Molecular heterogeneity in dMMR/MSI-H endometrial cancer in the US.

Abstract

e17643 Background: Deficient mismatch repair (dMMR)/microsatellite instability high (MSI-H) are actionable biomarkers in endometrial cancer (EC). KEYNOTE-B21 evaluated immunotherapy and chemotherapy vs chemotherapy with/without radiotherapy as adjuvant treatment in patients with EC at high risk (HR) of recurrence. HR EC includes patients with stage I/II non-endometrioid histology with myometrial invasion, stage I/II of any histology with TP53 mutation with MI and all stage III/IVA tumors. While the trial did not meet its primary endpoint, it showed clinical benefit in the dMMR sub-group. The objective of this study is to assess the prevalence of dMMR HR EC and associated molecular heterogeneity. Methods: A retrospective cohort study using Aster Insights clinical and tumor RNA/DNA data was conducted. Since data for dMMR was not available, microsatellite instability-high (MSI-H), a marker of dMMR, was used as a proxy. Eligible patients included those diagnosed with EC and tested for MSI and TP53 mutation (determined by Whole Exome Sequencing). Prevalence of HR EC by stage, histology, and TP53 -mutant status was estimated. Results: Of 668 patients tested, 141 (21.1%) were MSI-H. Within the MSI-H population, the median age was 64.6 years, 92.2% were white, and 4.3% were black. Prevalence by stage, histology, and TP53 status for the MSI-H population are provided in Table. Overall, of the 141 patients, 37 (26.2%) could be considered high risk based on having stage III/IV disease or non-endometrioid histology. An additional 15 (10.6%) patients had low stage disease and endometrioid histology but TP53 mutation. Conclusions: Our findings indicate considerable prevalence of HR EC among patients with MSI-H tumors. High-stage disease, non-endometrioid histology as well as TP53 mutation contribute to the burden of dMMR HR EC. Limitations include small sample size and, mostly early diagnosis tissue. Novel therapies that reduce recurrence in this patient population can help reduce the burden of disease. Molecular heterogeneity in MSI-H endometrial cancer in the US. MSI-High Patients F 141 (100%) Endometrioid histology118 (83.7%) Non-endometrioid histology23 (16.3%) Endometroid TP53 wildtype Endometroid TP53 mutation Non-endometroid TP53 wildtype Non-endometroid TP53 mutation Stage I/IIN, % (95% CI)ESGO Risk classification 8258.2% (50%, 66.3%)Not High Risk 1510.6% (5.5%, 15.7%)Ambiguous 96.4% (2.3%, 10.4%)High Risk 42.8% (0.1%, 5.6%)High Risk Stage III/IVN, % (95% CI)ESGO Risk classification 139.2% (4.4%, 14%)High Risk 21.4% (0%, 3.4%)High Risk 42.8% (0.1%, 5.6%)High Risk 53.5% (0.5%, 6.6%)High Risk Total Non-Endometrioid Histology or Stage III/IV 3726.2% (19%, 33.5%) Numbers may not add up to 100% due to missing stage information. F A total 668 patients with EC were tested and 141 (21.1%) were MSI-High. Prevalence expressed as a proportion of MSI-High patients.