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The objective of this study was to assess the role of postoperative radiotherapy (RT) in early-stage cervical carcinoma with risk factors other than positive nodes, parametrial invasion, or positive margins and to compare outcomes using the Leiden University Medical Center (LUMC) modification of the Gynecologic Oncology Group (GOG) system with the GOG prognostic scoring system itself. Between January 1984 and April 2005, 402 patients with early-stage cervical cancer underwent radical hysterectomy. A total of 51 patients (13%) had two of the three risk factors and had pathologic tumor size (≥40 mm), invasion (≥15 mm), and capillary lymphatic space involvement, and were identified as the so-called high-risk (HR). We compared 34 patients who received RT based on the LUMC risk profile (67%) with 17 who did not (33%). The GOG score was calculated as well. We compared the GOG scores within the LUMC risk groups: HR+ (two out of three risk factors) and HR− (less than two out of three risk factors). Differences in 5-year cancer-specific survival (CSS) and 5-year disease-free survival (DFS) between the HR group treated with RT (86%, 85%) and without RT (57%; 43%) were statistically significant. The LUMC criteria did not significantly differ from the GOG risk profile, concerning recurrence, CSS, and DFS. HR patients benefit from adjuvant RT. The LUMC modification of the GOG system seems to be simpler and has a slightly higher threshold for the indication for RT but without a difference in outcome.

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-molecularprofile (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.

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

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using immunohistochemistry for p53 (p53 wild-type "p53wt" or p53 aberrant "p53abn" expression) and mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), considering MMR deficiency (MMRd) when a loss of MMR nuclear staining for at least one protein was identified. Identification of POLE mutations (POLE-EDM) was made by sequencing exons 9e14. Only pathogenic variants described in COSMIC database were considered for further analysis. Clinicopathological variables and survival ([RFS, relapse free survival; OS, overall survival]) correlations were assessed by the Kaplan Meier method and log rank.Results: A cohort of 54 patients fulfilled clinical and pathological criteria. Distribution by histological subtype was: endometrioid (46.3%), serous (33.3%), undifferentiated (11.1%), mixed (5.6%), and clear cell (3.7%). Molecular profile was fully evaluable in 49 samples: MMRd (26.5%), POLE-EDM (12.2%), p53wt (22.5%), p53abn (38.8%). Regardless of molecular subtype, 5 year relapse rate was: POLE 0%, MMRd 31.6%, p53wt 35.7%, p53abn 48.9% (p¼0.23), and 5 year OS rate was: POLE-EDM 100%, MMRd 76.2%, p53wt 48% and p53abn 38.5% (p¼0.18). Considering only endometrioid subtype, there was a statistically significant correlation of the molecular classification with 5 year OS (p¼0.02).Conclusions: To our knowledge, this is the first series that has evaluated the molecular classification focused on early-stage HG-EC, including all histologies. Patients with POLE-EDM have an excellent prognosis, with no relapses in this subgroup, whereas patients with p53abn have the worst prognosis. The application of molecular classification in daily practice could be useful in a better design of adjuvant therapy.Legal entity responsible for the study: The authors.

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