Folate receptor alpha protein expression in ovarian serous cystadenocarcinoma tumors of The Cancer Genome Atlas: exploration beyond single-agent therapy

Epithelial ovarian cancer (EOC) can be highly lethal, with limited therapeutic options for patients with non-homologous recombination deficient (HRD) disease. Folate receptor alpha (FOLR1/FR)-targeting agents have shown promise both alone and in combination with available therapies, but the relationship of FR to other treatment-driving biomarkers is unknown. The Cancer Genome Atlas (TCGA) was queried to assess protein and mRNA expression and mutational burden in patients with differential FR protein-expressing ovarian tumors, and the results referenced against the standard 324 mutations currently tested through FoundationOne Companion Diagnostics to identify targets of interest. Of 585 samples within TCGA, 121 patients with serous ovarian tumors for whom FR protein expression was quantified were identified. FR protein expression significantly correlated with FOLR1 mRNA expression (p=7.19x10- 14). Progression free survival (PFS) for the FR-high group (Q1) was 20.7 months, compared to 16.6 months for the FR-low group (Q4, Logrank, p=0.886). Overall survival (OS) was 54.1 months versus 36.3 months, respectively; however, this result was not significant (Q1 vs. Q4, Logrank, p=0.200). Mutations more commonly encountered in patients with high FR-expressing tumors included PIK3CA and FGF family proteins. Combinations of FR-targeting agents with PI3K, mTOR, FGF(R) and VEGF inhibitors warrant investigation to evaluate their therapeutic potential. Simple SummaryEpithelial ovarian cancer can be highly lethal, with limited therapeutic options for patients without BRCA mutations or non-homologous recombination deficient disease. Folate receptor alpha (FR)-targeting agents have shown promise in the setting of platinum-sensitive and platinum-resistant ovarian cancer, both alone and in combination with available therapies, but the relationship of FR to other treatment-driving biomarkers is unknown. This study identifies potential targetable mutations in FR-expressing tumors, including PIK3CA and FGF/R family proteins, and provides a basis for future investigations of novel combinations of FR-targeting agents with PIK3CA, mTOR, FGF/R, and VEGF inhibitors.