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

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.

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

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

  2. 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

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

  4. 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.

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

  6. 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

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

  8. EBCTCG September 2010. Preliminary results

  9. 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

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

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

  12. 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

  13. EBCTCG OVERVIEW Outcomes  Recurrence  first reappearance of breast cancer  includes contralateral breast cancer

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

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

  16. EBCTCG OVERVIEW Outcomes  Other Deaths  cardiac  stroke  other cancers

  17. EBCTCG OVERVIEW 1984  Tamoxifen improved survival  CMF chemotherapy improved survival  Ovarian ablation improved survival

  18. 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

  19. 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

  20. EBCTCG OVERVIEW 2000  15 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?

  21. EBCTCG OVERVIEW 2000  15 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

  22. EBCTG OVERVIEW 2005  2000 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

  23. 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

  24. EBCTCG OVERVIEW 2010  Tamoxifen  AI’s  Chemotherapy  Locoregional therapy

  25. 2010 EBCTCG OVERVIEWTAMOXIFEN TAMOXIFEN VS NOT LONGER VS SHORTER TAM No of women No of women 2 – 4 vs 1 – 2 y 5 vs 1 - 2 y 10 vs 5 y 3200 20000 22000 1 yr vs not 2 yr vs not 5 yr vs not 9126 23940 21457 45200 54523 Median follow-up = 15y 22% are ER- PR- Median follow-up = 5y 50% are ER ?

  26. 2010 EBCTCG OVERVIEWTamoxifen for 5y vs same management but No Tam Risks (all) Benefits (ER+) Death w/o recurrence * RR 1.05 (+ 0.07) 2p>0.1 Endometrial incidence RR 2.33 (+ 0.25) 2p<0.00001 Absolute gain at 15y • Proportional risk reductions • Recurrence 38% (2p<0.00001) • BC mortality 30% (2p<0.00001) • All deaths 22% (2p<0.00001) • Contralateral BC 39% (2p<0.00001) 13% 9% * Numerical excess of deaths due to stroke, pulmonary embolus, uterine cancer (15 vs 13 ; 6 vs 0; 8 vs 1)

  27. 2010 EBCTCG OVERVIEWTamoxifen 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…

  28. 2010 EBCTCG OVERVIEWTamoxifen for 5y : Impact on BC events

  29. 2010 EBCTCG OVERVIEWTamoxifen for 5y: Benefits in subgroups

  30. 2010 EBCTCG OVERVIEWTamoxifen for 5y vs same management but no Tam

  31. 2010 EBCTCG OVERVIEWTamoxifen for 5y : Benefits in subgroups Nodal status AGE TAM for 5y : BENEFITS for whom ? Tumor diameter Tumor grade All do benefit !!

  32. 2010 EBCTCG OVERVIEW

  33. 2010 EBCTCG OVERVIEW

  34. 2010 EBCTCG OVERVIEWTamoxifen for 5y: Benefits in subgroups Yes No ER levels (fmol/mg prot) ER+ PR+ ER- PR- TAM for 5y : BENEFITS for whom ? ER- PR+ ER+ PR- Uncertain Yes

  35. 2010 EBCTCG OVERVIEWTamoxifen for 5y : Benefit over time

  36. 2010 EBCTCG OVERVIEW Duration of adjuvant Tam and outcome

  37. 2010 EBCTCG OVERVIEWImpact of TAM duration Even 1y only provides significant benefit 10y provide small benefit which could ↑ over time

  38. 2010 EBCTCG OVERVIEWTamoxifen for 10y : Benefits vs risks at 10 yMean follow-up only 5y Risks Benefits Absolute Xcess Absolute gain • 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=0.00004) 1% (2p 0.03) 2,9% (2p 0.55) 1.3% (2p 0.03) *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)

  39. 2010 EBCTCG OVERVIEWTAMOXIFEN 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

  40. 2010 EBCTCG OVERVIEWTAMOXIFEN 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=0.00004) reduces BC mortality by 3% (2p=0.55)  increases death without recurrence by 1.5% (2p=0.59)

  41. 2010 EBCTCG OVERVIEWTAMOXIFEN 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

  42. Aromatase inhibitors EBCTCG SEPTEMBER 2010

  43. Data from 1st 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

  44. 5 years AI vs tamoxifen: trial-specific recurrence data JCO, 2010, 28, 509-518

  45. 5 years AI vs tamoxifen: life table curve, recurrence JCO, 2010, 28, 509-518

  46. 5 years AI vs tamoxifen: life table curves, br ca mortality JCO, 2010, 28, 509-518

  47. 2-3yr AI vs tam after 2-3 yrs tam: life table curve, recurrence JCO, 2010, 28, 509-518

  48. 2-3yr AI vs tam after 2-3 yrs tam: life table curve, br ca mortality JCO, 2010, 28, 509-518

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