Update on neoadjuvant breast cancer trials : Lessons learnt

Transcription

1 Update on neoadjuvant breast cancer trials : Lessons learnt Gunter von Minckwitz German Breast Group, Neu-Isenburg/Frankfurt Luisenkrankenhaus Düsseldorf

2 Disclosure of potential conflicts of interest Honoraria: Amgen, Roche, Sanofi-Aventis Research Funding: Amgen, Celgene, Cephalon, GSK, Novartis, Roche, Sanofi-Aventis

3 New lessons learnt pcr can relief patients with high risk subtypes from poor prognosis Biomarkers so far unable to predict or discriminate targeted treatment effects Long-term effects of e.g. interim response guided treatments not predicted by pcr in low-risk subtypes Some (but which?) patients with locally advanced tumors and pcr require less locoregional treatment

4 % Disease-Free NSABP B-27: Disease- Free Survival Treatment and Pathologic Response P < TRT N Events AC No pcr ACT No pcr p = 0.42 ACpT No pcr AC pcr ACT pcr ACpT pcr H. Bear, personal communication Years after Surgery p = 0.21

5 Prognosis information of pcr by Subtype (N=4193) Luminal A Luminal B HER2-neg Luminal B HER2-pos HER2-pos (non-lum) TNBC von Minckwitz G et al, J Clin Oncol 2012

6 Increase in pcr by trastuzumab correlates with better prognosis (NOAH trial) Gianni L, et al. NOAH study Lancet 2010

7 Will the efficacy of lapatinib be predicted by neoadjuvant studies? Untch et al, GeparQuinto Lancet Oncology 2012

8 Pathologic complete response (%) San Antonio Breast Cancer Symposium Cancer Therapy and Research Center at UT Health Science Center December 6 10, 2011 Tryphaena to predict the outcome of adjuvant pertuzumab in the Aphinity study ypt0/is ypt0 ypn FEC+H+P x3 T+H+P x3 (n = 73) Schneeweiß et al.,, SABCS 2011 FEC x3 T+H+P x3 (n = 75) TCH+P x6 (n = 77) FEC, 5-fluorouracil, epirubicin, cyclophosphamide; H, trastuzumab; P, pertuzumab; T, docetaxel; TCH, docetaxel/carboplatin/trastuzumab Copyrights for this presentation are held by the author/presenter. Contact them at Andreas.Schneeweiss@med.uni-heidelberg.de for permission to reprint and/or distribute. 8

9 Conclusions from NeoSphere biomarker analyses HER2 expression (H-score) associated with sensitivity to pertuzumab PI3K mutations in exon 9 linked to lack of sensitivity to HER2- directed Mab s Intrinsic differences between HER2+ tumors based on hormone receptor status No predictive role for truncated forms of the HER2 receptor including p95 HER2 So far none of the analyses provided clinically useful assays for patient and/or regimen selection in addition or alternative to the conventional assessment of HER2 by IHC or FISH Gianni L, SABCS

10 IHC markers signaling resistance to trastuzumab (+chemotherapy) on 153 participants of GeparQuattro activates mtor pathway Marker % with no tumor regression Univariat e OR p Multivariate OR p-4ebp1 39% p signals stem-cell properties ALDH1 62% Notch 1 64% p27kip1 71% ,45 0,499 IGFR1 42% IR 37% Huober J et al, SABCS 2010

11 Neo-Altto Overall (Clinical) Response at 6 weeks (w/o chemo) and at surgery Baselga et al., SABCS 2010 L: lapatinib; T: trastuzumab; L+T: lapatinib plus trastuzumab

12 P95 HER2 mixed up by methodology?

13 Cytoplasmic PARP expression in 615 patients treated with neoadjuvant TAC (GeparTrio) 60% 50% Overall: < pcr 30% P< % 40% 30% 20% HR+/HER2- (N=305) HR+/HER2+ (N=143) HR-/HER2+ (N=58) HR-/HER2- (N=109) 25% 20% 15% 10% 8.0% 19.1% 10% 5% 0% Low (N=155) Medium (N=315) High (N=145) 0% Low (N=162) Medium (N=325) High (N=151) von Minckwitz G et al, J Clin Oncol 2011

14 The Magic Triangle pcr Rate Prognostic Impact of pcr Breast Cancer Subtypes Long-Term Treatment Effect

15 Sonography IMPAKT Breast Cancer Conference 2012 GeparTrio Trial Design N=2072 Core biopsy: uni/bilateral ct2-4a-d cn0-3 size 2 cm* *low risk patients were excluded (T2 + ER/PR pos. + cno + G1/2 + > 35 yrs) NC CR/ PR von Minckwitz G et al., SABCS 2011 R R NX von Minckwitz et al, JNCI 100: 542, 2008 von Minckwitz et al. JNCI 100; 552, 2008 TACx6 conventional arms TACx6 TACx8 responseguided arms

