Postoperative Adjuvant Chemotherapies. Stefan Aebi Luzerner Kantonsspital

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1 Postoperative Adjuvant Chemotherapies Stefan Aebi Luzerner Kantonsspital

2 Does Chemotherapy Work in Older Patients? ER : Chemotherapy vs nil Age <50 Age Age Lancet

3 Case 1 Chemotherapy? Which one? CMF 3 rd Generation

4 What s Wrong with CMF? IBCSG VIII and IX Cumulative Incidence of Relapse adapted from Colleoni JCO

5 Case 1 What About Other Regimens? Doxorubicin + Cyclophosphamide (AC) Equally effective as oral CMF in ER-negative breast cancer: N+, NSABP B-15; N, NSABP B-23 Fisher JCO Fisher JCO

6 Case 1 What About Other Regimens? Docetaxel + Cyclophosphamide 20% > 65 years, 25% ER Similar efficacy by ER status TC<65 AC<65 TC 65 AC 65 Jones JCO

7 Case 1 What About Other Regimens? Docetaxel + Cyclophosphamide 20% > 65 years, 25% ER Similar efficacy by ER status Similar toxicity Jones JCO

8 Case 2 Chemotherapy for ER+ Tumors? Oxford OverviewData: Similar efficacy in ER+ and ER breast cancer Lancet

9 Chemotherapy for ALL Patients with ER+ Tumors? A few examples of overall positive trials IBCSG IX (N, postmenopausal) No benefit of CMF for patients with ER+ tumors NSABP B-20 (N, ER+, pre- and postmenopausal) No benefit for postmenopausal patients with ER+ tumors and for low/intermediate Recurrence Score Intergroup 0100 (N+, ER+, postmenopausal) No benefit for patients with strongly positive ER+ tumors (Albain, SABCS 2004); and for low/inter-mediate Recurrence Score) IBCSG Ann Oncol Fisher Lancet Paik JCO Albain Lancet Oncol

10 Disease-Free Survival INT 0100 (S8814) No CAF Benefit if High ER Disease Free Survival Log rank p = 0.98 Tamoxifen + CAF (n=262, 104 failures) Tamoxifen alone (n=82, 34 failures) Years Since Registration Albain K et al. SABCS 2004 #37

11 Recurrence Score Predicts Chemotherapy Response NSABP B-20: ER+ N0 Low Score High Score SWOG8814: ER+ N1 Low Score Similar partitioning of trial populations have been reported for the 70 gene risk score (Mammaprint), the genomic grade index, and other prognostic/predictive indices. High Score Paik JCO Albain Lancet Oncol

12 Ten Years Ago Intrinsic Subtypes 78 breast cancers of 77 patients Microarrays with 8102 genes 456 genes for hierarchical clustering Perou C et al. Nature Sørlie T et al. PNAS

13 Intrinsic Subtype, Recurrence Score, and Mammaprint Fan NEJM

14 ER+ Breast Cancer Breast cancers with high Recurrence Score high Genomic Grade Index luminal B mrna profile high Ki67 are similar, with proliferation as the dominant common component

15 Subtypes Approximation Therapy? Intrinsic Subtype Approximation Therapy Luminal A Luminal B oder HER2 (erbb2) ER+ and/or PR+, HER2 non-amplified or IHC, Ki67 low* ER+ and/or PR+, HER2, Ki67 high* ER+ and/or PR+, HER2 amplified or IHC+++ HER2 amplified or IHC+++, ER and PR absent Endocrine therapy Chemotherapy + endocrine therapy Chemotherapy + endocrine therapy + trastuzumab Chemotherapy + trastuzumab Basal-like Triple negative Chemotherapy *SG Consensus 2011 recommends 14% cut-off or other measure of proliferation 80% concordance with basal-like

16 Efficacy Likely in Luminal B Cancers Intergroup 0100: CAF (Oncotype Dx) Albain Lancet Oncol PACS 01: FEC x3 Docetaxel x3 (Ki67) Penault Llorca JCO BCIRG 001: DAC x6 (ER, PR, HER2, Ki67) Martin NEJM , Hugh JCO ER+ and/or PR+ and (Her2+ or Ki67high [13%]) luminal B ER+ and/or PR+ and not (Her2+ or Ki67high) luminal A

17 Efficacy Likely in Luminal B Cancers more of the same CALGB 9344: AC P (q3wk) Berry Cancer Res Suppl 3 #606 luminal B luminal A US Oncology Trial 9735: DC Jones JCO

18 HERA 4-year Update

19 HERA Update % CI DFS ITT OS ITT % CI % CI DFS Censored OS Censored % CI Gianni Lancet Oncol

20 NSABP B-31/N year Update Perez JCO

21 NSABP B-31/N9831 Update DFS P =0.001; HR= % CI, 0.45 to 0.60 OS P=0.001; HR= % CI, 0.50 to 0.75 Perez JCO

22 N9831 Update Sequential vs. Concurrent Perez JCO

23 N9831 Update Sequential vs. Concurrent Trastuzumab Reasons for treatment discontinuation adapted from Perez JCO 2011 epub ahead of print

24 N9831 Update Sequential vs. Concurrent Trastuzumab October 2009 Independent Data Monitoring Board (IDMC) recommended the release of all NCCTG N9831 study data... Although the statistical boundary had not been reached before the first interim analysis of arm B and arm C, it was also recommended that data from this comparison be released because of a DFS event rate that was lower than anticipated... it would have taken at least 10 to 15 additional years of follow-up... lending support to the release of data in the context of their relevance to global patient care. Perez JCO 2011 epub ahead of print

25 BCIRG 006 Do we need anthracyclines? Slamon SABCS 2009

26 BCIRG 006 Do we need anthracyclines? Slamon BCIRG 006 NEJM

27 BCIRG 006 Do we need anthracyclines? Slamon BCIRG 006 NEJM

28 BCIRG 006 Do we need anthracyclines? Slamon BCIRG 006 NEJM

29 BCIRG 006 Do we need trastuzumab? 35% of cases with co-amplification of topoisomerase 2α Slamon BCIRG 006 NEJM

30 A few things you need not try in routine adjuvant therapy Doxorubicin > 60 mg/m2 per cycle Henderson JCO Cyclophosphamide > 600 mg/m2 per cycle Fisher JCO High dose chemotherapy with autologous bone marrow stem cell support Berry JCO Adjuvant gemcitabine Poole Proc ASCO 2008