FOLR1 as a therapeutic target in platinum-resistant ovarian carcinoma: unique expression patterns across ovarian carcinoma histotypes and molecular subtypes of low-grade serous carcinoma

Abstract

Objective: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: FRa; Folate Receptor Alpha; Low-Grade Serous Carcinoma; Mirvetuximab Soravtansine; Molecular Subtypes; Ovarian Cancer.

Fig. 1. FOLR1 protein expression levels across ovarian carcinoma histotypes. (A) Continuous data by H-score. (B) Categorical data by PS2+ score.

CCC, clear cell carcinoma; EC, endometrioid carcinoma; FOLR1, folate receptor alpha; HGSC, high-grade serous carcinoma; LGSC, low-grade serous carcinoma; MA, mesonephric-type adenocarcinoma; MC, mucinous carcinoma.

Fig. 2. Kaplan-Meier survival analyses for OS. (A) High-grade serous carcinoma, stage II–IV. (B) Low-grade serous carcinoma, stage II–IV. (C) Clear cell carcinoma, stage I. (D) Endometrioid carcinoma, stage I.

FOLR1, folate receptor alpha; OS, overall survival.

Fig. 3. FOLR1 immunohistochemistry in LGSC. Representative images of PS2+ categories from whole sections (back frame high power inset from whole section, note round holes from coring) and corresponding tissue microarrays cores. (A) LGSC with low FOLR1 expression showing weak intensity staining in most of the tumor cells with foci of moderate staining in less than 50% of tumor cells. (B) LGSC with moderate FOLR1 expression showing moderate to strong membranous intensity in >50% but less than 75% of tumor cells. (C) LGSC with high FOLR1 expression showing strong membranous and cytoplasmic intensity in 100% of the tumor cells.

FOLR1, folate receptor alpha; LGSC, low-grade serous carcinoma.

Fig. 4. Associations of categorical FOLR1 protein expression with key biomarker of low-grade serous carcinoma. (A) FOLR1 expression and MAPK pathway status. (B) FOLR1 expression and PR status. (C) FOLR1 expression and p16/CDKN2A status.

FOLR1, folate receptor alpha; PR, progesterone receptor.