High Expression of Folate Receptor Alpha in Lung Cancer Correlates with Adenocarcinoma Histology and Mutation

Introduction: Folate receptor alpha (FR alpha) and reduced folate carrier-1 (RFC1) regulate uptake of folate molecules inside the cell. FRa is a potential biomarker of tumors response to antifolate chemotherapy, and a target for therapies using humanized monocloncal antibody. Information on the protein expression of these receptors in non-small-cell lung carcinoma (NSCLC) is limited. Material and Methods: Expressions of FR alpha and RFC1 were examined by immunohistochemistry (IHC) in 320 surgically resected NSCLC (202 adenocarcinomas and 118 squamous cell carcinomas) tissue specimens and correlated with patients' clinico-pathologic characteristics. Folate receptor. gene (FOLR1) mRNA expression was examined using publicly available microarray datasets. FR alpha expression was correlated with thymidylate synthase and p53 expression in NSCLCs, and with epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten rat sarcoma viral (KRAS) gene mutations in adenocarcinomas. Results: NSCLC overexpressed FR alpha and RFC1. In a multivariate analysis, lung adenocarcinomas were more likely to express FR alpha in the cytoplasm (OR = 4.39; p < 0.0001) and membrane (OR = 5.34; p < 0.0001) of malignant cells than squamous cell carcinomas. Tumors from never-smokers were more likely to express cytoplasmic (OR = 3.35; p<0.03) and membrane (OR = 3.60; p=0.0005) FR alpha than those from smokers. In adenocarcinoma, EGFR mutations correlated with higher expression of membrane FR alpha and FOLR1 gene expressions. High levels of FR alpha expression was detected in 42 NSCLC advanced metastatic tumor tissues. Conclusions: FR alpha and RFC1 proteins are overexpressed in NSCLC tumor tissues. The high levels of FR alpha in lung adenocarcinomas may be associated to these tumors' better responses to antifolate chemotherapy and represents a potential novel target for this tumor type.