Detection Of Epithelial Ovarian Cancer Research Articles

Systematic Evaluation of Candidate Blood Markers for Detecting Ovarian Cancer

BackgroundEpithelial ovarian cancer is a significant cause of mortality both in the United States and worldwide, due largely to the high proportion of cases that present at a late stage, when survival is extremely poor. Early detection of epithelial ovarian cancer, and of the serous subtype in particular, is a promising strategy for saving lives. The low prevalence of ovarian cancer makes the development of an adequately sensitive and specific test based on blood markers very challenging. We evaluated the performance of a set of candidate blood markers and combinations of these markers in detecting serous ovarian cancer.Methods and FindingsWe selected 14 candidate blood markers of serous ovarian cancer for which assays were available to measure their levels in serum or plasma, based on our analysis of global gene expression data and on literature searches. We evaluated the performance of these candidate markers individually and in combination by measuring them in overlapping sets of serum (or plasma) samples from women with clinically detectable ovarian cancer and women without ovarian cancer. Based on sensitivity at high specificity, we determined that 4 of the 14 candidate markers-MUC16, WFDC2, MSLN and MMP7-warrant further evaluation in precious serum specimens collected months to years prior to clinical diagnosis to assess their utility in early detection. We also reported differences in the performance of these candidate blood markers across histological types of epithelial ovarian cancer.ConclusionsBy systematically analyzing the performance of candidate blood markers of ovarian cancer in distinguishing women with clinically apparent ovarian cancer from women without ovarian cancer, we identified a set of serum markers with adequate performance to warrant testing for their ability to identify ovarian cancer months to years prior to clinical diagnosis. We argued for the importance of sensitivity at high specificity and of magnitude of difference in marker levels between cases and controls as performance metrics and demonstrated the importance of stratifying analyses by histological type of ovarian cancer. Also, we discussed the limitations of studies (like this one) that use samples obtained from symptomatic women to assess potential utility in detection of disease months to years prior to clinical detection.

Application of Bayesian Modeling of Autologous Antibody Responses against Ovarian Tumor-Associated Antigens to Cancer Detection

Biomarkers for early detection of epithelial ovarian cancer (EOC) are urgently needed. Patients can generate antibodies to tumor-associated antigens (TAAs). We tested multiplex detection of antibodies to candidate ovarian TAAs and statistical modeling for discrimination of sera of EOC patients and controls. Binding of serum antibody of women with EOC or healthy controls to candidate TAA-coated microspheres was assayed in parallel. A Bayesian model/variable selection approach using Markov Chain Monte Carlo computations was applied to these data, and serum CA125 values, to determine the best predictive model. The selected model was subjected to area under the receiver-operator curve (AUC) analysis. The best model generated an AUC of 0.86 [95% confidence interval (95% CI), 0.78-0.90] for discrimination between sera of EOC patients and healthy patients using antibody specific to p53, NY-CO-8, and HOXB7. Inclusion of CA125 in the model provided an AUC of 0.89 (95% CI, 0.84-0.92) compared with an AUC of 0.83 (95% CI, 0.81-0.85) using CA125 alone. However, using TAA responses alone, the model discriminated between independent sera of women with nonmalignant gynecologic conditions and those with advanced-stage or early-stage EOC with AUCs of 0.71 (95% CI, 0.67-0.76) and 0.70 (95% CI, 0.48-0.75), respectively. Serum antibody to p53 and HOXB7 is positively associated with EOC, whereas NY-CO-8-specific antibody shows negative association. Bayesian modeling of these TAA-specific serum antibody responses exhibits similar discrimination of patients with early-stage and advanced-stage EOC from women with nonmalignant gynecologic conditions and may be complementary to CA125.

