Development and Preliminary Evaluation of a Multivariate Index Assay for Ovarian Cancer

Abstract

BackgroundMost women with a clinical presentation consistent with ovarian cancer have benign conditions. Therefore methods to distinguish women with ovarian cancer from those with benign conditions would be beneficial. We describe the development and preliminary evaluation of a serum-based multivariate assay for ovarian cancer. This hypothesis-driven study examined whether an informative pattern could be detected in stage I disease that persists through later stages.Methodology/Principal FindingsSera, collected under uniform protocols from multiple institutions, representing 176 cases and 187 controls from women presenting for surgery were examined using high-throughput, multiplexed immunoassays. All stages and common subtypes of epithelial ovarian cancer, and the most common benign ovarian conditions were represented. A panel of 104 antigens, 44 autoimmune and 56 infectious disease markers were assayed and informative combinations identified. Using a training set of 91 stage I data sets, representing 61 individual samples, and an equivalent number of controls, an 11-analyte profile, composed of CA-125, CA 19-9, EGF-R, C-reactive protein, myoglobin, apolipoprotein A1, apolipoprotein CIII, MIP-1α, IL-6, IL-18 and tenascin C was identified and appears informative for all stages and common subtypes of ovarian cancer. Using a testing set of 245 samples, approximately twice the size of the model building set, the classifier had 91.3% sensitivity and 88.5% specificity. While these preliminary results are promising, further refinement and extensive validation of the classifier in a clinical trial is necessary to determine if the test has clinical value.Conclusions/SignificanceWe describe a blood-based assay using 11 analytes that can distinguish women with ovarian cancer from those with benign conditions. Preliminary evaluation of the classifier suggests it has the potential to offer approximately 90% sensitivity and 90% specificity. While promising, the performance needs to be assessed in a blinded clinical validation study.

A Comparison of Optimal Biomarker Combinations for BenignCancer and Normal-Cancer Distinguishment in Ovarian Cancer Screening

“…These bootstrap estimates allowed us to assess the potential value of many models using only the training data. In this way we were able to maintain the independence of the hold-out testing set of samples [10]. Figure 2 shows the modeling process to find the optimum biomarkers and classify.…”

“…Therefore methods to distinguish women with ovarian cancer from those with benign conditions would be beneficial [10].…”

Screening for Ovarian Cancer in Women

“…CA125 is only promising tumor marker currently, but it is low specificity. In combination with CA125, other serum tumor markers have been evaluated to improve the accuracy with some limitations (Visintin, Feng et al 2008;Amonkar, Bertenshaw et al 2009;Nosov, Su et al 2009). The study in 2008 evaluated various combinations of 9 markers including CA125, HE4, SMRP, CA72-4, Osteopontin, ERBB2, Inhibin, Activin, and EGFR.…”

Comparison of the Diagnostic Performances of CA125 and Multiple Marker Combinations for Early Diagnosis of Ovarian Cancer

“…Thus, CA125 has low sensitivity in early-stage disease and additional ultrasonography or combinations of other markers are required [9][10][11]. In recent years, a number of studies have confirmed that combinations of CA125 and other biomarkers provided improved diagnostic performance for early-stage ovarian cancer [5][6][7][9][10][11].…”

“…Most of the women with clinical features that correspond to ovarian cancer have benign conditions, and thus it is important to detect early ovarian cancer in women with benign conditions [11].…”