Neoadjuvant chemotherapy as a research model

Transcription

1 Neoadjuvant chemotherapy as a research model Prof. Dr. Sibylle Loibl Co-Chair of the German Breast Group Sana Klinikum Offenbach Heilung durch Innovation, Kompetenz und Partnerschaft

2 DFS and OS after neoadjuvant chemotherapy according to pathologic response von Minckwitz G Loibl S. J Clin Oncol 2012

3 Prognostic Information of pcr by Subtype (N=4193) Luminal A Luminal B HER2-neg Luminal B HER2-po HER2-pos (non-lum) TNBC von Minckwitz G Loibl S. J Clin Oncol 2012

4 Correlation of effect measured as pcr (OR) with survival (HR) Cortazar P et al. Lancet 2014

5 Increase of pcr in TNBC 100% 90% 80% 70% ypt0/is ypn0 39% 33% 43% 44% 64% 49% 60% 60% 50% 40% 30% 20% 10% 0% TAC EC-Doc EC-Doc+B PM+B PMCb+B PCb-ddAC PCb+B-ddAC GeparTrio 1 GeparQuinto 2,3 GeparSixto CALGB Huober BCRT 2010, 2 von Minckwitz NEJM 2012, 3 Gerber, Annals Oncol ; Sikov 4 SABCS2013

6 Training Set Validation Set GO Terms/Canonical `Pathways 1. Basal-like subtype 1 (BL1) 2 Basal-like subtype 2 (BL2) Higher expression of cell cycle and DNA damage response genes 3. Immunomodulatory (IM) subtype Enriched for gene ontologies in immune cell processes 4. Mesenchymal (M) subtype 5. Mesenchymal stem-like (MSL) subtype Enriched in gene expression of epithelial-mesenchymal transition and growth factor pathways 6. Luminal androgen receptor (LAR) subtype Characterized by androgen receptor signaling Lehmann BD et al. J Clin Invest 2011

7 Vanderbilt Signature Masuda H, et al. Clin Cancer Res 2013

8 Ansprechen innerhalb der 7 Untergruppen 50% 0% 31% 30% 23% 10% 33% Masuda H, et al. Clin Cancer Res 2013

9 pcr in biological breast cancer subtypes according to PARP 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% * ** Low (N=155) Moderate (N=315) High (N=145) * HR+/HER2- (N=305) HR-/HER2+ (N=58) HR+/HER2+ (N=143) HR-/HER2- (N=109) ** Loibl S, et al. ASCO 2010; #10511

10 von Minckwitz G et al. J Clin Oncol 2010 PARP Survival

11 Androgen Receptor 60% 57,1% 50% 40% 30% 20% P< ,8% 25,4% P= ,9% 17,6% 29,5% 41,7% 33,3% 29,2% AR+ AR- 10% 7,9% 0% alle HR+/HER2- HR+/HER2+ HR-/HER2- TNBC Loibl S, et al. BCRT 2010

12 DFS all patients according to pcr and AR Androgenreceptor TNBC patients according to pcr and AR Loibl S et al. BCRT 2011

13 Increase of pcr in HER2+ Long CHT + duale anti- HER2 therapy long CHT +Tras =short CHT+dual anti- HER2 Short CHT +Trastuzumab CHT only

14 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 Sonography CR/ PR von Minckwitz G et al., JCO 2012 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

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

16 Disease-free and overall survival in (A, B) responding, (C, D) nonresponding, and (E, F) all patients comparing response-guided with conventional chemotherapy. von Minckwitz G et al. JCO 2013;31: by American Society of Clinical Oncology

17 Prognostic effect on overall survival of pathologic complete response (pcr) and the corresponding effect of response-guided compared with conventional chemotherapy in patients with (A, B) hormone receptor positive and (C, D) hormone receptor negative tumors. von Minckwitz G et al. JCO 2013;31: by American Society of Clinical Oncology

18 Detecting the target correctly is crucial! pcr (ypt0/is ypn0) % ,4 49, ,8 16,4 HER-2 locally negative (N=1050) HER2 locally positive (N=455) HER-2 local positive but centrally negative (N=60) HER2 central positive (N=171)

19 Study Design N=600 ct 2-4 OR ct 1c if N+ R Triple neg. OR Her2-pos. Surgery TNBC: Bevacizumab, 15 mg/kg q3w OR Her2 pos: Trastuzumab 6 mg/kg q3w (for 1y) + Lapatinib mg/daily 18 weeks Paclitaxel 80 mg/ m² weekly NPLD 20 mg/ m² weekly Carboplatin AUC 2 weekly

