Abstract 5772
Background
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).
Methods
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.
Results
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.
Conclusions
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’.
Clinical trial identification
Legal entity responsible for the study
Alexandra Leary.
Funding
Has not received any funding.
Editorial Acknowledgement
Disclosure
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.