycline (A) + Taxane vs A EARLY IMPACT EARLY and LATE IMPACT

2010 EBCTCG OVERVIEW Taxane + Anthracycline vs A : Impact on recurrence in subgroups No indication of reduced benefit !

2010 EBCTCG OVERVIEW POLYCHEMOTHERAPY Messages for clinical practice in 2010 Taxane-based regimens Reduced in recurrence (2.8%) Reduced mortality with recurrence (1.3%) Except when compared to very well dosed (total 2x2) anthracycline-based regimens Effect seems independent from the recorded tumor characteristics (with lack on information on HER2) Effect persists over 5 years

Effect of Radiotherapy after Breast-conserving Surgery on 10-year Recurrence and 15-year Mortality in Women with Early Breast Cancer EBCTCG September Preliminary results

Randomised trials of radiotherapy following breast-conserving surgery (BCS ± RT) that began before the year 2000

EBCTCG September Preliminary results Proportional effect of radiotherapy after breast-conserving surgery (BCS ± RT) women, pN0/pN+/pN? Any recurrence Breast cancer mortality

EBCTCG September Preliminary results Absolute effect of radiotherapy after breast conserving surgery (BCS ± RT): women pN0/pN+/pN? Any recurrence Breast cancer mortality Any death

EBCTCG September Preliminary results Effect of radiotherapy after breast-conserving surgery (BCS ± RT): 1100 pN+ women Any recurrence Breast cancer mortality “One-in-four rule” one breast cancer death avoided for every 4 recurrences avoided

EBCTCG September Preliminary results Absolute effect of radiotherapy after breast- conserving surgery (BCS ± RT): 7300 pN0 women Any recurrence Breast cancer mortality “One-in-four rule” one breast cancer death avoided for every 4 recurrences avoided

Conclusions Radiotherapy highly effective in reducing recurrence in both pN0 and pN+ women Radiotherapy also reduces 15-year breast cancer “One-in-four” rule applies for pN0 and pN1 women Benefits not substantially reduced by fatal side-effects EBCTCG September Preliminary results

The Oxford Overview: Is it Still Relevant in 2010 ?

YES

EBCTCG OVERVIEW Tamoxifen 5 +/- 5 years 30% - 40% in recurrence 25 in deaths

EBCTCG OVERVIEW AIs Better than Tam for all subgroups 25% in recurrence 0 – 25% in BC mortality

EBCTCG OVERVIEW AIs ? Stronger effect after two years of tamoxifen

EBCTCG OVERVIEW Chemotherapy vs None CMF/AC 20 – 30% recurrence 10 – 30% BC mortality A vs CMF

EBCTCG OVERVIEW Adriamycin vs Standard CMF 10 – 20% recurrence 10 – 20% mortality

EBCTCG OVERVIEW Taxanes vs Non-Taxanes 10 – 20% recurrence 10% BC mortality

EBCTCG OVERVIEW Natural History of Breast Cancer ER/PgR +ve ER and PgR -ve

EBCTCG OVERVIEW By having all data avoids publication bias gives average effect size clarifies time frames of effects process / outcomes both useful

EBCTCG OVERVIEW Future – Yes Publications 3 on radiation results one on chemotherapy 2011 one on AIs 2011 Meet Again September 19-22, 2012

EBCTCG OVERVIEW Future – Yes Publications 3 on radiation results one on chemotherapy 2011 one on AIs 2011 Meet Again September 19-22, 2012

EBCTCG SEPTEMBER

EBCTCG SEPTEMBER 2010