Somatic or germline BRCA mutations remain the best predictive biomarker for PARP inhibitor benefit and > 95% of high grade serous ovarian cancers (HGSOC) have a clonal somatic TP53 mutation. Combined tBRCA/TP53 testing might provide the advantages of i) rapid results, ii) identification of somatic BRCAm, and iii) indirect evidence of the ‘2nd hit’ event, ie loss of heterozygosity (LOH).
Between 1/1/2016 and 1/2/2018 182 pts with HGOC underwent tBRCA/TP53 testing with a capture NGS panel and were oriented to a germline BRCA (gBRCA) testing via a dedicated genetics consultation. The ratio of allelic fractions (AF) for BRCAm/TP53m was calculated to estimate the proportion of cells carrying the BRCAm and derive LOH.
At the time of data cut-off, gBRCA results were available for 125/182, and still pending for 61 pts. 15/125 (12%) demonstrated a deleterious (DEL) gBRCA1m (N = 12) or gBRCA2m (N = 3). Tumor testing was performed on 182 with a median testing turn-around time of 16 days (range 7-539 days). Twenty-seven (15%) were non-contributive. Among 155 contributive tumor samples, 31 DEL tBRCAm (21%) were identified. All gBRCAm (15/15) were identified on tumor testing including one large re-arrangement. 16 additional DEL BRCA1m or BRCA2m were detected: 10 somatic BRCAm in pts with confirmed wild-type (WT) germline status, and 6 among pts with pending germline results. Median TP53m AF was 0.48 (range 0.012-0.92) confirming a huge variability in tumor cellularity among samples. Among gBRCAm cases, ratio AF BRCAm/TP53m was always>1 confirming germline origin and suggesting LOH. AF BRCAm/TP53m was lower among known sBRCAm tumors (median AF BRCAm/TP53m=1.1) but always>0.8 suggesting acquired BRCA mutation was clonal and associated with LOH. For 3 gBRCA WT samples with <10% tumor cellularity and very low DEL BRCAm AF (0.04, 0.04 and 0.05), TP53m AF were also <0.05, thus validating the somatic BRCAm.
Combined BRCA/TP53 tBRCA testing is fast, sensitive and identifies somatic BRCA mutations. In addition, information on TP53 AF is useful to validate % neoplastic cells, identify somatic BRCAm in low cellularity samples and provides indirect evidence for LOH as the ‘2nd hit’.
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A. Leary: Honoraria: AstraZeneca; Consulting: AstraZeneca, GamaMabs Pharma, Clovis Oncology, Gritstone Oncology; Research funding (institution): AstraZeneca, GamaMabs Pharma, Clovis Oncology, AstraZeneca, Pfizer, MSD; Accommodation: AstraZeneca. P. Pautier: Honoraria: AstraZeneca; Consulting: AstraZeneca, Roche, Tesaro; Research funding (institution): AstraZeneca, Roche, ImmunoGen; Accommodation: AstraZeneca, PharmaMar. L. Lacroix, C. Genestie: Honoraria: AstraZeneca. J. Michels: Research funding (institution): Roche, MSD. E. Rouleau: Honoraria: AstraZeneca; Consulting: AstraZeneca, Roche, BMS UK; Research funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.