Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer

Abstract

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 can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials.

Experimental design: We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center.

Results: Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS₁). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC 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 with 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, of which 47% of these achieved clinical benefit.

Conclusions: Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.

Figure 1. Summary of cohort and comparison to TCGA

A. Progression-free survival of MSKCC and TCGA cohorts. MSKCC cohort is split by low- and high-grade tumors. TCGA cohort displays the full cohort and those cases that progressed or recurred as an additional curve. B. Histology and grade comparison between MSKCC and TCGA cohorts. C. Oncoprint of genomic alterations of MSS samples split by histology and grade.

Figure 2. Mutational signatures

A. MSK-IMPACT sequencing mutational burden, split by clinical MMR-D IHC results, POLE cases identified by MSK-IMPACT sequencing; *includes one inconclusive result. MMR-D = mismatch repair deficient and MMR-P = mismatch repair proficient. B. MSIsensor scores for the full cohort. C. Signature decomposition of hyper-mutated cases. D. Signature decomposition of POLE-mutant cases.

Figure 3. Somatic copy number alterations in endometrial carcinomas

A. Clustering of SCNAs. B. Kaplan-Meier curves of progression free survival for each CN cluster.

Figure 4. Clinical actionability and genomic study matching

A. Number of actionable alterations by OncoKB level; *BRAF, BRCA1, CDK4, KIT each x1; ^‡FGFR3, MAP2K1 each x1. B. Rates of matching to genomically targeted therapy by each actionable gene. C. Copy number tumor/normal log ratio highlighting an ERBB2 amplification D. CT scans showing a complete response in a patient with ERBB2- amplified serous carcinoma enrolled to a study of trastuzumab emtansine.