San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8– 12 2010 BCIRG 001 001 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 NCT00688740 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
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. - PowerPoint PPT Presentation
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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
NCT00688740Sponsored 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 Con behalf of the BCIRG 001 Investigators
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001
DisclosuresDr Martin has received speaker's
honoraria from Sanofi-Aventis
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Adjuvant 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;5:372–3802De Laurentiis M, et al. J Clin Oncol 2008;26:44–533Martin M, et al. N Engl J Med 2005;352:2302–2313
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Final 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
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Trial Design
Fluorouracil 500 mg/m2 Doxorubicin 50 mg/m2
Cyclophosphamide500 mg/m2
Docetaxel 75 mg/m2
Doxorubicin 50 mg/m2
Cyclophosphamide500 mg/m2
TAC
FAC
R
Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, days 5–14No primary G-CSF prophylaxis was allowed
Every 3 weeks for 6 cycles
Stratification• Nodal status
1-3 4+
• Center
n=149120 countries112 centers
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Post Chemotherapy Treatment
TAC
FAC
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
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Major 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
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001OS in Predefined Subgroups
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 statusNegative 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-menopausal0.85 (0.65 to 1.11) 661
In favor of TAC In favor of FAC
Hazard Ratio (95%CI)0.2 0.6 1.0 1.4 1.8 2.2
*Adjusted for nodal status
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Cardiac 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
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
Time from randomization to CHF event (months)0 12 24 36 48 60 72 84 96 108 120
0.02
0.05
0.07
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
13 12
TAC
FAC
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Changes in LVEF
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.
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Hematologic Malignancies at 10 Years
No. patients (%)TAC
n=744FAC
n=736Acute myeloid leukemia 4 (1) 1 (0.1)
Chronic lymphocytic leukemia
0 1 (0.1)
Myelodysplastic Syndrome 2 (0.3) 1 (0.1)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Serious 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%)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Efficacy 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
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Safety 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)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Conclusions
• 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
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
BCIRG 001Acknowledgments
• 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)
San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center – December 8–12 2010
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, 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
UK Coleman R, Price C, Sherwin E, Wardley A, Greece Georgoulias VHungary Boer K, Juhos E, Pinter T Germany Oberhoff CFrance Guastalla JP So. Africa Moodley DBrazil Teixeira LC, Vinholes J Egypt Abd-El-Azim H, El-Zawahry HSweden Fornander T, Nylen U Austria Schuller JIsrael Lurie H, Merimsky O, Steiner M Czech Rep Abrahamova J, Finek JArgentina Martinez JL, Mickiewicz E, Orti R Portugal Chumbo M, Goncalves I