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NCT00688740 Sponsored by sanofi-aventis

Ten-year follow-up analysis of the BCIRG 001 trial confirms superior DFS and OS benefit of adjuvant TAC ( docetaxel , doxorubicin, cyclophosphamide ) over FAC (fluorouracil, doxorubicin, cyclophosphamide ) in women with operable node-positive breast cancer.

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NCT00688740 Sponsored by sanofi-aventis

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  1. Ten-year follow-up analysis of the BCIRG 001 trialconfirms superior DFS and OS benefit of adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide) over FAC (fluorouracil, doxorubicin, cyclophosphamide)in women with operable node-positive breast cancer Martin M, Mackey J, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano M, Vinholes J, Pinter T, Childs B, Roessner M, Wilson V, Rupin M, Vogel Con behalf of the BCIRG 001 Investigators NCT00688740 Sponsored by sanofi-aventis

  2. Disclosures Dr Martin has received speaker's honoraria from Sanofi-Aventis

  3. Adjuvant Chemotherapy Adding a taxane to adjuvant anthracycline-based regimens improves survival in patients with early breast cancer1,2 The BCIRG 001 (TAX316) study showed that TAC reduces the risk of relapse and death compared with FAC in patients with node-positive early breast cancer3 Planned interim analysis; 399 DFS events Median follow-up 55 months; data cut-off 15 July 2003 DFS HR=0.72  (95%CI 0.59–0.88, P=0.001)  OS HR=0.70 (95%CI 0.53–0.91, P=0.008) • 1Nowak AK, et al. Lancet Oncol 2004;5:372–380 • 2De Laurentiis M, et al. J Clin Oncol 2008;26:44–53 • 3Martin M, et al. N Engl J Med 2005;352:2302–2313

  4. Final Analysis at 10-year Median Follow-up DFS (primary endpoint) and OS Rates of long-term toxicities, including cardiac events and hematologic malignancies Data cut-off 11 March 2010

  5. Trial Design T A C R n=1491 20 countries 112 centers Docetaxel 75 mg/m2Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 Every 3 weeks for 6 cycles • Stratification • Nodal status 1-3 4+ • Center F Fluorouracil 500 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 A C Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin500 mg bid, days 5–14 No primary G-CSF prophylaxis was allowed

  6. Post Chemotherapy Treatment T A C F A C • Tamoxifen 20 mg/day for 5 years • Patients with ER and/or PR positive tumors • Radiation Therapy • All patients having breast-conserving surgery • Each center’s guidelines after mastectomy

  7. Major Eligibility Criteria Histologically proven node-positive breast cancer Definitive surgery with axillary lymph node dissection Stage T1–3, N1, M0 Normal hematologic, hepatic, renal, and cardiac function No more than 60 days between surgeryand randomization Age ≤70 years and KPS ≥80% Written informed consent

  8. End Points and Follow-up Objectives Primary: disease-free survival Secondary: overall survival, safety,quality of life, tumor markers Timing for follow-up visits Every 3 months for the first 2 years Every 6 months up to year 5 Yearly from years 5 to 10 Annual LVEF monitoring to evaluate long-term cardiac risk

  9. Statistics DFS (primary analysis) Intention-to-treat (ITT) Log‑rank test, stratified for nodal status(1 to 3 versus 4+ positive nodes) HR and 95% CI by Cox proportional hazards regression model Adverse Events NCI‑CTC, version 1.0 Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART)

  10. Characteristics of the Patients (ITT) Enrollment: 11 June 1997 to 03 June 1999

  11. Tumor Characteristics *Centrally reviewed

  12. DFS Events (ITT) at 10 Years NED=no evidence of disease

  13. FAC 746 730 699 659 618 584 558 541 523 510 499 484 471 453 437 429 414 392 378 351 333 DFS at a Median 10-year Follow-up (ITT) 1.00 TAC: 76% 0.80 HR=0.7295%CI: 0.59–0.88Log-rank P=0.001 0.60 FAC: 69% Disease-free survival probability HR=0.8095%CI: 0.68–0.93Log-rank P=0.0043 0.40 0.20 0.00 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 Disease-free survival time (months) Number at Risk TAC 745 737 710 678 659 639 617 596 583 562 551 541 530 519 508 491 478 463 444 418 387

  14. DFS in Predefined Subgroups 0.2 0.6 1.0 1.4 1.8 2.2 In favor of TAC In favor of FAC Overall ITT Adjusted* 0.80 (0.68 to 0.93) 1491 Number of positive nodes [1-3] 0.72 (0.58 to 0.91) 926 Number of positive nodes [4+] 0.87 (0.70 to 1.09) 565 Hormonal Receptor status Negative 0.66 (0.49 to 0.89) 359 Hormonal Receptor status Positive 0.84 (0.70 to 1.01) 1132 HER2/NEU status Negative 0.88 (0.72 to 1.08) 943 HER2/NEU status Positive 0.60 (0.43 to 0.83) 319 HER2/NEU status Unknown 0.80 (0.54 to 1.18) 229 Menopausal status Pre-menopausal 0.69 (0.55 to 0.86) 830 Menopausal status Post-menopausal 0.93 (0.74 to 1.16) 661 *Adjusted for nodal status Hazard Ratio (95%CI)

