Genetic alterations and their therapeutic implications in epithelial ovarian cancer.

BACKGROUND

Genetic alterations for epithelial ovarian cancer are insufficiently characterized. Previous studies are limited regarding included histologies, gene numbers, copy number variant (CNV) detection, and interpretation of pathway alteration patterns of individual patients.

METHODS

We sequenced 410 genes to analyze mutations and CNV of 82 ovarian carcinomas, including high-grade serous (n = 37), endometrioid (n = 22) and clear cell (n = 23) histologies. Eligibility for targeted therapy was determined for each patient by a pathway-based approach. The analysis covered DNA repair, receptor tyrosine kinase, PI3K/AKT/MTOR, RAS/MAPK, cell cycle, and hedgehog pathways, and included 14 drug targets.

RESULTS

Postulated PARP, MTOR, and CDK4/6 inhibition sensitivity were most common. BRCA1/2 alterations, PTEN loss, and gain of PIK3CA and CCND1 were characteristic for high-grade serous carcinomas. Mutations of ARID1A, PIK3CA, and KRAS, and ERBB2 gain were enriched in the other histologies. PTEN mutations and high tumor mutational burden were characteristic for endometrioid carcinomas. Drug target downstream alterations impaired actionability in all histologies, and many alterations would not have been discovered by key gene mutational analysis. Individual patients often had more than one actionable drug target.

CONCLUSIONS

Genetic alterations in ovarian carcinomas are complex and differ among histologies. Our results aid the personalization of therapy and biomarker analysis for clinical studies, and indicate a high potential for combinations of targeted therapies.