Adjuvant Chemotherapy of Early Breast Cancer: When, Why, Prognostic factors, Regimens Tanja Cufer, MD, PhD University Clinic Golnik Medical Faculty, Ljubljana ESO Masterclass; Dubrovnik 2011
Cancer Mortality Rates in EU Member States Levi F et al.,Ann Oncol2007;18.
Adjuvant Therapy Help Reduce Breast Cancer Deaths
Breast cancer mortality decreased by 21.3% from 1975-2000 in USA
7 independent meta-analysis showed median decline in mortality of 30% (range: 25%-38%)
Due to screening: 15% (range: 7%-23%)
Due to adjuvant therapy: 19%(range: 12%-21%)
Berry DA et al. NEJM 2005
Effects of Endocrine Therapy and of Chemotherapy in Early Breast cancer EBCTCG Overview, Lancet 2005
Adjuvant HT with Tam (in ER-positive pts)
40% ↓ risk of recurrence
32 % ↓ risk of breast cancer mortality
33% ↓ risk of recurrence
17% ↓ risk of breast cancer mortality
5 10 5 10 5 10 Chemotherapy Update: EBCTCG Overview Data Taxanes > Anthra > CMF > No Chemo 50 Control36.4% Anthra 31.0% CMF31.3% 40 4.2% 4.3% 5.1% 30 CMF32.2% 20.5 19.9 Anthra27.0% 20 15.3 Taxane25.9% %+ SE 17.8 16.5 12.8 10 Years Years Years 0 0 0 0 EBCTCG 2005-06 Overview Peto SABCS 2007
2010 EBCTCG Overview: Anthracyclinevs CMF Recurrence BC mortality Any death A C X 4 ANTHRAC YCLINE M O R E
2010 EBCTCG Overview: Taxane+anthracycline(A) vs A Recurrence BC mortality Any death T + A vs S a m e A T + A vs. M o r e A
Poly-chemotherapy: Impact on Recurrence Anthracycline (A) + Taxanevs A Anthracyclinevs CMF Early benefit of anthracycline Taxane benefit is durable EBCTCG 2010 (unpublished overview)
Benefit from Chemotherapy According to Subgroups Taxane + Anthracycline (A) vs A AnthracyclinevsNoCTX All subgroups benefit from CT EBCTCG 2010 (unpublished overview)
ER- ER+ Genotype Luminal-like A, B HER-like Basal-like Phenotype Triple negative ER-neg PR-neg HER2-neg HER2-pos ER-neg PR-neg ER-pos HER2-neg (mostly) A: low proliferation rate B: high proliferation rate A variety of disease types: should all respond to the same therapy? Adapted from Sotiriou et al,.PNAS, 2003.
How to Select Adjuvant Systemic Therapy for Each Individual patient? A major determinant is a Target not a Risk Molecular targets in breast cancer: Endocrine receptors (ER) HER2 receptor St.Gallen recommendations 2007
Adjuvant systemic therapy is recommended if a relevant absolute risk reduction of recurrence and can can be expected with an acceptable level of treatment –related adverse effects ! EFFICACY TOXICITY
Triple-Negative Early Breast Cancer
Chemotherapy remains the mainstay of adjuvant ST in TNBC
The optimal duration of Cht is not known (4-6 cycles)
The addition of taxanes to anthracyclines improves survival rates significantly
Sequential use of taxanes might be beneficial to concurrent use
Triple negative HER2-positive ER-positive HER2- and Ki67 low ER-positive HER2+ or Ki67 high BCIRG001: Benefit of Docetaxel by ER and HER2 Status Hugh J. et al. J Clin Oncol 2009; 27:1168
CALGB 9344: Benefit of Paclitaxel by ER and HER2 Status Hayes DF, et al. N Engl J Med 2007
BIG 2-98: Sequential vs. Concomitant Doxorubicine-Docetaxel Di Leo A, et al. SABCS 2009. Abstract 601.
