The Prognostic Value of FOXL2 Mutant Circulating Tumor DNA in Adult Granulosa Cell Tumor Patients

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.