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Introduction/Background* The TransPORTEC Consortium was established in 2013 by the PIs and translational science representatives of the PORTEC-3 trial groups from the Netherlands, United Kingdom, Australia, Canada and France. Purpose of the collaboration is to improve treatment of endometrial cancer (EC) patients. Here, we evaluate our experience with international collaboration to identify challenges and strengths. Methodology Result(s)*: Since its establishment, TransPORTEC had a strong scientific team of chief investigators, translational leads and core members from participating groups. Twice-yearly TransPORTEC-meetings were organised to build and maintain friendships, share results and discuss new proposals. Over time, the TransPORTEC-biobank has expanded with PORTEC-trial tumour tissues and other cohorts, and is now the world’s largest set of molecularly classified ECs. The research focus has expanded to include molecular cancer immunology and digital pathology. The group’s output include 10 scientific papers and numerous posters and presentations on (inter)national meetings. Their analysis of PORTEC-3 showing differences in chemotherapy effect by molecular group led to initiating an international program with 4 clinical trials on Refining Adjuvant treatment IN endometrial cancer Based On molecular features (RAINBO) to compare personalised to standard treatment in terms of efficacy, toxicity, quality of life and cost-utility (figure 1). Tumour material of all participants will be collected for translational research. To achieve this, the consortium evolved: new talented members were attracted and trial-specific and expertise teams were installed (figure 2). Despite this impacting on group equilibrium, the collaboration is continuously productive. Keys to success were frequent meetings, sharing of draft protocols and experiences with contacting (inter)national research organisations and potential funders. The first of the RAINBO trials is expected to open by the end of 2021 and the program will probably fuel translational research for years to come. Conclusion* International research collaborations are dynamic and demanding. Challenges include: balancing between a stable organisational structure and flexibility to adapt to opportunities; providing all members with a satisfying share; and acquisition of funding for academic-sponsored international trials. Strengths are the profound interaction and trust between members with different expertise and backgrounds and shared ambitions and successes, resulting in unique and innovative academic research projects with leverage.

Introduction/Background* The molecular endometrial cancer (EC) classification has proven prognostic value and can direct adjuvant treatment decisions. Despite this, a relatively large group of EC is still molecularly unclassified (NSMP-EC). In this study we aimed to identify biomarkers among high-risk NSMP-EC patients with prognostic and/or predictive relevance. Methodology Paraffin-embedded tumour material (n=423) from the PORTEC-3 HREC trial were available for analysis. All patients with NSMP-EC were selected, hence those without pathogenic POLE mutations, mismatch repair deficiency and p53-abnormal immunohistochemistry (IHC). Protein expression of L1CAM, ER and PR (ongoing) were analysed by IHC using a 10% threshold for positivity. Tumour DNA was analysed for pathogenic somatic mutations using a next generation sequencing (NGS) cancer hotspot panel. Time to recurrence was analysed using the Kaplan-Meier method, log-rank tests and Cox’s proportional hazard models. Result(s)* In total, 126 NSMP-EC were identified in PORTEC-3, the majority were hormone receptor positive (ER n=106/121, 87.6%, PR will be presented at ESGO2021). L1CAM overexpression was observed in 11.2% (n=14/125) and mutations in CTNNB1-exon-3 were identified in 34.3% (n=36/105). Clustering showed that ER-positive NSMP-EC were predominantly endometrioid EC (n=99, 93.4%), low grade (n=88, 83.0%) and L1CAM-negative (n=102, 97.1%) (figure 1). PIK3CA and KRAS mutations were present in 27.3% (n=24) and 19.3% (n=17), respectively. ER-negative NSMP-EC were frequently non-endometrioid (n=11, 73.3%), L1CAM-positive (n=11, 73.3%) and rarely harboured PTEN and CTNNB1 mutations (n=1, 7.1% and 0%, respectively). ER-positivity was associated with lower risk of recurrence (HR 0.32 [95%CI 0.14-0.70]; figure 2A), while L1CAM-overexpression and CTNNB1-exon-3 mutations were not (HR 2.25 [95%CI 0.93-5.43] and HR 1.20 [95%CI 0.57-2.54], respectively). Multivariable analysis confirmed independent favourable prognostic impact of ER-positivity and LVSI. Figure 2B shows impact of LVSI on time to recurrence among patients with ER-positive NSMP-EC. Conclusion* The vast majority of NSMP-HREC are ER-positive (87.6%) and are likely sensitive to hormonal therapy. Other treatment targets might be found in this subgroup too as 27.3% had PIK3CA and 19.3% had KRAS mutations. NSMP-EC with loss of ER-expression were often of non-endometrioid histology and had a high risk of recurrence. Future studies should investigate whether this subgroup would benefit from other systemic therapies.

