Tumor and germline next generation sequencing in high grade serous cancer: experience from a large population-based testing program.

Melanie Care,Raymond H Kim,Blaise Clarke,Marjan Rouzbahman,Marcus Q Bernardini,Sylvie Grenier,Tracy L Stockley,Jeanna Mccuaig,Natalie Stickle

doi:10.1002/1878-0261.12817

Melanie Care, Raymond H Kim + Show 7 more

Open Access

https://doi.org/10.1002/1878-0261.12817

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Abstract

The aim of this study was to determine the prevalence of somatic and germline pathogenic variants (PVs) in high-grade serous cancer (HGSC) and to demonstrate the technical feasibility and effectiveness of a large-scale, population-based tumor testing program. It involved a retrospective review of genetic test results in 600 consecutive HGSC tumor samples and a subsequent comparison of germline and tumor results in a subset of 200 individuals. Tumor testing was successful in 95% of samples (570/600) with at least one BRCA1/2 PV identified in 16% (93/570) of cases. Among the 200 paired cases, BRCA1/2 PVs were detected in 38 tumors (19%); 58% were somatic (22/38); and 42% were germline (16/38). There was 100% concordance between germline and tumor test results. This is the largest series of BRCA1/2 testing in HGSC (tumor-only and paired cohorts), reported to date, and our data show that an effectively designed and validated population-based tumor testing program can be used to determine both treatment eligibility and hereditary cancer risk.

Highlights

High-grade serous cancers (HGSCs) of ovarian, fallopian tube, or primary peritoneal origin affect approximately 1 in 78 women over their lifetime and are the fifth leading cause of cancer deaths in women [1]
Patients were recorded as being either an incident or prevalent case, with incident cases defined as those sent for BRCA1/2 tumor testing within 6 months of procedure date, and all others classified as prevalent cases
There is a new urgency for tumor BRCA1/2 testing in HGSC to ensure timely identification of all patients eligible for poly (ADP-ribose) polymerase inhibitors (PARPi) therapy, including those who may be missed through traditional service delivery models aimed at germline variant detection

Summary

Introduction

High-grade serous cancers (HGSCs) of ovarian, fallopian tube, or primary peritoneal origin affect approximately 1 in 78 women over their lifetime and are the fifth leading cause of cancer deaths in women [1]. Large phase III clinical trials have demonstrated that treatment with poly (ADP-ribose) polymerase inhibitors (PARPi) results in increased progression-free and overall survival rates in women with HGSC associated with either inherited (germline) or acquired (somatic) BRCA1 or BRCA2 (BRCA1/2) pathogenic variants (PVs) [2,3,4,5,6]. Given these results, PARPi therapy is recommended for women with platinum-sensitive.

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