Predicting outcome in metastatic breast cancer

Transcription

1 Predicting outcome in metastatic breast cancer Aleix Prat, MD, PhD Medical Oncology Department Translational Genomics and Targeted Therapeutics in Solid Tumors Monday, 15 th January, Manchester, UK

2 Disclosures Consultancy Pfizer, Lilly, Novartis, Nanostring Technologies Research funding Novartis, Nanostring Technologies Scientific advisory board Oncolytics Biotech

3 The biological complexity of metastatic breast cancer disease today HER2 +3 HER2-negative tumor cells features tumor microenviroment ER-negative ER-positive mrna microrna Protein Tumor Infiltrating Lymphocytes (TILs) Courtesy of Dr. Pedro Fernández DNA Copy Number DNA Methylation DNA Mutations TCGA Nature 2012

4 Intrinsic Subtype distribution within IHC-based groups n= 9,768 n= 3,059 n= 2,512 Cejalvo et al. ESMO 2017 #1727P

5 Summary - EGF3008 First-line Phase III clinical trial - 1,286 patients with HR+ disease - No benefit of lapatinib in HR+/HER2-negative disease - Benefit of lapatinib in HR+/HER2+ disease R Letrozole+placebo Letrozole+lapatinib

6 PAM50 and Survival in First-line HR+/HER2-neg Metastatic Breast Cancer (N=644) PFS OS Prat Johnston. JAMA Oncology 2016

7 PAM50 and PFS in HR+/HER2-neg Metastatic Breast Cancer Likelihood (χ2) for PFS for all individual clinical variables Univariate Mutivariable Clinical variables χ 2 (P ) χ 2 (P ) PAM50 subtype < < Treatment Prior endocrine therapy < < Site of metastasis Performance status Num. of metastases < < Age Type of tissue Prat Johnston. JAMA Oncology 2016

8 Intrinsic subtype in HR+/HER2-negative metastatic breast cancer (PALOMA-2 retrospective data) Finn R et al. NEJM 2016 N=666 Finn R et al. SABCS 2017 <1% 1% mpfs (months) Palbociclib letrozole: 24.8 Placebo letrozole: % 30% 50% N=455 (68.3%)

9 Intrinsic subtype in HR+/HER2-negative metastatic breast cancer (PALOMA-2 retrospective data) Finn R et al. SABCS 2017 <1% 1% 19% 30% 50% N=455 (68.3%)

10 Primary Tumor Studying the Biological Differences Between 123 Paired Primary and Metastatic Breast Cancer Metastatic Site HER2-Enriched Signature Basal-like HER2-E LumA LumB Basal-like 12 (92%) 1 (8%) 0 0 HER2-E 2 (15%) 10 (77%) 1 (8%) 0 LumA 1 (2%) 6 (13%) 21 (46%) 18 (39%) LumB 0 4 (13%) 5 (17%) 21 (70%) Subtype Concordance=63% 54% of primary Luminal A tumors become non-luminal A 13% of primary Luminal A/B become HER2-E P< Prim Met Increased expression in MET Decreased expression in MET Cejalvo et al. Cancer Res 2017

11 FGFR4 expression is enriched in metastatic breast cancer Cejalvo et al. Cancer Res 2017 Levine et al. SABCS 2017 FGFR4 gene P<0.001 Prim Met Increased expression in MET Decreased expression in MET

12 Summary - Phase III first-line clinical trial - 1,286 patients with HR+ disease - No benefit of lapatinib in HR+/HER2-negative disease - Benefit of lapatinib in HR+/HER2+ disease R Letrozole+placebo Letrozole+lapatinib

13 HER2-E and lapatinib benefit in HR+/HER2-neg Metastatic Breast Cancer nonher2-e HER2-E 6.49 vs 2.60 months HR=0.24 [95% CI, ] interaction P = 0.02 Prat Johnston. JAMA Oncology 2016

14 The biological complexity of metastatic breast cancer disease today HER2 +3 HER2-negative tumor cells features tumor microenviroment ER-negative ER-positive mrna microrna Protein Tumor Infiltrating Lymphocytes (TILs) Courtesy of Dr. Pedro Fernández DNA Copy Number DNA Methylation DNA Mutations TCGA Nature 2012

15 CDK4/6 inhibitors in ER-positive/PIK3CAmut breast cancer PALOMA2 PALOMA3 (2:1) PIK3CA ctdna levels MONALEESA2 (ratio D15/Baseline) (1:1) Progression-free survival (%) Number of patients at risk PAL + FUL 347 PCB + FUL Time (months) Palbociclib + fulvestrant (n=374) Placebo + fulvestrant (n=174) HR 0.50 (95% CI: 0.40, 0.62) 1-sided P<0.0001* C D R P IK 3 C A C D R b y t r e a t m e n t p < palbociclib + fulvestrant placebo + fulvestrant Turner et al. NEJM 2015 Updated SABCS 2016 O Leary et al ASCO 2017

