Purpose: Copy number–high endometrial carcinomas were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy-number alterations (CNA), 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 endometrial carcinomas of four histologic types. Experimental Design: TP53-mutated endometrial carcinomas, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n = 238) in a cohort of 1,239 endometrial carcinomas 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 endometrial carcinomas encompassed uterine serous (n = 102, 55.1%), high-grade endometrial carcinoma with ambiguous features/not otherwise specified (EC-NOS; n = 44, 23.8%), endometrioid carcinomas of all tumor grades (n = 28, 15.1%), and clear cell carcinomas (n = 11, 5.9%). 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 endometrial carcinomas display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated endometrial carcinomas. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.

Purpose: We sought to determine whether sequencing analysis of circulating cell-free DNA (cfDNA) in patients with prospectively accrued endometrial cancer captures the mutational repertoire of the primary lesion and allows for disease monitoring. Experimental Design: Peripheral blood was prospectively collected from 44 newly diagnosed patients with endometrial cancer over a 24-month period (i.e., baseline, postsurgery, every 6 months after). DNA from the primary endometrial cancers was subjected to targeted next-generation sequencing (NGS) of 468 cancer-related genes, and cfDNA to a high-depth NGS assay of 129 genes with molecular barcoding. Sequencing data were analyzed using validated bioinformatics methods. Results: cfDNA levels correlated with surgical stage in endometrial cancers, with higher levels of cfDNA being present in advanced-stage disease. Mutations in cfDNA at baseline were detected preoperatively in 8 of 36 (22%) patients with sequencing data, all of whom were diagnosed with advanced-stage disease, high tumor volume, and/or aggressive histologic type. Of the 38 somatic mutations identified in the primary tumors also present in the cfDNA assay, 35 (92%) and 38 (100%) were detected at baseline and follow-up, respectively. In 6 patients with recurrent disease, changes in circulating tumor DNA (ctDNA) fraction/variant allele fractions in cfDNA during follow-up closely mirrored disease progression and therapy response, with a lead time over clinically detected recurrence in two cases. The presence of ctDNA at baseline (P < 0.001) or postsurgery (P = 0.014) was significantly associated with reduced progression-free survival. Conclusions: cfDNA sequencing analysis in patients with endometrial cancer at diagnosis has prognostic value, and serial postsurgery cfDNA analysis enables disease and treatment response monitoring. See related commentary by Grant et al., p. 305

Although the incidence of endometrial carcinoma (EC) is similar in Black and White women, racial disparities are stark, with the highest mortality rates observed among Black patients. Here, analysis of 1,882 prospectively sequenced ECs using a clinical FDA-authorized tumor–normal panel revealed a significantly higher prevalence of high-risk histologic and molecular EC subtypes in self-identified Black (n = 259) compared with White (n = 1,623) patients. Clinically actionable alterations, including high tumor mutational burden/microsatellite instability, which confer benefit from immunotherapy, were less frequent in ECs from Black than from White patients. Ultramutated POLE molecular subtype ECs associated with favorable outcomes were rare in Black patients. Results were confirmed by genetic ancestry analysis. CCNE1 gene amplification, which is associated with aggressive clinical behavior, was more prevalent in carcinosarcomas occurring in Black than in White patients. ECs from Black and White patients display important differences in their histologic types, molecular subtypes, driver genetic alterations, and therapeutic targets.Significance: Our comprehensive analysis of prospectively clinically sequenced ECs revealed significant differences in their histologic and molecular composition and in the presence of therapeutic targets in Black versus White patients. These findings emphasize the importance of incorporating diverse populations into molecular studies and clinical trials to address EC disparities.This article is featured in Selected Articles from This Issue, p. 2293