AUTHOR=Gonzalez-Bosquet Jesus , Weroha S. John , Bakkum-Gamez Jamie N. , Weaver Amy L. , McGree Michaela E. , Dowdy Sean C. , Famuyide Abimbola O. , Kipp Benjamin R. , Halling Kevin C. , Yadav Siddhartha , Couch Fergus J. , Podratz Karl C. 

TITLE=Prognostic stratification of endometrial cancers with high microsatellite instability or no specific molecular profile

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1105504

DOI=10.3389/fonc.2023.1105504

ISSN=2234-943X

ABSTRACT=<sec><title>Objective</title><p>To identify high-risk disease in clinicopathologic low-risk endometrial cancer (EC) with high microsatellite instability (MSI-H) or no specific molecular profile (NSMP) and therapeutic insensitivity in clinicopathologic high-risk MSI-H/NSMP EC.</p></sec><sec><title>Methods</title><p>We searched The Cancer Genome Atlas for DNA sequencing, RNA expression, and surveillance data regarding MSI-H/NSMP EC. We used a molecular classification system of <italic>E2F1</italic> and <italic>CCNA2</italic> expression and sequence variations in <italic>POLE</italic>, <italic>PPP2R1A</italic>, or <italic>FBXW7</italic> (ECPPF) to prognostically stratify MSI-H/NSMP ECs. Clinical outcomes were annotated after integrating ECPPF and sequence variations in homologous recombination (HR) genes.</p></sec><sec><title>Results</title><p>Data were available for 239 patients with EC, which included 58 MSI-H and 89 NSMP cases. ECPPF effectively stratified MSI-H/NSMP EC into distinct molecular groups with prognostic implications: molecular low risk (MLR), with low <italic>CCNA2</italic> and <italic>E2F1</italic> expression, and molecular high risk (MHR), with high <italic>CCNA2</italic> and <italic>E2F1</italic> expression and/or <italic>PPP2R1A</italic> and/or <italic>FBXW7</italic> variants. The 3-year disease-free survival (DFS) rate was 43.8% in the MHR group with clinicopathologic low-risk indicators and 93.9% in the MLR group (<italic>P</italic>&lt;.001). In the MHR group, wild-type HR genes were present in 28% of cases but in 81% of documented recurrences. The 3-year DFS rate in patients with MSI-H/NSMP EC with clinicopathologic high-risk indicators was significantly higher in the MLR (94.1%) and MHR/HR variant gene (88.9%) groups than in the MHR/HR wild-type gene group (50.3%, <italic>P</italic>&lt;.001).</p></sec><sec><title>Conclusion</title><p>ECPPF may resolve prognostic challenges for MSI-H/NSMP EC by identifying occult high-risk disease in EC with clinicopathologic low-risk indicators and therapeutic insensitivity in EC with clinicopathologic high-risk indicators.</p></sec>