Abstract
BackgroundCurrently, there are no FDA approved screening tools for detecting early stage ovarian cancer in the general population. Development of a biomarker-based assay for early detection would significantly improve the survival of ovarian cancer patients.MethodsWe used a multiplex approach to identify protein biomarkers for detecting early stage ovarian cancer. This new technology (Proseek® Multiplex Oncology Plates) can simultaneously measure the expression of 92 proteins in serum based on a proximity extension assay. We analyzed serum samples from 81 women representing healthy, benign pathology, early, and advanced stage serous ovarian cancer patients.ResultsPrinciple component analysis and unsupervised hierarchical clustering separated patients into cancer versus non-cancer subgroups. Data from the Proseek® plate for CA125 levels exhibited a strong correlation with current clinical assays for CA125 (correlation coefficient of 0.89, 95% CI 0.83, 0.93). CA125 and HE4 were present at very low levels in healthy controls and benign cases, while higher levels were found in early stage cases, with highest levels found in the advanced stage cases. Overall, significant trends were observed for 38 of the 92 proteins (p < 0.001), many of which are novel candidate serum biomarkers for ovarian cancer. The area under the ROC curve (AUC) for CA125 was 0.98 and the AUC for HE4 was 0.85 when comparing early stage ovarian cancer versus healthy controls. In total, 23 proteins had an estimated AUC of 0.7 or greater. Using a naïve Bayes classifier that combined 12 proteins, we improved the sensitivity corresponding to 95% specificity from 93 to 95% when compared to CA125 alone. Although small, a 2% increase would have a significant effect on the number of women correctly identified when screening a large population.ConclusionsThese data demonstrate that the Proseek® technology can replicate the results established by conventional clinical assays for known biomarkers, identify new candidate biomarkers, and improve the sensitivity and specificity of CA125 alone. Additional studies using a larger cohort of patients will allow for validation of these biomarkers and lead to the development of a screening tool for detecting early stage ovarian cancer in the general population.
Highlights
There are no Food and Drug Administration (FDA) approved screening tools for detecting early stage ovarian cancer in the general population
The healthy/benign patients had low Proseek® cancer antigen 125 (CA125) values (Fig. 1c, white) while the early/late stage ovarian cancer patients had high Proseek® CA125 values (Fig. 1c, black). This trend was evident when examining the distribution of CA125 values as determined by enzyme-linked immunosorbent assay (ELISA) (Fig. 1d); the healthy/benign patients tended to have ELISA CA125 values less than the clinical cutoff value of 35 U/ml, indicative of a “normal” CA125 value (Fig. 1d, white), whereas patients with early/late stage ovarian cancer had ELISA CA125 values greater than 35 U/ml, indicative of a risk for ovarian cancer (Fig. 1d, blue). These results illustrate the potential for using these proteins to discriminate by cancer status, and suggest that the first two principal components are mostly driven by CA125 and human epididymis protein 4 (HE4)
Our Proseek® results are in agreement with previous studies [58, 59], as we found that HE4 consistently performed very closely to CA125, with area under the receiver operating characteristic (ROC) curve (AUC) values of 0.85– 1.0 when comparing sera from early and late stage serous ovarian cancer patients to sera from healthy women or women with benign ovarian disease
Summary
There are no FDA approved screening tools for detecting early stage ovarian cancer in the general population. Boylan et al Clin Proteom (2017) 14:34 These two biomarkers are not adequately sensitive or specific by themselves to screen the general population of women for ovarian cancer. A statistical method was developed to measure longitudinal changes in CA125 levels, and screening trials have recently been performed in which the risk of ovarian cancer algorithm has been used in combination with transvaginal ultrasound [10,11,12] These trials showed an excellent specificity and positive predictive value in women with an average risk of ovarian cancer, and fared better than using a single cutoff for CA125 [13]
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