Complementary Longitudinal Serum Biomarkers to CA125 for Early Detection of Ovarian Cancer

Abstract

Early detection of ovarian cancer has the potential to impact mortality. A multi-modal screening strategy where rising CA125 values over time, analyzed with the risk of ovarian cancer algorithm (ROCA), triggers transvaginal sonography and possible surgery has high sensitivity and specificity, but still fails to detect the 20% of early stage cases that do not express CA125. Use of multiple biomarkers could detect cases missed by CA125. We have studied the sensitivity and lead time of a multi-marker panel (CA125, HE4, MMP-7 and CA 72–4) compared to CA125 alone. We used PRoBE design principles to select pre-clinical longitudinal specimens from 75 women (50 screen-positive, 25 screen-negative) who developed invasive epithelial ovarian cancer (3–5 serial specimens each) and 547 corresponding healthy controls (1–10 serial specimens each) from the ovarian cancer screening trial, UKCTOCS, in a blinded fashion. We measured the multi-marker concentrations in ultra-low serum volumes (16 μL) utilizing multiplexed bead-based immunoassays with low detection limits, high inter- and intra-assay precision, negligible cross-reactivity and good correlation with standard immunoassays. While, at least one of the complementary biomarkers rose with CA125 in 44% (22/50) of screen-positive cases, there was no advantage in lead time over CA125. Therefore, we developed single-marker longitudinal algorithms (ROCA-like) to determine the presence of a change point to distinguish between the cases and controls. Using these algorithms, at 98% specificity, HE4 and CA72–4 identified 16% (4/25) of screen-negative cases, while MMP-7 identified none. Taken together, HE4 and CA72–4 show promise as complementary biomarkers to CA125 for longitudinal screening.

Human epididymis protein 4 antigen‐autoantibody complexes complement cancer antigen 125 for detecting early‐stage ovarian cancer

“…Because of the prevalence of ovarian cancer in the general postmenopausal population at average risk (1:2500), a screening strategy must not only be sufficiently sensitive to detect early-stage or small-volume disease in 75% of asymptomatic women but also achieve a specificity of 99.6% to provide a positive predictive value of 10% (ie, 10 operations for each case of ovarian cancer detected). 28,29 Consequently, the ability of HE4 Ag-AAb complexes to improve the detection of early-stage disease by approximately 20% is a significant advance. 2 Recent studies suggest, however, that 2-stage strategies in which rising biomarkers trigger imaging can achieve adequate specificity.…”

“…1 Despite the evaluation of more than 110 biomarkers, only 2 protein biomarkers, HE4 and cancer antigen 72.4 (CA 72.4), have been identified, and they detect 16% of early-stage cases missed by CA 125. 28,29 Consequently, the ability of HE4 Ag-AAb complexes to improve the detection of early-stage disease by approximately 20% is a significant advance. As cited previously, 18 anti-TP53 autoantibodies could also detect approximately 20% of all ovarian cancers and 16% of cases missed by CA 125 in the UKCTOCS study.…”

Biomarkers and Strategies for Early Detection of Ovarian Cancer

“…40 Addition of HE4 and CA72.4 to CA125, for example, detects 16% of cases missed by CA125, but does not provide lead-time before elevation of CA125. 36 While CA125 and HE4 levels are elevated in serous 41,42 and endometrioid ovarian cancers 42,43 , they are less frequently elevated with the mucinous histotype, 41,44 whereas CA72.4 is expressed by a greater fraction of mucinous ovarian cancers. 45 CA72.4 has, however, proven difficult to model statistically, but a new longitudinal ROCA algorithm that combines CA125 and HE4 is being developed with support from the EDRN.…”

“…In developing panels of biomarkers for early detection, several studies have incorporated CA125 and HE4 in combination with CA72.4 36 , CA72.4 and CA15-3 37 , CEA and V-CAM1, 38 glycodelin 22 , E-cadherin and IL-6 39 or transthyretin. 40 Addition of HE4 and CA72.4 to CA125, for example, detects 16% of cases missed by CA125, but does not provide lead-time before elevation of CA125.…”

Proteome Profiling Uncovers an Autoimmune Response Signature That Reflects Ovarian Cancer Pathogenesis

“…However, subjects diagnosed with localized disease have a survival rate of 75-90% [4]. At present, cancer antigen 125 (CA125) is the most investigated early detection marker for ovarian cancer [5]. Sequential monitoring of subjects with ultrasound and for elevated circulating levels of CA125 can achieve moderate specificity [6], but with limited sensitivity.…”