Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings Nadia Harbeck Breast Center University of Cologne, Germany
Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings
Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings YES NOT YET NO Personal Bias: To date, anthracycline-free chemotherapy NOT sufficiently evaluated in order to replace our current standards in all patients
Open questions Consider different therapeutic goals: early Breast cancer: cure mbc: quality of life and prolongation of life Early BC: anthracycline-free regimens sufficient independent of risk? Predictive factor(s) for anthracycline benefit ready to use for clinical practice?
Anthracyclines in breast cancer: Clinical concerns
Anthracyclines: Longterm toxicity* n = 3577, follow-up 7 years (adjuvant epirubicin: n=2553) Cardiotoxicity symptomatic LV - dysfunction n = 3633, follow-up 8 years (adjuvant epirubicin**: n=2589) Secondary leucemia Epi 1.36% Epi N=7 0.3% p=0.004 no Epi 0.2% no Epi N=1 0.1% Risk factors Age > 65 years adipositas ** mainly FEC (50,75 oder 100) cumulative doses < 600mg/m 2 no G-CSF support * Data of the French Adjuvant Study Group (FASG), modified after M. Piccart, St. Gallen 2003
CAF none
Annual CM incidence Cumulative CM incidence
Anthracyclines in breast cancer: Clinical data
Adjuvant Chemotherapy in Breast Cancer and Survival Improvements: Step by Step CT + TT (trastuzumab) No CT ANTHRACYCLINES TAXANES 1980 CMF 4.5% OS improvement 1970 3.6% OS improvement 2000 6% OS improvement 2006 6% OS improvement
Study HR 95% CI NSABP B11 NSABP B15 GUN 3 Milan Overall survival Meta-analysis of pts with known HER2 status received an anthracycline vs nonanthracycline regimen DBCG-89-D NCIC MA-5 0.66 0.47-0.92 0.90 0.69-1.18 0.82 0.63-1.06 1.07 0.88-1.30 0.85 0.27-2.69 1.64 0.85-3.15 0.61 0.32-1.16 1.26 0.89-1.79 0.73 0.50-1.05 0.82 0.59-1.13 0.65 0.42-1.01 1.06 0.80-1.40 anthra better non-anthra better Total Overall 0.91 heterogeneity c25 = 5.2, p = 0.39 heterogeneity c25 = 5.5, p = 0.36 est for interaction chi 2 = 12.0, p < 0.001 0.73 0.62-0.85 1.03 0.92-1.16. Gennari, J Natl Cancer Inst. 2008;100:14 20 0.83-1.00 0.4 p = 0.056 p < 0.0001 p = 0.86 0.6 0.9 1 2 5 HER2+ve HER2-ve
Several studies demonstrate consistent DFS benefit for 1-year adjuvant Herceptin HERA CTx H 1 year B-31 / N9831 AC PH BCIRG 006 AC TH TCarboH DFS benefit Median follow-up, years 4 3 3 3 NOAH CTx / H H 1 year 3 FinHer a VH / TH CEF b PACS-04 a CTx H 1 year n=231 n=528 5 4 0 Favours 1 Favours no 2 Herceptin HR Herceptin a Based on small subgroups of patients with HER2-positive breast cancer; b distant DFS AC, doxorubicin, cyclophosphamide; P, paclitaxel; T, docetaxel; Carbo, carboplatin; V, vinorelbine; CEF, cyclophosphamide, epirubicin, 5-fluorouracil Gianni et al 2009; Perez et al 2007; Slamon et al 2006; Gianni et al 2008; Joensuu et al 2009; Spielmann et al 2007
von Minckwitz et al, SABCS 2006 Design n=2090 OP NX NX Vinorelbine Capecitabine ore biopsy: ni/bilateral T2-4 N0-3 ize 2 cm* NC Palpation / sonography R OP OP TAC TAC x 6 TAC Docetaxel Adriamycin Cyclophosphamide +G-CSF CR/ PR R OP TAC x 8 excluding low risk (T2 + ER/PR pos. + cno + G1/2 + > 35y.)
Conclusions II Locally advanced and inflammatory breast cancer show similar responses and do not need separate neoadjuvant trials. Significant predictors for path CR are: Complete response after 2 cycles (40.7%) Triple negative tumors (40.7%) High grade (37.9%) Hormone receptor negativity (33.5%) Age < 40 yrs (24.7%) Ductal type (17.3%) von Minckwitz et al, SABCS 2006
Disease-free Survival by Treatment Jones S, et al. SABCS 2007. Abstract 12.
Disease-free Survival by Treatment and Age Group
Jones S, et al. SABCS 2007. Abstract 12. Overall Survival by Treatment
Jones S, et al. SABCS 2007. Abstract 12. Overall Survival by Treatment and Age Group
Hematologic Toxicity by Treatment and Age Grade 3/4 hematologic toxicities (%) < 65 Years 65 Years TC AC TC AC Adverse Event (N=428) (N=428) (N=78) (N=82) Anemia <1 1 <1 5 Neutropenia 60 54 52 59 Thrombocytopenia <1 1 0 <1 Febrile neutropenia 4 2 8 4 Jones S, et al. SABCS 2007. Abstract 12.
