Folate receptor-α expression in resectable hepatic colorectal cancer metastases: patterns and significance

Abstract

Folate receptor alpha (FRa), encoded by folate receptor 1 (adult) gene, has emerged as a cancer biomarker and potential therapeutic target. In addition, its expression in tumors may offer prognostic information. The aim of this study was to assess the prognostic value of FRa expression and other common molecular markers in resected liver metastases from colorectal cancer. To maximize potential biological differences, we selected two groups of patients with markedly different outcomes as study subjects. Immunohistochemical analysis of FRa expression and other common markers (thymidylate synthase, p53, p27, BCL2, ki67, MLH1, MSH2 and MGMT) on tissue microarrays was carried out on samples from 160 patients; 56 patients survived at least 10 years following liver resection, and 104 died within 2 years of surgery. These markers were evaluated and compared with standard clinical predictors of outcome including a previously validated clinical risk score. Our results showed that in addition to known clinical risk factors, FRa positivity was significantly associated with the early death group (32% compared with 13%; P ¼ 0.03). None of the other common molecular markers were differentially expressed between the two groups. On multivariate analysis, clinical risk score, margin status and FRa expression were independently associated with outcome. Specific multivariate comparisons confirmed that FRa expression was associated with outcome independent of the clinical risk score and margin. These data demonstrate that FRa expression is present in a subset of resected hepatic colorectal cancer metastases, and this marker is independently associated with survival after hepatic resection. The prognostic value of FRa expression and the utility of FRa-targeted therapies in stage-IV colorectal cancer patients deserve further exploration. Modern Pathology (2011) 24, 1221-1228; doi:10.1038/modpathol.2011.82; published online 13 May 2011Keywords: folate receptor 1 (adult); folate-targeted therapy; liver metastasisThe liver is the most common site of metastasis from colorectal carcinoma. Although 20 to 25% of colorectal carcinoma patients present with synchronous liver metastases, another 60% develop such metastases after the diagnosis of the primary tumor. 1,2 Surgical resection is potentially curative for colorectal cancer metastases confined to the liver, with a 5-year survival rate between 30 and 50%. 3 Some patients, however, recur early after resection and have a poor outcome. A clinical risk score developed by Fong et al 1 incorporates five preoperative criteria including nodal status of the primary lesion, disease-free interval, number of hepatic metastases, size of the largest metastasis and preoperative carcinoembryonic antigen (CEA) level. This

Rational Combination Therapy of Vintafolide (EC145) with Commonly Used Chemotherapeutic Drugs

“…Because at any given time a relatively small proportion of proliferating tumor cells are in mitosis, transient exposure to a bolus-administered, nontargeted vinca alkaloid (i.e., DAVLBH or vindesine) would not likely be able to harm every cancer cell within a solid tumor. But with an FRtargeted drug like vintafolide, specific high-affinity binding to the FR allows it to dock to the cancer cell surface for prolonged retention within the tumor tissue 2 . When combined with its moderately slow FR-recycling rate 3 , it is likely that vintafolide remains associated with the tumor cells for multiple M phases of the tumor cell cycle.…”

“…The FR is functionally expressed in high quantities by many primary and metastatic cancers (2)(3)(4)(5)(6)(7)(8). As a result, "folate targeting" has been successfully applied toward the delivery of a wide variety of therapeutic-and imaging-based agents to tumors that express the FR protein (9)(10)(11)(12).…”

Polymersome-based drug-delivery strategies for cancer therapeutics

“…For example, folate (Vitamin B 6 ) is a small, organic molecule that has been widely used for targeted delivery systems because of the folate receptor’s overexpression on the cells’ surface with cancers of the ovary [46,47], urinary bladder [48], lung [49], breast [50] and colon [51]. …”

Metastatic Liver Disease: Colorectal Carcinomas

“…Certain molecules expressed in CRC metastases affect outcome. For example, expression of folate receptor-alpha is present in a subset of resected hepatic CRC metastases, and this marker was independently associated with survival after resection (D'Angelica et al 2011). Expression of the E-cadherin-catenin complex was also associated with tumor progression (Nanashima et al 1999;Ikeguchi et al 2001).…”