Comprehensive Serum Profiling for the Discovery of Epithelial Ovarian Cancer Biomarkers

Abstract

FDA-cleared ovarian cancer biomarkers are limited to CA-125 and HE4 for monitoring and recurrence and OVA1, a multivariate panel consisting of CA-125 and four additional biomarkers, for referring patients to a specialist. Due to relatively poor performance of these tests, more accurate and broadly applicable biomarkers are needed. We evaluated the dysregulation of 259 candidate cancer markers in serum samples from 499 patients. Sera were collected prospectively at 11 monitored sites under a single well-defined protocol. All stages of ovarian cancer and common benign gynecological conditions were represented. To ensure consistency and comparability of biomarker comparisons, all measurements were performed on a single platform, at a single site, using a panel of rigorously calibrated, qualified, high-throughput, multiplexed immunoassays and all analyses were conducted using the same software. Each marker was evaluated independently for its ability to differentiate ovarian cancer from benign conditions. A total of 175 markers were dysregulated in the cancer samples. HE4 (AUC = 0.933) and CA-125 (AUC = 0.907) were the most informative biomarkers, followed by IL-2 receptor α, α1-antitrypsin, C-reactive protein, YKL-40, cellular fibronectin, CA-72-4 and prostasin (AUC>0.800). To improve the discrimination between cancer and benign conditions, a simple multivariate combination of markers was explored using logistic regression. When combined into a single panel, the nine most informative individual biomarkers yielded an AUC value of 0.950, significantly higher than obtained when combining the markers in the OVA1 panel (AUC 0.912). Additionally, at a threshold sensitivity of 90%, the combination of the top 9 markers gave 88.9% specificity compared to 63.4% specificity for the OVA1 markers. Although a blinded validation study has not yet been performed, these results indicate that alternative biomarker combinations might lead to significant improvements in the detection of ovarian cancer.

Serum human epididymis protein 4 vs carbohydrate antigen 125 for ovarian cancer diagnosis: a systematic review

“…Only a few studies adopted restrictive selection criteria by excluding pregnant women,22 28 subjects with presence or previous history of cancer,19 22 28 oophorectomy26 or positive to breast cancer gene expression 32. One study included in the case group patients with low-malignant tumours potentially not detectable by biomarkers and another included in the control group only women with endometriosis 23 30.…”

“…Most studies seem to adopt decision thresholds suggested by the assay manufacturer, differentiated for menopausal status only for the Architect assay. Others derived threshold values from a parallel cohort of healthy controls or from a training group,18 27 29 32 or by maximising sensitivity and specificity 28 30…”

“…Notably, in a minority of studies an overestimation of diagnostic accuracy may be suspected because of the application of data-driven cut-off values (ie, the best threshold) 28 30…”

Breast regression protein-39 (BRP-39) promotes dendritic cell maturation in vitro and enhances Th2 inflammation in murine model of asthma

“…BRP-39 is secreted by cultured articular chondrocytes [15] , synovial cells [16] [Johansen, 1993 #1550], macrophages [17] , epithelial cells [18] , vascular smooth muscle cells [19] , and some cancer cells [20][21][22][23][24] . BRP-39 was identified and termed by Johansen et al in a search for new bone proteins in 1989 [25] .…”

Molecular Biomarkers in Ovarian Carcinoma

“…In their study, a preliminary multivariate analysis, using a logistic regression model on the nine most informative biomarkers appeared to have significantly improved performance over OVA1 biomarkers. [89] Novel Therapeutics in Ovarian Carcinoma TRAP1: TRAP1 (TNF receptor-associated protein 1) is a mitochondrial heath shock protein 75 that has antioxidant and antiapoptotic functions. [90,91] It is evident that mitochondrial defects and dysfunctions of oxidative phosphorylation and energy production inovarian cancercells are directly related to their resistanceto platinum drugs.…”