Genomic similarities of HGSOC and TNBC include germline pathogenic variants (GPV) in BRCA1/2 and somatic mutations in homologous recombination (HR) genes. Non-BRCA GPV in HGSOC and TNBC pts have also been identified through multi-gene Next Generation Sequencing (NGS). Somatic multi-gene analysis can identify pts with acquired HR mutations for trials with novel targeted drugs, like PARP inhibitors.
Study cohort included HGSOC and TNBC pts unselected for family history or age at diagnosis, enrolled in an institutional molecular screening program (NCT01505400). DNA extracted from matched blood and tumor samples (FFPE) was additionally tested using a lab-developed NGS Hereditary Cancer Panel of 52 cancer predisposition genes, including 11 HR genes. Medical records were reviewed for clinical course, pathology and prior germline testing results. All pts consented for research on banked samples and return of GPV by a genetic counsellor.
Of 58 analyzed pts 48 (83%; 8/17 TNBC and 40/41 HGSOC) had prior germline testing, which revealed GPV in 17 pts: BRCA1 (12 pts), BRCA2 (4 pts) and PALB2 (1 pt). We identified previously unknown GPV in five pts (9%; see table) and a potentially clinically relevant RAD51 variant in a previously known germline BRCA1 carrier with HGSOC.
|Pt||Cohort||New GPV||Prior germline testing|
|2||TNBC||BRCA1 + CHEK2||Provincial testing criteria not met|
|3||HGSOC||CHEK2||BRCA1/2 wild type (WT)|
Comprehensive germline and tumor analysis with 52 gene panel in advanced HGSOC and TNBC found previously unidentified GPV in 9% of pts and somatic mutations in HR genes in 14% of germline WT pts. This increases options for targeted therapeutics with investigational agents, such as PARP inhibitors.
Clinical trial identification
Legal entity responsible for the study
Princess Margaret Cancer Centre
M. Wilson, S. Lheureux: Consulting/Advisory for AstraZeneca. L. Siu: Consulting-Advisory: Oncoethix, Novartis, Daiichi Sankyo, Boehringer, Merck/Family Member-Leadership: Agios; Ownership Interests: Agios,Entremed/Research. Funding: Abraxis, Celgene, BMS, Genentech/Roche, GSK, Merck, Novartis, Pfizer, MedImmune, AstraZeneca, Boehringer. P. Bedard: Consulting/Advisory: Pfizer, Genentech/Roche, Sanofi Research Funding: Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/Roche, SERVIER, GlaxoSmithKline, Oncothyreon, Novartis, SignalChem, PTC Therapeutics. A. Oza: Consulting/Advisory: Amgen, Verastem, Clovis Oncology, Immunovaccine Honoraria: WebRx Research Funding: AstraZeneca, Roche, Merck, AstraZeneca Travel, Accommodations, Expenses: AstraZeneca. All other authors have declared no conflicts of interest.