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

Abstract Endometrial cancer is the most common gynecological malignancy in high-income countries. Molecular classification using POLE sequencing and assessing p53 and mismatch repair (MMR) protein status by immunohistochemistry (IHC) improves prognostication. We examined whether classifications from primary biopsies (PBs) are retained in matched metastatic biopsies (MBs). IHC was performed on 250 PB–MB pairs, POLE (155 PBs and 122 MBs) and TP53 (75 PB–MB pairs) mutational status was obtained from Sanger or whole exome sequencing (WES). ProMisE-based molecular classification ( n = 155) was discordant in 19% of patients. The most frequent shift was from No Specific Molecular Profile (NSMP) PBs to MMR deficient MBs (6%), while 3% shifted from MMR deficient PBs to MMR proficient MBs. p53 status also changed: 5% had p53abn PBs but NSMP MBs, and 3% showed the opposite pattern. Additionally, 3% of p53abn PBs were MMRd in MBs. POLE mutations were fully conserved across all PB-MB pairs investigated ( n = 122). Inter-MB heterogeneity was observed for p53 by IHC and TP53 by WES. In this aggressive cohort, MB-based classification correlated with prognosis ( p = 0.01), while PB-based classification did not (p = 0.31). These findings highlight the importance of reassessing molecular features in metastatic lesions to guide precision therapy.