BackgroundCA125, human epididymis protein 4 (HE4), mesothelin, B7-H4, decoy receptor 3 (DcR3), and spondin-2 have been identified as potential ovarian cancer biomarkers. Except for CA125, their behavior in the prediagnostic period has not been evaluated.MethodsImmunoassays were used to determine concentrations of CA125, HE4, mesothelin, B7-H4, DcR3, and spondin-2 proteins in prediagnostic serum specimens (1–11 samples per participant) that were contributed 0–18 years before ovarian cancer diagnosis from 34 patients with ovarian cancer (15 with advanced-stage serous carcinoma) and during a comparable time interval before the reference date from 70 matched control subjects who were participating in the Carotene and Retinol Efficacy Trial. Lowess curves were fit to biomarker levels in cancer patients and control subjects separately to summarize mean levels over time. Receiver operating characteristic curves were plotted, and area-under-the curve (AUC) statistics were computed to summarize the discrimination ability of these biomarkers by time before diagnosis.ResultsSmoothed mean concentrations of CA125, HE4, and mesothelin (but not of B7-H4, DcR3, and spondin-2) began to increase (visually) in cancer patients relative to control subjects approximately 3 years before diagnosis but reached detectable elevations only within the final year before diagnosis. In descriptive receiver operating characteristic analyses, the discriminatory power of these biomarkers was limited (AUC statistics range = 0.56–0.75) but showed increasing accuracy with time approaching diagnosis (eg, AUC statistics for CA125 were 0.57, 0.68, and 0.74 for ≥4, 2–4, and <2 years before diagnosis, respectively).ConclusionSerum concentrations of CA125, HE4, and mesothelin may provide evidence of ovarian cancer 3 years before clinical diagnosis, but the likely lead time associated with these markers appears to be less than 1 year.

BACKGROUND Prior studies suggest that combining the Symptom Index (SI) with a serum HE4 test or a CA125 test may improve prediction of ovarian cancer. However, these three tests have not been evaluated in combination. METHODS A prospective case-control study design including 74 women with ovarian cancer and 137 healthy women was used with logistic regression analysis to evaluate the independent contributions of HE4, CA125, and the SI to predict ovarian cancer status in a multivariate model. The diagnostic performance of various decision-rules for combinations of these tests was assessed to evaluate potential use in predicting ovarian cancer. RESULTS The SI, HE4, and CA125 all made significant independent contributions to ovarian cancer prediction. A decision-rule based on any one of the three tests being positive had a sensitivity of 95% with specificity of 80%. A rule based on any two of the three tests being positive had a sensitivity of 84% with a specificity of 98.5%. The SI alone had sensitivity of 64% with specificity of 88%. If the SI index is used to select women for CA125 and HE4 testing, specificity is 98.5% and sensitivity is 58% using the 2-of-3-positive decision rule. CONCLUSIONS A 2-of-3-positive decision rule yields acceptable specificity, and higher sensitivity when all 3 tests are performed than when the SI is used to select women for screening by CA125 and HE4. If positive predictive value is a high priority, testing by CA125 and HE4 prior to imaging may be warranted for women with ovarian cancer symptoms.