Abstract

The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics. Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort. Most endometrial cancers included in the final analysis (n = 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24% (n = 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P = 0.014). All but 1 of the HRD cases harbored either a pathogenic BRCA1 variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC (P < 0.001). HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.

Highlights

  • Endometrial cancer is the most common gynecologic malignancy in developed countries [1], with surgery as its primaryNote: Supplementary data for this article are available at Clinical Cancer Research Online.M.P.G

  • homologous recombination deficiency (HRD) was observed in 24% (n 1⁄4 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P 1⁄4 0.014)

  • HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers

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Summary

Introduction

Endometrial cancer is the most common gynecologic malignancy in developed countries [1], with surgery as its primaryNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).M.P.G. A heterogeneous group of 15%–25% of endometrial cancers are currently considered at high-risk of disease recurrence This group consists of patients with non-endometrioid endometrial carcinomas [NEEC; uterine serous carcinoma (USC), uterine carcinosarcoma (UCS), clear cell carcinoma (CCC), undifferentiated carcinoma (UC), mixed endometrial cancers], endometrioid endometrial cancers (EEC) grade 3 stage IB–IV and EEC grade 1 and 2 stage II–IV [2,3,4,5,6]. These patients have the poorest clinical outcome, despite optimum adjuvant treatment, which currently comprises a combination of pelvic radiotherapy with or without (platinum–taxane based) chemotherapy [3,4,5]. In the cohort of Hamilton and colleagues, high-risk EEC grade 3, USC, and CCC represented only 28% of the total endometrial cancer cohort but accounted for 74% of endometrial cancer–related deaths [4], emphasizing the need for better systemic treatments to improve outcomes for these patients

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