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Ten-year follow-up analysis of the BCIRG 001 trial confirms superior DFS and OS benefit of adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide) over.

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Presentation on theme: "Ten-year follow-up analysis of the BCIRG 001 trial confirms superior DFS and OS benefit of adjuvant TAC (docetaxel, doxorubicin, cyclophosphamide) over."— Presentation transcript:

1 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 NCT Sponsored by sanofi-aventis 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

2 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 Disclosures Dr Martin has received speaker's honoraria from Sanofi-Aventis

3 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 Adjuvant Chemotherapy Adding a taxane to adjuvant anthracycline-based regimens improves survival in patients with early breast cancer 1,2 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 cancer 3 –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) 1 Nowak AK, et al. Lancet Oncol 2004;5:372–380 2 De Laurentiis M, et al. J Clin Oncol 2008;26:44–53 3 Martin M, et al. N Engl J Med 2005;352:2302–2313

4 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 Trial Design Fluorouracil 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide500 mg/m 2 Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide500 mg/m 2 T A C F A C R Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, days 5–14 No primary G-CSF prophylaxis was allowed Every 3 weeks for 6 cycles Stratification Nodal status Center n= countries 112 centers

6 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 centers guidelines after mastectomy

7 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 Characteristics of the Patients (ITT) TAC (n=745) FAC (n=746) Median age, range49 (26–70)49 (23–70) Median KPS100 Premenopausal, %5755 Mastectomy, %6059 Radiotherapy, %6972 Tamoxifen, %68 Enrollment: 11 June 1997 to 03 June 1999

11 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 % patients TAC (n=745) FAC (n=746) Tumor size, cm >2 to <586 Nodal status 1 to ER+ and/or PR+* 76 HER2/neu+ (FISH)* 2122 Tumor Characteristics * Centrally reviewed

12 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 No. patients (%) TAC (n=745) FAC (n=746) All (n=1491) First DFS event Local relapse32 (4)36 (5)68 (5) Regional relapse9 (1)14 (2)23 (2) Distant relapse174 (23)214 (29)388 (26) 2 nd primary malignancy56 (8)53 (7)109 (7) Death NED15 (2)16 (2)31 (2) Undefined DFS event 1 (0.1)0 1 (<0.1) Lost to follow-up 43 (6)39 (5)82 (6) DFS Events (ITT) at 10 Years NED=no evidence of disease

13 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 TAC: 76% FAC: 69% DFS at a Median 10-year Follow-up (ITT) Number at Risk TAC FAC Disease-free survival probability Disease-free survival time (months) HR= %CI: 0.59–0.88 Log-rank P=0.001 HR= %CI: 0.68–0.93 Log-rank P=0.0043

14 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 DFS in Predefined Subgroups OverallITT 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 statusNegative0.66 (0.49 to 0.89)359 Hormonal Receptor statusPositive0.84 (0.70 to 1.01)1132 HER2/NEU statusNegative0.88 (0.72 to 1.08)943 HER2/NEU statusPositive0.60 (0.43 to 0.83)319 HER2/NEU statusUnknown0.80 (0.54 to 1.18)229 Menopausal statusPre-menopausal0.69 (0.55 to 0.86)830 Menopausal statusPost-menopausal0.93 (0.74 to 1.16)661 In favor of TACIn favor of FAC Hazard Ratio (95%CI) *Adjusted for nodal status

15 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 OS at a Median 10-year Follow-up (ITT) 429 deaths: 188 TAC; 241 FAC Number at Risk TAC FAC Overall survival probability TAC: 87% FAC: 81% HR= %CI: 0.53–0.91 Log-rank P=0.008 HR= %CI: 0.61–0.90 Log-rank P=0.002 Survival time (months)

16 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 OS in Predefined Subgroups OverallITT 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 statusNegative0.69 (0.49 to 0.96)359 Hormonal Receptor statusPositive0.76 (0.60 to 0.96)1132 HER2/NEU statusNegative0.79 (0.61 to 1.01)943 HER2/NEU statusPositive0.66 (0.45 to 0.96)319 HER2/NEU statusUnknown0.71 (0.44 to 1.14)229 Menopausal statusPre-menopausal0.65 (0.49 to 0.85)830 Menopausal statusPost-menopausal0.85 (0.65 to 1.11)661 In favor of TACIn favor of FAC Hazard Ratio (95%CI) *Adjusted for nodal status

17 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 event23 (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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 Cumulative Incidence of CHF Number at Risk TAC FAC Probability of CHF Time from randomization to CHF event (months) TAC (n=744) FAC (n=736) Number of CHF events2617 Reported in the first 55 months of follow-up135 Reported in months 55 to 120 of follow-up1312 TAC FAC

19 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 Changes in LVEF TAC (n=744) FAC (n=736) Nonevaluable patients, n Evaluable patients, n 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 Hematologic Malignancies at 10 Years No. patients (%) TAC n=744 FAC n=736 Acute myeloid leukemia 4 (1)1 (0.1) Chronic lymphocytic leukemia 01 (0.1) Myelodysplastic Syndrome 2 (0.3)1 (0.1)

21 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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; Fishers exact test)

24 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– BCIRG 001 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, ORourke 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 PolandKarnicka-Mlodkowska H, Pienkowski T, Rolski J UK Coleman R, Price C, Sherwin E, Wardley A, GreeceGeorgoulias V HungaryBoer K, Juhos E, Pinter TGermanyOberhoff C FranceGuastalla JPSo. AfricaMoodley D BrazilTeixeira LC, Vinholes JEgyptAbd-El-Azim H, El-Zawahry H SwedenFornander T, Nylen UAustriaSchuller J IsraelLurie H, Merimsky O, Steiner MCzech RepAbrahamova J, Finek J ArgentinaMartinez JL, Mickiewicz E, Orti RPortugalChumbo M, Goncalves I UruguayViola ASlovak RepKoza I Investigators


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