16 Women surviving progression free (%) ctdna dynamics and resistance to palbociclib in PALOMA3 100 Median PFS 11.2m (95%CI 11.1 X) Median PFS 4.1m (95%CI ) 0 Low CDR High CDR HR % CI (1.98, 12.26) p= Time from randomization (months) Number at risk (events) Low CDR: 30 (4) 26 (1) 20 (2) 13 (2) 1 High CDR: 22 (5) 16 (11) 4 (0) 1 (0) 0 O Leary et al ASCO 2017

17 Frequency of ESR1 somatic mutations in breast cancer Metastatic disease Primary disease N ESR1mut PRIMARY TUMOR Schiavon et al. Sci Transl Med 2015 Jeselsohn et al. Clin Cancer Res 2014 Lefebvre et al. Plos Medicine 2016 Miller et al. Nat Communications 2016 Toy et al. Cancer Discovery 2016 Fribbens et al. JCO 2016 Chandarlapaty et al. JAMA Oncol 2016

18 Chandarlapaty et al. JAMA Oncol 2016 ESR1 mutations predict overall survival in HR+ metastatic breast cancer Retrospective Analyses from BOLERO-2 Phase III trial (n=541/724) Exemestane +/- Everolimus 32.1 months 20.7 months

19 Fribbens et al. JCO 2016 ESR1 mutations might predict Fulvestrant vs. AI survival benefit in HR+ metastatic breast cancer Retrospective Analyses from SoFEA Phase III trial (n=161/723) Fulvestrant-containing regimen vs. Exemestane ESR1-mut ESR1-WT Interaction P=0.07

20 The biological complexity of metastatic breast cancer disease today HER2 +3 HER2-negative tumor cells features tumor microenviroment ER-negative ER-positive mrna microrna Protein Tumor Infiltrating Lymphocytes (TILs) Courtesy of Dr. Pedro Fernández DNA Copy Number DNA Methylation DNA Mutations TCGA Nature 2012

21 Tumor-infiltrating lymphocytes in advanced HER2+ breast cancer treated with trastuzumab and docetaxel +/- pertuzumab Retrospective Analysis from CLEOPATRA trial (n=678/808) 93% Primary Tissue vs 7% Metastatic Tissue No significant association between TILs and PFS TILs was significantly associated with longer OS (adjusted HR 0 89, 95% CI , p=0 0014). The treatment effect of pertuzumab did not differ by stromal TILs Luen et al. Lancet Oncol 2017

22 2017 SAN ANTONIO BREAST CANCER SYMPOSIUM December 5-9, 2017 Study Design: PANACEA IBCSG 45-13/BIG 4-13/KEYNOTE-014 Patients Centrally confirmed HER2+ ECOG 0-1 Tumor biopsy sample <1yr Measurable disease No limit of prior systemic treatment Documented PD on trastuzumab or TDM-1 PD-L1 + PD-L1 - Phase Ib Pembrolizumab 2mg/kg and 10mg/kg IV + trastuzumab Q3W Phase II Pembrolizumab 200mg IV + trastuzumab Q3W Phase II Pembrolizumab 200mg IV + trastuzumab Q3W Protocol specified follow-up. Treatment until progression, toxicity, patient withdrawal, investigator decision, or maximum 2 years Loi et al. SABCS 2017 INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact ibcsgcc@ibcsg.org for permission to reprint and/or distribute.

23 2017 SAN ANTONIO BREAST CANCER SYMPOSIUM December 5-9, 2017 stils 5% as Potential Predictive Marker: PD-L1 Positive Cohorts 41% of PD-L1 positive cohort had stils 5% For stils 5% v. stils < 5% ORR 39% vs. 5% Sensitivity: 85.7% Specificity: 61.8% NPV: 95.5% PPV: 31.6% DCR 47% vs. 5% Sensitivity: 90.0% Specificity: 67.7% NPV: 95.5% PPV: 47.4% Loi et al. SABCS 2017 INTERNATIONAL BREAST CANCER STUDY GROUP This presentation is the intellectual property of IBCSG. Contact for permission to reprint and/or distribute.

24 Take-home messages: advanced/metastatic disease Non-luminal subtypes within HR+/HER2-neg have a poor outcome and might not benefit from endocrine therapy +/- CDK4/6 inhibition. HR+/HER2-neg/HER2-enriched might benefit from an EGFR/HER2 TKI. HER2-E profile is increased in metastatic samples versus primary disease. FGFR4 overexpression is a recurrent event in M1 disease that deserves attention. ctdna dynamics within HR+/HER2-neg might predict on-treatment benefit. ESR1 mutations might predict poor outcome and benefit from ER-degraders. Within HER2+, stromal TILs predict OS, and might predict anti-pd1 benefit.

25 Thank you