Prospective studies of total and ionized serum calcium in relation to incident and fatal ovarian cancer.

OBJECTIVE Biological markers that could aid in the detection of ovarian cancer are urgently needed. Many ovarian cancers express parathyroid hormone-related protein, which acts to raise calcium levels in serum. Thus, we hypothesized that high serum calcium levels might predict ovarian cancer. METHODS We examined the associations between total and ionized serum calcium and ovarian cancer mortality in the Third National Health and Nutrition Survey (NHANES III) using Cox proportional hazard models. We then examined the associations of serum calcium with incident ovarian cancer in a second prospective cohort, the NHANES Epidemiological Follow-up Study (NHEFS). RESULTS There were eleven deaths from ovarian cancer over 95,556 person-years of follow-up in NHANES III. After multivariable adjustment, the risk for fatal ovarian cancer was 52% higher for each 0.1 mmol/L increase in total serum calcium (RH=1.52, 95% CI 1.06-2.19) and 144% higher for each 0.1 mmol/L increase in ionized serum calcium (RH=2.44, 95% CI=1.45-4.09). Associations persisted after adjusting for nulliparity and the use of oral contraceptives. Eight incident ovarian cancers occurred over 31,089 person-years of follow-up in the NHEFS. After adjusting for covariates, there was a 63% higher risk for ovarian cancer with each 0.1 mmol/L increase in total serum calcium (95% CI 1.14-2.34). Similar results were observed for albumin-adjusted serum calcium. CONCLUSIONS Higher serum calcium may be a biomarker of ovarian cancer. This is the first report of prospective positive associations between indices of calcium in serum and ovarian cancer. Our findings require confirmation in other cohorts.