Serum folate receptor alpha, mesothelin and megakaryocyte potentiating factor in ovarian cancer: association to disease stage and grade and comparison to CA125 and HE4

Daniel J O’Shannessy,Pankaj Oberoi,Ryan Heath,Elizabeth B Somers,Robert P Thiel,Lisa Marcucci,Leslie M Palmer

doi:10.1186/1757-2215-6-29

Abstract

BackgroundEvaluate and compare the utility of serum folate receptor alpha (FRA) and megakaryocyte potentiating factor (MPF) determinations relative to serum CA125, mesothelin (MSLN) and HE4 for the diagnosis of epithelial ovarian cancer (EOC).MethodsElectrochemiluminescent assays were developed for FRA, MSLN and MPF and used to assess the levels of these biomarkers in 258 serum samples from ovarian cancer patients. Commercial assays for CA125 and HE4 were run on a subset of 176 of these samples representing the serous histology. Data was analyzed by histotype, stage and grade of disease. A comparison of the levels of the FRA, MSLN and MPF biomarkers in serum, plasma and urine was also performed in a subset of 57 patients.ResultsSerum and plasma levels of FRA, MSLN and MPF were shown to be highly correlated between the two matrices. Correlations between all pairs of markers in 318 serum samples were calculated and demonstrated the highest correlation between HE4 and MPF, and the lowest between FRA and MPF. Serum levels of all markers showed a dependence on both stage and grade of disease. A multi-marker logistic regression model was developed resulting in an AUC=0.91 for diagnosis of serous ovarian cancer, a significant improvement over the AUC for any of the individual markers, including CA125 (AUC=0.84).ConclusionsFRA has significant potential as a biomarker for ovarian cancer, both as a stand-alone marker and in combination with other known markers for EOC. The lack of correlation between the various markers analyzed in the present study suggests that a panel of markers can aid in the detection and/or monitoring of this disease.

Highlights

Evaluate and compare the utility of serum folate receptor alpha (FRA) and megakaryocyte potentiating factor (MPF) determinations relative to serum CA125, mesothelin (MSLN) and human epididymis protein 4 (HE4) for the diagnosis of epithelial ovarian cancer (EOC)
ECL assay reproducibility, sensitivity and reliability The intraday reproducibility and sensitivity of the ECL assays for FRA, MSLN and MPF were assessed at levels between 0.01 and 5000 pg/mL (Figure 1)
Comparison of matrices: serum, plasma and urine To assess the most appropriate matrix for determination of the various biomarker levels, matched serum/plasma pairs from 20 normal women and 37 women with ovarian cancer were measured for FRA, MSLN and MPF using the described ECL assays

Summary

Introduction

Evaluate and compare the utility of serum folate receptor alpha (FRA) and megakaryocyte potentiating factor (MPF) determinations relative to serum CA125, mesothelin (MSLN) and HE4 for the diagnosis of epithelial ovarian cancer (EOC). Ovarian cancer is considered a “silent killer” because of the absence of specific symptoms until late in the disease when 75% of the cases are diagnosed, five year survival rates are less than 30%, and CA125, a membrane-associated mucin found on the apical membrane of epithelial cells of the ocular surface, respiratory tract and female reproductive tract, is elevated in approximately 80% of women with late-stage ovarian cancer. It is the gold standard diagnostic marker to detect recurrent ovarian cancer and monitor response to treatment. CA125, HE4 and MSLN have been approved by the United States Food and Drug Administration (FDA) as biomarkers for recurrent ovarian cancer (CA125 and HE4) and diagnosis of mesothelioma (MSLN)

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