Diagnostic Markers of Ovarian Cancer by High-Throughput Antigen Cloning and Detection on Arrays

A noninvasive screening test would significantly facilitate early detection of epithelial ovarian cancer. This study used a combination of high-throughput selection and array-based serologic detection of many antigens indicative of the presence of cancer, thereby using the immune system as a biosensor. This high-throughput selection involved biopanning of an ovarian cancer phage display library using serum immunoglobulins from an ovarian cancer patient as bait. Protein macroarrays containing 480 of these selected antigen clones revealed 65 clones that interacted with immunoglobulins in sera from 32 ovarian cancer patients but not with sera from 25 healthy women or 14 patients having other benign or malignant gynecologic diseases. Sequence analysis data of these 65 clones revealed 62 different antigens. Among the markers, we identified some known antigens, including RCAS1, signal recognition protein-19, AHNAK-related sequence, nuclear autoantogenic sperm protein, Nijmegen breakage syndrome 1 (Nibrin), ribosomal protein L4, Homo sapiens KIAA0419 gene product, eukaryotic initiation factor 5A, and casein kinase II, as well as many previously uncharacterized antigenic gene products. Using these 65 antigens on protein microarrays, we trained neural networks on two-color fluorescent detection of serum IgG binding and found an average sensitivity and specificity of 55% and 98%, respectively. In addition, the top 6 of the most specific clones resulted in an average sensitivity and specificity of 32% and 94%, respectively. This global approach to antigenic profiling, epitomics, has applications to cancer and autoimmune diseases for diagnostic and therapeutic studies. Further work with larger panels of antigens should provide a comprehensive set of markers with sufficient sensitivity and specificity suitable for clinical testing in high-risk populations.

Detection of epithelial ovarian cancer using 1H‐NMR‐based metabonomics

Currently available serum biomarkers are insufficiently reliable to distinguish patients with epithelial ovarian cancer (EOC) from healthy individuals. Metabonomics, the study of metabolic processes in biologic systems, is based on the use of (1)H-NMR spectroscopy and multivariate statistics for biochemical data generation and interpretation and may provide a characteristic fingerprint in disease. In an effort to examine the utility of the metabonomic approach for discriminating sera from women with EOC from healthy controls, we performed (1)H-NMR spectroscopic analysis on preoperative serum specimens obtained from 38 patients with EOC, 12 patients with benign ovarian cysts and 53 healthy women. After data reduction, we applied both unsupervised Principal Component Analysis (PCA) and supervised Soft Independent Modeling of Class Analogy (SIMCA) for pattern recognition. The sensitivity and specificity tradeoffs were summarized for each variable using the area under the receiver-operating characteristic (ROC) curve. In addition, we analyzed the regions of NMR spectra that most strongly influence separation of sera of EOC patients from healthy controls. PCA analysis allowed correct separation of all serum specimens from 38 patients with EOC (100%) from all of the 21 premenopausal normal samples (100%) and from all the sera from patients with benign ovarian disease (100%). In addition, it was possible to correctly separate 37 of 38 (97.4%) cancer specimens from 31 of 32 (97%) postmenopausal control sera. SIMCA analysis using the Cooman's plot demonstrated that sera classes from patients with EOC, benign ovarian cysts and the postmenopausal healthy controls did not share multivariate space, providing validation for the class separation. ROC analysis indicated that the sera from patients with and without disease could be identified with 100% sensitivity and specificity at the (1)H-NMR regions 2.77 parts per million (ppm) and 2.04 ppm from the origin (AUC of ROC curve = 1.0). In addition, the regression coefficients most influential for the EOC samples compared to postmenopausal controls lie around delta3.7 ppm (due mainly to sugar hydrogens). Other loadings most influential for the EOC samples lie around delta2.25 ppm and delta1.18 ppm. These findings indicate that (1)H-NMR metabonomic analysis of serum achieves complete separation of EOC patients from healthy controls. The metabonomic approach deserves further evaluation as a potential novel strategy for the early detection of epithelial ovarian cancer.

CE Test: Early Diagnosis Key to Epithelial Ovarian Cancer Detection

CE Test: Early Diagnosis Key to Epithelial Ovarian Cancer Detection

Early Diagnosis Key to Epithelial Ovarian Cancer Detection

Ovarian cancer is the fourth leading cause of cancer death for women and the most fatal of all gynecologic malignancies. Labeled "the whispering disease," ovarian cancer has an insidious onset with vague symptoms such as gastrointestinal upset, abdominal bloating and fatigue. Early diagnosis is often delayed and patients present with advanced disease. This article provides an overview of ovarian cancer, including epidemiology, classification, risk factors, screening and early detection.