20 Total 400µm FFPE tumor samples RESPONSIFY workflow of samples - GeparSixto 12µm 10µm central Pathology 6x2um HER2 pos only central Pathology 2x5um HE, ER, PR, HER2, Ki67, ERCC1 HER2 SISH, CH 17 SISH central pathology 30µm RNA/DNA samples 6 x 5um (last two are optional) DNA PIK3CA RNA Isolation Responsify RESPONSIFY Backup Backup Backup Backup 10µm Total: 62µm (=estimated 15% of sample) Optional backup slides 5x2um TMA production Evaluate protein markers on TMA Tumorbank

21 Lymphozytic infiltration as predictor of pcr Denkert C, Loibl S, et al. J Clin Oncol 2010

22 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 pcr rates in GeparSixto: LPBC vs non-lpbc 80,00 70,00 P< test for interaction p=0.002 P< % 60,00 60% pcr rate (%) 50,00 40,00 30,00 40% P= % 44% 37% 34% 34% 34% 20,00 10,00 0,00 n= both Tx groups StandardTx CarboplatinTx all patients PM - therapy PMCarbo - therapy This presentation is the intellectual property of the author/presenter. Contact them at carsten.denkert@charite.de for permission to reprint and/or distribute. pcr: ypt0ypn0

23 pcr rate according to PIK3CA mutation status in bei HER2+ patients pcr 50% P=0.009 PIK3CA mut PIK3CA wt 40% 37,1% P= ,3% P= % 20% 17,0% 18,2% 17,6% 18,6% 10% 0% Trastuzumab + Lapatinib N=240 Geparsixto Trastuzumab Lapatinib N=60 N=59 Geparquinto Loibl S, et al. SABCS 2013; S5-6

24 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 pcr rate according to PIK3CA mutation status in GeparSixto study pc R 60% P=0.009 PIK3CA mut PIK3CA wt P= % P= ,1% 40% 37,1% 40,0% 30% 29,9% 20% 17,0% 10% 0% 6,3% HER2+ HER2+/HR+ HER2+/HR- N= 241 N= 149 N= 92 This presentation is the intellectual property of the authors. Contact them at sibylle.loibl@germanbreastgroup.de for permission to reprint and/or distribute.

25 NeoPHOEBE: Pi3k inhibition in Her2 OverExpressing Breast cancer: Phase II, randomized, two stage, placebo-controlled 6 Weeks 12 Weeks HER2+ >2cm Newly diagnose d Biopsy PIK3CA mutant PIK3CA Wild-type R A N D O M I Z A T I O N R A N D O M I Z A T I O N Trastuzumab + Placebo Trastuzumab + BKM120 Trastuzumab + Placebo Trastuzumab + BKM120 Trastuzumab + Paclitaxel + Placebo Trastuzumab + Trastuzumab + Paclitaxel + BKM120 + BKM120 Paclitaxel Trastuzumab + Paclitaxel + Placebo Trastuzumab + Trastuzumab + Paclitaxel + BKM120 + BKM120 Paclitaxel S U R G E R Y ENDPOIN T: RATE OF pcr PER COHORT Ultrasound (or MRI) FDG-PET

26 SPARC in BC and Correlation with pcr % P<0.001 pcr P=0.039 SPARC positive 27% SPARC negative SPARC positive 0 all TNBC Untch M et al. SABCS 2012

27 Study design incl. Window substudy with anti-her2 treatment Core biopsy* (before study entry) R* N=60 (HER2 positive) Core biopsy* (after anti-her2 treatment / before study entry) N=1200 Arm A R* Arm B 12 weeks 12 weeks Surgery If HR positive: tamoxifen, aromatase inhibitors If HER2 positive: trastuzumab acc. to AGO Guidelines Core biopsy 6 weeks Paclitaxel 80 mg/m 2 weekly *Centrally confirmed: - Subtypes HER2/HR - Ki67 - SPARC nab-paclitaxel 150 mg/m 2 weekly * Randomizations carried out simultaneously Epirubicin 90 mg/m 2 Cyclophosphamide 600 mg/m 2 Core biopsy optional Core biopsy optional If HER2 positive: Trastuzumab 8 mg/kg (loading dose) followed by 6 mg/kg Pertuzumab (absolute dose per application) 840 mg (loading dose) followed by 420 mg

28 Study Design Stanzbiopsie Zentrale HER2-Bestimmung 2 Wo.* 4 Wochen** 4 Wochen Afatinib 2 Wo.** 11 Wochen 12 Wochen 12 Wochen N=65 P a c l i t a x e l Tras tuzu mab 30 Wochen E C E E E C C C Operation 24 Wochen Trastuzumab lt. AGO-Leitlinien Stanzbiopsie Afatinib: 20 mg täglich (*CAVE: während der ersten 2 Wochen zweitägig). Trastuzumab: Startdosis 8 mg/kg KG, danach 6 mg/kg KG. Paclitaxel: 80 mg/m 2 wöchentlich. Epirubicin: 90 mg/m 2 Tag 1 q22. Cyclophosphamid: 600 mg/m 2 Tag 1 q22. ** Primärprophylaxe mit Loperamid obligat ab Beginn der Afatinib-Trastuzumab-Behandlung für 4 Wochen und ab Beginn der Afatinib-Paclitaxel-Trastuzumab-Behandlung für 2 Wochen.

