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Introduction: The role of molecular classification and L1CAM in high-risk endometrial cancer is uncertain. We aimed to determine the association of molecular profiling and L1CAM with patterns of relapse and survival., Material and Methods: This retrospective cohort study included patients referred to Department for Gynecologic Oncology, Oslo University Hospital between January 1, 2006 and December 31, 2017. L1CAM expression and molecular profiling according to ProMisE was performed. Main outcome was time to recurrence (TTR) and cancer specific survival (CSS)., Results: Of 489 patients, 486 could be molecular classified. Thirty-seven (8 %) had POLE mutated tumors, 148 (30 %) had MMRd tumors, 189 (39 %) had p53 abnormal tumors, and 112 (23 %) had NSMP tumors. High L1CAM expression was observed in 256 (53 %), low in 227 (46 %) tumors (6 (1 %) missing). ProMisE was significant for TTR but not for CSS in multivariable analysis. L1CAM was significant in multivariable analysis for both TTR and CSS. In a multivariable model with ProMisE and L1CAM expression in the same multivariable model, ProMisE lost significance while L1CAM remained significant. Patients with POLE mutated tumors entailed an excellent prognosis while patients with p53 abnormal or L1CAM overexpressing tumors entailed a poor prognosis with a high frequency of distant recurrences. Patients with MMRd tumors, NSMP and p53 abnormal tumors with low L1CAM had an intermediate prognosis., Conclusions: L1CAM is an additional adverse factor in the p53 abnormal and NSMP groups. These groups need special attention in studies intensifying adjuvant treatment., Competing Interests: Declaration of competing interest KL reports the following conflicts of interest outside the submitted work: Participation on data safety monitoring or advisory boards of Eisai, MSD, Nykode, AstraZeneca, GSK and Karyopharm (honoraria paid to institution); and research funding paid to institution from GSK. All other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The treatment for stage IB grade 3 endometrioid endometrial adenocarcinoma is challenging with variable practice. Molecular characterization may help identify adjuvant therapy strategies beyond stage. We aimed to better understand the molecular features of these tumors by characterizing them by ProMisE classification, mutational signature, and commonly mutated genes., Methods: Patients with stage IB grade 3 EEC at two institutions were included. Immunohistochemistry and whole exome sequencing were performed on archival FFPE tissue sections to determine ProMisE classification. Personal Cancer Genome Reporter was used for somatic variant annotation, and mutational signatures were generated based on COSMIC single base substitution mutational signatures., Results: 46 patients were included with variable adjuvant treatment. Nine patients recurred (19.6%), most with extra-abdominal disease (n = 5, or 55.6%). 10 had POLE mutations (21.7%), 18 were MMR deficient (39.1%), 6 had abnormal p53 (13.0%), and 12 were p53 wildtype (26.1%). There were no recurrences in the POLE subgroup. A dominant mutational signature was identified in 38 patients: 17 SBS5 signature (44.7%), 10 SBS15 or SBS44 signature (26.3%), 7 SBS10a or SBS10b signature (18.4%), 3 SBS14 signature (7.9%), and 1 SBS40 signature (2.6%). The six patients that recurred had a SBS5 signature. Frequently mutated genes included ARID1A (n = 30, 65%), PTEN (n = 28, 61%), MUC16 (n = 27, 59%), and PIK3CA (n = 25, 54%)., Conclusions: This comprehensive evaluation found a molecularly diverse cohort of tumors, despite the same histology, stage and grade. Mutational signature SBS5 correlated with a high risk of recurrence. Further refining of endometrial cancer classification may enable more precise patient stratification and personalized treatment approaches., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze the expression and prognostic role of L1CAM in tubo-ovarian high-grade serous carcinoma (HGSC)., Methods: L1CAM protein expression by immunohistochemistry was analyzed in 644 HGSC (413 effusions, 231 surgical specimens). Expression was analyzed for association with clinicopathologic parameters and survival., Results: L1CAM protein expression was found in 401/413 (97%) effusions and 209/231 (90%) surgical specimens, with significantly higher staining extent in effusions (p < 0.001). L1CAM protein expression in effusions was unrelated to clinicopathologic parameters (p > 0.05). In surgical specimens, higher L1CAM expression was significantly related to primary (intrinsic) chemoresistance (p = 0.017). High (>25%) L1CAM expression in HGSC effusions (p = 0.02), older patient age (p = 0.013), FIGO stage IV disease (p < 0.001) and larger residual disease volume (p = 0.001) were significantly associated with shorter overall survival (OS) in univariate analysis. In Cox multivariate analysis, only FIGO stage (p = 0.001) and residual disease volume (p = 0.003) were independent prognosticators of OS. L1CAM expression in effusions was unrelated to progression-free survival (PFS). There was no association between L1CAM expression in surgical specimens and survival., Conclusion: L1CAM is overexpressed in HGSC effusions compared to surgical specimens. Its overexpression in effusions is significantly associated with shorter OS, but not