Clinicopathologic vs. Molecular Integrated Prognostication of Endometrial Carcinoma by European Guidelines

SIMPLE SUMMARY: The European Society of Gynaecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) published joint guidelines in January 2021 that provide recommendations on all relevant issues of diagnosis and treatment in endometrial carcinoma. Assessment of prognosis and adjuvant therapy decisions are based on classification of endometrial carcinomas into five risk groups with specific clinicopathologic features. Integration of molecular classification, originally described by The Cancer Genome Atlas, is encouraged for a more personalized risk assessment when molecular tools are available. We found that clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses. The p53 abnormal molecular subgroup and mismatch repair deficient molecular subgroup were associated with poor survival within clinicopathologic low-risk and high-intermediate-risk carcinomas, respectively. Molecular classification caused a risk-group shift in 6–7% of patients. Comprehensive molecular classification was needed in 40% of patients for molecularly directed adjuvant therapy. ABSTRACT: This was a retrospective study of 604 patients with endometrial carcinoma, classified into ESGO-ESTRO-ESP 2021 clinicopathologic and molecular integrated risk groups. The Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) and Leiden classifier were employed for molecular classification. Median follow-up time was 81 months. Clinicopathologic and molecular integrated risk groups were similarly associated with distinct prognoses (p < 0.001). Disease-specific survival was similar for all molecular subgroups within clinicopathologic intermediate-risk, high-risk, and advanced/metastatic groups. In contrast, the p53 abnormal subgroup (hazard ratio 9.1, 95% confidence interval 2.0–41; p = 0.004) and mismatch repair deficient subgroup (hazard ratio 3.5, 95% confidence interval 1.2–10; p = 0.024) were associated with disease-related death within clinicopathologic low-risk and high-intermediate-risk carcinomas, respectively. A risk-group shift occurred in 6.0% (36/604) and 7.4% (38/515) of patients classified by ProMisE and Leiden, respectively (p = 0.341). Of the 36 patients shifted in the ProMisE cohort, 27 were upshifted and 9 downshifted. Based on the Leiden classifier, polymerase-ϵ sequencing could be omitted in 60% (311/515) of patients without affecting the risk-group assessment. ESGO-ESTRO-ESP 2021 guidelines provide a platform for risk classification in future trials on molecularly directed treatment of endometrial carcinoma.