OBJECTIVE:This study investigates treatment quality and survival outcomes in elderly patients (≥75 years) with early-stage (International Federation of Gynecology and Obstetrics stage I/II) epithelial ovarian cancer documented in the German national quality-assurance program. It examines associations between surgical and systemic treatment quality and disease-free and overall survival. METHODS:Patients with a first diagnosis of ovarian cancer during the third quarter of 2012, 2016, and 2021 were documented. Surgical quality was defined as optimal when no more than one required staging procedure was omitted and sub-optimal when two or more procedures were missing. Chemotherapy quality was considered optimal when aligned with national guidelines. Overall treatment quality was classified as optimal, mixed, or sub-optimal according to surgical and chemotherapy quality. RESULTS:A total of 228 elderly patients with presumed early-stage epithelial ovarian cancer were included. Among them, 24.6% received both optimal surgery and optimal chemotherapy, 10.1% received optimal surgery with sub-optimal chemotherapy, 25.4% received sub-optimal surgery with optimal chemotherapy, and 39.9% received sub-optimal treatment in both modalities, with marked differences in age, Eastern Cooperative Oncology Group performance status, and comorbidity burden across treatment groups. At 24 months, 64% (95% confidence interval, 58% to 71%) of elderly patients remained disease-free. Within the elderly cohort, 24-month disease-free and overall survival were 90% (95% confidence interval, 82% to 99%) and 98% (95% confidence interval, 94% to 100%) with optimal surgery and chemotherapy, 68% (95% confidence interval, 56% to 81%) and 79% (95% confidence interval, 68% to 90%) with sub-optimal surgery and optimal chemotherapy, and 49% (95% confidence interval, 32% to 76%) and 62% (95% confidence interval, 45% to 87%) with optimal surgery and sub-optimal chemotherapy. CONCLUSIONS:In elderly patients with assumed early-stage ovarian cancer, guideline-concordant surgery and chemotherapy showed deficits that were associated with unfavorable outcomes. Chemotherapy quality showed a strong association with outcome, underscoring the need to optimize evidence-based treatment in elderly patients. Nonetheless, these findings are associative only, given possible selection of fitter patients and treatment of occult advanced disease in surgically under-staged patients.

PURPOSE Constitutional epimutations arise early in development and are present across normal tissues, including peripheral blood. Constitutional BRCA1 promoter methylation has emerged as a risk factor for BRCA1 -associated cancers, such as ovarian cancer (OC), and may serve as a biomarker for OC risk. This study retrospectively evaluated the clinical relevance of constitutional BRCA1 promoter methylation in 473 patients with OC enrolled in the observational AGO-TR1 study (ClinicalTrials.gov identifier: NCT02222883 ). MATERIALS AND METHODS BRCA1 promoter methylation was quantified by the methylation-specific real-time polymerase chain reaction using whole blood-derived DNA from 476 female controls and 473 patients with OC along with 473 corresponding tumor-derived DNA samples. Methylation levels ≥1.0% were considered methylation-positive. RESULTS BRCA1 promoter methylation in blood-derived DNA was detected in 42 of 473 patients with OC and in 26 of 476 controls (8.9% v 5.5%; odds ratio [OR], 1.69 [95% CI, 1.02 to 2.80], P = .0432), with the strongest association observed with methylation levels ≥10% (OR, 6.17 [95% CI, 1.37 to 27.72], P = .018). Patients with BRCA1 promoter methylation in blood-derived DNA were diagnosed at a younger median age than those without (54.0 v 60.0 years, P = .018). Constitutional BRCA1 promoter methylation was less frequent in patients carrying pathogenic germline variants in OC predisposition genes than in noncarriers (4.1% v 10.5%; OR, 0.37 [95% CI, 0.14 to 0.96], P = .04) and showed no association with a family history of cancer or platinum-based chemotherapy before blood draw. BRCA1 promoter methylation in blood-derived DNA was correlated with tumor BRCA1 promoter methylation ( P < .001). Tumor BRCA1 promoter methylation was observed in 64 of 473 samples (13.5%), half (32 of 64) of which were attributable to constitutional BRCA1 promoter methylation also detectable in the blood. CONCLUSION Constitutional BRCA1 promoter methylation accounts for a substantial proportion of OCs and represents a robust biomarker for individual OC risk.

