Germline <i>BRCA</i>-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity.

Abstract

Whether endometrial carcinoma (EC) should be considered part of the <i>gBRCA1/2-</i>associated hereditary breast and ovarian cancer (HBOC) syndrome is topic of debate. We sought to assess whether ECs occurring in <i>gBRCA</i> carriers are enriched for clinicopathologic and molecular characteristics, thereby supporting a causal relationship. Thirty-eight <i>gBRCA</i> carriers that developed EC were selected from the nationwide cohort study on hereditary breast and ovarian cancer in the Netherlands (HEBON), and these were supplemented with four institutional cases. Tumor tissue was retrieved via PALGA (Dutch Pathology Registry). Nineteen morphologic features were scored and histotype was determined by three expert gynecologic pathologists, blinded for molecular analyses (UCM-OncoPlus Assay including 1213 genes). ECs with LOH of the <i>gBRCA</i>-wild-type allele (<i>gBRCA</i>/LOHpos) were defined "<i>gBRCA</i>-associated," those without LOH (<i>gBRCA</i>/LOHneg) were defined "sporadic." LOH could be assessed for 40 ECs (30 <i>gBRCA1</i>, 10 <i>gBRCA2</i>), of which 60% were <i>gBRCA</i>/LOHpos. <i>gBRCA</i>/LOHpos ECs were more frequently of nonendometrioid (58%, <i>P</i> = 0.001) and grade 3 histology (79%, <i>P</i> < 0.001). All but two were in the <i>TP53</i>-mutated TCGA-subgroup (91.7%, <i>P</i> < 0.001). In contrast, <i>gBRCA</i>/LOHneg ECs were mainly grade 1 endometrioid EC (94%) and showed a more heterogeneous distribution of TCGA-molecular subgroups: <i>POLE</i>-mutated (6.3%), MSI-high (25%), NSMP (62.5%), and <i>TP53</i>-mutated (6.3%). We provide novel evidence in favor of EC being part of the <i>gBRCA</i>-associated HBOC-syndrome. <i>gBRCA</i>-associated ECs are enriched for EC subtypes associated with unfavorable clinical outcome. These findings have profound therapeutic consequences as these patients may benefit from treatment strategies such as PARP inhibitors. In addition, it should influence counseling and surveillance of <i>gBRCA</i> carriers.