CLINICAL UTILITY OF PROSPECTIVE MOLECULAR CHARACTERIZATION IN ADVANCED ENDOMETRIAL CANCER

Purpose: Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease revealed grade and histology-specific differences, facilitating enrollment onto clinical trials. Experimental Design: We integrated prospective clinical sequencing and immunohistochemical data with clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering. Results: Patients had advanced disease, high-grade histologies, and poor progression-free survival on first-line therapy (PFS1). Matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by The Cancer Genome Atlas (TCGA). Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein immunohistochemical staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1. Clustering the pattern of DNA copy number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared to other clusters (median PFS1 9.6 months vs. 17.0 and 17.4 months, p=0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials; 47% of these achieved clinical benefit. Conclusions: Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis aiding treatment decision-making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small proportion of all patients tested received investigational, genomically-matched therapy in clinical trials.

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