Evolving Insights into Adjuvant Chemotherapy Joyce O Shaughnessy, MD Baylor Sammons Cancer Center Texas Oncology US Oncology
80 70 60 50 40 30 20 10 0 EBCTCG 2005/6 Overview Control Arms with No Systemic Treatment at 15 Years 72 69 45 48 65 62 33 33 N+ER+ N+ER- N-ER+ N-ER- Recurrence Mortality Albain, KS. SABCS 2012
Dilemmas in Adjuvant Chemotherapy Is adjuvant chemotherapy effective in ER+ disease? In T1a/b disease? Locally recurrent disease? If adjuvant chemotherapy will be administered Clinical utility of various treatment options Duration/sequence of adjuvant chemotherapy
Reduction in Relative Risk of Recurrence Advances in Chemotherapy Have Dramatically Improved Outcomes in ER-Negative Breast Cancer 60 50 40 30 20 Corresponds to an absolute improvement in 5-year DFS of 23%, and to an absolute improvement in 5-year OS of 17% in ER-negative subset 55% 26% ER- ER+ 10 0 CALGB Trial 8541 9344 9741 Overall Optimizing anthracycline Adding taxane Optimizing taxane Berry et al, JAMA 295:1658-67, 2006
Tam vs CMF/Tam: NSABP 20 1546 Node neg, ER+ pre 46%: post 53% 49 years: 45% 50-59 years: 27% 60 years: 28% Tam [5] CMF [6,oral] +Tam [5] Fisher et al Lancet 364:858, 2004
Fisher, et al, Lancet 364: 858-868, 2004 NSABP B20: 12 yr Overall Survival 87% 83% P=0.063
B-20: Hazard Ratios CMFT vs T 49 yrs 50-59 yrs 60 yrs DFS RFS OS 0.25 0.5 1.0 2.0 0.25 0.5 1.0 2.0 0.25 0.5 1.0 2.0 DFS, DDFS, RFS, OS benefits with CMF in ages < 49 and 50-59, but not in > 60
Most Important Paradigm Shift: Breast Cancer is not one disease ER+ 65-75% A B Breast Cancer HER2+ 15-20% Basal 15% Triple Negative
NSABP B-20 Distant RFS by Recurrence Score 651 All pts, p=.02 Low risk, p=.61 353 134 Inter risk, p=.39 High risk, p<.001 164 Paik, S. et al. J Clin Oncol; 24:3726-3734 2006 Copyright American Society of Clinical Oncology
0.2.4.6.8 1 Five Year Probability of an Event CAF Benefit Greatest in Higher RS for Both Nodal Subsets, with No Benefit in Lower RS Five-Year Probability of Death or Disease Recurrence Linear model for Recurrence Score and interactions with treatment Tam, 4+ nodes (n=54) CAF-T, 4+ nodes (n=86) Tam, 1-3 nodes (n=94) CAF-T, 1-3 nodes (n=133) Chemo benefit 4+ nodes Chemo benefit 1-3 nodes 0 20 40 60 80 100 Recurrence Score Albain, et al. Lancet Oncology 11:55-65, 2010
TransATAC: 21-gene recurrence score to predict risk of distant recurrence in postmenopausal pts treated with AI Results Node- (N=872) Node+ (N=306) % pts 9-year DR rate % pts 9-year DR rate Low RS <18 59% 4% 52% 17% Int RS 18-30 26% 12% 31% 28% High RS 30 15% 25% 17% 49% High vs. Low RS: HR 5.2 Int vs. Low RS: HR 2.5 High vs. Low RS: HR 2.7 Int vs. Low RS: HR 1.8 P<.001 for RS in predicting time to distant recurrence (DR) in N+ and N- patients Dowsett et al. J Clin Oncol 2010; 28: 1829-34.
