OPTIMIZING NONANTHRACYLINES FOR EARLY BREAST CANCER Stephen E. Jones, M.D. US Oncology Research, McKesson Specialty Health The Woodlands, Tx
ANTHRACYCLINES AND TAXANES ARE COMMONLY USED USED IN MOST REGIMENS LEVEL I EVIDENCE IN TRIALS AROUND THE WORLD OXFORD OVERVIEW CONFIRMS THE VALUE OF BOTH BUT ONLY A SMALL FRACTION OF PTS BENEFIT FROM ANTHRACYCLINES (HER2+)
WHAT DO ANTHRACYCLINES DO FOR YOU? Significant cardiac toxicity, some of it appearing late Increased nausea and vomiting, some delayed Rare, but real, risk of leukemia or MDS
BCIRG 001 - Trial Design n=1491 20 countries 112 centers T A C Docetaxel 75 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 R Every 3 weeks for 6 cycles Stratification Nodal status 1-3 4+ Center F A C Fluorouracil 500 mg/m 2 Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 Dexamethasone premedication, 8 mg bid, 3 days Prophylactic ciprofloxacin 500 mg bid, days 5 14 No primary G-CSF prophylaxis was allowed San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 8 12 2010
Disease-free survival probability DFS at a Median 10-year Follow-up (ITT) 1.00 0.80 TAC: 76% 0.60 HR=0.72 95%CI: 0.59 0.88 Log-rank P=0.001 FAC: 69% 0.40 HR=0.80 95%CI: 0.68 0.93 Log-rank P=0.0043 0.20 0.00 Number at Risk 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) 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 8 12 2010
Overall survival probability OS at a Median 10-year Follow-up (ITT) 1.00 TAC: 87% 0.80 HR=0.70 95%CI: 0.53 0.91 Log-rank P=0.008 FAC: 81% 0.60 0.40 HR=0.74 95%CI: 0.61 0.90 Log-rank P=0.002 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 8 12 2010
Probability of CHF Cumulative Incidence of CHF 0.08 0.07 0.06 0.05 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 0.04 0.03 0.02 TAC FAC 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 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 8 12 2010
Conclusions CHF was reported in 3.5% and 2.3% of patients treated with TAC and FAC, 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 (leukemia or MDS) were reported in 9 patients (0.6% or 1 in 200) San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 8 12 2010
E2197 Study Design and Results #1021 Study Design Patient Characteristics AC Doxorubicin 60 mg/m2 Cyclophosphamide 600 mg/m2 Every 3 weeks x 4 cycles Tamoxifen x 5 years If HR-Positive (Amended to Allow A.I.s) Plus RT if Indicated PRESENTED BY: Hope S. Rugo Operable Breast Cancer 0-3 Positive Nodes T > 1 cm if Node Negative N=2885 Eligible Patients AT Doxorubicin 60 mg/m2 Docetaxel 60 mg/m2 Every 3 weeks x 4 cycles Tamoxifen x 5 years If HR-Positive (Amended to Allow A.I.s) Plus RT if Indicated AML/MDS: 17 cases ( 0.5%) 68% ER positive 65% LN negative Grade 48% low or intermediate Median T-size 2.0 cm Results At 5 years: DFS (85%) and OS (92%) identical between the 2 arms RS predicted recurrence Now: Median follow-up 11.5 yrs DFS (77%) and OS (84%) still identical No difference based on hormone receptor status
THE TWO NON-ANTHRACYCLINE ALTERNATIVES TC (Docetaxel/Cyclophosphamide) TCH (Docetaxel/Carboplatin/Trastuzumab)
US Oncology 9735: Study Design N=1016 71% ER+ 48% N R 4 x TC q3w Docetaxel (75 mg/m 2 ) Cyclophosphamide (600 mg/m 2 ) n=506 4 x AC q3w Doxorubicin (60 mg/m 2 ) Cyclophosphamide (600 mg/m 2 ) n=510 Eligibility: Stage I, II, or III disease Median follow up: 5.5 years Chemotherapy doses based on actual BSA (no cap) Chemotherapy given prior to radiation Tamoxifen for all ER+ patients after chemotherapy +/- radiation Jones et al. J Clin Oncol. 2006;24:5381-87.
USO 9735: Effectiveness of TC Over AC Single study robust outcome Worked in 65+ years (subset analysis) 26% DFS 31% OS Jones et al, 2009.
WHAT HAS CHANGED WITH TC? Practice patterns around the world Should we use paclitaxel instead? Number of cycles of TC? Should growth factors be used with TC? What if TC was combined with trastuzumab? Finally for the nonbelievers, a study.
