Clinicopathologic and Genomic Analysis of

PURPOSE: Copy number-high endometrial carcinomas (ECs) were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy number alterations (CNAs), low mutational burden (i.e. non-hypermutant), near universal TP53 mutation and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered ECs of four histologic types. DESIGN: TP53-mutated ECs, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n=238) in a cohort of 1,239 ECs subjected to clinical massively parallel sequencing of 410–468 cancer-related genes. Somatic mutations and CNAs (n=238), and clinicopathologic features were determined (n=185, initial treatment planning at our institution). RESULTS: TP53-mutated ECs encompassed uterine serous (n=102, 55.1%), histologically ambiguous high-grade EC-NOS (n=44, 23.8%), endometrioid carcinomas of all tumor grades (n=28, 15.1%), and clear cell (n=11, 5.9%) carcinomas. PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across TP53-mutated histologic types (7.7%−18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival. CONCLUSIONS: TP53-mutated ECs display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated ECs. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.