Folate receptor alpha as a tumor target in epithelial ovarian cancer

doi:10.1016/j.ygyno.2007.11.020

Gynecologic Oncology

Volume 108, Issue 3, March 2008, Pages 619-626

https://doi.org/10.1016/j.ygyno.2007.11.020 Get rights and content

Abstract

Objectives.

Folate receptor α (FRα) is a folate-binding protein overexpressed on ovarian and several other epithelial malignancies that can be used as a target for imaging and therapeutic strategies. The goal of this study is to improve historical data that lack specific information about FRα expression in rare histological subtypes, primary disease versus metastatic foci, and recurrent disease.

Methods.

FRα expression was analyzed by immunohistochemistry on 186 primary and 27 recurrent ovarian tumors, including 24 pairs of samples obtained from the same individuals at diagnosis and at secondary debulking surgery. For 20 of the 186 primaries, simultaneous metastatic foci were also analyzed. FRα staining was analyzed in light of disease morphology, stage, grade, debulking status, and time from diagnosis to recurrence and death.

Results.

FRα expression was apparent in 134 of 186 (72%) primary and 22 of 27 (81.5%) recurrent ovarian tumors. In 21 of 24 (87.5%) matched specimens, recurrent tumors reflected the FRα status detected at diagnosis. Metastatic foci were similar to primary tumors in FRα staining. FRα status was not associated with time to recurrence or overall survival in either univariate or multivariable analyses.

Conclusion.

FRα expression occurs frequently, especially in the common high-grade, high-stage serous tumors that are most likely to recur. New findings from this study show that FRα expression is maintained on metastatic foci and recurrent tumors, suggesting that novel folate-targeted therapies may hold promise for the majority of women with either newly diagnosed or recurrent ovarian cancer.

Introduction

The folate receptor alpha (FRα) is a glycosylphosphatidyl-inositol-linked protein that is overexpressed in several epithelial malignancies, including ovarian, renal, lung, and breast cancers [1]. While the function of FRα in tumors is unclear, in the kidney it serves as a high-affinity salvage receptor that retrieves folate from the filtrate and returns it via transcytosis to the blood [2]; in the brain, it likely concentrates folate in cerebrospinal fluid [3]. Expression of FRα in normal tissues is restricted to the apical surfaces of polarized epithelial cells [4], where it is not exposed to the blood stream. Unlike the more ubiquitously expressed reduced folate carrier and proton-coupled folate transporter that regulate folate homeostasis, FRα allows internalization of folic acid that has been conjugated to low molecular weight compounds, proteins, or nanoparticles [5]. This property has implications for targeting of chemotherapeutic drugs, cytotoxic viruses, or imaging agents to FRα-expressing cells.

FRα is an attractive candidate for targeted biologic therapy of ovarian cancer [6], [7]. It is reported to be expressed in the majority of non-mucinous epithelial ovarian tumors at levels 10- to 100-fold higher than its normal expression in the kidney and on lung and breast epithelial cells [8]. In addition, FRα is a tumor antigen, with 70% of women with ovarian or breast cancer showing measurable immune responses against this protein [9]. The tumor specificity and high levels of FRα expression and the potential to boost immunity to tumors with FRα-specific approaches have generated significant enthusiasm for testing strategies targeting FRα in ovarian cancer patients. For example, MORAb-003, a humanized, high-affinity monoclonal antibody against FRα based on the murine LK26 clone, is currently undergoing phase II testing in ovarian cancer patients after showing cell-mediated cytotoxicity, complement-dependent killing, and non-immune mediated, FRα-dependent inhibition of growth under folate-limiting conditions [10]. What is unknown in attempting to apply novel FRα-based therapeutics is the FRα-expression status of tumors with more rare histologies, the stability of expression of FRα across the multiple sites of disease typically present at diagnosis in ovarian cancer and whether FRα expression is lost or maintained with disease recurrence. In addition, although one investigative team has stated that FRα overexpression is an indicator of platinum resistance in ovarian cancer, the study was small and performed in the pre-taxane era [11].

We performed this study to define the extent of FRα expression in ovarian cancers of different histologies, grades, and stages and to determine whether FRα status was associated with time to recurrence and overall survival. In addition, we examined multiple metastatic sites from a subset of patients with advanced disease at diagnosis as well as matched samples from patients at diagnosis and subsequent recurrence.

Section snippets

Tissues studied

Ovarian cancer specimens from women who had surgery at Mayo Clinic Rochester between June 15, 1991 and June 15, 2005 were eligible for inclusion in the study. Invasive tumors encompassing serous, endometrioid, clear cell, mucinous, or mixed morphologies were selected prior to retrieval of any clinical information. Borderline tumors and non-epithelial malignancies were excluded. The specimens chosen for the study were similar to all available patients in this time period in terms of patient age,

Patient and tumor characteristics

The median time from diagnosis to date of last contact or death for the 186 patients with newly diagnosed disease was 43.7 months (range of 0.2 to 178 months), with 122 women in the study being deceased and 64 alive at last follow-up. 159 patients (85.5%) had optimal debulking surgery; 26 patients (14%) had unresected tumor larger than 1 cm and 1 patient's debulking status could not be determined. Chemotherapy was given to 159 patients (85.5%); 18 patients (14 with stage I disease) received no

Discussion

We analyzed FRα expression in a cohort of women with ovarian cancer who were treated at our institution with rigorous surgical debulking followed by chemotherapy when indicated by their disease stage and debulking status. We examined the extent of FRα expression in 186 primary and 27 recurrent ovarian cancers, including matched samples from 24 patients who had primary and secondary debulking surgeries at our institution. In addition, we examined primary disease and concomitant metastatic

Acknowledgments

We gratefully acknowledge Dr. Wilbur L. Franklin for the gift of the FBP343 monoclonal antibody, Linda Murphy for expert technical assistance with immunohistochemistry, Darren Riehle for tissue imaging, Karin Goodman for clinical follow-up, Dr. William Cliby for helpful discussions, and Vicki Shea for assistance with the manuscript. This work was supported by the Minnesota Ovarian Cancer Alliance, the CanCurables Foundation, the Paul Calabresi Program in Clinical–Translational Research at Mayo

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