Clinical Outcomes in Endometrial Carcinomas with Overlap in MMRd, POLE, and TP53: Analysis of TCGA/ProMisE "Multiple Classifiers" in a Cohort of > 4500 Endometrial Tumors
Recommended Citation
Ali-Fehmi R, Krause H, Morris R, Wallbillich J, Wong T, Bandyopadhyay S, Zaeim F, Jain D, Smith W, Alkaram W, Chapel D, Kheil M, Abu-Jamea A, Al-saghir M, Lou E, Quddus M, Winer I, Gogoi R, Ketch P, Herzog T, Toboni MD, Antonarakis E, Thaker P, Braxton D, Swensen J, Hirst J, Karnezis A, Bryant D, Oberley M. Clinical Outcomes in Endometrial Carcinomas with Overlap in MMRd, POLE, and TP53: Analysis of TCGA/ProMisE "Multiple Classifiers" in a Cohort of > 4500 Endometrial Tumors. Lab Invest 2024; 104(3S):S1098-S1099.
Document Type
Conference Proceeding
Publication Date
3-1-2024
Publication Title
Lab Invest
Abstract
Background: Molecular profiling of endometrial cancers (EC) for mismatch repair (MMR) deficiency, TP53 and POLE biomarkers (ProMisE criteria) has led to changes in categorization and management of EC. Herein, we report the frequency that these biomarkers overlap, and their clinical outcomes to identify the phenotypic penetrance of biomarkers in overlapping subtypes. Design: A total of 4,611 EC were analyzed by NGS (592 genes or WES) and a subset of those tumors by immunohistochemistry (IHC). Mismatch repair deficiency (MMRd) was defined as complete loss of ≥1 IHC stains (MLH1, MSH2, MSH6, or PMS2) and mismatch repair proficient (MMRp) as intact staining for all four proteins. MSI-High (determined from over 7000 targeted microsatellite loci covered by NGS) was used as a surrogate for MMRd and MSI-Stable for MMRp. TP53 mutant (MT) was defined as any pathogenic or likely pathogenic (PLP) SNV, or indel mutations. POLE-MT was defined as PLP mutations in the exonuclease domain, and wild type (WT) was defined as any tumor that lacked PLP alterations. Real-world overall survival was obtained from insurance claims and calculated from either tissue collection or treatment start to last contact (OS); Kaplan-Meier estimates were calculated for molecularly defined patients. Results: Concurrence between MMRd, TP53-MT and/or POLE-MT alterations was observed in 5.8% of cases (Table 1). Median OS for the MMRp/TP53-MT/POLE-WT (TP53 ) was significantly shorter compared to MMRd/TP53-MT/POLE-WT (TP53/MMRd overlap) and MMRd/TP53-WT/POLE-WT (MMRd) cohorts (26 vs 35 and 51 months, respectively; p < 0.001). Median time on treatment with immune checkpoint inhibitors (TOT ICI) was longest for the TP53 overlap cohort (6.78 months), followed by the MMRd cohort (6.71months) and the TP53 cohort (3.45 months) (p < 0.001). Median OS for the MMRp/TP53-WT/POLE-MT (POLE cohort) was significantly longer compared to MMRd/TP53-WT/POLE-WT (MMRd) and MMRd/TP53-WT/POLE-MT (POLE/MMRd overlap) cohorts (78 vs 51 and 49 months, respectively; p < 0.001). (Fig. 1). Results for TOT ICI were unavailable due to lack of data in the POLE and POLE/MMRd overlap cohorts. Conclusions: We report on the co-loss of MMR, TP53-MT, and POLE-MT from > 4,500 endometrial cancers. We note that these overlapping subtypes have OS that differs significantly from the non-overlapping subtype, future work will investigate treatment options tailored for these distinct subtypes.
Volume
104
Issue
3S
First Page
S1098
Last Page
S1099
