Folate Receptor Alpha Expression in Lung Cancer: Diagnostic and Prognostic Significance

Abstract

ABSTRACT:With the advent of targeted therapies directed towards folate receptor alpha, with several such agents in late stage clinical development, the sensitive and robust detection of folate receptor alpha in tissues is of importance relative to patient selection and perhaps prognosis and prediction of response. The goal of the present study was to evaluate the expression of folate receptor alpha in non-small cell lung cancer specimens to determine its frequency of expression and its potential for prognosis. The distribution of folate receptor alpha expression in normal tissues as well as its expression and relationship to non-small cell lung cancer subtypes was assessed by immunohistochemistry using tissue microarrays and fine needle aspirates and an optimized manual staining method using the recently developed monoclonal antibody 26B3. The association between folate receptor alpha expression and clinical outcome was also evaluated on a tissue microarray created from formalin fixed paraffin embedded specimens from patients with surgically resected lung adenocarcinoma. Folate receptor alpha expression was shown to have a high discriminatory capacity for lung adenocarcinomas versus squamous cell carcinomas. While 74% of adenocarcinomas were positive for folate receptor alpha expression, our results found that only 13% of squamous cell carcinomas were FRA positive (p<0.0001). In patients with adenocarcinoma that underwent surgical resection, increased folate receptor alpha expression was associated with improved overall survival (Hazard Ratio 0.39, 95% CI 0.18-0.85). These data demonstrate the diagnostic relevance of folate receptor alpha expression in non-small cell lung cancer as determined by immunohistochemistry and suggest that determination of folate receptor alpha expression provides prognostic information in patients with lung adenocarcinoma.

IMGN853, a Folate Receptor-α (FRα)–Targeting Antibody–Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors

“…Analysis of ovarian and non-small cell lung tumor samples with this new assay revealed a wide variation in expression levels and incidence of FRa-positivity. Serous and endometrioid ovarian carcinomas and adenocarcinoma of the lung had the highest percentage of FRa positive tumors, consistent with previously reported data (6,8). Most tumors of these subtypes were strongly positive, with 71%, 51%, and 59% having a score of !2 heterogeneous and homogeneous, respectively (Supplementary Table S6).…”

“…Thus, there is an unmet medical need for these patients, and the effort is ongoing to develop novel therapeutic strategies, including the development of ADCs. FRa is an attractive therapeutic target for an ADC treatment for these cancers because, as the previous reports (3,4,6,8) and this study show, it is highly and widely expressed on many types of ovarian and non-small cell lung cancer, while being absent or expressed only at low levels on most normal tissues.…”

“…Most normal tissues do not express FRa, and transport of physiologic folates into most cells is thought to be mediated by several other proteins, most notably, reduced folate carrier (2). High levels of FRa have been found in serous and endometrioid epithelial ovarian cancer, endometrial adenocarcinoma, and non-small cell lung cancer of the adenocarcinoma subtype (3)(4)(5)(6)(7)(8). Importantly, FRa expression is maintained in metastatic foci and recurrent carcinomas in ovarian cancer patients (9), and after chemotherapy in epithelial ovarian and endometrial cancers (10).…”

The antitumor activity of the human FOLR1-specific monoclonal antibody, farletuzumab, in an ovarian cancer mouse model is mediated by antibody-dependent cellular cytotoxicity

“…[1][2][3][4] FOLR1 is also frequently expressed in other gynecologic malignancies 5 as well as lung adenocarcinoma. 6 It is hypothesized that the presence of elevated levels of FOLR1 can be correlated with the transformed phenotype in ovarian cancer, cisplatin sensitivity, and growth in depleted folate conditions. 2,[7][8][9][10][11] The highly restricted distribution of FOLR1 in normal tissues and its expression in tumors suggest that this antigen might have potential as a diagnostic marker 6 as well as a target for passive immunotherapy.…”

“…6 It is hypothesized that the presence of elevated levels of FOLR1 can be correlated with the transformed phenotype in ovarian cancer, cisplatin sensitivity, and growth in depleted folate conditions. 2,[7][8][9][10][11] The highly restricted distribution of FOLR1 in normal tissues and its expression in tumors suggest that this antigen might have potential as a diagnostic marker 6 as well as a target for passive immunotherapy. In a previous report, 7 we described the in vitro and in vivo activity exerted by the anti-FOLR1 monoclonal antibody MORAb-003, which recently acquired the generic name of farletuzumab.…”