Folate Receptor Alpha (FRα/FOLR1) Immunohistochemical Expression Across Molecularly Classified Endometrial Carcinomas

The approval of Mirvetuximab soravtansine, a folate receptor alpha (FOLR1)-targeting antibody-drug conjugate, for platinum-resistant ovarian cancer, has prompted interest in FOLR1 as a target in endometrial carcinoma (EC). Characterization of FOLR1 expression across EC histotypes, TCGA molecular subtypes, and clinically relevant biomarkers using the FDA-approved companion diagnostic assay has not been performed. FOLR1 immunohistochemistry was performed on tissue microarrays from 169 molecularly classified ECs using the VENTANA FOLR1-2.1 assay and scored by proportion score PS2 and PS1 criteria at the ovarian cancer eligibility cutoff (PS2 ≥75) as well as exploratory thresholds. Associations with histotype, molecular subtype, biomarker (ER, PR, HER2) status, survival outcomes, intratumoral heterogeneity, and matched primary-recurrence expression were assessed. Only 3% (5/169) of ECs met the PS2 ≥75 threshold; all 5 were p53-abnormal (p53abn). In all, 9% (15/169) showed PS2 ≥25, predominantly in p53abn and no specific molecular profile (NSMP) subgroups. Uterine serous carcinoma had the highest expression; FOLR1 was absent in 3/3 clear cell carcinomas. Higher FOLR1 expression was associated with inferior survival, though this largely reflected molecular subtype and grade. FOLR1 was homogeneous across cores but variable between primary and recurrent tumors. FOLR1 testing in EC may be most relevant in p53abn and NSMP tumors and may not be useful in clear cell carcinomas. FOLR1 may have prognostic value in low-grade endometrioid and ER/PR-positive EC. Retesting at tumor recurrence is recommended. Given the frequency of lower-level FOLR1 expression, trials with treatment-response data are needed to test eligibility criteria below the current ovarian cancer threshold.