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3rd International BCIRG Conference Anaheim, June 20 to 22, 2002

HOT TOPICS IN BREAST CANCER FROM ASCO 2002 Controversies in Endocrine Therapy of Early Breast Cancer: Adjuvant CT and tamoxifen: Concurrent or sequential? Miguel Martin Medical Oncology Dptment Hospital Universitario San Carlos Madrid (Spain). 3rd International BCIRG Conference

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3rd International BCIRG Conference Anaheim, June 20 to 22, 2002

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  1. HOT TOPICS IN BREAST CANCER FROM ASCO 2002Controversies in Endocrine Therapy of Early Breast Cancer:Adjuvant CT and tamoxifen: Concurrent or sequential?Miguel MartinMedical Oncology DptmentHospital Universitario San CarlosMadrid (Spain) 3rd International BCIRG Conference Anaheim, June 20 to 22, 2002

  2. Tamoxifen and CT: Concurrently or sequentally? • Preclinical data • Clinical data: • Intergroup 0100 (abstract 143) • GEICAM 9401 (abstract 144) • Clinical implications

  3. Tamoxifen and CT: Concurrently or sequentally? • Preclinical data • Clinical data: • Intergroup 0100 (abstract 143) • GEICAM 9401 (abstract 144) • Clinical implications

  4. CT-tamoxifen interactions:preclinical data (1) • Tamoxifen induces a G1/G0 cell cycle blockade of MCF-7 cells in vitro1 • Tamoxifen inhibits the cytotoxic effects of melphalan and fluorouracil in estrogen receptor-negative breast cancer cell lines in vitro2 • Both additive2 and antagonic3 effects have been described with doxorubicin 1. Clarke R et al, Biochem Soc Trans 15:243,1987 2. Osborne CK et al, J Clin Oncol 7:710,1989 3. Woods KC et al, Biochem Pharmacol 47:1449,1994

  5. CT-tamoxifen interactions:preclinical data (2) • Tamoxifen revers in vitro the multidrug resistance to certain drugs such as doxorubicin1 • Tamoxifen and taxotere are synergistic in estrogen receptor-negative cell lines2 1. Greenberg DA et al, Cancer Res 47:70,1987 2. Ferlini C et al, Br J Cancer 75: 884,1997

  6. Preclinical data onCT-tamoxifen interactions:Summary • The interaction (antagonistic or ever synergistic) of CT and tamoxifen seems to be drug-specific • The NET interaction between a polichemotherapy regimen and tamoxifen results difficult to predict • In vitro data is only useful for developing hypothesis that can be tested in clinical trials

  7. Tamoxifen and CT: Concurrently or sequentally? • Preclinical data • Clinical data: • Intergroup 0100 (abstract 143) • GEICAM 9401 (abstract 144) • Clinical implications

  8. Adjuvant Chemohormonal Therapy for Primary Breast Cancer Should Be Sequential Instead of Concurrent Initial Results from North American Intergroup Trial 0100 (SWOG-8814) • Southwest Oncology Group (coordinator) • Eastern Cooperative Oncology Group • Cancer and Leukemia Group B • North Central Cancer Treatment Group • NCI Canada Clinical Trials Group Proc ASCO 21: 143,2002

  9. Breast Intergroup Trial 0100 Study Design STRATIFY Nodes 1-3+ vs 4+ PgR+(ER+ or ER-) vs PgR-(ER+) Time from surgery  6 vs >6-12 weeks RANDOMIZE Tamoxifen CAFx6, then CAFx6,concurrent tamoxifen tamoxifen

  10. Breast Intergroup Trial 0100Postmenopausal, Node (+), Receptor (+)Objectives • Determine if anthracycline-based adjuvant therapy with CAF plus T is superior to T alone Results: Significant DFS and S advantage to the combination (Proc. ASCO 2001)

  11. Breast Intergroup Trial 0100Postmenopausal, Node (+), Receptor (+)Objectives 2. Assess if CAF followed by T (CAFT) is superior to concurrent therapy followed by T (CAFTT) Results: This report

