What question did this study set out to answer?

This research aims to determine if molecular classifications from primary tumors are maintained in metastatic tumors, impacting treatment strategies.

April 5, 2026

Abstract 1077: Discordance in molecular classification of primary and metastatic endometrial cancer: Implications for precision treatment

Key Points

This research aims to determine if molecular classifications from primary tumors are maintained in metastatic tumors, impacting treatment strategies.
Analyzed 155 patients with matched primary and metastatic tumor biopsies.
Used Sanger sequencing to identify POLE mutations in specific exons.
Employed immunohistochemistry to assess MMR protein expression and p53.
Utilized whole-exome sequencing to generate mutational profiles for POLE and TP53 in both tumor types.
Classified tumors into four molecular groups using the ProMisE algorithm.
19% of cases showed discordance in molecular classification between primary and metastatic tumors.
10% of primary tumors had MMR proficiency, while metastatic counterparts showed deficiency.
9% of primary tumors exhibited aberrant p53 expression, but it was wildtype in metastases.
All POLE mutations were conserved across primary and metastatic pairs.
Molecular classification from metastatic tumors correlated significantly with prognosis, unlike from primary tumors.

Abstract

Abstract Background: Endometrial cancer is the most prevalent gynecological cancer in high-income countries, and the incidence rate is increasing. Molecular classification with POLE sequencing and immunohistochemistry (IHC) for mismatch-repair (MMR) proteins and p53, refines prognostic accuracy when integrated with existing risk models. This study investigates whether molecular classification derived from primary tumor biopsies (PBs) is retained in matched metastatic biopsies (MBs), as reclassification may influence treatment strategies for advanced and recurrent disease. Material and methods: We analyzed 155 patients with matched PBs and MBs. POLE mutations were identified via Sanger sequencing of exons 9, 11, 13, and 14. IHC was used to assess expression of MSH2, MSH6, PMS2, MLH1, and p53. For 75 patients, whole-exome sequencing (WES) data provided mutational profiles for POLE and TP53 in both PBs and MBs. Molecular classification was assigned using the ProMisE algorithm to separately classify PBs and MBs in four molecular groups. Results: Molecular classification was discordant between PBs and MBs in 19% of cases. The most frequent discrepancy involved MMR status, with 10% (n = 16) showing MMR proficiency in PBs and deficiency in MBs. For p53, 9% (n = 20) had aberrant expression in PBs but wildtype in MBs. Notably, inter-MB heterogeneity was observed in both IHC-detected p53 expression and WES-derived TP53 mutations. All POLE mutations were conserved across PB-MB pairs. Molecular classification based on MBs was significantly associated with prognosis (p = 0.01), whereas classification from PBs was not (p = 0.31). Conclusions: This comprehensive molecular profiling reveals substantial shifts in molecular classification between primary and metastatic lesions, particularly in MMR and p53 status. These changes have prognostic implications and underscore the importance of reassessing molecular features in metastatic biopsies to guide precision treatment strategies for advanced endometrial cancer. Citation Format: Mari Kyllesø Halle, Janka Babickova, Hege Fredriksen Berg, Erling Andre Hoivik, Rose M. Gold, Kadri Madissoo, Marta Hjelmeland, Hilde Eide Lien, Jone Trovik, Ingfrid S. Haldorsen, Kathrine Woie, Gema Moreno-Bueno, Rameen Beroukhim, Camilla Krakstad. Discordance in molecular classification of primary and metastatic endometrial cancer: Implications for precision treatment 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 1077.

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