Introduction/Background* The molecular endometrial cancer (EC) classification has proven prognostic impact. However, patients included in previous studies were not always staged by lymphadenectomy (LND) and often received adjuvant treatment (AT). This may have moderated the prognostic effect of the molecular classification. We evaluated the prognostic significance of the molecular classification in high-grade EC patients staged by LND and those without AT. Methodology Targeted DNA-sequencing for 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 Gynecological 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. Analyses were performed on patients staged by LND and on patients without AT. Time to recurrence analyses were performed using the Kaplan-Meier method, log-rank test and Cox proportional hazard’s models. Pre-specified multivariate regression analyses were performed including age, ASA class, stage, lymphovascular space invasion and in the LND subgroup a propensity score to correct for confounding by indication. Result(s)* Molecular analysis was successful in 367 EC; 251 patients had undergone LND, see table 1. Median follow-up was 11 years (range 7.5-15.4). Multivariable analysis showed that molecular subgroup was a strong independent prognostic factor for recurrence: p53abn HR 3.88 (95%CI 1.89-7.94, p Among 264 patients without AT, 247 (94%) had stage I-II disease and 17 (6%) stage III. None of the patients with POLEmut EC (n=26, 10%) had a recurrence (figure 1B). Multivariable analysis showed that the significant prognostic impact of molecular subgroup was independent of clinicopathological factors. Conclusion* The molecular EC classification has strong prognostic value, independent of clinicopathological factors, also among patients staged by LND and those without AT. This implies that the unfavourable prognosis of p53abn EC is not caused by undetected lymph node metastasis. POLEmut EC is inherently associated with an excellent prognosis even in the absence of adjuvant treatment.

Introduction/Background* Microcystic, elongated fragmented (MELF) pattern of myometrial invasion is a distinct histologic feature occasionally seen in low-grade endometrial carcinomas (EC). The prognostic relevance of the presence of MELF is uncertain due to conflicting data and has not appropriately been studied in the context of the novel molecular EC classification. We aimed to determine the relation of MELF pattern of invasion with clinicopathological and molecular characteristics, and define its prognostic relevance in early stage (high)intermediate risk EC. Methodology Single haematoxylin and eosin (H&E) stained whole tumour slides of 929 of the 1141 early stage (high)intermediate risk EC of patients included in the post-operative radiation therapy in endometrial carcinoma (PORTEC)-1/-2 trials were available for review for the presence of MELF. Histological type, stage and grade, presence and extent of lymph-vascular-space-invasion (LVSI), molecular subclass, L1-cell-adhesion-molecule (L1CAM) overexpression, and β-catenin exon-3 (CTNNB1) and KRAS mutational status were compared between MELF-positive and negative cases. Differences in patient and tumour characteristics were analysed with chi-square or Fisher’s exact test for categorical and Mann-Whitney U test for continuous variables. Time-to-event analyses were done using the Kaplan-Meier method, log-rank tests and Cox’ proportional hazards models. Result(s)* MELF pattern of invasion was identified in 129 (16%) cases, and was associated with grade 1-2 and deep myometrial invasion (table 1). MELF positive tumours were significantly more often found in the no-specific-molecular-profile (NSMP) subclass (n=95, 84.8%). Of these NSMP MELF positive tumours 91.1% were CTNNB1-wildtype (n=82) and 26.5% KRAS-mutated (n=22). Uncorrected survival analysis showed a significantly favourable impact of MELF on risk of recurrence (p=0.031). After correction for stage, grade, LVSI, molecular EC class, L1CAM and CTNNB1, MELF pattern of invasion did not significantly impact clinical outcome (HR 0.63 95%CI 0.28 – 1.41, p=0.26), table 2. Conclusion* MELF-pattern of invasion was identified in 16% of early stage (high)intermediate risk EC, and had no independent prognostic impact. However, our results show that MELF pattern of invasion is more frequently found in NSMP KRAS-mutated EC without CTNNB1 mutations. These distinct molecular features could contribute to further refinement of the NSMP-subgroup of EC pointing to potential novel treatment targets.