Animal models of ovarian cancer

Ovarian cancer is the most lethal of all of the gynecological cancers and can arise from any cell type of the ovary, including germ cells, granulosa or stromal cells. However, the majority of ovarian cancers arise from the surface epithelium, a single layer of cells that covers the surface of the ovary. The lack of a reliable and specific method for the early detection of epithelial ovarian cancer results in diagnosis occurring most commonly at late clinical stages, when treatment is less effective. In part, the deficiency in diagnostic tools is due to the lack of markers for the detection of preneoplastic or early neoplastic changes in the epithelial cells, which reflects our rather poor understanding of this process. Animal models which accurately represent the cellular and molecular changes associated with the initiation and progression of human ovarian cancer have significant potential to facilitate the development of better methods for the early detection and treatment of ovarian cancer. This review describes some of the experimental animal models of ovarian tumorigenesis that have been reported, including those involving specific reproductive factors and environmental toxins. Consideration has also been given to the recent progress in modeling ovarian cancer using genetically engineered mice.

The scientific basis of early detection of epithelial ovarian cancer: the National Ovarian Cancer Early Detection Program (NOCEDP).

In the United States ovarian cancer is the leading cause of death from gynecologic malignancies and is the fifth most common female malignancy. Each year approximately 24,000 women will be newly diagnosed with ovarian cancer and 14,000 will die from this disease. In industrialized countries ovarian cancer accounts for more deaths than uterine and cervical cancer combined. The incidence of ovarian cancer has been steadily increasing over the past ten years, now with an overall lifetime risk of 1.8%. Ovarian cancer rapidly increases in occurrence after age 40 with the mean age of occurrence at 60 (1). Epidemiologic factors associated with ovarian cancer include nulliparity, a personal history of colon or breast cancer, an affected first degree relative with ovarian cancer, a family history of a recognized inherited malignancy syndrome, as well as a history of prolonged use of fertility drugs (2). Due to our current inability in detecting cancer confined to the ovary (stage I disease), the majority of women (75%) are diagnosed with tumor spread throughout the abdominal cavity (stage III or IV). This extensive spread of ovarian carcinoma often is associated with subtle symptoms such as bloating, early satiety, abdominal discomfort, or changes in bowel or bladder habits; vague symptoms that may often be dismissed by patient and/or healthcare provider or simply misdiagnosed. It is the anatomic location of the ovaries that contributes to our inability to detect early stage ovarian carcinoma. Despite significant improvements in surgical techniques, critical care and new chemotherapeutic regimens, the overall 5-year survival for women with stage III/IV epithelial ovarian carcinoma has remained constant (12 – 20%) over the past 30 years. Conversely, those patients diagnosed with stage I disease usually only require surgical intervention without chemotherapy and have an overall 5-year survival approximating 90%. Therefore the early detection of early stage epithelial ovarian cancer is essential in curbing the morbidity and mortality from this disease.

Detection of epithelial ovarian cancer in asymptomatic postmenopausal women

Detection of epithelial ovarian cancer in asymptomatic postmenopausal women

Molecular approaches to prevention and detection of epithelial ovarian cancer.