Decline in the Use of Anthracyclines for Breast Cancer Sharon H. Giordano, Yu-Li Lin, Yong-Fang Kuo, Gabriel N. Hortobagyi, and James S. Goodwin The University of Texas MD Anderson Cancer Center, The University of Texas Medical Branch at Galveston JCO 30: 2232-2239, 2012
Changes in adjuvant breast cancer chemotherapy regimens over time in the community. Patt D et al: ASCO abstract 6109, 2012 16
ASCO abstract 6109, 2012 17
WHY NOT USE PACLITAXEL? CALGB 40101* 2 X 2 FACTORIAL DESIGN TESTED 4 v 6 CYCLES OF AC OR PACLITAXEL 6 WAS NOT BETTER PACLITAXEL WAS INFERIOR 5 yr RFS AC 91% v paclitaxel 88% AML/MDS OCCURRED ON AC ARMS * Shulman L et al, ASCO abstract 1007, 2013
NUMBER OF CYCLES OF TC? Original trial: 4 cycles BCIRG 005 and NSABP B30 node + TAC6 or AC/docetaxel (8) 4 of TAC was inferior B38 compared 6 TAC with ddac/paclitaxel and ddac/paclitaxel and gemcitibine No difference in outcome What if the anthracycline does not matter?
FEBRILE NEUTROPENIA WITH TC: ARE WBC GROWTH FACTORS NEEDED? USON 9735: FN 5% (OLDER: 8%) SABCS 2011 MORE DATA Kaiser Permanente data USON data
FEBRILE NEUTROPENIA WITH TC: ARE WBC GROWTH FACTORS NEEDED? USON 9735: FN 5% (OLDER: 8%) Kaiser data* Prophylaxis 128 pts: FN 8.6% No prophylaxis 204 pts: FN 24.5% Captured ER and hospitalization data in an integrated health care system *Lee, J et al, SABCS 2011
FEBRILE NEUTROPENIA WITH TC: ARE WBC GROWTH FACTORS NEEDED? USON 9735: FN 5% (OLDER: 8%) USON 06090 TC v TAC* 593 pts received TC; 70% of cases of FN occurred with the first course of treatment 214 received prophylaxis: FN 2.5% 379 no prophylaxis: FN 7.4% *Jones, S et al, SABCS 2011
FEBRILE NEUTROPENIA WITH TC: ARE WBC GROWTH FACTORS NEEDED? USON 9735: FN 5% (OLDER: 8%) Kaiser Permanente data 2011 USON data 2011 Other reports with high rates of FN but no randomized data Many oncologists use growth factors
WHAT ABOUT TC IN HER2+EARLY BC? USON STUDY 06038: HER TC Presented at SABCS 2011 Submitted for publication 2013 Single arm phase II trial of 4 TC combined with trastuzumab for 1 year
San Antonio Breast Cancer Symposium-Cancer Therapy and Research Center at UT Health Science Center, December 6-10, 2011 Results No. Patients DFS (%) 2-Year DFS (%) 3-Year OS (%) 2-Year OS (%) 3-Year 486 safety population 97.8 96.3 99.4 98.5 101 node positive 96.9 91.9 100 96.5 385 node negative 98.1 97.7 99.2 99.2 94 <1.0-cm node-ve 100 100 100 100 In 486 patients, there were 14 cases of recurrent breast cancer (local 5, or local/distant 9), which resulted in a 3-year disease-free survival of 96.3%. This presentation is the intellectual property of the author/presenter. Contact them at steve.jones@usoncology.com for permission to reprint and/or distribute.
Disease-free Probability San Antonio Breast Cancer Symposium-Cancer Therapy and Research Center at UT Health Science Center, December 6-10, 2011 DFS by Nodal Status 1.0 0.9 0.8 0.7 0.6 Node negativee Node positive Event indicator 0.5 0 12 24 36 48 Months This presentation is the intellectual property of the author/presenter. Contact them at steve.jones@usoncology.com for permission to reprint and/or distribute.
Survival Probability San Antonio Breast Cancer Symposium-Cancer Therapy and Research Center at UT Health Science Center, December 6-10, 2011 OS by Nodal Status 1.0 0.9 0.8 0.7 0.6 Node negative Node positive Event indicator 0.5 0 12 24 36 48 Months This presentation is the intellectual property of the author/presenter. Contact them at steve.jones@usoncology.com for permission to reprint and/or distribute.
US Oncology 06-090 Node-Positive, High Risk Node Negative, HER2 Negative Breast Cancer STRATIFICATION Stage (IA, IIA, IIB, IIIA, IIIB, IIIC) TC x 6 TAC x 6 Accrual goal - 2000 patients DFS - Primary endpoint Study stopped at 1200 pts.
B-46 USOR 07132 R TAC TC TCB N=3900; 3y DFS; HR.75 TCB USON TC v TAC closed (N=1200) Total TC v TAC N=3600 non inferiority
B-49 (CTEP) R Dox-based TC N=1843 (4200 with B-46I and TicTacToe); Median 4+ yr IDFS; 80% Power for Non-Inferiority (HR <1.18) Accrual opened 4/4/2012
NO TO ANTHRACYCLINES Very small benefit to use of anthracyclines and this benefit is almost entirely in the HER2+ population TC, TCH and HER TC represent real world options for many patients Results from the anthracycline question trials should finally settle the debate
THANK YOU