Medicina de precisión en cáncer de ovario: Determinación de BRCA germinal y somático
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1 Medicina de precisión en cáncer de ovario: Determinación de BRCA germinal y somático Dra. Cristina Martin Lorente Hospital de la Santa Creu i Sant Pau. Barcelona
2 Introduction Ovarian cancer is the fifth leading cause of cancer death in women in developed countries. Estimated incidence of 225,000 women and 140,000 deaths per year worldwide Optimal surgery and platinum-based chemotherapy are the mainstay of front-line treatment but about 80% will relapse Up to 15% of epithelial OC cases are familial. Inherited mutations in BRCA1/2 account for the majority of familial OC with an increased lifetime risk of developing OC 40-60% BRCA1 and 11-30% BRCA2 Globocan Ford D et al Am J Hum Genet National Cancer Institute Ford D et al Am J Hum Genet 1998
3 Ovarian Cancer (OC): Multiples Diseases Different types with different behaviour Most Common High grade serous ovarian cancer (HGSOC) HGSOC: Associated with characteristics of genomic instability (TP53) and homologous recombination deficiency (BRCA)
4 Defining BRCAness Phenotype Ovarian cancers in women with BRCA1/2 germline mutations are characterized by an improved response to platinum-based chemotherapy at first and subsequent relapses and better outcomes (PFS, OS) Tan D JCO 2008; Fong FC JCO 2010; Audeh MW Lancet 2010; Ledermann J Lancet 2014; Fong FC NEJM 2009
5 Defining BRCAness Phenotype BRCA1/2 germline mutated populations have also shown exceptional sensitivity to PARP inhibitors (PARPi) Tan D JCO 2008; Fong FC JCO 2010; Audeh MW Lancet 2010; Ledermann J Lancet 2014; Fong FC NEJM 2009
6 Use BRCA deficiency for treatment Olaparib Rucaparib Veliparib Niraparib BMN-673 Tewari Clin Cancer Res 2015
7 Targeting BRCA in Ovarian Cancer: An approach for personalizing management of OC
8 PARP inhibitors in clinical trials
9 Response by BRCA status: ORR 41% with BRCAm vs 24% BRCAwt Gelmon et al. Lancet Oncol 2011
10 Study 19: To assess the efficacy and safety of oral Olaparib as maintenance treatment A randomised, double-blind, placebo-controlled Phase II maintenance study 265 patients in 82 investigational sites in 16 countries Patients: Platinum-sensitive high-grade serous ovarian cancer 2 previous platinum regimens Last chemotherapy was platinumbased, to which they had a maintained PR or CR prior to enrolment Olaparib 400 mg po bid Randomised 1:1 Placebo po bid Treatment until disease progression Primary end point: Progression free survival Ledermann J et al. N Engl J Med 2012
11 Olaparib met the primary endpoint of improving PFS in the OVERALL study population Ledermann J et al. N Engl J Med 2012
12 More than 50% patients had a known deleterious BRCAm (Pre-planned BRCA testing) Patients with a known BRCA status increased from 98 (37%) to 254 (95.8%) out of 265: 136 (51.3%) patients had a known deleterious BRCAm (BRCAm dataset) 118 (44.5%) patients were defined as BRCA1/2 wild type for this analysis 11 (4.2%) patients had neither a tumour nor a germline result available Ledermann J et al. N Engl J Med 2012
13 Proportion of patients progression-free Olaparib significantly prolonged PFS in platinum-sensitive relapsed HGSOC Patients with a BRCA mutation receive greater treatment benefit Non-mutation carriers may also benefit from olaparib treatment Median PFS, months BRCAm (n=136) BRCAwt (n=118) Olaparib Placebo Olaparib Placebo HR=0.18 HR=0.53 P< P= Olaparib BRCAm Placebo BRCAm Olaparib BRCAwt Placebo BRCAwt Time from randomization (months) Ledermann et al. N Eng J Med Ledermann et al. Lancet Oncol 2014
14 BRCA germline mutations BRCA somatic mutations BRCAness Phenotype Similar to germline BRCAm, PFS was longer in somatic BRCAm population compared with wildtype Germline or somatic HR mutations was highly predictive of primary platinum and PARPi sensitivity and improved overall survival Hennessy JCO 2010/ Pennington CCR 2014
15 WHO TO TEST? In the past we used to refer patients to genetic counseling based on their family history and personal history Nowadays we have a broaden vision of the disease which supports that this policy is not accurate enough
16 Frequency of BRCA1/2 mutations in women with OC is unclear (3-27%) women enrolled onto a population-based case-control study were screened Germ-line mutations were found in 14.4% of patients (22.6% HGSOC; 8.4% endometrioid; 6%CC; 0% carcinosarcoma) 44% had not reported family history of breast or OC BRCAm was associated with better outcomes (RR, PFS, OS) Conclusions: BRCA status has a major influence on survival, treatment outcomes and treatment selection and SHOULD BE OFFERED TO ALL WOMEN DIAGNOSED WITH NON-MUCINOUS OC REGARDLESS OF FAMILY HISTORY Alsop K JCO 2012
