Ovarian cancer early detection by circulating CA125 in the context of anti-CA125 autoantibody levels: Results from the EPIC cohort

Abstract

CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; p_het = 0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection.

Keywords: CA125; MUC16; anti-CA125 antibodies; autoantibodies; early detection markers; ovarian cancer.

Figure 1

(a) LOESS plot showing distribution of log-transformed CA125 among controls [blue] and, among cases, with cases classified in tertiles of anti-CA125 antibody levels. Tertiles of antibody level are represented by green (tertile 1; lowest), pink (tertile 2), and red (tertile 3; highest); (b) aAUC for CA125 by antibody tertiles for cases diagnosed within 2 years of blood collection (c) and between 2 and 4 years of blood collection. P_het represents the heterogeneity between aAUCs in the first and third tertiles.