Adjuvant chemotherapy is recommended for all patients with HER2-positive EBC in which a risk of relapse justifyiesadjuvant systemic therapy
HER2-directed therapy is the mainstay of adjuvant systemic therapy in HER2-positive EBC;5/6 trials have shown substantial DFS and OS benefits of adding trastuzumab to Cht
The optimal chemotherapy to combine with HER2-directed therapy and the optimal schedule of trastuzumab, sequential or concomitant to chemotherapy, still need to be defined.
Standard chemotherapy (CT) Adjuvant Chemotherapy +Trastuzumab: Six Large Adjuvant BC Trials, all N+ or High risk N (>14,000 patients) Paclitaxel AC/FEC Docetaxel Carbo+Doce Trastuzumab (T) FEC or ED Doce/ or Vinorelbine
Adjuvant Chemotherapy ± Trastuzumab Trials: Overall Survival Median FU yrs p Reference Difference at 4y/3ya HR Combined US (n=3969)b 0.63 3.2% 3 0.0004 Perez 2007 HERA (n=3401) 0.66 2.7%* 2 0.0115 Smith 2007 BCIRG AC-TH (n=1074) 0.59 6% 3 0.004 Slamon 2006 BCIRG TCarboH (n=1075) 3 0.017 0.66 5% Slamon 2006 FinHER (n=232) 5 0.09 6.6%* 0.55 Joensuu 2009 n.s. 1.27 –1.0% 4 Spielmann 2009 PACS-04 (n=528) 2 1 0 Favours trastuzumab Favours chemotherapy only *Benefit at 3y a Absolute difference in percentage of patients with OS at 4 or 3 years b Combined US: Joint analysis of NSABP B-31 and NCCTG N9831
Optimal Chemotherapy to Combine with Trastuzumab
HER-2 + tumors benefit from anthracycline treatment (Meta-analysis, Gennari et al., 2008; Watanabe T et al. ASCO 2009)
Demonstrated efficacy in randomized clinical trials (NSABP B-31 / NCCTG N9831 and BCIRG 006)
Demonstrated effective in one randomized clinical trial (BCIRG 006) and could be considered in patients with risk factors for cardiac toxicity
HER2 status and Anthracyclines in Early Breast Cancer Pooled analysis: Overall survival Non-anthracycline better Anthracycline better Study HR 95% CI 0.660.90 0.821.07 0.851.64 0.611.26 0.730.82 0.651.06 0.91 0.731.03 0.47–0.920.69–1.18 0.63–1.060.88–1.30 0.27–2.690.85–3.15 0.32–1.160.89–1.79 0.50–1.050.59–1.13 0.42–1.010.80–1.40 0.83–1.00 0.62–0.850.92–1.16 NSABP B11 NSABP B15 GUN3 Milan DBCCG-89-D NCIC MA-5 Total p=0.056 p<0 .0001 Overall p=0.86 Heterogeneity c25=5.2; p=0.39Heterogeneity c25=5.5; p=0.36 0.6 1 2 5 0.4 0.9 ErbB2+ ErbB2– Test for interaction chi2=12.0; p<0.001 Gennariet al. J Natl Cancer Inst 2008;100:14.
BCIRG 006: DFS Benefit of Adjuvant Trastuzumab Treatment by TOPO II Coamplification and Treatment Arm (all patients, 2nd interim analysis) % disease free % disease free Slamon. 2006. www.bcirg A, anthracycline; C, cyclophosphamide; D, docetaxel; T, trastuzumab; Carbo, carboplatin
NCCTG N9831: DFS Sequential vs Concurrent Trastuzumab AC -> T + H -> H (138 events) 100 89.1 % 90 84.2 % 85.7 % 80 79.8 % AC -> T -> H (174 events) 70 Alive and Disease Free (%) 60 Log rank P = .0190 HR=0.77 50 949954 837830 788766 740705 676641 456418 No. at risk 40 5 1 2 0 3 4 Yrs From Randomization Perez EA, et al. SABCS 2009. Abstract 80.
