Tracy L. Stockley

Tumor and germline testing with next generation sequencing in epithelial ovarian cancer: a prospective paired comparison using an 18‐gene panel

Genetic testing in epithelial ovarian cancer (EOC) in Ontario includes germline next‐generation sequencing (NGS) for 19 genes. Additionally, tumor tissue undergoes reflex NGS testing for BRCA1/2 to assess eligibility for PARPi. Although parallel testing confers advantages, this model duplicates healthcare resources. Here, we prospectively assessed the feasibility of tumor‐first multigene testing by comparing tumor tissue with germline testing of peripheral blood. An 18‐gene NGS panel was used to test tumor and germline DNA ( n  = 106 patients). In 26 patients, 27 tumor Tier I or II variants were identified, with 16/27 (59%) being germline pathogenic variants (PV) (13 BRCA1/2 ; 3 other genes) and 11/27 (41%) somatic variants (9 BRCA1/2 ; 2 other). In 51/106 patients, there were no tumor variants (excluding TP53 ), of which one patient had a germline BRCA1 copy number variant deletion in exon 12. Tumor‐first testing detected variant‐positive and variant‐negative germline cases in 105/106 patients (99.1%). Among 50 BRCA ‐negative patients, 14/50 (28%) were homologous recombination deficiency (HRD)‐positive. Therefore, we demonstrate that multigene NGS tumor‐testing is effective in identifying germline variants in EOC with a < 1% false‐negative rate.

Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma

AbstractThis multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9–39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0–20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16–53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3–35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling (PTEN, TP53, homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.

Practice guidelines for BRCA1/2 tumour testing in ovarian cancer

The purpose of this document is to provide pre-analytical, analytical and post-analytical considerations and recommendations to Canadian clinical laboratories developing, validating and offering next-generation sequencing (NGS)-based BRCA1 and BRCA2 (BRCA1/2) tumour testing in ovarian cancers. This document was drafted by the members of the Canadian College of Medical Geneticists (CCMG) somatic BRCA Ad Hoc Working Group, and representatives from the Canadian Association of Pathologists. The document was circulated to the CCMG members for comment. Following incorporation of feedback, this document has been approved by the CCMG board of directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. The current CCMG Practice Guidelines were developed as a resource for clinical laboratories in Canada; however, they are not inclusive of all information laboratories should consider in the validation and use of NGS for BRCA1/2 tumour testing in ovarian cancers.