17 WHO TO TEST?
18 What about SOMATIC Testing? Ovarian cancer in women with BRCA somatic mutation (BRCAg wt) is also characterized by an improved response to platinum-based chemotherapy and PARP inhibitors and by better outcomes with longer PFS and improved OS Olaparib approved by EMA as first-in-class treatment for advanced BRCA-MUTATED (germline and somatic) ovarian cancer (January 2015) BRCA somatic mutation testing expands the number of patients who would benefit from personalized medicine
19 WHEN TO TEST? Initial diagnosis preferable PRO Access to pathology Biomarker of response to platinum-based chemotherapy Prognostic factor Likely PARPi will be approved in front-line setting Genetic counselling CON: Evidence supporting temporal heterogeneity in OC
20 WHICH ONE FIRST? GERMLINE TESTING Well-established Lymphocyte DNA more reliable Need for genetic counselling Wildtype, still need to test somatic mutation SOMATIC TESTING Streamline testing Less need for genetic counselling Require good quality of DNA Technical Considerations
21 BRCAness Phenotype BRCA germline mutations BRCA somatic mutations (Hennessy JCO 2010) Other Homologous Recombination DNA repair defects (Kristeleit ECC Pennington CCR 2014) Levine. Nature 2011
22 HRD Assays: Lines of Research Next-generation sequencing assays. Gene expression analysis. BROCA: analysis of mutations of key HR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, RAD51D). 60-genes signature of BRCAness High correlation with response to platinum-based therapy an overall survival. NOT VALIDATED. Functional ex-vivo assays: RAD51 nuclear foci formation by immunofluorescence or other DNA repair complexes by immunohistochemistry PRO: Dynamic and functional biomarker CON: Requires fresh tissue. Reproducibility. Genome scars. ARIEL 2. Rucaparib and genomic LOH assay (Foundation Medicine) NOVA trial. Niraparib and HRD score (mychoice HRDTM Myriad)
23 HRD Assays: ARIEL 2 Different mechanisms can lead to HRD with the final result of genomic instability and large areas of genomic scaring (uniparental deletions) HRD causes genome wide LOH that can be measured by NGS TCGA and AOCS developed LOH cutoff based on overall survival to identify patients with HGSOC with BRCA-like signature McNeish IA ASCO TCGA Nature Wang Clin Cancer Res 2012
24 CONCLUSIONS BRCAness profile is now beyond mutations in BRCA germline This profile predicts platinum and PARPi sensitivity and better clinical outcomes BRCA testing in the germline and in the tumor expands up to 20% the number of patients who would benefit from targeted treatments Ideally, patients should be tested at diagnosis The validation of HRD assays and multiple gene sequencing panels to guide treatment selection is under evaluation Clinical trials on-going will offer additional insight
25 GRACIAS
26 ARIEL 2 (Part 1): Phase 2 trial to prospectively identify OC responders to rucaparib using tumor genetic analysis Kristeleit et al ECCO 2015
27 Efficacy Analysis ARIEL 2 (Part 1) PFS in tbrca mut and tbrcalike vs. biomarker negative patients Duration of response in tbrca mut and tbrca-like vs. biomarker negative patients Kristeleit et al ECCO 2015
28 ENGOT-OV16/NOVA Phase 3 randomized double-blind of maintenance with niraparib vs. placebo in patients with platinum sensitive OC Mirza ESMO 2016
29 HRD Assays: HRD Score Tesaro. WorldCDx 2015
30 HRD Assays: HRD Score The HRD test does not identify origin of mutation (germline or somatic) It is based on sequencing ~54,000 SNP regions of the genome and the BRCA1/2 genes (mychoice HRDTM Myriad) Tesaro. WorldCDx 2015
31 NOVA Trial: PFS by gbrca status gbrca Mutated gbrca Wild Type Mirza ESMO 2016
32 NOVA Trial: Exploratory Analysis PFS in gbrcawt Subgroups Mirza ESMO 2016
33 Conclusions To identify potential biomarker drivers of efficacy is urgently needed The presence of HRD may be a valid strategy for selection for DNA repair inhibitors as PARPi The actual HRD assays do not seem to be accurate enough to identify patients who don t benefit from PARPi
34
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