Endocrine Responsive Early Breast Cancer
The absolute benefit of chemotherapy in HR-positive EBC depends on the remaining risk of recurrence and death, after endocrine therapy
A wide spectrum ranging from those at a low risk to those with high risk
Benefits of Adjuvant Chemotherapy in Endocrine Responsive Disease Results from two IBCSG Trials (VIII,IX) in Node-negative EBC Cumulative incidence of relapse over time according to treatment group for patients with different molecular subtypes:
Colleoni M et al, JCO 2010; 28: 2966
Benefits of Adjuvant Chemotherapy in Endocrine Responsive Disease
p = 0.39 Intermediate RS p = 0.61 Low RS Proportion without Distant Recurrence High RS p < 0.001 High Risk Patients (RS≥31) N Events TAM + Chemo 117 13 TAM 47 18 Int Risk Patients (RS 18-30) N Events TAM + Chemo 89 9TAM 45 4 Low Risk Patients (RS<18) N Events TAM + Chemo 218 8 TAM 135 4 B-20 Results: TAM vs Chemo + TAM Oncotype DX: N0 28% absolute benefit from Chemo - TAM Paik et al. J Clin Oncol. 2006
Postmenopausal women with N+ HR+ disease (n = 1470) TAM CAF-T CAFT SWOG 8814, INT0100 Trial Disease-Free Survival by Treatment Low risk (21-gene RS < 18) 1.00 0.75 Disease-free survival 0.50 Stratified log-rank p = 0.97 at 10 years 0.25 Tamoxifen (n=55, 15 events) CAF-T (n=51, 26 events) 0.00 0 2 4 6 8 10 Years since registration Intermediate risk (21-gene RS 18- 30) High risk (21-gene RS ≥ 31) 1.00 1.00 0.75 0.75 Disease-free survival Disease-free survival 0.50 0.50 Stratified log-rank p = 0.033 at 10 years Stratified log-rank p = 0.48 at 10 years 0.25 0.25 Tamoxifen (n=47, 26 events) CAF-T (n=71, 25 events) Tamoxifen (n=46, 22 events) CAF-T (n=57, 20 events) 0.00 0.00 0 2 4 6 8 10 0 2 4 6 8 10 Years since registration Years since registration Albain K, et. al. SABCS 2007.Abstract 10
Prospective Randomized Trials Evaluating Benefit of Chemotherapy in Patients with Good Signature Profiles TAILORx (n = 10,500) and MINDACT (n =6000) Pre- and postmenopausal pts MINDACT: HR-/+ N-/+(1-3) TAILORx: HR+ N- High-risk 21-gene RS or high-risk 70-gene signature +high-risk Adjuvant! Online Medium-risk 21-gene RS or discordant risk group (mostly low-risk 70-gene signature but high risk adjuvant on line) Low-risk 21-gene RS or low-risk 70-gene signature +low-risk Adjuvant! Online Chemotherapy
Randomize chemo: yes or no (TAILORx)
Randomize chemo: yes or no (MiNDACT)
Endocrine therapy Potential CT sparing in 10-15% pts
Predicting Sensitivity to Chemotherapy PCR Probability With Neoadjuvant Chemotherapy - 33% ER + 7% 3 26% GRADE 1 or 2 7% 20% 21% Ki67 <20% 5% (Colleoni M et al.)
Predicting Sensitivity to Chemotherapy
Chromosome 17 polysomy…
TOPO2A and TIMP-1 ?
Tau protein ?
All patients p53 wild type p53 mutated p=0.27 p=0.12 p=0.58 BIG 01-00/EORTC 10994 p53 Tial : Taxane Benefit in Neoadjuvant Setting All patients Bonnefoi H etal., ASCO 2010
Chemotherapy remains an important adjuvant breast cancer therapy
Effective biomarkers are needed to optimize chemotherapy in two directions:
To identify patients that can be spared from toxic chemotherapy
To define the optimal Cht regimen for each individual patient
Better understanding of long term side effects of Cht might help us to further refine our strategies.