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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 (POLE mut), 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 POLE mut 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 POLE mut 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 POLE mut EC is independent of adjuvant treatment. • The molecular endometrial cancer (EC) classification has independent prognostic value among women with high-grade EC. • P53 abnormal EC have a poor clinical outcome, also those staged by lymphadenectomy as stage I. • Patients with POLE- ultramutated EC have an excellent clinical outcome even when not receiving adjuvant treatment. [ABSTRACT FROM AUTHOR]

Aims: Human epidermal growth factor receptor 2 (HER2) amplification in endometrial cancer (EC) is almost completely confined to the p53‐abnormal (p53abn) molecular subtype and independent of histological subtype. HER2 testing should therefore be molecular subtype‐directed. However, the most optimal approach for HER2 testing in EC has not been fully established. Therefore, we developed an EC‐specific HER2 immunohistochemistry (IHC) scoring method and evaluated its reproducibility and performance to establish an optimal diagnostic HER2 testing algorithm for p53abn EC. Methods and results: HER2 IHC slides of 78 p53abn EC were scored by six gynaecopathologists according to predefined EC‐specific IHC scoring criteria. Interobserver agreement was calculated using Fleiss' kappa and the first‐order agreement coefficient (AC1). The consensus IHC score was compared with HER2 dual in‐situ hybridisation (DISH) results. Sensitivity and specificity were calculated. A substantial interobserver agreement was found using three‐ or two‐tiered scoring [κ = 0.675, 95% confidence interval (CI) = 0.633–0.717; AC1 = 0.723, 95% CI = 0.643–0.804 and κ = 0.771, 95% CI = 0.714–0.828; AC1 = 0.774, 95% CI = 0.684–0.865, respectively]. Sensitivity and specificity for the identification of HER2‐positive EC was 100 and 97%, respectively, using a HER2 testing algorithm that recommends DISH in all cases with moderate membranous staining in >10% of the tumour (IHC+). Performing DISH on all IHC‐2+ and ‐3+ cases yields a sensitivity and specificity of 100%. Conclusions: Our EC‐specific HER2 IHC scoring method is reproducible. A screening strategy based on IHC scoring on all cases with subsequent DISH testing on IHC‐2+/‐3+ cases has perfect test accuracy for identifying HER2‐positive EC. [ABSTRACT FROM AUTHOR]

Abstract: Endometrial cancer is a clinically heterogeneous disease and it is becoming increasingly clear that this heterogeneity may be a function of the diversity of the underlying molecular alterations. Recent large‐scale genomic studies have revealed that endometrial cancer can be divided into at least four distinct molecular subtypes, with well‐described underlying genomic aberrations. These subtypes can be reliably delineated and carry significant prognostic as well as predictive information; embracing and incorporating them into clinical practice is thus attractive. The road towards the integration of molecular features into current classification systems is not without obstacles. Collaborative studies engaging research teams from across the world are working to define pragmatic assays, improve risk stratification systems by combining molecular features and traditional clinicopathological parameters, and determine how molecular classification can be optimally utilized to direct patient care. Pathologists and clinicians caring for women with endometrial cancer need to engage with and understand the possibilities and limitations of this new approach, because integration of molecular classification of endometrial cancers is anticipated to become an essential part of gynaecological pathology practice. This review will describe the challenges in current systems of endometrial carcinoma classification, the evolution of new molecular technologies that define prognostically distinct molecular subtypes, and potential applications of molecular classification as a step towards precision medicine and refining care for individuals with the most common gynaecological cancer in the developed world. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Simple Summary: HER2 testing in endometrial cancer (EC) has gained renewed interest as a therapeutic target. However, HER2 status has not been investigated in the context of the molecular 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. HER2 status of 407 high-risk EC was determined by HER2 immunohistochemistry and HER2 dual in situ hybridization. Twenty-four (5.9%) HER2-positive EC of various histological subtypes were identified, 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. 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. [ABSTRACT FROM AUTHOR]