Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer

Toffoli, Giuseppe; Russo, Antonio; Gallo, Angelo; Cernigoi, C.; Miotti, Silvia; Sorio, Roberto; Boiocchi, Mauro

doi:10.1002/(sici)1097-0215(19980417)79:2<121::aid-ijc4>3.0.co;2-v

Cited by 147 publications

(124 citation statements)

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“…Such an observation is in line with our previous findings in primary colorectal cancers, as well as that observed in ovarian, breast and endometrial carcinoma. [9][10][11] In all of these tumor types including both primary and metastatic colorectal cancer, overexpression of FRa detected by immunohistochemistry had either a strong trend towards, or significantly correlated with a worse survival. Interestingly, however, a study that evaluated 119 non-small cell lung cancers found high FRa expression to be correlated with a better survival.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7][8] Its expression in certain epithelial tumors such as ovarian, breast, endometrial and non-small cell lung carcinoma has been associated with tumor behavior. [9][10][11][12] Importantly, FRa expression is tumor specific, as it is significantly higher in tumor cells than in normal cells. 13 FRa also has a high affinity for folic acid; and the high affinity is maintained when folic acid is conjugated with other molecules.…”

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confidence: 99%

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

et al. 2011

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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

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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…In the most widely investigated and FRa-positive tumor, nonmucinous epithelial ovarian carcinoma, protein expression is associated with tumor progression, 6 and also with ovarian cancers of high grade, platinum-therapy resistance, and poor prognosis, 7 suggesting that metabolic defects related to its upregulation occur early in carcinogenesis. Toffoli et al 7 investigated whether FRa in epithelial ovarian cancer specimens is a predictor of response to chemotherapy and survival. Among 58 patients with residual epithelial ovarian cancer after primary surgery, failure to respond to chemotherapy (complete or partial remission) was about 15-fold higher (95% confidence interval, 2.96-77.43) when tumors had elevated (>median) FRa levels following multivariable adjustment, although this estimate was based on 8 cases.…”

Section: Fra and Prognosismentioning

confidence: 99%

“…5 In the most widely studied tumor epithelial ovarian cancer expression increases in concentration with tumor progression and grade, 6 and is associated with decreased survival. 7 The reasons for its expression and function in tumor relative to normal tissue are unknown. Possibly, FRa might confer a growth advantage to the tumor by modulating folate uptake from serum 8 or by generating regulatory signals.…”

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The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Kelemen

2006

Intl Journal of Cancer

448

340

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Folate receptor a (FRa) is a membrane-bound protein with high affinity for binding and transporting physiologic levels of folate into cells. Folate is a basic component of cell metabolism and DNA synthesis and repair, and rapidly dividing cancer cells have an increased requirement for folate to maintain DNA synthesis, an observation supported by the widespread use of antifolates in cancer chemotherapy. FRa levels are high in specific malignant tumors of epithelial origin compared to normal cells, and are positively associated with tumor stage and grade, raising questions of its role in tumor etiology and progression. It has been suggested that FRa might confer a growth advantage to the tumor by modulating folate uptake from serum or by generating regulatory signals. Indeed, cell culture studies show that expression of the FRa gene, FOLR1, is regulated by extracellular folate depletion, increased homocysteine accumulation, steroid hormone concentrations, interaction with specific transcription factors and cytosolic proteins, and possibly genetic mutations. Whether FRa in tumors decreases in vivo among individuals who are folate sufficient, or whether the tumor's machinery sustains FRa levels to meet the increased folate demands of the tumor, has not been studied. Consequently, the significance of carrying a FRa-positive tumor in the era of folic acid fortification and widespread vitamin supplement use in countries such as Canada and the United States is unknown. Epidemiologic and clinical studies using human tumor specimens are lacking and increasingly needed to understand the role of environmental and genetic influences on FOLR1 expression in tumor etiology and progression. This review summarizes the literature on the complex nature of FOLR1 gene regulation and expression, and suggests future research directions. ' 2006 Wiley-Liss, Inc.

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“…Consistent with this observation, higher-grade and later-stage ovarian cancers have been reported to express more FR on their cell surfaces than their earlier-stage counterparts. 3 Further, cancers that are resistant to standard hormone therapy 14 or chemotherapy 15 may also express higher levels of FR than more responsive tumors of the same type. Taken together, these results suggest that cancers that may be difficult to treat by classical methods may also be especially targetable with folate-linked drugs.…”

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confidence: 99%

Folate receptor-targeted immunotherapy: Induction of humoral and cellular immunity against hapten-decorated cancer cells

Sega

Low

2005

Int. J. Cancer

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We previously exploited the frequent overexpression of folate receptors on cancer cells to decorate malignant cell surfaces selectively with folate-hapten conjugates. In antihapten-immunized hosts, this targeted localization of foreign haptens to tumor cells led to rapid accumulation of autologous antihapten IgG, which in turn yielded potent antitumor activity upon stimulation with cytokines (IL-2, IFN-a). In an effort to understand the effector mechanisms responsible for tumor regression, we have now investigated the involvement of both humoral and cellular immune components in the tumor destruction process. We report that the dependence of therapeutic efficacy on folate-hapten concentration is bimodal, suggesting that the conjugate must bridge between a cell surface FR and an antihapten IgG in order to mediate killing. Studies with cancer cells in vitro further demonstrate that folatefluorescein-marked tumor cells are killed primarily by antibodydependent cellular cytotoxicity and phagocytosis, with no contribution from complement-dependent mechanisms. Investigations of specific immune cell involvement also reveal that asialo-GM1 1 -natural killer cells, macrophages, CD41 T cells and CD8 1 T cells contribute significantly to recognition/removal of the cancer mass, and that elimination of these cell types markedly compromises the therapy. Because the initial antibody-dependent stage of tumor cell killing is shown to lead to a long-term antibody-independent cellular immunity that involves both CD4 1 and CD8 1 T cells, we propose that F c receptor-expressing immune cells not only initiate destruction of the IgG-marked tumor cells, but also participate in presentation of endogenous tumor antigens in a manner that leads to long-term cellular immunity. ' 2005 Wiley-Liss, Inc.

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Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer

Cited by 147 publications

References 28 publications

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

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

The role of folate receptor α in cancer development, progression and treatment: Cause, consequence or innocent bystander?

Folate receptor-targeted immunotherapy: Induction of humoral and cellular immunity against hapten-decorated cancer cells

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