PACCT-1: TAILORx Pre-REGISTER n = 7047 21 Gene RS Assay REGISTER Specimen Banking Results expected in 2014 Secondary Study Group 1 RS < 11 ~29% of Population Primary Study Group RS 11-25 ~44% of Population Secondary Study Group 2 RS > 25 ~27% of Population ARM A Hormonal Therapy Alone RANDOMIZE n = 4390 ARM D Chemotherapy Plus Hormonal Therapy Albain, KS. St. Gallen 2013 ARM B Hormonal Therapy ARM C Chemotherapy Plus Hormonal Therapy
Theoretical Spectrum of Sensitivity to Adjuvant Systemic Therapy by Intrinsic Subtypes Hayes DF. J Clin Oncol 30:1264, 2012
N=51246 T 1ab N 0 M 0 breast cancers from SEER Program 1988-2001 Breast cancer-specific & non BC-related mortality Unselected by Biology mm mm Other deaths B.C. deaths T1b T1a Hanrahan E.O. et al, JCO 2007, 25: 4952-60
T 1A,B N 0 M 0 : 21-gene Recurrence Score and 70-gene Assays 21 Gene RS Assay 2 NSABP trials, one population-based study (N= 461 pts with ER+ disease + tamoxifen) Low R.S. Intermediate R.S. High R.S. Paik S, et al, New Engl J Medicine 2004 Mook S et al; Ann Surg Oncol 2010 Tumor size -pt1ab -pt1c 70 Gene Assay (N= 139 pts; about half untreated; most HER2-, ER+) 70 gene (Good prognosis) 84 (60%) 441 (53%) 70 gene (Poor prognosis) 55 (40%) 384 (47%) Similar proportion as 21 gene RS assay
NCCN Breast Cancer Guidelines (v.1.2011) T1/N0, HER2-positive Tumor Size > 1cm 0.6-1.0 cm 0.5cm Recommendation Chemotherapy + trastuzumab* Consider chemotherapy + trastuzumab* No adjuvant therapy* * endocrine therapy if HR +
T 1a,b N 0 M 0 Summary Literature: few large population-based studies, many small single institutional studies subject to bias; all studies are retrospective; few have mature follow-up Clinical trials: mostly not open to T 1a,b N 0 M 0 TO TREAT? Age 35y T 1a,b N 0 NOT TO TREAT? Comorbidities Vascular invasion HER2 positivity Triple negative Luminal subtype with High Risk Genomic Profile T 1a : ask yourself if it can be an underestimated T size Piccart M. PSABCS 2012
Adjuvant CMF or AC vs Capecitabine in women >65 Give Effective Chemotherapy for Virulent BC Muss et al, NEJM 360:2055-65, 2009 Muss et al, NEJM 2009
CALOR: Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer First, isolated, ipsilateral, resectable recurrence IBTR or CW recurrence Axillary or SC LN Fully excised and radiation planned > 1 drug, 3-6 cycles NSABP, BIG, IBCSG, GEICAM Aebi et al., SABCS 2012; abstract S3-2
CALOR: Challenges INADEQUATE POWER Sample size (optimal 977) = 162 PROTOCOL DEVIATIONS Polychemotherapy recommended 31% monotherapy CHEMOTHERAPY BENEFIT UNCERTAIN ~65% hormone receptor-positive > 50% IBTR Average disease-free interval = 5-6 years 42% pts chemotherapy arm and 32% pts no chemotherapy arm had had no prior chemotherapy
CALOR: Disease-Free Survival ER+ ER- 5-yr OS 0.41 (0.19-0.89) Aebi S et al, SABCS 2012
Dilemmas in Adjuvant Chemotherapy Is adjuvant chemotherapy effective in ER+ disease? In T1a/b disease? Locally recurrent disease? If adjuvant chemotherapy will be administered Clinical utility of various treatment options Duration/sequence of adjuvant chemotherapy
EBCTCG 2007 Update Unselected for HER2 status
EBCTCG 2011 Chemotherapy Meta-analysis Summary: Breast Cancer Mortality Trial Grouping ER+ and ER poor RR SE 2p CMF vs no chemo 0.76 (0.05) <0.0001 CAF vs no chemo 0.64 (0.09) <0.0001 4AC/EC vs no chemo 0.78 (0.09) 0.01 4AC vs CMF 0.98 (0.05) 0.67 CAF/CEF vs 4AC 0.78 (0.06) 0.0004 Anthra then T vs shorter anthra 0.86 (0.04) 0.0005 Anthra + taxane vs expanded anthracycline alone 0.94 (0.06) 0.33 EBCTCG, Lancet 379:432-44, 2012
ER+ Anthra/CMF plus ET vs ET Control Age < 55 Age 55-69 EBCTCG, Lancet 379:432-44, 2012
Anthracyclines vs No Chemotherapy by Subsets of ER+ EBCTCG, Lancet 379:432-44, 2012
SWOG 8814 CAF-Tam vs Tamoxifen Recurrences Only ER 10-99 fm/mg ER100+ Interaction p = 0.04 Peto R, Personal Communication to Albain K, 2011
Adjuvant Chemotherapy Regimens CMF = AC CAF/FAC DAC(Tac) CEF/FEC FEC P/D DC AC P/D AC -> wkly P ddac P
OS Gennari, A, et al. J Natl Cancer Inst 100:14-20, 2008
