Implementation of Multigene Germline and Parallel Somatic Genetic Testing in Epithelial Ovarian Cancer: SIGNPOST Study

Abstract

We present findings of a cancer multidisciplinary-team (MDT) coordinated mainstreaming pathway of unselected 5-panel germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 and parallel somatic BRCA1/BRCA2 testing in all women with epithelial-OC and highlight the discordance between germline and somatic testing strategies across two cancer centres. Patients were counselled and consented by a cancer MDT member. The uptake of parallel multi-gene germline and somatic testing was 97.7%. Counselling by clinical-nurse-specialist more frequently needed >1 consultation (53.6% (30/56)) compared to a medical (15.0% (21/137)) or surgical oncologist (15.3% (17/110)) (p < 0.001). The median age was 54 (IQR = 51–62) years in germline pathogenic-variant (PV) versus 61 (IQR = 51–71) in BRCA wild-type (p = 0.001). There was no significant difference in distribution of PVs by ethnicity, stage, surgery timing or resection status. A total of 15.5% germline and 7.8% somatic BRCA1/BRCA2 PVs were identified. A total of 2.3% patients had RAD51C/RAD51D/BRIP1 PVs. A total of 11% germline PVs were large-genomic-rearrangements and missed by somatic testing. A total of 20% germline PVs are missed by somatic first BRCA-testing approach and 55.6% germline PVs missed by family history ascertainment. The somatic testing failure rate is higher (23%) for patients undergoing diagnostic biopsies. Our findings favour a prospective parallel somatic and germline panel testing approach as a clinically efficient strategy to maximise variant identification. UK Genomics test-directory criteria should be expanded to include a panel of OC genes.

Cost-Effectiveness of Genetic Testing for All Women Diagnosed with Breast Cancer in China

“…Expansion in local laboratory infrastructure is needed to improve access and manage throughput, as genetic testing is currently mainly performed through laboratories at major hospitals affiliated with top-ranked universities [ 55 ]. Given the volume of BC cases diagnosed annually, newer implementation approaches such as ‘mainstreaming’ genetic counseling and testing, which have been successfully implemented across OC treatment pathways [ 56 ], will be needed for the successful large-scale implementation of testing at BC diagnosis too. Given the increasing applicability of genetics to cancer care and prevention, most cancer clinicians will need to be trained to improve their understanding of genetics and counsel patients.…”

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

“…Furthermore, beyond the LODs related to tumor cellularity, HRD assays evaluating tBRCA* barely detect LRs, although LRs are present in up to 16% of HGSOC patients, thus leading to false tBRCA wt statuses [ 33 ]. Recently, SIGNPOST showed that approximately 20% of gBRCA* was missed by the initial tBRCA* assessment, with the stunning revelation that none of the LRs of the cohort (representing 11% of gBRCA* ) were detected by the tBRCA* evaluation [ 138 ].…”

Hereditary gynecologic tumors and precision cancer medicine

“…BRIP1, RAD51C, and RAD51D have been suggested as the most important OCpredisposing genes, with 1.3%-4.3% of patients with OC having GPVs of BRIP1/RAD51C/RAD51D. 17,42,96,97 The estimated cumulative OC risks are 5.8%, 5.2%-11%, and 12% for mutant carriers of BRIP1 (to 80 years), 98 RAD51C, and RAD51D, 99,100 respectively. RRSO is currently recommended for carriers of BRIP1, RAD51C, and RAD51D mutations from the age of 45-50 years.…”

“…As each gene plays a different role in the HR pathway, phenotypes also differ. BRIP1 , RAD51C , and RAD51D have been suggested as the most important OC‐predisposing genes, with 1.3%–4.3% of patients with OC having GPVs of BRIP1/RAD51C/RAD51D 17,42,96,97 . The estimated cumulative OC risks are 5.8%, 5.2%–11%, and 12% for mutant carriers of BRIP1 (to 80 years), 98 RAD51C , and RAD51D , 99,100 respectively.…”