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<p>Endometrial cancer is the most common gynecological malignancy in high-income countries. Molecular classification using <i>POLE</i> 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, <i>POLE</i> (155 PBs and 122 MBs) and <i>TP53</i> (75 PB–MB pairs) mutational status was obtained from Sanger or whole exome sequencing (WES). ProMisE-based molecular classification (<i>n</i> = 155) was discordant in 19% of patients. The most frequent shift was from No Specific Molecular Profile (NSMP) PBs to MMR<i>deficient</i> MBs (6%), while 3% shifted from MMR<i>deficient</i> PBs to MMR<i>proficient</i> 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. <i>POLE</i> mutations were fully conserved across all PB-MB pairs investigated (<i>n</i> = 122). Inter-MB heterogeneity was observed for p53 by IHC and <i>TP53</i> by WES. In this aggressive cohort, MB-based classification correlated with prognosis (<i>p</i> = 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月24日

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  • Mari Kyllesø Halle,
  • Janka Babickova,
  • Hege F. Berg,
  • Erling A. Hoivik,
  • Rose M. Gold,
  • Kadri Madissoo,
  • Marta E. Hjelmeland,
  • Hilde E. Lien,
  • Hans Kristian Haugland,
  • Jone Trovik,
  • Ingfrid S. Haldorsen,
  • Kathrine Woie,
  • Gema Moreno-Bueno,
  • Rameen Beroukhim,
  • Camilla Krakstad

摘要

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 MMRdeficient MBs (6%), while 3% shifted from MMRdeficient PBs to MMRproficient 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.