independently of established prognostic factors such as FIGO stage and residual disease volume., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Uterine serous carcinoma is a rare but aggressive subtype of endometrial adenocarcinoma. Our objective was to compare adjuvant treatment strategies for patients with early stage uterine serous carcinoma., Methods: This multi-institutional, retrospective cohort study evaluated patients with early stage uterine serous carcinoma. Patients with FIGO Stage IA-II disease after surgery, whose tumors had serous or any mixed serous/non-serous histology were included. Patients with carcinosarcoma were excluded. Clinical data were abstracted from local medical records. Summary statistics, Fisher's exact, and Kruskal-Wallis tests were used to analyze demographic and clinical characteristics. Univariable and multivariable analyses were performed for recurrence-free and overall survival., Results: There were 737 patients included. Most patients had Stage IA disease (75%), 49% of which had no myometrial invasion. Only 164 (24%) tumors had lymphatic/vascular space invasion. Adjuvant treatment varied: 22% received no adjuvant therapy, 17% had chemotherapy alone, 19% had cuff brachytherapy, 35% had cuff brachytherapy with chemotherapy, and 6% underwent pelvic radiation. Adjuvant treatment was significantly associated with a decreased risk of recurrence (p = 0.04). Compared with no adjuvant therapy, patients who received brachytherapy or brachytherapy/chemotherapy had improved recurrence-free survival (HR 0.59, 95% CI 0.40-0.86; HR 0.65, 95% CI 0.49-0.88, respectively) and overall survival (HR 0.53, 95% CI 0.35-0.79; HR 0.49, 95% CI 0.35-0.69, respectively). Improved survival with brachytherapy and brachytherapy/chemotherapy persisted on multivariable analyses. Chemotherapy alone was also associated with improved overall survival compared with no adjuvant treatment (HR 0.55, 95% CI 0.37-0.81)., Conclusions: Adjuvant therapy was associated with a decreased risk of recurrence relative to observation alone. Adjuvant cuff brachytherapy with and without chemotherapy was associated with improved survival outcomes in patients with early stage uterine serous carcinoma., Competing Interests: Declaration of Competing Interest KCK reports: advisory board (LEAP Therapeutics), outside the submitted work; BMF reports: research support to his institution for the submitted work (MD Anderson Cancer Center Support Grant [CA016672]); DAI reports: advisory board (Novocure), outside the submitted work; KL reports: research support to her institution (GSK) and advisory board roles (AstraZeneca, Eisai, GSK, MSD), outside the submitted work; BA reports: payment or honoraria (Roche, Eisai, AstraZeneca, Celgene, MSD, Novartis), advisory board (Roche, MSD, GSK), and travel support (Roche, GSK), all outside the submitted work; SNW reports: research support to her institution for the submitted work (NCI SPORE for Uterine Cancer [2P50 CA098258-06]), and research support to her institution (AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, GSK, Mereo, Novartis, OncXerna, Roche/Genentech, Zentalis) and consulting fees (Agenus, AstraZeneca, Clovis Oncology, Eisai, EQRX, GSK, Immunogen, Lilly, Merck, Mereo, Novartis, Roche/Genentech, Zentalis), outside the submitted work. PTS reports: research support (Incyte, Novartis), consulting (Medscape) and advisory board (Amgen, Eisai), all outside the submitted work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to compare response rates and survival in women with "platinum resistant" epithelial ovarian cancer (EOC) who received further platinum-based or non‑platinum chemotherapy for treatment at first relapse., Methods: Patients with high-grade EOC (including fallopian tube and peritoneal cancer) of all histologies recruited to the Australian Ovarian Cancer Study (AOCS) and treated with platinum-based primary chemotherapy were included. Response to second-line chemotherapy, overall survival (OS) and survival after treatment for first progression (OS2) were determined in all histologies and separately in women with high-grade serous tumors., Results: Of the 341 patients classified as platinum-resistant by the 6-month threshold, 243 (71%) were treated with chemotherapy at relapse. CA-125 response rates to platinum-based chemotherapy were significantly higher compared to non‑platinum chemotherapy (51% vs 21%, P < 0.001). Among patients with a platinum-free interval (PFI) of 3-6 months, OS2 in patients treated with platinum was significantly longer compared to individuals receiving non‑platinum-based treatment (median 17.67 months, 95% CI: 14.79-20.75 vs. 10.62 months, 95% CI: 8.02-12.72, P = 0.022). The patterns were similar when restricted to patients with high-grade serous histology. In patients with PFI <3 months, there was no significant difference in response or survival according to type of second-line treatment., Conclusions: Our findings further question the use of a 6-month PFI as an arbitrary threshold for subsequent treatment decision-making. Some patients considered "platinum resistant" still derive clinical benefit from platinum-based chemotherapy. Biomarkers of platinum sensitivity are needed in clinical practice to identify potential responders who should be offered re-treatment with platinum., (Copyright © 2018. Published by Elsevier Inc.)

