Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas

Abstract

Purpose: 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.Experimental Design: 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.Results: Most endometrial cancers included in the final analysis (n ¼ 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24% (n ¼ 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 ¼ 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).Conclusions: 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. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity

“…e P value was calculated over negative nuclear WT-1 expression or positive nuclear WT-1 expression (encompassing both heterogeneous and diffuse positive staining). BRCA1/2-mediated HR is commonly abrogated in TP53-mutated serous-like ECs (24). Cells that are HRD are more prone to DNA damage due to the error-prone repair of the DNA double-strand breaks caused by ROS and estrogen metabolites (58).…”

“…The "serous-like/SCNA-high" molecular subclass has poorest clinical outcome and interestingly displays molecular similarities to both basal-like breast cancer and HGSOC, including a high number of SCNAs and frequent TP53 mutations. Moreover, recent studies demonstrated that serouslike/SCNA-high ECs also frequently are HRD (22)(23)(24). This raises the question whether ECs occurring in gBRCA1/2 carriers might be enriched for certain features, but studies comprehensively evaluating this have not been performed to date.…”

Incorporation of molecular characteristics into endometrial cancer management

“…Homologous recombination repair capacity has been successfully used as a marker to identify patients that benefit from poly (ADP ribose) polymerase inhibitors (PARPi) in high‐grade serous ovarian cancer (HGSOC) . HGSOC and serous EC have very similar molecular genetic alterations; recent data show that a subset of p53mut EC are homologous recombination‐deficient, and some of these EC can arise in the context of germline BRCA1/2 mutations . The exact prevalence of HRD in p53mut EC is currently unknown; in a small and selected set of cases it was 46% .…”

“…66,67 HGSOC and serous EC have very similar molecular genetic alterations 4 ; recent data show that a subset of p53mut EC are homologous recombination-deficient, and some of these EC can arise in the context of germline BRCA1/2 mutations. [68][69][70][71] The exact prevalence of HRD in p53mut EC is currently unknown; in a small and selected set of cases it was 46%. 68 Together, these data build upon a rationale to target homologous recombination in p53mut EC, particularly those that are HRD.…”

“…[68][69][70][71] The exact prevalence of HRD in p53mut EC is currently unknown; in a small and selected set of cases it was 46%. 68 Together, these data build upon a rationale to target homologous recombination in p53mut EC, particularly those that are HRD. Currently, several clinical trials investigating the efficacy of different PARP-inhibitors in recurrent or metastatic…”