Development of a Multiprotein Classifier for the Detection of Early Stage Ovarian Cancer

Abstract

Background: Individual serum biomarkers are neither adequately sensitive nor specific for use in screening the general population for ovarian cancer. The purpose of this study was to develop a multiprotein classifier to detect the early stages of ovarian cancer, when it is most treatable. Methods: The Olink Proseek Multiplex Oncology II panel was used to simultaneously quantify the expression levels of 92 cancer-related proteins in sera. Results: In the discovery phase, we generated a multiprotein classifier that included CA125, HE4, ITGAV, and SEZ6L, based on an analysis of sera from 116 women with early stage ovarian cancer and 336 age-matched healthy women. CA125 alone achieved a sensitivity of 87.9% at a specificity of 95%, while the multiprotein classifier resulted in an increased sensitivity of 91.4%, while holding the specificity fixed at 95%. The performance of the multiprotein classifier was validated in a second cohort comprised of 192 women with early stage ovarian cancer and 467 age-matched healthy women. The sensitivity at 95% specificity increased from 74.5% (CA125 alone) to 79.2% with the multiprotein classifier. In addition, the multiprotein classifier had a sensitivity of 95.1% at 98% specificity for late stage ovarian cancer samples and correctly classified 80.5% of the benign samples using the 98% specificity cutpoint. Conclusions: The inclusion of the proteins HE4, ITGAV, and SEZ6L improved the sensitivity and specificity of CA125 alone for the detection of early stages of ovarian cancer in serum samples. Furthermore, we identified several proteins that may be novel biomarkers of early stage ovarian cancer.

Identifying Novel Candidate Biomarkers of Early Epithelial Ovarian Cancer

“…As a potential solution to the lack of specificity of the upregulated miRNAs, this study also identified four miRNAs (miR-486a-3p/5p and miR-486b-3p/5p) that were in lower abundance in the EVs secreted from ovaries of 3-month Fancd2 -/mice and exhibited reduced expression in micro-dissected sex cords and tubulostromal adenomas. Even though upregulated biomarkers are more likely to be detectable in the circulation, it is not unrealistic to utilise the lack of a biomarker for a diagnostic panel, as is the case for the Proseek Multiplex Oncology Panel II [325]. Therefore, the absence of these miRNAs are also potential unique biomarkers that are not deficient in EVs at later stages, but are representative of the tumour tissue, thus are potential unique early ovarian cancer markers in this model.…”

“…Interestingly, many multivariate serum protein assays focus on markers that are upregulated in cancer patients over controls. However, recently an adaptation of the Oncology II panel studied the specificity and sensitivity of a biomarker panel with CA-125 and HE4 that also included serum proteins, integrin subunit alpha V (ITGAV) and seizure related 6 homolog like (SEZ6L), which are significantly downregulated in all epithelial subtypes of Stage I and II OC [325]. However, even with the proliferation of multivariate protein serum diagnostic panels targeted toward earlier OC detection, they have yet to be rigorously tested and made available for clinical use.…”