CA 125: the past and the future.
ABSTRACT Over the last 15 years, substantial progress has been made in understanding the potential and the limitations of the CA 125 assay. More than 2000 papers have been published concerning laboratory and clinical studies of CA 125. The original CA 125 assay utilized the OC 125 antibody that recognizes the CA 125 epitope on a high molecular weight glycoprotein. Despite repeated attempts, the gene encoding the peptide component has not yet been cloned. Monoclonal antibodies have been raised against other epitopes expressed by this molecule, leading to the development of the CA 125-II assay that exhibits less day-to-day variation. Using either assay, elevated levels of CA 125 are detected in a number of benign conditions, including endometriosis. CA 125 is most consistently elevated in epithelial ovarian cancer, but can be expressed in a number of gynecologic (endometrial, fallopian tube) and non-gynecologic (pancreatic, breast, colon and lung) cancers. The best established application of the CA 125 assay is in monitoring ovarian cancer. The rate of decline in CA 125 during primary chemotherapy has been an important independent prognostic factor in several multivariate analyses. Persistent elevation of CA 125 at the time of a second look surgical surveillance procedure predicts residual disease with > 95% specificity. Rising CA 125 values have preceded clinical detection of recurrent disease by at least 3 months in most, but not all studies. Given the modest activity of salvage chemotherapy, this information has not yet impacted on survival. Rising CA 125 during subsequent chemotherapy has been associated with progressive disease in more than 90% of cases. CA 125 may serve as an effective surrogate marker for clinical response in phase II trials of new drugs. CA 125 levels can aid in distinguishing malignant from benign pelvic masses, permitting effective triage of patients for primary surgery. Early detection of ovarian cancer remains the most promising application of CA 125. An algorithm has been developed that estimates the risk of ovarian cancer (ROC) based upon the level and trend of CA 125 values. A major trial has been initiated that uses the ROC algorithm to trigger transvaginal sonography and/or subsequent laparotomy. Such a trial could demonstrate improvement in survival through early detection. This strategy should provide adequate specificity, but sensitivity for early stage disease may not be optimal. In the future, improved sensitivity may be attained using multiple markers and neural network analysis. Most serum tumor markers have been proteins or carbohydrates, but lipid markers such as lysophosphatidic acid deserve evaluation. Genomic and proteonomic technologies should identify additional novel markers.
SourceAvailable from: Tracey Colpitts[Show abstract] [Hide abstract]
ABSTRACT: Objectives “PAULA’s” test (Protein Assays Utilizing Lung cancer Analytes) is a novel multiplex immunoassay blood test that incorporates both tumor antigens and autoantibodies to determine the risk that lung cancer (LC) is present in individuals from a high-risk population. The test’s performance characteristics were evaluated in a study using 380 retrospective clinical serum samples. Methods PAULA’s test is performed on the Luminex xMAP technology platform, and detects a panel of 3 tumor antigens (CEA, CA-125, and CYFRA 21–1) and 1 autoantibody marker (NY-ESO-1). A training set (n = 230) consisting of 115 confirmed diagnoses of non-small cell lung carcinoma (NSCLC) cases and 115 age- and smoking history-matched controls was used to develop the LC predictive model. Data from an independent matched validation set (n = 150) was then used to evaluate the model developed, and determine the ability of the test to distinguish NSCLC cases from controls. Results The 4-biomarker panel was able to discriminate NSCLC cases from controls with 74% sensitivity, 80% specificity, and 0.81 AUC in the training set and with 77% sensitivity, 80% specificity, and 0.85 AUC in the independent validation set. The use of NY-ESO-1 autoantibodies substantially increased the overall sensitivity of NSCLC detection as compared to the 3 tumor markers alone. Overall, the multiplexed 4-biomarker panel assay demonstrated comparable performance to a previously employed 8-biomarker non-multiplexed assay. Conclusions These studies confirm the value of using a mixed panel of tumor antigens and autoantibodies in the early detection of NSCLC in high-risk individuals. The results demonstrate that the performance of PAULA’s test makes it suitable for use as an aid to determine which high-risk patients need to be directed to appropriate noninvasive diagnostic follow-up testing, especially low-dose CT (LDCT).Journal of Translational Medicine 02/2015; 13(1):55. DOI:10.1186/s12967-015-0419-y · 3.99 Impact Factor
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ABSTRACT: Despite its importance, the death rate of ovarian cancer has remained unchanged over the past five decades, demanding an improvement in prevention and treatment of this malignancy. With no known carcinogens, targeted prevention is currently unavailable, and efforts in early detection of this malignancy by screening biomarkers have failed. The inhibition of angiogenesis, also known as angioprevention, is a promising strategy to limit the growth of solid tumors, including ovarian cancers. Nobiletin, a polymethoxy flavonoid compound isolated from the tiansheng plant, has been shown to inhibit the growth of multiple types of human cancers. However, there are no reports involving the effect on nobiletin on human ovarian cancer. The present report shows that nobiletin potently decreases the viability of ovarian cancer cells in vitro. However, nobiletin does not affect the viability of normal ovarian epithelial cells at <40 µM. The antitumor activity of nobiletin was also observed in athymic mouse models and in chicken chorioallantoic membrane (CAM) models. The anti-neoplastic activity of nobiletin was due to its ability to inhibit angiogenesis. We also studied the molecular mechanisms by which nobiletin suppresses angiogenesis. We observed that nobiletin inhibits secretion of the key angiogenesis mediators, Akt, HIF-1α, NF-κB and vascular epithelial growth factor (VEGF) by ovarian cancer cells. Transient transfection experiments showed that nobiletin inhibits production of HIF-1α by downregulation of Akt. Such decreased levels of HIF-1α were responsible for nobiletin-induced suppression of VEGF. Our data suggest that nobiletin may be a promising anti-angiogenic agent relevant for therapy of ovarian cancers.International Journal of Oncology 04/2015; 46:2629-2638. DOI:10.3892/ijo.2015.2946 · 2.77 Impact Factor
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ABSTRACT: Clinical outcomes, such as recurrence-free survival and overall survival, in ovarian cancer are quite variable, independent of common characteristics such as stage, response to therapy, and grade. This disparity in outcomes warrants further exploration and therapeutic targeting into the interaction between the tumor and host. One compelling host characteristic that contributes both to the initiation and progression of ovarian cancer is the immune system. Hundreds of studies have confirmed a prominent role for the immune system in modifying the clinical course of the disease. Recent studies also show that anti-tumor immunity is often negated by immune regulatory cells present in the tumor microenvironment. Regulatory immune cells also directly enhance the pathogenesis through the release of various cytokines and chemokines, which together form an integrated pathological network. Thus, in the future, research into immunotherapy targeting ovarian cancer will probably become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression. In this article, we summarize important immunological targets that influence ovarian cancer outcome as well as include an update on newer immunotherapeutic strategies.Cancer and metastasis reviews 12/2014; 34(1). DOI:10.1007/s10555-014-9540-2 · 6.45 Impact Factor