Molecular variations in uterine carcinosarcomas identify therapeutic opportunities

Objective To perform comprehensive genomic profiling on a large cohort of patients with uterine carcinosarcomas to identify potential therapeutic targets. Methods Molecular profiling was conducted on 168 retrospectively de-identified patients with uterine carcinosarcomas using the Caris Life Sciences platform. Specimens were evaluated for aberrations in protein expression by immunohistochemistry, DNA sequence mutation using a 592-gene next generation sequencing panel, copy number amplification using next generation sequencing or in situ hybridization, and fusion events using NextGen RNA sequencing. Tumor mutational load and microsatellite instability were also evaluated. Results We identified 168 patients with uterine carcinosarcoma; median age of the cohort was 67 years. The most common mutations were observed in the following genes: TP53 (86%), PIK3CA (34%), FBXW7 (23%), PTEN (18%), KRAS (16%), PPP2R1A (10%). Tumor mutational load was low to moderate in most cases (50% and 45%, respectively). HER2/neu (ERBB2) was amplified in 9% of tumors. Immunohistochemistry protein expression was elevated in TOP2A (95%), TS (80%), PTEN (76%), and TUBB3 (66%). Mismatch repair deficiency was rare (4%). Conclusions Multiple somatic mutations and copy number alterations in genes that are therapeutic targets were identified in half of cases. Uterine carcinosarcomas represent an aggressive histology with limited treatment options and poor outcomes, and clinical trials are needed to validate new therapeutic targets.