Nadia Harbeck Breast Center University of Cologne, Germany

Transcription

1 Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings Nadia Harbeck Breast Center University of Cologne, Germany

2 Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings

3 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

4 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?

5 Anthracyclines in breast cancer: Clinical concerns

6 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

7 CAF none

8 Annual CM incidence Cumulative CM incidence

9 Anthracyclines in breast cancer: Clinical data

10 Adjuvant Chemotherapy in Breast Cancer and Survival Improvements: Step by Step CT + TT (trastuzumab) No CT ANTHRACYCLINES TAXANES 1980 CMF 4.5% OS improvement % OS improvement % OS improvement % OS improvement

11 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 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 < Gennari, J Natl Cancer Inst. 2008;100: p = p < p = HER2+ve HER2-ve

12 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 NOAH CTx / H H 1 year 3 FinHer a VH / TH CEF b PACS-04 a CTx H 1 year n=231 n= 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

13 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.)

14 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

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16 Disease-free Survival by Treatment Jones S, et al. SABCS Abstract 12.

17 Disease-free Survival by Treatment and Age Group

18 Jones S, et al. SABCS Abstract 12. Overall Survival by Treatment

19 Jones S, et al. SABCS Abstract 12. Overall Survival by Treatment and Age Group

20 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 Thrombocytopenia <1 1 0 <1 Febrile neutropenia Jones S, et al. SABCS Abstract 12.

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22 Anthracyclines in breast cancer: Predictive factors

23 BCIRG 006: HER2 and TOPO2A Co-amplification 2990 of 3222 patients analyzed 17 q q 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 Abstract 52.

24 DFS Non-Coamplified Topo IIα by Arm: 2nd Interim Analysis 1.0 Patients Disease Free (%) Patients Events AC T AC TH TCH 91% 90% 83% P <.001 P < % 84% 78% 83% 81% 71% Year From Randomization Slamon D, et al. SABCS Abstract 13.

25 DFS Coamplified Topo IIα by Arm: 2nd Interim Analysis Patients Disease Free (%) Patients Events AC T AC TH TCH 95% 94% 92% P =.336 P = % 87% 87% 83% 83% 85% Year From Randomization Slamon D, et al. SABCS Abstract 13.

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27 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

28 Predictive Factors Adjuvant Therapy AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 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

29 Anthracyclines in breast cancer: Current status

30 Evidence in Favor of Taxane Based Combinations and No Anthracycline in Adjuvant and Metastatic Settings

31 Non-Anthracycline Containing Regimens without Trastuzumab* AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 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

32 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.

33 Adjuvant Treatment with Trastuzumab: Schedules AGO e. V. in der DGGG e.v. sowie in der DKG e.v. Guidelines Breast Version 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 +

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35 Evidence-based breast cancer therapy Annually updated, evidence-based guidelines for diagnosis and treatment of breast cancer AGO (DKG, DGGG)