Real-World Data on Detection of Germline and Somatic Pathogenic/Likely Pathogenic Variants in BRCA1/2 and Other Susceptibility Genes in Ovarian Cancer Patients Using Next Generation Sequencing

Abstract

Detection of germline and somatic pathogenic/likely pathogenic variants (PV/LPV) in BRCA genes is at the moment a prerequisite for use of PARP inhibitors in different treatment settings of different tumors. The aim of our study was to determine the most appropriate testing workflow in epithelial ovarian cancer (EOC) patients using germline and tumor genotyping of BRCA and other hereditary breast and/or ovarian cancer (HBOC) susceptibility genes. Consecutive patients with advanced non-mucinous EOC, who responded to platinum-based chemotherapy, were included in the study. DNA extracted from blood and FFPE tumor tissue were genotyped using NGS panels TruSightCancer/Hereditary and TruSight Tumor 170. Among 170 EOC patients, 21.8% had BRCA germline or somatic PV/LPV, and additionally 6.4% had PV/LPV in other HBOC genes. Sensitivity of tumor genotyping for detection of germline PV/LPV was 96.2% for BRCA genes and 93.3% for HBOC genes. With germline genotyping-only strategy, 58.8% of HBOC PV/LPV and 68.4% of BRCA PV/LPV were detected. By tumor genotyping-only strategy, 96.1% of HBOC PV/LPV and 97.4% of BRCA PV/LPV were detected. Genotyping of tumor first, followed by germline genotyping seems to be a reasonable approach for detection of PV/LPV in breast and/or ovarian cancer susceptibility genes in non-mucinous EOC patients.

Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches

“…All patients with non-mucinous or non-borderline ovarian cancer should be tested for the somatic BRCA mutation status at the time of disease diagnosis [ 22 ]. In the presence of a positive test on the tumor, a genetic test must always be performed on a blood sample to distinguish germline mutations, which require counselling and genetic testing in family members, from somatic ones [ 23 , 24 ].…”

“…In patients with negative germline BRCA tests, the somatic BRCA tests can reveal an additional 6–7% of patients with BRCA mutations that have arisen during cancer development or progression [ 26 ]. There is evidence that offering tumor tissue testing first, followed by germline testing for pathogenic or likely pathogenic variants (PV/LPV) detected in the tumor or additional NGS germline testing in cases of positive personal or family history for hereditary breast and/or ovarian cancer, would allow nearly all PV/LPV to be detected as quickly as parallel blood and tumor testing while significantly reducing the cost and workload involved [ 23 ].…”

Intraperitoneal Chemotherapy without Bevacizumab versus Intravenous Chemotherapy plus Bevacizumab as Frontline Therapy in Advanced Ovarian Cancer

“…Various treatment approaches, such as different dosing schedules, routes of administration and integration of maintenance therapy, have been tested in prospective trials in an attempt to improve survival. National guidelines including the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology and European Society of Gynecological Oncology (ESMO-ESGO) have recommended genetic testing (germline and/or somatic) that may inform future options for maintenance therapy in women with ovarian cancer, albeit there is no consensus on the standard testing strategy [1][2][3].…”

Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study

“…Therefore, high-throughput next-generation sequencing (NGS)-based FFPE-derived DNA sequencing approaches are being implemented, given that they permit fast multiplex testing on small quantities of DNA, improving both the capacity and the cost-effectiveness of mutational analysis compared with traditional methods such as Sanger sequencing [13].…”