5595 Background: Low-grade serous ovarian cancer (LGSOC), a rare ovarian malignancy, exhibits a very limited responsiveness to chemotherapy. There is a pressing need for new therapeutic combinations with modern agents to enhance response rates and prognosis in this patient subgroup. Immune checkpoint inhibitors offer a promising pathway, having shown effectiveness in various malignant diseases, including selected cases of ovarian cancer. If our trial should show pembrolizumab effectivity in LGSOC, it would be a signal and impulse for future clinical studies in this rare disease. Methods: This multi-center, single-arm phase II study evaluates pembrolizumab in combination with platinum-based chemotherapy (carboplatin plus pegylated liposomal doxorubicin [PLD] or carboplatin plus gemcitabine) and as maintenance therapy in recurrent LGSOC. Eligible patients include those with disease progression or recurrence ≥6 months post prior platinum-based therapy and ECOG performance status 0-1. The primary endpoint is the 12-month progression-free survival (PFS) rate. Secondary endpoints include response rate (RR), PFS and ORR based on Ki67 expression. Using Simon’s two-stage design, 33 patients were enrolled. Success is defined as ≥11 patients achieving 12-month PFS. Assuming a true PFS rate of 40%, the study has 5% type I error and 80% power. Results: Data from 33 patients were evaluated. At data cut-off, 12 patients were progression free at 12-months (median PFS 15.5 months) while 19 patients progressed or died within 12 months (median PFS 5.6 months). Overall PFS median was 8.4 months. Comparing the subgroups of pre-treatment Ki67 expression <3.6% vs. ≥ 3.6%, the median PFS was 5.1 vs. 8.8 months. Four patients remain on pembrolizumab treatment; two of these have not yet reached the 12-month PFS endpoint. Median patient age was 52 years (range: 37-81), with ECOG performance status 0 in 30 patients (90.9%). Most patients had one prior chemotherapy line (61.1%; range: 1-5). Chemotherapy regimens included carboplatin + PLD (75.8%) and carboplatin + gemcitabine (24.2%). SAEs were reported in 22 patients (66.7%), with 11 (33.3%) considered treatment-related. Conclusions: The study achieved its primary objective in terms of the 12-months PFS and thus suggests efficacy of pembrolizumab in patients with platinum-sensitive recurrent LGSOC. Clinical trial information: 2023-508155-40-00.

BACKGROUND:Antibody-drug conjugates (ADCs) are approved for use in treating certain types of cancer and are now in clinical development for many others, as they are therapeutically effective. Some of these agents commonly cause ocular side effects, typically manifesting themselves as blurred vision or a foreign-body sensation. METHODS:For this narrative review of the literature, we carried out a database search and a cross-reference search at the German Federal Institute for Drugs and Medical Devices (BfArM) to identify publications on the diagnosis, prevention, and treatment of ocular side effects associated with ADCs. RESULTS:Of the 13 ADCs that have been approved to date, 4 cause ocular side effects in 5% to 89% of patients. Ocular side effects are severe in up to 43% of the cases in which they occur. Appropriate prophylactic measures must be taken to limit their frequency and intensity; these include not wearing contact lenses, using lubricating eye drops multiple times a day, and cooling the eyes during the administration of treatment. Severe ocular side effects can arise despite such measures and require treatment by a specialist. Ocular side effects can be managed successfully by rapid detection and adequate evaluation of their extent followed by proper treatment, thereby enabling the patient's cancer to be treated appropriately. CONCLUSION:Interdisciplinary collaboration between oncologists and ophthalmologists must be well-coordinated to ensure effective oncological treatment.

