Objectives: The purpose of the study is to determine whether FOXL2 circulating tumor DNA can be used as a prognostic biomarker and marker for monitoring treatment response in patients with an adult-type granulosa cell tumor (aGCT). Methods: Plasma samples of patients included in the multicenter GRANULOSA study were collected before and after surgery for primary or recurrent aGCT, during follow-up, and during systemic treatment. The presence of ctDNA containing the FOXL2 402C>G mutation was analyzed in 284 samples from 20 primary and 34 recurrent aGCT patients, using digital droplet PCR. Clinical data were retrieved from electronic patient records, and patients were followed through January 2025. Results:FOXL2 mutant ctDNA was detected in 28 of 54 patients (48%). In primary aGCT, recurrences were more frequently seen in patients with detectable ctDNA (33% vs. 18%), and ctDNA remained detectable postoperatively in some cases despite complete cytoreduction. In recurrent aGCT patients, detectable ctDNA was associated with significantly worse overall survival (p = 0.023), and the postoperative presence of ctDNA following complete debulking surgery was significantly associated with a shorter recurrence-free survival (4.7 vs. 11.6 months, p = 0.025). Conclusions:FOXL2 mutant ctDNA could be a prognostic biomarker in aGCT, being associated with worse overall survival in recurrent aGCT patients. In addition, the presence of ctDNA after surgery could reflect the presence of minimal residual disease, negatively impacting the disease course. The implementation of FOXL2 ctDNA measurement in clinical practice may help to identify high-risk aGCT patients.

Purpose: There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Recently, patient-derived organoid (PDO) cultures of patients with OC have been established that faithfully represent the histopathological features and genomic landscape of the patient tumor. In this study, we evaluate the capacity of OC PDOs to predict clinical drug response and functional consequences of tumor heterogeneity. Experimental design: 36 genomically characterized PDOs from 23 patients with known clinical histories were exposed to chemotherapeutics and targeted drugs. Results: OC PDOs maintained genomic features of the original tumor lesion and recapitulated patient response to neoadjuvant carboplatin and paclitaxel combination treatment, according to distinct clinical outcomes (histopathological, biochemical and radiological). PDOs displayed inter-as well as intrapatient drug response heterogeneity, which could in part be explained by genetic aberrations. All PDOs were resistant to PARP-inhibitors, in accordance with homologous recombination pathway fidelity and genome-wide mutation context. KRAS, BRAF and NRAS mutation status predicted response to BRAF-inhibitor vemurafenib and pan-HER-inhibitor afatinib, and explained differential response among four PDOs derived from distinct tumor locations of an individual patient. Importantly, PDO drug screening identified sensitivity to at least one drug for the majority of patients (88%). Conclusions: OC PDOs are a valuable preclinical model system that can provide insights in drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge on genetic and drug response heterogeneity.