16 Short Term Efficacy (pcr = ypt0 ypn0) Responder N=1344 Non-Responder N=604 30% P=0.27 P= % 10% TACx6 TACx8 5.3 TACx6 6.0 TAC-NX von Minckwitz G et al., SABCS 2011 von Minckwitz et al, JNCI 100: 542, 2008 von Minckwitz et al. JNCI 100; 552, 2008

17 DFS and OS after conventional (TACx6) vs. response-guided (TACx8/TAC-NX) treatment von Minckwitz G et al., SABCS 2011 Median follow up 62 months

18 DFS in Luminal A tumors by pcr by treatment von Minckwitz G et al., SABCS 2011

19 DFS in Triple Negative Tumors by pcr by treatment von Minckwitz G et al., SABCS 2011

20 New lessons learnt pcr can relief patients with high risk subtypes from poor prognosis Biomarkers so far unable to predict or discriminate targeted treatment effects Long-term effects of e.g. interim response guided treatments not predicted by pcr in low-risk subtypes Some (but which?) patients with locally advanced tumors and pcr require less locoregional treatment

21 Loco-regional recurrence risk (LRR) after neoadjuvant chemotherapy by tumor stage ypt stage and type of surgery but not ct, cn, ypn, and intrinsic subtype, were independent predictors of LRR in a multivariate model! von Minckwitz et al., SABCS 2011

22 Loco-regional recurrence risk after neoadjuvant chemotherapy No factor except Luminal B (HER2+) identified to predict LRR in a multivariate model! von Minckwitz et al., SABCS 2011

23 What to learn more from neoadjuvant trials in 2010 / 2011 More precise and easy applicable subtyping to fully benefit from subtypespecific approaches Strategies exploring less treatment for high-risk subtypes with high pcr probability Better identification of low-risk subtypes which benefit from more & better chemotherapy

24 Methodological Issues of Biomarker Research in Neoadjuvant Setting Remain unsolved in 2012! Prediction of Resistance or Sensitivity (pcr vs gross residual disease) Tissue size & heterogeneity Functional Markers even more complex Predictor and/or Prognosticator Predicting the Surrogate Multimodal Treatment Multiple Testing

25 GBG Subboards Neoadjuvant Board Jens Uwe Blohmer Serban Costa Carsten Denkert Holger Eidtmann Bernd Gerber Claus Hanusch Jörn Hilfrich Jens Huober Christian Jackisch Andreas Schneeweiss Stefan Paepke Michael Untch Translational Board Carsten Denkert Peter Fasching Jens Huober Thomas Karn Cornelia Liedtke Ivo Meinhold Heerlein Volkmar Müller Brigitte Rack Christian Schem Sibylle Loibl Gunter v. Minckwitz Sherko Kümmel Sibylle Loibl Gunter v. Minckwitz

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27 pcr rates were higher in rec neg. tumors pcr GeparQuinto NeoSphere NeoAltto ypt0 ypn0 ypt0/is ypn0 ypt0/is ypn0

28 Reasons for unchanged BCT rates Persisting contra-indications T4 tumors Multi-centric disease Large microcalcifications Insufficient preoperative imaging 53 (10.7%) of 496 Pts. with mastectomy had a pcr additional 31 (6.2%) had only in situ residuals Untch M, von Minckwitz et al. submitted

29 Duration of chemotherapy or use of anthracyclines impact pcr rate! Untch M, von Minckwitz G, GeparQuinto Lancet Oncology 2012

30 Projekt Vorhersagewert einer präoperativen Core-Biopsie für eine pcr N= 28 Pat. 7x 10x 11x Luminal/Her2-, HER2+, TNBC 4 x Stanze positiv 1x Invasiver Tumor, aber pcr im Op-Präparat) 1x DCIS, aber pcr im Op-Präparat)

31 Projekt Vorhersagewert einer präoperativen Core-Biopsie für eine pcr 24 x Stanze negativ 18x pcr, 1x yptis, 5x ypt>=1! 6 Pat Resttumor bei OP: 2xTNBC, 2x HER2+, 2xLuminal/HER2- Rate falsch-negativer Stanzen TNBC: 2/11 (18%), HER2+: 2/ 7 (28%) Luminal/HER2-: 2/ 6 (33%)

32 Which is the group with the highest pcr rate? pcr rates Unselected patients* 25% Selected patients (HER2+ or TNBC) (approx. 40% of all) 40-45% Unselected patients with clinical CR before surgery (approx. 25% of all) 65% Selected patients with clinical CR HER2 + (35% of all HER2+) 74% TNBC (27% of all TNBC) 72% Selected patients with clinical CR and negative core biopsy (approx. 10% of all)??% *based on GeparQuattro (treatment with A/T, > 18 weeks, trastuzumab for HER2+ pts)