Folate receptor alpha (FRA) expression in breast cancer: identification of a new molecular subtype and association with triple negative disease

Abstract

Given that several targeted therapies directed towards folate receptor alpha (FRA) are in late stage clinical development, the sensitive and robust detection of FRA in tissues is of paramount importance relative to patient selection, prognosis and prediction. In the present study we undertook an immunohistochemical evaluation of expression of FRA in breast cancer samples using formalin-fixed, paraffin-embedded (FFPE) tissues, primarily invasive ductal carcinomas, using a newly described monoclonal antibody, 26B3. Samples assessed included both tissue microarrays (TMA) and whole tissue sections from archival tissue blocks. Normal breast shows a highly restricted expression of FRA to luminal membrane staining of secretory ductal cells, consistent with FRA secretion into milk. In early stage (stages I-III) invasive ductal carcinomas, FRA staining was observed in approximately 30% of all samples, independent of molecular subtype (estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor type 2 (Her2)). However, FRA expression was shown to associate with ER/PR negative tumors relative to ER/PR positive tumors (p = 0.012) and perhaps more importantly, with triple negative breast cancers (TNBC; p < 0.0001). FRA immunoreactivity was also shown to be retained in stage IV metastatic breast cancer samples from diverse anatomic sites including lymph node and bone. In metastatic breast cancer, FRA was shown to be expressed in 86% of TNBC patients. Taken together, these data suggest that FRA expressing breast cancer represents a novel molecular subtype and, further, may represent a new therapeutic target for this devastating disease.

177Lu-Dendrimer Conjugated to Folate and Bombesin with Gold Nanoparticles in the Dendritic Cavity: A Potential Theranostic Radiopharmaceutical

“…The overexpression of FR protein has been confirmed in all clinical breast cancer subtypes, comprised of estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), human epidermal growth factor receptor-positive (HER2+), and triple negative (ER−, HER2−, and PR−) tumors [16][17][18]. Recent polymerase chain reaction studies confirmed that FR is highly expressed in T47D cells [19].…”

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

“…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).…”

Folate Receptor Alpha Immunohistochemistry in Cytology Specimens of Metastatic Breast Carcinoma

“…To date, various studies have shown FRA overexpression by IHC analysis, as summarized in table 3. The FRA expression by IHC ranged from 10-14% in ER/PR-positive carcinoma to 40-74% in ER/PR-negative tumors and 50-86% of TNBC cases [21,22,23,40]. Of note, all the prior studies for FRA IHC have been conducted on surgically excised tissue specimens obtained exclusively from primary breast cancers [22,23], except the work by O'Shannessy et al [21], who utilized both primary and metastatic breast cancer specimens.…”

“…Traditional cytotoxic chemotherapeutic agents are still being employed for TNBC, which remains a poor prognostic subgroup of breast cancer. Therefore, new therapeutic approaches for the TNBC subtype are urgently needed [21]. Poly ADP ribose polymerase inhibitors have recently been studied in clinical trials in the TNBC patient population, but failed to improve survival and outcome [27].…”

“…Recently, investigators have examined the prognostic significance of FRA expression in breast carcinoma and found a potential clinical usefulness of FRA overexpression as a prognostic biomarker [21,22,23]. Nonetheless, the utility of FRA as a diagnostic marker of metastatic breast carcinoma in cytology specimens has not been fully established.…”