What question did this study set out to answer?

This analysis aims to explore the heterogeneity in the tumor microenvironment of endometrial cancer based on MMR subtypes.

April 5, 2026

Abstract 3881: Heterogeneity in tumor microenvironment across MMR subtypes of endometrial cancer: Analysis from the ENGOT-EN6-NSGO/GOG-3031/RUBY trial.

Key Points

This analysis aims to explore the heterogeneity in the tumor microenvironment of endometrial cancer based on MMR subtypes.
Conducted RNA sequencing and whole exome sequencing on 400 tumor samples.
Classified tumors as dMMR or MMRp based on enrollment testing methods.
Analyzed genomic alterations and RNA sequencing signatures associated with cell types.
Identified two distinct clusters of tumor transcriptional profiles related to histological subtypes.
High immune cell signatures were significantly enriched in the dMMR subgroup.
Observed genomic alterations in genes such as TP53, PTEN, and PIK3CA, with elevated mutation rates in dMMR tumors.

Abstract

Abstract Background: In RUBY Part 1 (NCT03981796), dostarlimab + carboplatin-paclitaxel (D+CP) significantly improved PFS and OS vs CP alone in pts with primary advanced or recurrent endometrial cancer (EC). Although MMR deficiency (dMMR) is a predictive biomarker for clinical response, benefit is also observed in the MMR proficient (MMRp) subgroup. Additional insights into the underlying biology and heterogeneity of these tumors are needed to inform potential drivers of response to D+CP. Methods: RNA sequencing (RNASeq) and whole exome sequencing were performed on 400 tumor samples from RUBY Part 1. Tumors were categorized as dMMR or MMRp per the testing method used for study enrollment. Genomic alterations and RNAseq signatures associated with infiltrating cell types or oncogenic processes were analyzed. Results: Unsupervised clustering of tumor transcriptional profiles revealed two distinct histological subtype-associated clusters. dMMR tumors were predominantly in the endometrioid cluster; MMRp tumors were distributed across both clusters. Gene signature analysis revealed significant enrichment for tumors with high immune cell signature scores in the dMMR subgroup (Table); however, considerable overlap was observed with a subset of MMRp tumors demonstrating similarly high signature scores. Conversely, signatures associated with tumor senescence and interferon-stimulated genes were enriched in the MMRp subgroup. Genomic analysis revealed frequent alterations in TP53, PTEN, PIK3CA, and ARID1A, with higher mutation rates of several genes (eg, JAK1 and RNF43) observed in dMMR tumors, concomitant with higher tumor mutational burden. Conclusions: These results highlight the molecular and transcriptomic heterogeneity of EC, providing hypotheses to explore the impact of tumor characteristics beyond MMR status on response to dostarlimab+CP in EC. Exploration of the association between these biomarkers and outcomes is ongoing. Citation Format: Lucy Gilbert, Annika Auranen, Mitchell I. Edelson, Mikalai Pishchyk, Joseph Buscema, Tamar Safra, Nicole S. Nevadunsky, Christine Gennigens, Kari Ring, Line Bjørge, Bhavana Pothuri, Helen D. Eshed, Iwona Podzielinski, Noelle G. Cloven, Tashanna K. Myers, Kathryn P. Pennington, Claire Rooney, Rumen Kostadinov, Robert W. Holloway, Trine Nøttrup. Heterogeneity in tumor microenvironment across MMR subtypes of endometrial cancer: Analysis from the ENGOT-EN6-NSGO/GOG-3031/RUBY trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3881.

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