More than 90% of epithelial ovarian cancers arise from single cells. Malignant transformation can be associated with a number of molecular alterations including upregulation of tyrosine kinases and phosphatases, physiologic activation o ras, mutation of p53, amplification of myc, and increased activity of matrix metalloproteinases 2 and 9. Proliferation of transformed epithelial cells can be enhanced through the persistence of autocrine growth stimulation by TGF-alpha, loss of autocrine growth inhibition by TGF-beta, as well as paracrine growth stimulation by macrophage derived cytokines and OCAF, a novel lyso-phospholipid. Ascites tumor cells retain responsiveness to growth inhibition by TGF-beta which induces apoptosis in malignant ovarian epithelial cells, but not in normal ovarian surface epithelium. Proliferation of surface epithelial cells following ovulation may contribute to the pathogenesis of ovarian cancer. Use of oral contraceptives that suppress ovulation has been associated with reduced risk of ovarian cancer in later life. Retinoids also deserve further evaluation for chemoprevention. Treatment with fenretinide was associated with decreased incidence of ovarian cancer. Additive or synergistic inhibition of ovarian tumor cell proliferation has been observed with TGF-beta in combination with all-trans-retinoic acid. Early detection of ovarian cancer could improve survival. Transvaginal sonography (TVS) and serum markers such as CA-125 have been evaluated in multiple clinical trials. The former lacks adequate specificity, whereas the latter is not sufficiently sensitive. Use of multiple serum markers can improve sensitivity. A combination of CA-125, M-CSF and OVX-1 has detected > 95% of Stage I ovarian cancers. If similar results are obtained with different data sets, multiple serum markers could be used to trigger the performance of TVS, providing a potentially cost effective screening strategy. Prospective trials will be required to demonstrate that screening for early stage ovarian actually impacts on survival.

Is early detection of ovarian cancer possible?

Advances in medical technology have led to potentially useful techniques for the early detection of epithelial ovarian cancer. Early detection of ovarian cancer is crucial for survival as women found to have Stage I or II disease have a 5-year survival of 90% and 70%, respectively, whereas those with advanced disease (Stage III and IV) have a survival of approximately 20%. The circulating tumour marker CA-125 has been extremely useful in following women known to have epithelial ovarian cancers. It has been employed in differentiating benign tumours from malignancies, and is now being tested in a variety of programmes for its role in the early detection of ovarian cancer. The application of endovaginal ultrasound and colour Doppler flow techniques to early detection of ovarian cancer have resulted in several large series identifying ovarian cancer in 1:1000 to 1:2000 postmenopausal women screened. However, a high false positivity rate persists using CA-125 and ultrasound techniques alone or in sequence. Developments in molecular genetics may be extremely useful in evaluating women with inherited susceptibilities for this disease, but this probably represents only about 3% of the population of the women who develop epithelial ovarian cancer. The cost-benefit analysis of isolated screening for epithelial ovarian cancer using CA-125 and ultrasound techniques, even in women at high risk for the disease, would suggest that such screening is not cost-effective at this time.

Adjuvant Therapy for Early-Stage Ovarian Cancer

Of all the lesions of the female genital tract, ovarian cancer represents the most difficult challenge. It has the highest fatality-to-case ratio of the gynecologic cancers, with more than 20,000 new cases and 12,000 deaths from ovarian cancer expected in the United States in 1990.1 Epithelial ovarian cancer accounts for about 90 percent of all malignant ovarian tumors. This form of ovarian cancer often spreads without symptoms, and in three quarters of patients the disease is not diagnosed until it has spread beyond the pelvis.2 The early detection of epithelial ovarian cancer generally still relies on the finding of a . . .

Confirmation of a false-positive result in CA 125 immunoradiometric assay caused by human anti-idiotypic immunoglobulin.

An immunoradiometric assay (IRMA) involving a monoclonal antibody (MAb OC125) to an ovarian carcinoma-associated antigenic determinant (CA 125) has been tested as one component in a strategy for early detection of epithelial ovarian cancer. We characterized one confirmed "false-positive" sample by murine antibody blocking studies, Western blotting, immunoaffinity, size-exclusion chromatography, and reactivity with polyclonal rabbit antisera to CA 125 antigen. The positive response of this serum in the CA 125 IRMA was due to a human IgM. The discrepant IgM was isolated from the serum by successive immunoaffinity steps with nonspecific murine MAb, MAb OC125, and goat antibodies to human IgM Fc. Purified IgM inhibited the binding of MAb OC125 to CA 125. Furthermore, rabbit antisera to CA 125 antigen competitively inhibited the binding of MAb OC125 to both CA 125 and the discrepant IgM. The discrepant activity thus appears to reflect binding of this human IgM to a idiotope of MAb OC125. Radioiodination of MAb OC125 by a different technique eliminated the discrepant activity and decreased the incidence of CA 125 positivity in an at-risk population of apparently healthy women, increasing the specificity of the IRMA to 99.8% in this group.