Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis, prognosis and predicting its local tumor expression

Abstract

Folate receptor alpha (FRA) is a GPI-anchored glycoprotein and encoded by the FOLR1 gene. High expression of FRA is observed in specific malignant tumors of epithelial origin, including ovarian cancer, but exhibits very limited normal tissue expression, making it as an attractive target for the ovarian cancer therapy. FRA is known to shed from the cell surface into the circulation which allows for its measurement in the serum of patients. Recently, methods to detect the soluble form of FRA have been developed and serum FRA (sFRA) is considered a highly promising biomarker for ovarian cancer. We prospectively investigated the levels of sFRA in patients clinically suspected of having malignant ovarian tumors. A total of 231 patients were enrolled in this study and analyzed for sFRA as well as tumor expression of FRA by immunohistochemistry. High sFRA was predominantly observed in epithelial ovarian cancer patients, but not in patients with benign or borderline gynecological disease or metastatic ovarian tumors from advanced colorectal cancers. Levels of sFRA were highly correlated to clinical stage, tumor grade and histological type and demonstrated superior accuracy for the detection of ovarian cancer than did serum CA125. High sFRA was significantly associated with shorter progression-free survival in both early and advanced ovarian cancer patients. Finally, tumor FRA expression status was strongly correlated with sFRA levels. Taken together, these data suggest that sFRA might be a useful noninvasive serum biomarkers for future clinical trials assessing FRA-targeted therapy.Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Because of difficulties in detection, diagnosis and treatment, the overall survival (OS) rate of ovarian cancer patients is still poor. It is therefore necessary to overcome these difficulties. A majority of cases (61%) of EOC are diagnosed at an advanced stage, with a corresponding 5-year survival rate of only 27%. 1 The fact that survival of patients with stages I-II disease ranges from 60 to 90%, depending on tumor grade, suggests the potential for a high cure rate with earlier disease detection. 2,3 As physical symptoms are absent in early stages of ovarian cancer, efforts are being made to develop assays for blood or tissue biomarkers. Although the serum CA125, an ovarian cell surface glycoprotein of unknown biological significance, is elevated in 80% of patients with advanced EOC, this marker has a positive predictive value (PPV) of only 10% in early-stage disease. 3 One of the limitations for CA125 is its relatively low specificity. Elevated CA125 is often associated with various nonmalignant conditions, such as pregnancy, endometriosis, adenomyosis, uterine fibroids, pelvic inflammatory disease, menstruation and benign ovarian cysts. Abnormal CA125 is also associated with other malignant conditions such as pancreatic, breast, lung, gastric and colorectal cancers especially when they are associated with peritoneal spreading. [4][5][6][7][8] Although CA125 is hel...

Validation of a Novel Biomarker Panel for the Detection of Ovarian Cancer

“…Logistic regression modeling also demonstrated some complementarity between FOLR1 and CA125, in which a model combining the two markers with mesothelin and megakaryocyte potentiating factor displayed an AUC of 0.91 [24]. In a similar study by Kurosaki et al, not only did serum FOLR1 demonstrate comparable diagnostic ability to CA125, but as well, serum FOLR1 consistently demonstrated higher specificity than the FDA-approved marker without significant compromise to sensitivity [25]. These findings are relatively consistent with our observations of FOLR1 in this study.…”

Candidate genes and pathways downstream of PAX8 involved in ovarian high-grade serous carcinoma

“…Among the 38 genes exclusively expressed in SKOV-3 cells (Supplementary Table S2), ALDH1A1 [26], GABRA3 [27], FOLR1 [28], DPYSL5 [29], CGB8 [30], C8orf4 [31] and MAGEB2 [32] could be intriguing for the development and maintenance of the neoplastic phenotype. Similarly, among the 82 genes expressed only in FT194 cells (Supplementary Table S2) CDKN2A [33], MT1G [34], GPX7 [35], HCK [36], ZBTB16 [37] could be looked at as interesting genes being tumor suppressor epigenetically silenced in cancer cells.…”

“…A recent study identified a 5-marker panel for early detection of ovarian cancer that includes five serum biomarkers, namely macrophage-stimulating protein alpha, tissue inhibitor of metalloproteinases-4, platelet-derived growth factor receptor alpha (PDGF-R alpha), osteoprotegerin, and CA-125 [77]. Preliminary insights that we obtained using ProteINSIDE, a novel web service [78], suggest that among the genes highly expressed in SKOV-3 cells there are some that encode for secreted proteins like CGB5 [79], CGB8 [79], FOLR1 [28], SPP1 [80], IGFBP3 [81], NFASC [82] emphasizing that our study may indeed provide a solid basis for the identification of new biomarkers. Of interest, among the top genes highly expressed in SKOV-3 cells there is PRAME that in a wide variety of human malignancies correlates with poor clinical outcome [83].…”

Biological markers of prognosis, response to therapy and outcome in ovarian carcinoma

“…It is a GPI-anchored glycoprotein encoded by the FOLR1 gene, which can be shed from the cell surface into the circulation [36]. Kurosaki et al investigated serum levels of sFRA in 231 patients and found high sFRA in sera of EOC patients, but not in patients with benign or borderline gynecological disease or with OvCa metastasizing from colorectal cancers.…”

“…Serum levels of sFRA were highly correlated to the clinical stage, tumor grade and histological tumor type and demonstrated greater accuracy for the detection of OvCa than did serum CA125 (Table 2). In both early and advanced stage patients, high sFRA levels were significantly associated with shorter PFS [36]. …”