  15. HR=0.7495%CI: 0.61–0.90Log-rank P=0.002 OS at a Median 10-year Follow-up (ITT) 1.00 TAC: 87% HR=0.7095%CI: 0.53–0.91Log-rank P=0.008 0.80 FAC: 81% 0.60 Overall survival probability 0.40 0.20 0.00 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 Survival time (months) Number at Risk TAC 745 742 732 718 704 693 677 661 650 645 635 622 612 603 594 584 571 563 547 524 495 FAC 746 740 731 724 704 684 657 642 625 608 591 581 573 557 546 532 517 501 482 460 443 • 429 deaths: 188 TAC; 241 FAC

  16. OS in Predefined Subgroups 0.2 0.6 1.0 1.4 1.8 2.2 In favor of TAC In favor of FAC Overall ITT Adjusted* 0.74 (0.61 to 0.90) 1491 Number of positive nodes [1–3] 0.62 (0.46 to 0.82) 926 Number of positive nodes [4+] 0.87 (0.67 to 1.12) 565 Hormonal Receptor status Negative 0.69 (0.49 to 0.96) 359 Hormonal Receptor status Positive 0.76 (0.60 to 0.96) 1132 HER2/NEU status Negative 0.79 (0.61 to 1.01) 943 HER2/NEU status Positive 0.66 (0.45 to 0.96) 319 HER2/NEU status Unknown 0.71 (0.44 to 1.14) 229 Menopausal status Pre-menopausal 0.65 (0.49 to 0.85) 830 Menopausal status Post-menopausal 0.85 (0.65 to 1.11) 661 *Adjusted for nodal status Hazard Ratio (95%CI)

  17. Cardiac Toxicities Reported as an AE *Comparison of CHF rates not statistically significant:TAC 3.5% (95%CI: 2.3–5.1) vs FAC 2.3% (95%CI: 1.4–3.7); Chi‑square P=0.18

  18. Cumulative Incidence of CHF 0.08 0.07 0.06 0.05 Probability of CHF 0.04 TAC FAC 0.03 0.02 0.01 0.00 0 12 24 36 48 60 72 84 96 108 120 Time from randomization to CHF event (months) Number at Risk TAC 744 713 679 647 620 591 566 540 515 484 437 FAC 736 716 672 621 588 554 522 490 466 429 392

  19. Changes in LVEF *Evaluable patients had an LVEF assessment at baseline and during the study period. †Lower normal limit was 50% if normal limit was unknown.

  20. Hematologic Malignancies at 10 Years

  21. Serious Adverse Events SAEs occurred more frequently with TAC, but at lower rates during follow-up  treatment (TAC 36%; FAC 9%) follow‑up (TAC 7%; FAC 5%) During treatment, main AEs were hematologic grade 3 or 4 neutropenia 66% TAC; 49% FAC febrile neutropenia 25% TAC; 3% FAC Most common AEs persisting into follow-up period asthenia (TAC 32%; FAC 24%) amenorrhea (TAC 47%; FAC 30%) Rates of AEs starting or worsening during the follow‑up period were similar except for peripheral sensory neuropathy(TAC 4%; FAC 1%)

  22. Efficacy Summary The survival benefit of TAC over FAC is maintainedat a median follow-up of 10 years DFS 20% reduction in risk of relapse (P=0.0043) 10-year DFS rates: TAC 62%, FAC 55% OS 26% reduction in risk of death (P=0.002) 10-year OS rates: TAC 76%, FAC 69% TAC improves DFS irrespective of nodal, hormone receptor, or HER2/neu status

  23. Safety Summary CHF was reported in 3.5% and 2.3% of patients treated with TAC and FAC, respectively (P=0.18) Most CHF cases were grade 3 CHF was fatal in 2 TAC patients and 4 FAC patients Significant LVEF decreases (>20%) were similar between treatment groups (TAC 17%, FAC 15%) Hematological malignancies were reported in 6 (0.8%) and 3 (0.4%) patients treated with TAC and FAC (P=0.51; Fisher’s exact test)

  24. Conclusions The 10-year follow-up analysis confirms that adjuvant docetaxel combined with doxorubicin and cyclophosphamide (TAC) provides a long-term disease-free survival and overall survival benefit in the treatment of women with node-positive early breast cancer

  25. Acknowledgments The women who participated in the study and those who returned for follow-up The investigators and their staff The Independent Data Monitoring Committee The Study Co-Chairs (John Mackey, Charles Vogel) The CIRG staff (Agathe Garcia, Matthieu Rupin)

  26. Investigators

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