Serum protein markers for early detection of ovarian cancer

Abstract

Early diagnosis of epithelial ovarian cancer (EOC) would significantly decrease the morbidity and mortality from this disease but is difficult in the absence of physical symptoms. Here, we report a blood test, based on the simultaneous quantization of four analytes (leptin, prolactin, osteopontin, and insulin-like growth factor-II), that can discriminate between disease-free and EOC patients, including patients diagnosed with stage I and II disease, with high efficiency (95%). Microarray analysis was used initially to determine the levels of 169 proteins in serum from 28 healthy women, 18 women newly diagnosed with EOC, and 40 women with recurrent disease. Evaluation of proteins that showed significant differences in expression between controls and cancer patients by ELISA assays yielded the four analytes. These four proteins then were evaluated in a blind cross-validation study by using an additional 106 healthy females and 100 patients with EOC (24 stage I͞II and 76 stage III͞IV). Upon sample decoding, the results were analyzed by using three different classification algorithms and a binary code methodology. The four-analyte test was further validated in a blind binary code study by using 40 additional serum samples from normal and EOC cancer patients. No single protein could completely distinguish the cancer group from the healthy controls. However, the combination of the four analytes exhibited the following: sensitivity 95%, positive predictive value (PPV) 95%, specificity 95%, and negative predictive value (NPV) 94%, a considerable improvement on current methodology.insulin-like growth factor-II ͉ leptin ͉ osteopontin ͉ prolactin E pithelial ovarian cancer (EOC) is the fourth leading cause of cancer-related death in women in the U.S. and the leading cause of gynecologic cancer death. EOC is characterized by few early symptoms, presentation at an advanced stage, and poor survival. Despite being one tenth as common as breast cancer, EOC is three times more lethal. This year Ϸ22,220 women will be newly diagnosed with ovarian cancer, and 16,210 will die from the disease (1). The high mortality rate is due to the difficulties with the early detection of ovarian cancer. Indeed, Ϸ80% of patients are diagnosed with advanced staged disease. In patients who are diagnosed with early disease (stage I or II), the 5-yr survival ranges from 60% to 90%, depending on the degree of tumor differentiation (2, 3). In patients with advanced disease, 80-90% will initially respond to chemotherapy, but Ͻ10-15% will remain in permanent remission (4). Although advances in treatment have led to an improved 5-yr survival rate approaching 45%, overall survival has not been enhanced (2, 5).Two alternative strategies have been reported for early detection by using serum biomarkers. One approach is the analysis of serum samples by mass spectrometry to find proteins or protein fragments of unknown identity that detect the presence͞absence of cancer (6-8). Alternatively, analysis of the presence͞absence͞abundance of known proteins͞peptides ...

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