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

Chandrasekaran, Dhivya; Sobocan, Monika; Blyuss, Oleg; Miller, Rowan E; Evans, Olivia; Crusz, Shanthini M; Mills-Baldock, Tina; Sun, Li; Hammond, Rory F L; Gaba, Faiza; Jenkins, Lucy A; Ahmed, Munaza; Kumar, Ajith; Jeyarajah, Arjun; Lawrence, Alexandra C; Brockbank, Elly; Phadnis, Saurabh; Quigley, Mary; El Khouly, Fatima; Wuntakal, Rekha; Faruqi, Asma; Trevisan, Giorgia; Casey, Laura; Burghel, George J; Schlecht, Helene; Bulman, Michael; Smith, Philip; Bowers, Naomi L; Legood, Rosa; Lockley, Michelle; Wallace, Andrew; Singh, Naveena; Evans, D Gareth; Manchanda, Ranjit

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.