Homologous recombination deficient endometrial serous carcinoma: implications for PARPi therapy

Objectives: Endometrial serous carcinoma (EMSC) is an aggressive variant of uterine cancer with limited therapeutic options. We analyzed the genomics of the largest EMSC cohort to date (n=2,159) to determine the extent of homologous recombination deficiency (HRD) and potential for targeted therapies. Methods: EMSC was assayed via hybrid capture-based comprehensive genomic profiling. HRD status was determined using genome wide loss of heterozygosity (gLOH) scores with validated methods for PARP inhibitor effectiveness in ovarian carcinoma. gLOH-high was defined as a score of ≥16%, similar to previously described for ovarian carcinomas. Tumor mutational burden (TMB) was determined on 0.8Mbp of sequenced DNA, and TMB-high was defined as ≥10mut/Mb using an FDA-approved companion diagnostic cutoff for pembrolizumab in patients with unresectable or metastatic solid tumor based on the KEYNOTE-158 trial. Microsatellite instability (MSI) was determined on 95 loci. Clinicopathological and genomic data was centrally re-reviewed. Results: EMSC is characterized by TP53 mutations (92%), microsatellite stability (99%), low tumor mutational burden (96%), and less frequent recurrent alterations in PIK3CA (35%), PPP2R1A (25%), CCNE1 (19%), ERBB2 (17%), FBXW7 (17%) and MYC (12%). Evidence for HRD via high gLOH was identified in 21% of EMSC. There was no difference in age, MSI and TMB-high status between gLOH-high vs gLOH-low EMSC. However, alterations in BRCA1/2 and HRD genes as a group were significantly enriched in gLOH-high EMSC (14% vs 2% and 23% vs 9%, both p Conclusions: EMSC has overall distinct genomic signatures compared to endometrioid endometrial carcinomas with a significant proportion of gLOH-high EMSC, compatible with HRD. Our study provides the framework for future studies to test the susceptibility of EMSC to PARP inhibitor therapy in a molecularly defined EMSC subgroup with evidence for HRD.