FOLR1

Folate receptor alpha (FOLR1) is a folate-binding protein and a member of the folate receptor family. It is encoded by the FOLR1 gene on chromosome 11q. The primary role of folate receptor alpha is to transport folate (vitamin B9) into cells through receptor-mediated endocytosis. In immunohistochemistry, the staining reaction pattern is membranous. In normal adult tissues, expression is typically restricted and low, localized to the apical or luminal surface of polarized epithelia such as kidney proximal tubules, choroid plexus, lung and fallopian tube. This apical localization often makes the receptor inaccessible to circulating therapeutic agents in non-neoplastic tissues.

In tumors, folate receptor alpha is frequently overexpressed on the neoplastic cell membrane and, unlike in most normal epithelia, is accessible from the circulation. Overexpression is particularly characteristic of high-grade serous carcinomas of Müllerian origin.

The principal clinical application of folate receptor alpha immunohistochemistry is predictive. Folate receptor alpha expression is used to identify patients who are candidates for FOLR1-targeted antibody–drug conjugates, such as mirvetuximab soravtansine, in ovarian, fallopian tube and primary peritoneal high-grade serous carcinoma. Higher FOLR1 expression correlates with a greater likelihood of clinical benefit as demonstrated in clinical trial populations. The Ventana FOLR1 (FOLR1-2.1) RxDx assay is the clinically validated assay used in clinical trials of mirvetuximab soravtansine. Results are reported as positive when at least 75% of viable tumor cells show 2+ or 3+ (moderate to strong) membranous staining (apical, circumferential, or dot-like patterns). Cases below this threshold are reported as negative.

Normal fallopian tube serves both as positive and negative on slide tissue control. Normal epithelium exhibits moderate to high expression levels of the folate receptor alpha protein, characterized by predominantly moderate circumferential membranous staining reaction and strong apical membranous staining reaction. Normal fallopian tube stroma should not show any staining reaction.