Surgical trials have been among the most important drivers of practice change in gynecologic oncology, generating evidence across ovarian, endometrial, cervical, and vulvar cancer. These studies have demonstrated that the surgical approach, extent of resection, treatment sequence, and integration with systemic therapies profoundly affect survival, perioperative morbidity, and long-term quality of life, yet the credibility, interpretability, and clinical impact of surgical trials depend not only on their design but also on the way they are conducted. Unlike pharmacologic trials, surgical trials are uniquely vulnerable to bias arising from variability in surgeon expertise, intraoperative decision-making, institutional infrastructure, and adherence to protocol-defined techniques. Failure to adequately standardize or consistently implement treatment protocols may obscure the true effects of an intervention, compromise the internal validity of the study, and diminish the external validity and generalizability of the findings. Conversely, rigorous and well-executed trials enable researchers to make definitive, practice-changing conclusions. This review provides a comprehensive framework for the conduct of multicenter, surgical trials, focusing on key domains including eligibility determination, the timing and implementation of randomization, surgical credentialing, the standardization of surgical procedures, quality assurance, outcome selection, the integration of patient-reported outcomes, patient accrual and informed consent, and equitable trial participation. By outlining principles that balance methodological rigor with pragmatic relevance, this review highlights how optimized trial conduct is essential to generating reliable evidence, accelerating surgical innovation, and improving oncologic and patient-centered outcomes for women with gynecologic cancers.

BACKGROUND:Malignant ovarian germ cell tumours (MOGCT) are rare tumours that disproportionally affect younger women. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) study group has established a clinico-pathological database (Current Ovarian geRm cell and SEx cord stromal Tumour Treatment strategies, CORSETT) to provide an overview of the current treatment strategies and survival of MOGCT patients. METHODS:Twenty German centres provided mixed retro- and prospective data of patients with tumour specimens treated between 2001 and 2014. A second opinion pathology board reviewed the tumour specimens. Descriptive analyses of the treatment strategies and fertility outcomes were conducted. Kaplan-Meier curves were plotted for disease-free and overall survival data. RESULTS:Seventy-seven MOGCT patients were included, 36 malignant dysgerminoma (MD), 21 malignant teratoma (MT) and 20 mixed MOGCT (MM) patients. Patients had a median age of 28 (MD), 38 (MT) and 33 (MM) years and fertility-sparing surgery (FSS) was offered in most (83% MD, 81% MT and 75% MM) patients. Final FIGO stage I disease was diagnosed in 78% (MD), 81% (MT) and 60% (MM) and adjuvant systemic treatment was given to 56% (MD), 53% (MT) and 70% (MM) patients. After a median observation time of 78.2 months, 5% (MD), 14% (MT) and 45% (MM) experienced disease recurrence. Overall survival was excellent in all groups (100% MD, 100% MT and 95% MM). DISCUSSION:In this descriptive analysis, FSS was the surgical method of choice for patients with MOGCT in AGO centres without negative impact on OS. MOGCTs appeared however as a heterogeneous group of tumours with particularly high recurrence rates for patients with MM.

BACKGROUND:We analyzed health-related quality of life (HRQoL) and time until definitive HRQoL deterioration (TUDD) for patients with newly diagnosed advanced ovarian cancer receiving olaparib plus bevacizumab or placebo plus bevacizumab in PAOLA-1. METHODS:HRQoL and TUDD, prespecified secondary endpoints, were assessed by EORTC Core Quality of Life Questionnaire (QLQ-C30) and Ovarian Cancer module (QLQ-OV28) at baseline and then every 12 weeks for 2 years. HRQoL and TUDD by homologous recombination deficiency (HRD) status and effect of progression on HRQoL were post hoc analyses. RESULTS:806 patients were randomized (olaparib plus bevacizumab n = 537; placebo plus bevacizumab n = 269). There were no clinically meaningful between-group differences in adjusted mean global change from baseline in QLQ-C30 or QLQ-OV28 domains overall (between-group difference in QLQ-C30 Global Heath Status (GHS) score [95% CI] 1.65 [-0.27, 3.56]) or in the HRD-positive subgroup (1.23 [-1.25, 3.71]). TUDD estimates of QLQ-C30 GHS scores did not differ between treatment arms in the modified intention-to-treat population (hazard ratio [HR]=0.88; 95% CI = 0.72, 1.07) and favored olaparib plus bevacizumab vs placebo plus bevacizumab in the HRD-positive subgroup (HR = 0.70; 95% CI = 0.52, 0.93). Analyses of patients (103/465 [22.2%]) following disease progression showed clinically meaningful deterioration in QLQ-C30 emotional and social scores. CONCLUSION:Adding maintenance olaparib to bevacizumab showed no clinically meaningful detrimental effect on global HRQoL either overall or in the HRD-positive subgroup. ClinicalTrials.gov ID: NCT02477644.

