Ovarian Cancer Biomarker Performance in Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Specimens

Brigham and Women's Hospital, Ob/Gyn, Division of Epidemiology, Boston, MA 02115, USA.
Cancer Prevention Research (Impact Factor: 4.44). 03/2011; 4(3):365-74. DOI: 10.1158/1940-6207.CAPR-10-0195
Source: PubMed


Establishing a cancer screening biomarker's intended performance requires "phase III" specimens obtained in asymptomatic individuals before clinical diagnosis rather than "phase II" specimens obtained from symptomatic individuals at diagnosis. We used specimens from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to evaluate ovarian cancer biomarkers previously assessed in phase II sets. Phase II specimens from 180 ovarian cancer cases and 660 benign disease or general population controls were assembled from four Early Detection Research Network or Ovarian Cancer Specialized Program of Research Excellence sites and used to rank 49 biomarkers. Thirty-five markers, including 6 additional markers from a fifth site, were then evaluated in PLCO proximate specimens from 118 women with ovarian cancer and 474 matched controls. Top markers in phase II specimens included CA125, HE4, transthyretin, CA15.3, and CA72.4 with sensitivity at 95% specificity ranging from 0.73 to 0.40. Except for transthyretin, these markers had similar or better sensitivity when moving to phase III specimens that had been drawn within 6 months of the clinical diagnosis. Performance of all markers declined in phase III specimens more remote than 6 months from diagnosis. Despite many promising new markers for ovarian cancer, CA125 remains the single-best biomarker in the phase II and phase III specimens tested in this study.

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    • "A recent multi-center effort to test the sensitivity and specificity of panels of markers conducted using the serum samples obtained from PLCO has been reported [51]. None of the panels of markers tested in this trial improve on the sensitivity and specificity of CA125 in screening or ovarian cancer diagnosis [52,53]. The conclusion from the important trials and studies described in this section is that CA125 continues to be, and for the foreseeable future will persist as, the predominant and most clinically useful biomarker for ovarian cancer. "
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    ABSTRACT: Over three decades have passed since the first report on the expression of CA125 by ovarian tumors. Since that time our understanding of ovarian cancer biology has changed significantly to the point that these tumors are now classified based on molecular phenotype and not purely on histological attributes. However, CA125 continues to be, with the recent exception of HE4, the only clinically reliable diagnostic marker for ovarian cancer. Many large-scale clinical trials have been conducted or are underway to determine potential use of serum CA125 levels as a screening modality or to distinguish between benign and malignant pelvic masses. CA125 is a peptide epitope of a 3-5 million Da mucin, MUC16. Here we provide an in-depth review of the literature to highlight the importance of CA125 as a prognostic and diagnostic marker for ovarian cancer. We focus on the increasing body of literature describing the biological role of MUC16 in the progression and metastasis of ovarian tumors. Finally, we consider previous and on-going efforts to develop therapeutic approaches to eradicate ovarian tumors by targeting MUC16. Even though CA125 is a crucial marker for ovarian cancer, the exact structural definition of this antigen continues to be elusive. The importance of MUC16/CA125 in the diagnosis, progression and therapy of ovarian cancer warrants the need for in-depth research on the biochemistry and biology of this mucin. A renewed focus on MUC16 is likely to culminate in novel and more efficient strategies for the detection and treatment of ovarian cancer.
    Full-text · Article · May 2014 · Molecular Cancer
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    • "CA125 is currently used and is an important biologic marker for ovarian cancer ( 39 ) . Other plasmatic proteins such as IGFII, IL-13rα, MIP1α and MMP-7 were reported as ovarian cancer biomarkers associated with poor prognosis ( 40 ) . In a recent study we demonstrated a close correlation between increase in sEPCR and CA125 ( 18 ) . "
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    ABSTRACT: In spite of the growing importance of endothelial protein C receptor/active protein C (EPCR/aPC) in tumor biology, their impact on immunological homeostasis remains largely unexplored. The objective of this study was to assess whether soluble plasma endothelial protein C receptor (sEPCR), which is a regulator of circulating aPC, is involved in innate immune response in cancer patients. In the Ovcar-3 ovarian cancer line, the role of aPC in secretion of cytokines was analyzed. In parallel, in 33 patients, with a diagnosis of ovarian epithelial cancer, sEPCR was quantified, blood immune cell phenotypes were determined by flow cytometry and plasma cytokines were evaluated using a protein array. Spearman's rank correlation coefficients (r) and coefficient significance was determined by a statistical hypothesis test (α=0.05). Our results show that i) aPC induced the secretion of several cytokines in Ovcar-3 cells; ii) 61% of patients exhibited a concentration of plasma sEPCR well above the baseline (normal plasma level, 100±28 ng/ml); iii) comparing immune cell phenotypes in patients having a normal level of sEPCR with those having a high level of sEPCR, it was found that sEPCR levels were correlated with high intensity of cells expressing CD45ra, CD3, CD8, CD25 and low intensity of cells expressing CD56 (NK cells), CD294 (TH2 cells), IL-2, IL-10, IL-17a (TH17 cells), IL-21 (TH21 cells) and CD29 markers (r ≥0.60); and iv) high levels of sEPCR correlate with high levels of plasma bioactive proteins such as insulin-like growth factor-2 (IGFII), IL-13rα, macrophage inflammatory protein (MIP1α) and matrix metalloproteinase-7 (MMP-7) that have already been proposed as biomarkers for ovarian cancer and particularly those with poor prognosis. In conclusion, sEPCR produced by ovarian cancer cells, by modulating circulating aPC, influences the secretory behavior of tumor cells (cytokines and interleukins). Consequently, sEPCR in turn acts on the innate immune response by decreasing effector cells such as natural killer and T helper cells (TH2, TH17 and TH21).
    Full-text · Article · Jul 2013 · International Journal of Oncology
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    • "An example is the novel ovarian cancer biomarker, B7-H4 (discovered by diaDexus Inc., San Francisco, CA, USA), which was validated for its ability to diagnose ovarian cancer [5]. Recently, an independent group confirmed the diagnostic ability of this biomarker, but also demonstrated that it is not better than the classical biomarker, CA125 [6]. Consequently, the company that discovered it, in the absence of a clear clinical utility, decided not to market it. "
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