Anthracyclines in breast cancer: Predictive factors
BCIRG 006: HER2 and TOPO2A Co-amplification 2990 of 3222 patients analyzed 17 q 12 17 q 21.1 17 q 21.2 N=2990 HER2 Core region TOPO2A region onoamplified oamplified 1788 pts (60%) 145 pts (5%) 1057 pts (35%) Normal Amplified Deletion Slamon et al. SABCS 2006. Abstract 52.
DFS Non-Coamplified Topo IIα by Arm: 2nd Interim Analysis 1.0 Patients Disease Free (%) 0.9 0.8 0.7 0.6 0.5 Patients Events 643 146 AC T 643 87 AC TH 618 92 TCH 91% 90% 83% P <.001 P <.001 85% 84% 78% 83% 81% 71% 0 1 2 3 4 5 Year From Randomization Slamon D, et al. SABCS 2006. Abstract 13.
DFS Coamplified Topo IIα by Arm: 2nd Interim Analysis Patients Disease Free (%) 1.0 0.9 0.8 0.7 0.6 0.5 Patients Events 328 42 AC T 357 35 AC TH 359 42 TCH 95% 94% 92% P =.336 P =.648 89% 87% 87% 83% 83% 85% 0 1 2 3 4 5 Year From Randomization Slamon D, et al. SABCS 2006. Abstract 13.
HER2, TOP2A and Anthracyclines Role of Anthracyclines in the Treatment of Early Breast Cancer Gianni L, et al, J Clin Oncol epub ahead of print August 2009 Several trials show increased benefit for anthracyclines in HER2+ tumors Others show conflicting results Meta-anaylsis suggests DFS benefit for higher dose vs standard dose anthracycline in HER2+ (not sig) Role of TOP2A as a predictive factor for anthracycline activity unclear Anthracyclines have mechanisms of action other than topoisomerase inhibition Highly proliferating tumors generally more likely to respond to chemotherapy TOP2A and HER2 may not be specific enough on their own to discriminate between cytotoxic agents
Predictive Factors Adjuvant Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2009.1.0 Further information References Treatment Factor Endocrine therapy ER/PgR Status 1a A ++ HER-2 2b D - Oncotype DX TM 2b B +/-* Tamoxifen therapy Cyp2D6 polymorphism 2b B +/-* Ovarian ablation menopausal status 1c A ++ Aromatase inhib. menopausal status 1c A ++ Chemotherapy HER-2 2b D - ER/PgR status 2a B +/- upa/pai-1 2a C +/- Oncotype DX TM 2b B +/-* HER-2 directed therapies HER-2 2b D ++ Anthracyclines Topoisomerase IIα 2b a B - Oxford / AGO LoE / GR *Study participation recommended
Anthracyclines in breast cancer: Current status
Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings
Non-Anthracycline Containing Regimens without Trastuzumab* AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2009.1.0 Equivalent OS efficacy to 4 x A / EC: Oxford / AGO LoE / GR 6 x CMF 1a A +/- Superior OS efficacy to 4 x AC : 4 x DC 1b a B + Further information References *Study participation for non-anthracycline regimens recommended D = Docetaxel; C = Cyclophosphamide
PlanB a-free W S G HER2-negative breast cancer M0 T1-4 R0 adequate axillary dissection N+* N- high risk* R A N D O MI S A T IO N TC x 6 Docetaxel (75 mg/m 2 ) + Cyclophosphamide (600 mg/m 2 ) q3wk x 6 EC x 4 Doc x 4 Epirubicin (90 mg/m 2 ) + Cyclophosphamide (600 mg/m 2 ) q3wk x 4 Docetaxel 100 mg/m2 q3w x 4 n=2448 *Risk-selection N0 and 1-3 LN: Recurrence Score (vs. upa/pai-1) Translational program: upa/pai-1 (NNBC-4), anthracycline-response (cooperation with SUCCESS studygroup), CTCs, etc.
Adjuvant Treatment with Trastuzumab: Schedules AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 2009.1.0 Simultaneously Oxford / AGO LoE / GR with paclitaxel / docetaxel after AC / EC 1b B ++ with docetaxel and carboplatin 1b a B + with anthracyclines 2b B +/- with taxanes dose-dense 2b B +/- with taxanes in other regimes 3b a B +/- Further information References Radiotherapy concurrent with Trastuzumab 2 B +
Evidence-based breast cancer therapy Annually updated, evidence-based guidelines for diagnosis and treatment of breast cancer AGO (DKG, DGGG) www.ago-online.org www.karger.com/brc