  12. Breast Intergroup Trial 0100 Acute Toxicity and Late Effects CAF  T vs CAFTT • No difference in recorded grade 2, 3, or 4 acute toxicities • Rates of congestive heart failure, thromboembolic events, uterine cancer and secondary AML/MDS were very similar

  13. CAF T 67% CAFT T 62% Breast INT 0100 100% Median follow-up: 8.5 y 80% 60% p = .03 (log rank) 40% 8-year disease-free survival RR: 1.18 20% 0% 144 0 24 48 72 96 120 Months After Registration

  14. CAFT 73% CAFT T 71% Breast INT 0100 100% 80% 60% 40% 8-year overall survival 20% P=0.23 0% 0 24 48 72 96 120 144 Months After Registration

  15. Breast Intergroup Trial 0100 Conclusions • There is an estimated 18% improvement in DFS by delaying tamoxifen until the completion of CAF • Long follow-up of a large cohort was necessary to ascertain this benefit • Data consistent with hypothesis that tamoxifen may antagonize drugs used in this or similar regimens

  16. GEICAM 9401 (Spanish Breast Cancer Research Group) • Adjuvant Epirubicin-Cyclophosphamide Chemotherapy Plus Tamoxifen Administered Concomitant vs. Sequential: Randomized Phase III Trial in Postmenopausal Node-Positive Breast Cancer Patients Proc ASCO 21:144,2002

  17. GEICAM 9401: Clinical Trial Design Postmenopausal patients Stage II and III-A (node positive) Up to 70 years old HR positive & negative • Primary End-point: 5-year DFS ECx4 + Tam R Surgery ECx4 Tam

  18. Recruitment • Number of randomized patients: 485* • Recruitment period: • June 1995 / July 2000 • A decision was made to stop enrollment due to persistent low accrual anddelay in planned recruitment *planned sample size: 762

  19. Results • Median follow-up: 54 mo • No difference in prognostic factors between arms • No difference in toxicity • Non-statistically significant trend toward better outcome with sequential administration

  20. Number of Events Median follow-up: 54 months

  21. GEICAM 9401: Disease Free Survival Sequential Log Rank; p=0.43 Concomitant Seq 219 127 42 Con 220 145 33 Patients at risk

  22. Hazard Ratio HR (95% C.I.) = 1.147 (0.769- 1.709) p = 0.5 0 0.5 1 1,5 2 Concomitant better Sequential better

  23. No difference or not enough power? a = 5%

  24. Conclusions • No statistically significant difference • However, a 5% difference, if true,would be clinically relevant • This extra-benefit does not require any extra effort, toxicity, or cost • Our results are still immature, and further follow-up is needed to getless uncertain data

  25. INT 0100 and GEICAM 9401:Summary • Both trials have similar design: • Potmenopausal • Anthracycline-containing chemotherapy • Toxicity in both arms was similar • Results favouring the sequential arm: • Statistically significant difference in DFS in the INT 0100 trial • Clear trend of similar amount in DFS in GEICAM 9401 trial

  26. Hazard Ratio Sequential better Concomitant better 1.18 (1.01-1.39) Intergroup INT 0100 1.147 (0.769-1.709) GEICAM 9401 0 0.5 1 1,5 2

  27. Clinical Implications • Concurrent chemo-hormonal therapy may result in suboptimal benefit from the chemotherapy • Unless new data became available, we should use CT and tamoxifen sequentially • Are these results extrapolable to all chemotherapy regimens? • CMF? • Taxanes? (NSABP B-28 trial?)

  28. Cyclophosphamide Paclitaxel 225 mg/m2 Doxorubicin NSABP B-28 Stage II-IIIA No additional chemotherapy Concomitant tamoxifen (x 5 years) in tamoxifen-sensitive patients

  29. Special thanks to: • Dr. S. Albain (SWOG) • Dr C. Picó (GEICAM)

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