Proteomic biomarkers apolipoprotein A1, truncated transthyretin and connective tissue activating protein III enhance the sensitivity of CA125 for detecting early stage epithelial ovarian cancer

Abstract

Objective The low prevalence of ovarian cancer demands both high sensitivity (>75%) and specificity (99.6%) to achieve a positive predictive value of 10% for successful early detection. Utilizing a two stage strategy where serum marker(s) prompt the performance of transvaginal sonography (TVS) in a limited number (2%) of women could reduce the requisite specificity for serum markers to 98%. We have attempted to improve sensitivity by combining CA125 with proteomic markers. Methods Sera from 41 patients with early stage (I/II) and 51 with late stage (III/IV) epithelial ovarian cancer, 40 with benign disease and 99 healthy individuals, were analyzed to measure 7 proteins [Apolipoprotein A1 (Apo-A1), truncated transthyretin (TT), transferrin, hepcidin, ß-2-microglobulin (ß2M), Connective Tissue Activating Protein III (CTAPIII), and Inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4)]. Statistical models were fit by logistic regression, followed by optimization of factors retained in the models determined by optimizing the Akaike Information Criterion. A validation set included 136 stage I ovarian cancers, 140 benign pelvic masses and 174 healthy controls. Results In a training set analysis, the 3 most effective biomarkers (Apo-A1, TT and CTAPIII) exhibited 54% sensitivity at 98% specificity, CA125 alone produced 68% sensitivity and the combination increased sensitivity to 88%. In a validation set, the marker panel plus CA125 produced a sensitivity of 84% at 98% specificity (P= 0.015, McNemar's test). Conclusion Combining a panel of proteomic markers with CA125 could provide a first step in a sequential two-stage strategy with TVS for early detection of ovarian cancer.

Clinical performance of two multi-marker blood tests for predicting malignancy in women with an adnexal mass

“…Notably, OVA1 appears to detect non-epithelial ovarian cancers more readily than ROMA, which is likely a function of its inclusion of β2-microglobulin [21].…”

Association Between Pretreatment Serum Apolipoprotein A1 and Prognosis of Solid Tumors in Chinese Population: A Systematic Review and Meta-Analysis

“…Elevated apoA1 transgenic expression has shown a reduction of tumor burden and a survival benefit in mouse models of ovarian cancer and melanoma [19, 20]. The US Food and Drug Administration also approved the application of apoA1 along with transthyretin, transferring, β2-microglobulin, prealbumin, and CA125 for detecting early stage ovarian cancer, and these combined biomarkers test is known as OVA1® [21, 22]. Several publications have recently reported that low serum apoA1 level was associated with poor prognosis of solid tumors in Chinese population.…”

Ovarian Cyst Fluids Are a Cache of Tumor Biomarkers That Include Calgranulin A and Calgranulin B Isoforms

“…Secretion of the calgranulins (and other acute phase reactants such as apolipoprotein A1, transthyretin, inter-α-trypsin inhibitor heavy chain H4, and cytokines such as EGF, G-CFS, IL-6, IL-8, MCP-1, and VEGF) by malignant ovarian epithelial cells or infiltrating leukocytes, therefore, may indicate an acute phase/cytokine immune response during tumor initiation and/or disease progression to early stage EOC (79,89,102,121). Our observation that calgranulin A and B concentrations are higher in cyst fluids of early stage compared to late stage malignant ovarian tumors, but not borderline ovarian tumors, and that calgranulin A and B combined have 63.6% sensitivity to detect early stage disease among malignant tumors is consistent with an acute phase/cytokine immune response by the tumor as opposed to normal tissues elsewhere in the host, which may be advantageous for maximizing the sensitivity to detect early stage EOC in prediagnostic blood samples (8,122).…”

“…Notably, the sensitivity to detect stage I/II vs. stage III/V disease is 63.6% and 18.5% among malignant tumors, respectively, but 28.6% and 62.5% among borderline tumors. We surmise that calgranulin A and B together may have utility for the early detection of malignant ovarian tumors, and that serum concentrations of calgranulin A and B may warrant investigation to complement other promising biomarkers of EOC (e.g., CA125, HE4, mesothelin, M-CSF, osteopontin, kallikrein(s), soluble EGFR (sEGFR), β-2-microglobulin, transferrin, apolipoprotein A1, inter-α-trypsin inhibitor heavy chain 4, connective tissue activating protein III, and transthyretin) (79,88,89). We conclude that ovarian cyst fluids may epitomize the ideal biospecimen to identify physiologically germane, differentially expressed biomarkers, which may be developed further as blood-based tests to detect, diagnose, and biochemically classify ovarian tumors.…”