Development of multimarker panel for detection of endometrial cancer

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Endometrial carcinoma is the most common gynecologic cancer. Lack of screening test for this type of cancer is associated with excess mortality for women who do not present with vaginal bleeding and other early warning signs for endometrial cancer. Although the prognosis for endometrial cancer is generally good, cancers identified at later stages are associated with high levels of morbidity and mortality. Therefore, prevention and early detection represent our best hope to overcome this disease. We hypothesize that a multi-marker panel would provide the requisite high sensitivity and specificity for early detection of endometrial cancer, to be utilized for screening of target populations. A panel of 64 biomarkers was analyzed in sera of patients with stages I-VI endometrial cancer and age-matched healthy women, utilizing a multiplex xMAP^® bead-based immunoassay. The tested panel included cancer antigens, growth/angiogenic factors, apoptosis-related molecules, adipokines, cytokines, chemokines, hormones, metastasis-related molecules, and other cancers associated proteins. The adaptive bandwidth kernel based density estimator combined with projection pursuit technique (ADEPT) and Monte-Carlo simulation was used to create a diagnostic model, based on the cross-validation set consisting of sera from 115 patients with endometrial cancer and 135 healthy women. Patients with endometrial cancer have significantly different expression patterns of several serum biomarkers than healthy individuals. Prolactin was the strongest discriminative biomarker for endometrial cancer providing alone 95% sensitivity at 98% specificity. None of the other biomarkers was able to provide classification accuracy higher than 40% sensitivity at 50% specificity. ADEPT algorithm has identified an 8-biomarker panel that discriminated endometrial cancer cases from healthy controls with a sensitivity of greater than 99% at a specificity of 99% in a case/control cross-validation set. This panel included Prolactin, TTR, CA 19-9, ULBP-2, CD40L, MMP-9, FSH, and adiponectin. High degree discrimination between cancer and control groups indicates that serum cytokine profiles could potentially be used for development of blood-based diagnostic test for early detection of endometrial cancer. These studies demonstrate that combining the information in multiple markers using flexible statistical methods results in improved sensitivity while maintaining high specificity.