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1 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 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 C on behalf of the BCIRG 001 Investigators NCT Sponsored by sanofi-aventis

2 Dr Martin has received speaker's honoraria from Sanofi-Aventis
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 R Trial Design T A C Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2
20 countries 112 centers T A C Docetaxel 75 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 R Every 3 weeks for 6 cycles Stratification Nodal status Center F Fluorouracil 500 mg/m2 Doxorubicin 50 mg/m2 Cyclophosphamide 500 mg/m2 A C Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, days 5–14 No primary G-CSF prophylaxis was allowed

6 Post Chemotherapy Treatment
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 T A C F A C

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 surgery and 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) Adverse Events
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)
TAC (n=745) FAC (n=746) Median age, range 49 (26–70) 49 (23–70) Median KPS 100 Premenopausal, % 57 55 Mastectomy, % 60 59 Radiotherapy, % 69 72 Tamoxifen, % 68 Enrollment: 11 June 1997 to 03 June 1999

11 Tumor Characteristics
% patients TAC (n=745) FAC (n=746) Tumor size, cm ≤2 40 43 >2 to 5 53 51 <5 8 6 Nodal status 1 to 3 63 62 4+ 37 38 ER+ and/or PR+* 76 HER2/neu+ (FISH)* 21 22 *Centrally reviewed

12 DFS Events (ITT) at 10 Years
No. patients (%) TAC (n=745) FAC (n=746) All (n=1491) First DFS event Local relapse 32 (4) 36 (5) 68 (5) Regional relapse 9 (1) 14 (2) 23 (2) Distant relapse 174 (23) 214 (29) 388 (26) 2nd primary malignancy 56 (8) 53 (7) 109 (7) Death NED 15 (2) 16 (2) 31 (2) Undefined DFS event 1 (0.1) 1 (<0.1) Lost to follow-up 43 (6) 39 (5) 82 (6) NED=no evidence of disease

13 DFS at a Median 10-year Follow-up (ITT)
1.00 TAC: 76% 0.80 HR= %CI: 0.59–0.88 Log-rank P=0.001 0.60 FAC: 69% Disease-free survival probability 0.40 HR= %CI: 0.68–0.93 Log-rank P=0.0043 0.20 0.00 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 FAC 746 730 699 659 618 584 558 541 523 510 499 484 471 453 437 429 414 392 378 351 333

14 DFS in Predefined Subgroups
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 0.2 0.6 1.0 1.4 1.8 2.2 *Adjusted for nodal status Hazard Ratio (95%CI)

15 OS at a Median 10-year Follow-up (ITT)
1.00 HR= %CI: 0.61–0.90 Log-rank P=0.002 TAC: 87% HR= %CI: 0.53–0.91 Log-rank P=0.008 0.80 FAC: 81% 0.60 Overall survival probability 0.40 0.20 0.00 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
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 0.2 0.6 1.0 1.4 1.8 2.2 *Adjusted for nodal status Hazard Ratio (95%CI)

17 Cardiac Toxicities Reported as an AE
No. patients (%) TAC (n=744) FAC (n=736) Congestive heart failure* (cardiac function grade 3-4) Grade 3 (mild, responsive to therapy) Grade 4 (severe, refractory) 26 (4) 21 (3) 5 (1) 17 (2) 14 (2) 3 (0.4) Serious adverse event 23 (3) 16 (2) Death due to CHF 2 (0.3) 4 (1) *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 TAC (n=744) FAC (n=736) Number of CHF events 26 17 Reported in the first 55 months of follow-up 13 5 Reported in months 55 to 120 of follow-up 12 0.07 0.06 0.05 Probability of CHF 0.04 TAC 0.03 FAC 0.02 0.01 0.00 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 Nonevaluable patients, n Evaluable patients, n 396 348
TAC (n=744) FAC (n=736) Nonevaluable patients, n Evaluable patients, n 396 348 467 269 LVEF decrease >20%, n (% evaluable) LVEF Decrease below normal limit, n (% evaluable) 58 (17) 41 (12) 41 (15) 27 (10) *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
No. patients (%) TAC n=744 FAC n=736 Acute myeloid leukemia 4 (1) 1 (0.1) Chronic lymphocytic leukemia Myelodysplastic Syndrome 2 (0.3)

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 maintained at 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 Canada Allan S, Chang J, Colwell B, Drolet Y, Dufresne J, Gelmon K, Holland D, Lesperance B, Laing K, Mackey J, Potvin C, Provencher L, Rubin S, Sami A, Sehdev S, Trudeau M, Verma S, Spadafora S, Whitlock P, Yelle L, Mackinnon J USA Avery B, Beck T, Begas A, George C, Glaspy J, Graham B, Hainsworth J, Iannotti N, Limentani S, Marcom K, Modiano M, O’Rourke M, Robert N, Schnell F, Theall K, Tongol J, Vogel C Spain Alba Conejo E, Alvarez Lopez I, Anton Torres A, Aranda Aguilar E, Cassinello J, Garcia Puche JL, Lobo Samper F, Lopez Lopez R, Lopez Vega JM, Martin M, Munarriz Gandia B, Murias Rosales A, Rodriguez Lescure A, Torres A Poland Karnicka-Mlodkowska H, Pienkowski T, Rolski J UK Coleman R, Price C, Sherwin E, Wardley A, Greece Georgoulias V Hungary Boer K, Juhos E, Pinter T Germany Oberhoff C France Guastalla JP So. Africa Moodley D Brazil Teixeira LC, Vinholes J Egypt Abd-El-Azim H, El-Zawahry H Sweden Fornander T, Nylen U Austria Schuller J Israel Lurie H, Merimsky O, Steiner M Czech Rep Abrahamova J, Finek J Argentina Martinez JL, Mickiewicz E, Orti R Portugal Chumbo M, Goncalves I Uruguay Viola A Slovak Rep Koza I


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