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

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.