29 WSG-ADAPT: HR+/HER2- Teil I Einschätzung der Prognose Drei Wochen Therapie Einschätzung der Wirksamkeit Hohes Risiko Chemotherapie B I O P S I E B I O P S I E o. Operation Intermediäres Risiko Niedriges Risiko Schlechtes proliferations Ansprechen Gutes profilerations Ansprechen Endokrine Therapie RS Ki-67 RS Ki Initiierungspräsentation Version WSG GmbH 29

30 Courtesy from Mitch Dowsett 1. Does perioperative endocrine therapy influence RFS? 2. Does 2-week Ki67 on AI predict long-term outcome better sufficiently to merit routine implementation? 3. Can on-treatment (2-week AI) molecular profiles predict RFS better than PreRx?

31 Courtesy from Mitch Dowsett POETIC: Window of opportunity study Presentation biopsy 2w 4,000 pats ±AI Surgery biopsy or excision biopsy Biological studies c.15%% pairs RNA later (c.40%) postrx rest FFPE +leukocytes/plasma Intermediate end-points Ki67 metagenes core genes

32 POETIC: Window of opportunity study Presentation biopsy 2w 4,000 pats ±AI Surgery biopsy or excision biopsy Biological studies c.15%% pairs RNA later (c.40%) postrx rest FFPE +leukocytes/plasma Intermediate end-points Ki67 metagenes core genes Pretreatment determinants Courtesy from Mitch Dowsett IHC, acgh, RNA profiles (illumina/q-rtpcr/nanostring) NGS bookend studies candidate mutations SNPs (methylation)

33 POETIC: Window of opportunity study Presentation biopsy 2w 4,000 pats ±AI Surgery biopsy or excision biopsy Biological studies c.15%% pairs RNA later (c.40%) postrx rest FFPE +leukocytes/plasma On-treatment predictive molecular profiles Intermediate end-points Ki67 metagenes core genes Pretreatment determinants Courtesy from Mitch Dowsett IHC, acgh, RNA profiles (illumina/q-rtpcr/nanostring) NGS bookend studies candidate mutations SNPs (methylation)

34 POETIC: Window of opportunity study Presentation biopsy 2w 4,000 pats ±AI Surgery biopsy or excision biopsy Biological studies c.15%% pairs RNA later (c.40%) postrx rest FFPE +leukocytes/plasma Intermediate end-points Ki67 metagenes core genes Pretreatment determinants Courtesy from Mitch Dowsett On-treatment predictive molecular profiles Tumour heterogeneity and treatment effects IHC, acgh, RNA profiles (illumina/q-rtpcr/nanostring) NGS bookend studies candidate mutations SNPs (methylation)

35 CPS + EG Staging System Mittendorf EA, J Clin Oncol 2011

36 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 CPS + EG Staging System German meta-database (N=2454 HR+/HER2- tumors) Mittendorf EA, J Clin Oncol 2011 Marmé F, manuscript in prep This presentation is the intellectual property of GBG and AGO-B. Contact them at gunter.vonminckwitz@germanbreastgroup.de for permission to reprint and/or distribute.

37 San Antonio Breast Cancer Symposium - Cancer Therapy and Research Center at UT Health Science Center December 10-14, 2013 Study Design N=800 pts. with HR+/HER2- breast cancer no pcr and CPS-EG score 3 : Palbociclib 125 mg once daily p.o. d1-21, q28d for 13 cycles Neoadjuvant Chemotherapy Surgery +/- Radiotherapy R Placebo d1-21, q28d for 13 cycles All patients will receive concomitantly endocrine therapy according to local standards von Minckwitz G, SABCS 2013 OT This presentation is the intellectual property of GBG and AGO-B. Contact them at gunter.vonminckwitz@germanbreastgroup.de for permission to reprint and/or distribute.

38 Conclusion Pathological complete repsonse as surrogate for pcr HER2+, TNBC Investigate biomarker in prospectively collected cohorts within a randomised trial Design a prospective study using the biomarker as stratification marker or selection/entry criteria (central pathology/testing) Design a window of opportunity study to identify new markers Postneoadjuvant studies neoadjvant therapy as a selection criterion