5506 Background: Mirvetuximab soravtansine (MIRV) has demonstrated single agent activity in patients with platinum-resistant ovarian cancer with FRα high expression. However, its activity and safety in combination with carboplatin has not been defined in platinum eligible patients so far. Methods: Randomized phase II trial comparing 6 cycles of carboplatin AUC5+MIRV 6 mg/kg AIBW every 3 weeks followed by MIRV versus 6 cycles of carboplatin combined with either paclitaxel, gemcitabine or pegylated liposomal doxorubicin followed by maintenance PARP inhibitor (PARPi) if applicable. All histologic subtypes were eligible with a platinum-free interval >3 months and FRα high expression (≥75% with PS2+ scoring) confirmed by central laboratory. Prior PARPi therapy in BRCAmut patients was mandatory. Strata were BRCA-Status, TFIp and number of prior lines of chemotherapy. The primary endpoint was PFS. Results: In total, 145 patients were randomized. Of them, 112/145 (77.2%) patients had received prior bevacizumab and 97/145 (66.9%) had prior PARPi, 15.2% were BRCAmut. In the standard arm, 39.15% received PARPi as maintenance. Median PFS in the standard arm was 9.79 months versus 9.53 months in the experimental arm (p=0.996; HR=1.00; 95% CI: 0.68; 1.46). Conclusions: MIROVA/AGO-OVAR 2.34 is the first randomized trial evaluating the activity and safety of the combination of carboplatin with an antibody-drug conjugate in the setting of platinum-eligible relapsed ovarian cancer. The primary endpoint regarding improvement of PFS was not met. Further analysis will be presented. Clinical trial information: NCT04274426 .

BACKGROUND:The GOG Foundation and the European Network of Gynaecological Oncological Trial Groups have collaborated on industry-partnered gynecologic oncology trials since the formation of their joint Liaison Committee in 2016. Their 2019 joint publication established shared requirements for trial sponsorship, conduct, and authorship. Since then, the scope and global complexity of co-branded trials have grown substantially, with an increasing number of third-party cooperative groups and consortia participating alongside GOG Foundation and European Network of Gynaecological Oncological Trial groups, and with as an expanded volume of secondary and ancillary publications arising from major trials. PURPOSE:To address these evolving needs, the GOG Foundation/European Network of Gynaecological Oncological Trial groups Liaison Committee has developed updated publication and authorship guidelines (Version 2.0), replacing and substantially expanding the authorship provisions of the 2019 framework. SUMMARY:Key updates include the formalization of the Third-Party Group designation for non-GOG Foundation/non-European Network of Gynaecological Oncological Trial groups cooperative participants; detailed accrual-based authorship calculation and positioning rules for primary and secondary publications; guidance on ancillary and translational research authorship; conference presentation rotation; and explicit governance provisions for enrollment-related exceptions and deviations from these guidelines. CONCLUSIONS:These updated guidelines provide a transparent and equitable framework for publication and authorship in GOG Foundation-European Network of Gynaecological Oncological Trial groups industry-partnered trials, reinforcing scientific integrity, encouraging broad participation, and supporting the responsible dissemination of results in gynecologic oncology.