US Oncology 06090/NSABP B49 TC X 6 HER-2 Negative Operable Early-Stage Breast Cancer (N=5900) R TAC or AC then T
Meta-analysis: Adjuvant taxane vs no taxane: DFS De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008 De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008 Copyright American Society of Clinical Oncology
Meta-analysis: Adjuvant taxane vs no taxane: OS Copyright American Society of Clinical Oncology De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008 De Laurentiis, M. et al. J Clin Oncol; 26:44-53 2008
BCIRG 001 FAC vs. TAC by biologic subtype TNBC HER2+ LUM B LUM A Copyright American Society Hugh, of Clinical J. Oncology et al. J Clin Oncol; 27:1168-1176 2009
PACS 01 DFS FEC vs FEC-Doc by Ki67 Arm B: FEC - DOC Arm A: FEC Luminal A Luminal B Penault-Llorca, F. et al. J Clin Oncol; 27:2809-2815 2009 Copyright American Society of Clinical Oncology
[TITLE] Budd, GT, et al 2013 ASCO
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Adjuvant weekly vs q3 weekly paclitaxel E1199 Sparano et al. NEJM, 2008; 358:1663
Duration of Adjuvant Chemotherapy
CALGB 40101: 4 Versus 6 Cycles of AC Versus Paclitaxel as Adjuvant Therapy Stratification factors: Prepostmenopausal ER/PgR HER2 R A N D O M I Z E Doxorubicin/ cyclophosphamide (AC) Paclitaxel 4 cycles 6 cycles 4 cycles 6 cycles Tam or AI if HR+; Trastuzumab is HER2+ after 2005 Protocol Changes Years Trial design Pts enrolled 2002-2003 2003-2008 2008-2010 AC q3w 4 or 6 cycles T wkly for 12 or 18 wks AC q2w 4 or 6 cycles Tq2w 4 or 6 cycles AC q3w 4 Tq2w 4 570 3173 3873 6% 1-3 Node+ 94% Node Negative Shulman L, et al. J Clin Oncol Epub, July, 2012.
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USON 9735 TC vs AC: DFS and OS N=1016 71% ER+ 48% N From: Jones, S. et al. J Clin Oncol; 27:1177-1183 2009 Copyright American Society of Clinical Oncology
NSABP B-30: Combinations of doxorubicin, cyclophosphamide and docetaxel for earlystage node-positive breast cancer Stage II or IIIA BC Node Positive HR+ or HR- No metastatic disease Stratification: # Nodes Radiotherapy Surgery Tamoxifen R a n d o m i z e N=5351 AC T: A (60 mg/m2) + C (600 mg/m2) q3w x 4 T (100 mg/m2) q3w x 4 AT: A (50 mg/m2) + T (75 mg/m22) q3w x 4 TAC: A (50 mg/m2) + C (500 mg/m2) + T (75 mg/m2) q3w x 4 Primary aims: - Concurrent vs. sequential: effect on DFS, OS - Utility of cyclophosphamide Swain S, et al. NEJM 363:2268, 2010
% Disease-Free NSABP B-30 Disease-Free Survival (Intention-To-Treat) 0 20 40 60 80 100 N # Events HR p-value AC T 1,753 388 0.83 vs.tac 0.006 0.80 vs. AT 0.001 AT 1,753 468 TAC 1,758 457 0.96 vs. AT 0.58 0 2 4 6 8 10 Years After Randomization Swain S, et al. NEJM 363:2268, 2010
Disease free probability BCIRG 005 6 TAC vs 4 AC then 4 Docetaxel Disease-free Survival 1.0 0.9 0.8 0.7 78.9% 78.6% 0.6 0.5 0.4 0 Patients Events TAC 1649 352 AC T 1649 356 Total 3298 708 Logrank p=0.98 HR = 1.002 (95% CI, 0.86-1.16) 12 24 36 48 60 72 84 96 Months Eiermann, W, et al. J Clin Oncol 29:3877, 2011
Conclusions Does indolent ER+ EBC benefit from adjuvant chemorx beyond OFS? TailoRx; MINDACT, RxPonder ongoing CMF benefits ER-poor and high RS ER+ node negative Anthracyclines improve survival in ER+ and ER-poor disease (advantage over non-a confined to HER2+?) Taxanes are effective regardless of ER and HER2 status and improve OS Dose dense and weekly paclitaxel are superior to q 3w paclitaxel. Pts with locally recurrent ER- disease benefit from adjuvant chemorx (probably virulent ER+ disease, too)
Conclusions 6 cycles = 4 cycles AC or paclitaxel in node negative pts and 6 is more toxic 6TAC and AC/T superior to 4-cycle regimens in node positive pts (duration matters in node +) Is 4 cycles TC enough in chemotherapy-sensitive node + breast cancer? (B49 6 TC vs 6TAC) Single agent capecitabine or paclitaxel are inferior to AC/CMF Consider adjuvant chemorx for virulent > T1bN0 Give most effective chemotherapy for biologically aggressive disease regardless of age AC/T is standard of care