Objective: Primary peritoneal cancer is rare and considered equivalent to stage III/IV ovarian cancer, but questions remain concerning its underlying biology, prognosis and optimal management., Methods: Clinico-pathological and treatment details of primary peritoneal (n=120) and ovarian cancer (n=635) were obtained on women recruited to the Australian Ovarian Cancer Study. Log-rank test was used to compare survival and cox proportional hazards models were fitted to obtain hazard ratios and 95% confidence intervals, both unadjusted and adjusted for age, grade, FIGO stage, residual disease and treatment with neoadjuvant chemotherapy. Molecular subtype was determined by gene expression profiling using published data., Results: Compared with advanced serous ovarian cancer, primary peritoneal cancer patients were older (mean age 65.5 vs. 60.2years, p<0.001), more often treated with neoadjuvant chemotherapy (38.4% vs. 11.4%, p<0.001). Gene expression profiling classified a substantially higher proportion of primary peritoneal carcinomas as C1 (mesenchymal, reactive stromal infiltration) subtype (70.6% vs. 32.1%, p=0.029), which was associated with lower complete surgical resection rate. Women with primary peritoneal cancer had significantly shorter progression-free (11.6 vs. 13.6months, p=0.007) and overall survival (31.7 vs. 39.8months, p=0.012). In multivariate analysis, residual disease and neoadjuvant chemotherapy were both independently associated with increased risk of progression and death., Conclusions: Primary peritoneal cancer patients were more frequently treated with neoadjuvant chemotherapy and had inferior survival. Different tumor biology characterized by activated stromal fibrosis in primary peritoneal cancer may underlie the differences in treatment and clinical outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: We studied the association of body mass index (BMI) and diabetes with all-cause death and endometrial cancer-specific death among women with endometrial cancer (EC)., Methods: Included were 337 women in the Health Surveys in North-Trøndelag, Norway who were followed from EC diagnosis to death or end of follow-up, 30th June 2012. Risks of death associated with BMI and diabetes were estimated as hazard ratios (HRs) with 95% confidence intervals (95% CI). The risks of EC-specific death were estimated as sub-HRs, after adjustment for competing causes of death. We also studied the risk of death associated with diabetes in women with BMI<25kg/m(2) and in women with BMI≥25kg/m(2)., Results: During the median follow-up time of 6.7years, 166 women (49.3%) died. Diabetes increased the risk of all-cause death (HR 2.14, 95% CI: 1.26-3.63) and endometrial cancer-specific death (SHR, 2.62, 95% CI: 1.07-6.43) after adjustment for age, histological type and stage of EC. BMI was not associated with risk of all-cause or EC-specific death. The increased risk of both all-cause death and EC specific death in diabetic women seemed to be more pronounced in women with BMI<25kg/m(2) (HR 6.35, 95% CI: 1.90-21.14) compared to women with BMI>25kg/m(2) (HR 1.80, 95% CI: 0.98-3.33)., Conclusions: Diabetes, but not BMI, was associated with increased risk of all-cause death and death from EC. The increased risk of death associated with diabetes seemed to be most pronounced in women with BMI<25kg/m(2)., (Copyright © 2015 Elsevier Inc. All rights reserved.)