Simmons, AR;
Fourkala, E-O;
Gentry-Maharaj, A;
Ryan, A;
Sutton, MN;
Baggerly, K;
Zheng, H;
... Bast, RC; + view all
(2019)
Complementary longitudinal serum biomarkers to CA125 for early detection of ovarian cancer.
Cancer Prevention Research
10.1158/1940-6207.CAPR-18-0377.
(In press).
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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.
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