Comparison of Longitudinal CA125 Algorithms as a First-Line Screen for Ovarian Cancer in the General Population

Abstract

Purpose: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), women in the multimodal (MMS) arm had a serum CA125 test (first-line), with those at increased risk, having repeat CA125/ultrasound (second-line test). CA125 was interpreted using the "Risk of Ovarian Cancer Algorithm" (ROCA). We report on performance of other serial algorithms and a single CA125 threshold as a first-line screen in the UKCTOCS dataset.Experimental Design: 50,083 post-menopausal women who attended 346,806 MMS screens were randomly split into training and validation sets, following stratification into cases (ovarian/tubal/peritoneal cancers) and controls. The two longitudinal algorithms, a new serial algorithm, method of mean trends (MMT) and the parametric empirical Bayes (PEB) were trained in the training set and tested in the blinded validation set and the performance characteristics, including that of a single CA125 threshold, were compared.Results: The area under receiver operator curve (AUC) was significantly higher (P = 0.01) for MMT (0.921) compared with CA125 single threshold (0.884). At a specificity of 89.5%, sensitivities for MMT [86.5%; 95% confidence interval (CI), 78.4-91.9] and PEB (88.5%; 95% CI, 80.6-93.4) were similar to that reported for ROCA (sensitivity 87.1%; specificity 87.6%; AUC 0.915) and significantly higher than the single CA125 threshold (73.1%; 95% CI, 63.6-80.8).Conclusions: These findings from the largest available serial CA125 dataset in the general population provide definitive evidence that longitudinal algorithms are significantly superior to simple cutoff values for ovarian cancer screening. Use of these newer algorithms requires incorporation into a multimodal strategy. The results highlight the importance of incorporating serial change in biomarker levels in cancer screening/early detection strategies. Clin Cancer Res; 24(19); 4726-33. ©2018 AACR.

Figure 1

Performance characteristics of of CA125 interpreted using MMT, threshold rules, PEB and ROCA for detection of iEOC/PPC cases. Circle points give particular values of sensitivity and specificity provided by MMT and PEB corresponding to cut-offs obtained from the training set (MMT and PEB), CA125 using 22 and 30 U/ml cut-offs and ROCA as reported in (6). Abbreviations: PEB, parametric empirical Bayes; MMT, method of mean trends; CA125, cancer antigen 125; AUC, area under roc-curve

Figure 2

Secondary analysis ROC curves for CA125 interpreted using MMT, threshold rules and PEB for detection of iEOC/PPC cases. Circle points on the ROC curves give particular values of sensitivity and specificity provided by MMT and PEB corresponding to cut-offs obtained from the training set (MMT and PEB). Abbreviations: PEB, parametric empirical Bayes; MMT, method of mean trends; CA125, cancer antigen 125; AUC, area under roc-curve