Glycovariants of CA-125 in the early detection of ovarian cancer

Importance Two randomized trials have shown that screening with CA-125 is not of value for reducing ovarian cancer mortality. This appears to be because changes in CA-125 occur too late in the disease process to allow for surgical cure of early-stage disease. Objective To determine whether glycovariants of CA-125 could detect ovarian cancer years before clinical diagnosis. Design Case-control study of cryopreserved blood samples and data from the population-based Malmo Diet and Cancer cohort. Setting Population-based study in Sweden. Participants Serum was available for 17,297 women aged 44 to 73 collected at baseline in 1991to1996 and from 2,168 women re-sampled in 2007 to 2012. Participants' records were linked to the Swedish cancer registry to identify 82 women with incident ovarian cancer diagnosed up to 10 years after blood draw. Cases were matched 1:3 with controls by age and venipuncture date. Exposure Serum was measured for CA-125 glycovariants Sialyl-Thomsen-nouveau (STn) and Macrophage-Galactose-Lectin (MGL) using GLYVAR Ovarian I and II assays (Uniogen), conventional CA-125 (CanAg CA125 EIA, Fujirebio) and HE4 EIA (Fujirebio). Main outcome measure Ovarian cancer. Results The CA-125-STn was associated with subsequent ovarian cancer (p=0.002). In the primary analysis restricted to cases within 5 years, the area-under-the-curve for CA-125-STn was 0.68; with moving window analysis suggesting retained predictiveness up to 5-7 years. Of the cases diagnosed within 5 years, 27% were in the top 5% of CA-125-STn levels (>=2.3 U/ml), with 35% and 49% of cases diagnosed in the top 10% and 20% respectively. Our findings were replicated by independent measurements of a separate aliquot from a subset of cases and controls. Neither CA-125, HE4 nor CA-125 glycovariants detected by MGL importantly predicted subsequent ovarian cancer. Conclusions and Relevance CA-125-STn can detect ovarian cancer several years before clinical diagnosis. Further research is warranted on larger cohorts with sequential samples to determine the shape of the relationship between CA-125-STn and risk, the value of longitudinal sampling of CA-125-STn, and whether other markers could be combined with CA-125-STn to more accurately predict ovarian cancer risk.