Homologous recombination deficient endometrial serous carcinoma: implications for PARPi therapy

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<h3>Objectives:</h3> 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. <h3>Methods:</h3> 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. <h3>Results:</h3> EMSC is characterized by <i>TP53</i> mutations (92%), microsatellite stability (99%), low tumor mutational burden (96%), and less frequent recurrent alterations in <i>PIK3CA</i> (35%), <i>PPP2R1A</i> (25%), <i>CCNE1</i> (19%), <i>ERBB2</i> (17%), <i>FBXW7</i> (17%) and <i>MYC</i> (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 <i>BRCA1/2</i> and HRD genes as a group were significantly enriched in gLOH-high EMSC (14% vs 2% and 23% vs 9%, both p<1E-8). gLOH-high EMSC exhibited significantly higher frequency of solid, pseudo-endometrioid or transitional-like (i.e. SET) variant morphology (52% vs 24%, p<0.05). Genomic ancestry calling revealed similar ancestry prevalence in HRD vs. non-HRD subgroups; however, in EMSC patients of African descent, there was an overall higher prevalence of <i>CCNE1</i> amplification (26%) and lower prevalence of <i>PIK3CA</i> (24%) and <i>PPP2R1A</i> (18%) alterations compared with patients of non-African descent (p<0.05). Finally, EMSC exhibited significantly higher frequency of gLOH-high (21% vs 8%, p=19E-24) as well as different genomic signatures (MSI-H 1% vs 28%; TMB-high 4% vs 33%, and distinct alteration frequencies of 134 genes, all p<0.05) compared with endometrioid-type endometrial carcinomas (n=2,346). <h3>Conclusions:</h3> 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.