FOLR1 as a therapeutic target in platinum-resistant ovarian carcinoma: unique expression patterns across ovarian carcinoma histotypes and molecular subtypes of low-grade serous carcinomaLeung, Llaurado-Fernandez, Cameron
et alJ Gynecol Oncol (2025)
Abstract: With the development of novel antibody-drug conjugates (ADCs), folate receptor alpha (FOLR1) is a promising therapeutic target for the treatment of platinum-resistant tubo-ovarian carcinomas. The main aims of this study were to assess FOLR1 protein expression in a large cohort of ovarian carcinoma histotypes. To inform future clinical trial design we identified molecular correlates of FOLR1 expression in low-grade serous carcinoma (LGSC).One thousand five hundred forty-seven ovarian carcinoma samples from 5 different Canadian cohorts were successfully evaluated by immunohistochemistry for FOLR1 expression using the PS2+ system. Statistical analyses with clinicopathological parameters, LGSC molecular subtypes, and overall survival (OS) were performed.High FOLR1 expression was detected in 44% of high-grade serous carcinomas, and in 30% LGSC, 8% clear cell, 6% endometrioid, and 0% mucinous and/or mesonephric-type adenocarcinomas. In 160 LGSC cases, FOLR1 expression was more frequent in cases with normal MAPK pathway status (37% MAPK wild type vs. 14% canonical MAPK pathway mutations; p=0.002), low progesterone receptor (PR) expression (41%) vs. 23% (Allred score >2; p=0.02), and p16 loss (48% p16 absent vs. 26% normal; p=0.03). Canonical MAPK mutation status and PR expression remained significant on multivariable analysis. No significant associations between OS and FOLR1 expression were observed.A significant proportion of LGSC express high FOLR1 levels supporting the development of clinical trials to investigate ADCs targeting FOLR1 as novel agents for treating this disease. In LGSC, high FOLR1 expression was associated with fewer MAPK pathway alterations, low PR expression, and p16 loss.© 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.
Patient outcomes in advanced ovarian cancer treated with an anti-FOLR1 antibody-drug conjugateJohannet, Flint, Chui
et alGynecol Oncol (2025) 195, 173-179
Abstract: Mirvetuximab soravtansine-gynx (MIRV) is a FOLR1-binding antibody-drug conjugate (ADC) with a microtubule inhibitor payload. We investigated MIRV's efficacy, toxicity profile, and determinants of resistance in a cohort of patients with recurrent/persistent high FOLR1-expressing high-grade serous ovarian cancer (HGSOC).This retrospective study included 170 patients with recurrent/persistent FOLR1-high (≥75 % of tumor cells with ≥2+ membranous staining intensity) HGSOC who received standard-of-care MIRV monotherapy. We evaluated progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method and multivariable Cox proportional hazards models. We classified adverse events using CTCAE v5.0.Overall, median PFS was 3.5 months (95 % CI, 3.0-4.1). However, 22.4 % had PFS ≥6 months and were less likely to have progressed on or within one month of prior taxane-based therapy (P = 0.008). Patients with previous progression on a taxane had worse PFS (HR, 1.69; 95 % CI, 1.19-2.40; P = 0.003) and OS (HR, 2.34; 95 % CI, 1.45-3.77; adjusted P = 0.0005). FOLR1 expression was lower in post-MIRV samples (n = 12; P = 0.005). New or worsening neuropathy was observed in 37.6 % of patients. Among the 34.1 % who experienced ocular toxicity, median onset was 42.5 days. Treatment was discontinued in 5.3 % of patients due to toxicity.MIRV confers meaningful PFS benefit for a subset of individuals with HGSOC. Resistance may be associated with decreased FOLR1 target expression or payload resistance. FOLR1-targeted ADCs with a different payload should be evaluated for patients who progress on MIRV but retain high tumor FOLR1 expression.Copyright © 2025. Published by Elsevier Inc.
Evaluation of Laboratory-Derived Immunohistochemical Assays for Folate Receptor α Expression in Epithelial Ovarian Cancer and Comparison With a Companion DiagnosticDeutschman, Fulton, Sloss
Arch Pathol Lab Med (2025)
Abstract: The VENTANA FOLR1 (FOLR1-2.1) RxDx (FOLR1 CDx) assay, developed by Roche Tissue Diagnostics, is a Food and Drug Administration-approved immunohistochemical assay intended for use in the assessment of folate receptor α (FRα) expression in formalin-fixed, paraffin-embedded epithelial ovarian, fallopian tube, and primary peritoneal tumor specimens. No published reports have compared the performance of other available FRα antibodies with the approved FOLR1 CDx.To assess the performance of research FRα laboratory-developed tests compared with the FOLR1 CDx.The performance of 6 FRα-targeting antibodies was compared with the approved FOLR1 CDx in normal fallopian tube specimens. Two antibodies were selected for further assessment and compared with the FOLR1 CDx in ovarian tumor specimens.Of the 6 antibodies tested, 4 displayed a lack of specific membrane staining and/or high background, whereas 2 antibodies, produced by Leica Biosystems and Biocare Medical, respectively, exhibited specific and sensitive FRα staining. When assessed for their ability to correctly identify FRα-positive samples (per the FOLR1 CDx label, ≥75% of viable tumor cells with moderate and/or strong membranous staining intensity), both assays overpredicted FRα positivity compared with the FOLR1 CDx in archival ovarian tumor samples.These data highlight the need for caution in antibody selection when developing immunohistochemistry-based assays, as some antibodies failed to cleanly and specifically identify FRα expression. We identified 2 antibodies appropriate for further investigation; however, as developed, these antibodies may overselect patients for treatment with FRα-targeted therapies.© 2025 College of American Pathologists.