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The Prognostic Value of FOXL2 Mutant Circulating Tumor DNA in Adult Granulosa Cell Tumor Patients
by
, , , , , , , and
Geertruid J. Brink
1,*,
Nizar Hami
2,
Hans W. Nijman
3,
Jurgen M. J. Piek
4
,
Luc R. C. W. van Lonkhuijzen
5,
Eva Maria Roes
6,
Ward Hofhuis
7,
Christianne A. R. Lok
8,
Cor D. de Kroon
9,
Eelke H. Gort
10,
Petronella O. Witteveen
10,
Ronald P. Zweemer
1 and
Jolijn W. Groeneweg
1,* 1
Department of Gynecologic Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
2
Department of Molecular Cancer Research, University Medical Center Utrecht, 3584 CXUtrecht, The Netherlands
3
Department of Obstetrics and Gynecology, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
4
Department of Obstetrics and Gynecology, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
5
Center for gynecologic oncology Amsterdam, Cancer Center Amsterdam, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
6
Department of Gynecologic Oncology, Erasmus MC Cancer Institute, 3015 GD Rotterdam, The Netherlands
7
Department of Obstetrics and Gynecology, Franciscus Gasthuis en Vlietland, 3045 PM Rotterdam, The Netherlands
8
Department of Gynecological Oncology, Center Gynaecologic Oncology Amsterdam, 1066 CX Amsterdam, The Netherlands
9
Department of Gynecology, Leiden University Medical Center, 2333 ZG Leiden, The Netherland
10
Department of Medical Oncology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
*
Authors to whom correspondence should be addressed.
Cancers 2025, 17(11), 1894; https://doi.org/10.3390/cancers17111894
Submission received: 23 April 2025
/
Revised: 28 May 2025
/
Accepted: 30 May 2025
/
Published: 5 June 2025
(This article belongs to the Special Issue Rare Gynecological Cancers)
Simple Summary
Adult-type granulosa cell tumor is a rare form of ovarian cancer that can come back years after initial treatment. Current blood tests are not always reliable for detecting the disease or predicting how it will progress. In this study, we investigated whether a small fragment of tumor DNA found in the blood—called circulating tumor DNA (ctDNA)—could help identify patients at higher risk of their cancer returning or not responding well to treatment. We detected this ctDNA using a specific genetic alteration, the FOXL2 mutation, which is common in this tumor type. Our results show that patients with detectable ctDNA often have worse outcomes, even after surgery. This suggests that ctDNA analysis could help doctors predict which patients need closer monitoring or additional treatment, potentially improving long-term care for people with this rare cancer.
Abstract
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.
Keywords:
granulosa cell tumor; ovarian cancer; circulating tumor DNA; prognostic; diagnostic; FOXL2
