The clinical role of the molecular endometrial cancer (EC) classification has not been fully explored in patients staged with lymphadenectomy or without adjuvant treatment, conditions that could potentially moderate the prognostic value of the classification. We aimed to evaluate the clinical outcome of the molecular subgroups in patients with high-grade EC staged by lymphadenectomy and those without adjuvant treatment. DNA-sequencing for the detection of pathogenic POLE-exonuclease domain mutations and immunohistochemistry for mismatch repair (MMR) proteins and p53 expression were performed on 412 high-grade EC from the Danish Gynaecological Cancer Database (2005-2012) to classify them as POLE-ultramutated (POLEmut), MMR-deficient (MMRd), p53-mutant (p53abn), or no specific molecular profile (NSMP). Patients with stage IV or residual disease after surgery were excluded. Kaplan-Meier method, log-rank test and Cox proportional hazard models were used for analysis. Molecular analysis was successful in 367 EC; 251 patients had undergone lymphadenectomy. Five-year recurrence rates in this subgroup of patients was 36.7% for women with p53abn EC, 0.0% for POLEmut EC, 13.4% for MMRd EC and 42.9% for NSMP EC (p < 0.001). Similar results were observed among stage IA-IB patients. Among patients without adjuvant treatment (n = 264), none with POLEmut EC (n = 26) had a recurrence. The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among high-grade EC patients staged by lymphadenectomy and those without adjuvant treatment. The unfavourable prognosis of early-stage p53abn EC is not due to undetected lymph node metastasis, and the indolent behaviour of POLEmut EC is independent of adjuvant treatment.

HER2 status has not been investigated in the context of the molecular endometrial cancer (EC) classification. Here, we aimed to determine the clinicopathological features and prognostic significance of the HER2 status in the molecularly classified PORTEC-3 trial population of patients with high-risk EC (HREC). HER2 testing was performed on tumor tissues of 407 molecularly classified HREC. HER2 status was determined by HER2 immunohistochemistry (IHC; all cases) and subsequent HER2 dual in situ hybridization for cases with any (in) complete moderate to strong membranous HER2 IHC expression. The Χ² test and Spearman’s Rho correlation coefficient were used to compare clinicopathological and molecular features. The Kaplan–Meier method, log-rank test, and Cox proportional hazards models were used for survival analysis. We identified 24 (5.9%) HER2-positive EC of various histological subtypes including serous (n = 9, 37.5%), endometrioid (n = 6, 25.0%), and clear cell (n = 5, 20.8%). HER2 positivity was highly associated with the p53-abnormal subgroup (p53abn, 23/24 cases; p < 0.0001). The correlation between p53abn and the HER2 status (ρ = 0.438; p < 0.0001) was significantly stronger (p < 0.0001) than between serous histology and the HER2 status (ρ = 0.154; p = 0.002). HER2 status did not have independent prognostic value for survival after correction for the molecular classification. Our study strongly suggests that molecular subclass-directed HER2 testing is superior to histotype-directed testing. This insight will be relevant for future trials targeting HER2.