Summary Background Valid stratification factors for patients with epithelial ovarian cancer (EOC) are still lacking and individualisation of care remains an unmet need. Radiomics from routine Contrast Enhanced Computed Tomography (CE-CT) is an emerging, highly promising approach towards more accurate prognostic models for the better preoperative stratification of the subset of patients with high-grade-serous histology (HGSOC). However, requirements of fine manual segmentation limit its use. To enable its broader implementation, we developed an end-to-end model that automates segmentation processes and prognostic evaluation algorithms in HGSOC. Methods We retrospectively collected and segmented 607 CE-CT scans across Europe and United States. The development cohort comprised of patients from Hammersmith Hospital (HH) (n=211), which was split with a ratio of 7:3 for training and validation. Data from The Cancer Imagine Archive (TCIA) (United States, n=73) and Kliniken Essen-Mitte (KEM) (Germany, n=323) were used as test sets. We developed an automated segmentation model for primary ovarian cancer lesions in CE-CT scans with U-Net based architectures. Radiomics data were computed from the CE-CT scans. For overall survival (OS) prediction, combinations of 13 feature reduction methods and 12 machine learning algorithms were developed on the radiomics data and compared with convolutional neural network models trained on CE-CT scans. In addition, we compared our model with a published radiomics model for HGSOC prognosis, the radiomics prognostic vector. In the HH and TCIA cohorts, additional histological diagnosis, transcriptomics, proteomics, and copy number alterations were collected; and correlations with the best performing OS model were identified. Predicated probabilities of the best performing OS model were dichotomised using k-means clustering to define high and low risk groups. Findings Using the combination of segmentation and radiomics as an end-to-end framework, the prognostic model improved risk stratification of HGSOC over CA-125, residual disease, FIGO staging and the previously reported radiomics prognostic vector. Calculated from predicted and manual segmentations, our automated segmentation model achieves dice scores of 0.90, 0.88, 0.80 for the HH validation, TCIA test and KEM test sets, respectively. The top performing radiomics model of OS achieved a Concordance index (C-index) of 0.66 ± 0.06 (HH validation) 0.72 ± 0.05 (TCIA), and 0.60 ± 0.01 (KEM). In a multivariable model of this radiomics model with age, residual disease, and stage, the C-index values were 0.71 ± 0.06, 0.73 ± 0.06, 0.73 ± 0.03 for the HH validation, TCIA and KEM datasets, respectively. High risk groups were associated with poor prognosis (OS) the Hazard Ratios (CI) were 4.81 (1.61-14.35), 6.34 (2.08-19.34), and 1.71 (1.10 - 2.65) after adjusting for stage, age, performance status and residual disease. We show that these risk groups are associated with and invasive phenotype involving soluble N -ethylmaleimide sensitive fusion protein attachment receptor (SNARE) interactions in vesicular transport and activation of Mitogen-Activated Protein Kinase (MAPK) pathways. Funding This article represents independent research funded by 1) the Medical Research Council (#2290879), 2) Imperial STRATiGRAD PhD program, 3) CRUK Clinical PhD Grant C309/A31316, 4) the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College, London 5) and the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London. Research In Context Evidence before this study Epithelial ovarian cancer (EOC) is the deadliest of all gynaecological cancers, causing 4% of all cancer deaths in women. The most prevalent subtype (70% of EOC patients), high-grade serous ovarian cancer (HGSOC), has the highest mortality rate of all histology subtypes. Radiomics is a non-invasive strategy that has been used to guide cancer management, including diagnosis, prognosis prediction, tumour staging, and treatment response evaluation. To the best of our knowledge, Lu and colleague’s radiomics prognostic vector was the first radiomics model developed and validated to predict overall survival (OS) in HGSOC individuals, from contrast enhanced computed tomography (CE-CT) scans. Both this study and subsequent studies utilised manual segmentations, which adds to the radiologist’s/clinician’s workload and limits widespread use. Additionally, while the models by Lu and co-workers were validated in additional datasets, they were neither harmonised through image resampling – a present requirement for radiomics analysis outlined by the image biomarker standardization initiative – nor compared across machine learning/deep learning models, which could potentially improve predictive performance. Added value of this study The use of adnexal lesion manually delineated segmentations alone to predict outcome is considered demanding and impractical for routine use. By developing a primary ovarian lesion segmentation, our radiomics-based prognostic model could be integrated into the routine ovarian cancer diagnostic workflow, offering risk-stratification and personalised surveillance at the time of treatment planning. Our study is the first to develop an end-to-end pipeline for primary pre-treatment HGSOC prognosis prediction. Several deep learning and machine learning models were compared for prognosis from CE-CT scan-derived, radiomics and clinical data to improve model performance. Implications of all the available evidence Our research demonstrates the first end-to-end HGSOC OS prediction pipeline from CE-CT scans, on two external test datasets. As part of this, we display the first primary ovarian cancer segmentation model, as well as the largest comparative radiomics study using machine learning and deep learning approaches for OS predictions in HGSOC. Our study shows that physicians and other clinical practitioners with little experience in image segmentation can obtain quantitative imaging features from CE-CT for risk stratification. Furthermore, using our prognosis model to stratify patients by risk has revealed sub-groups with distinct transcriptomics and proteomics biology. This work lays the foundations for future experimental work and prospective clinical trials for quantitative personalised risk-stratification for therapeutic-intent in HGSOC-patients.