Elevated Serum Calcium as a Biological Marker For Ovarian Cancer

Background: Biological markers useful for detecting ovarian cancer at early stages are urgently needed. Because a subset of ovarian cancers is associated with hypercalcemia (serum calcium greater than the normal reference range), we hypothesized that high-normal serum calcium levels might be associated with ovarian cancer in general. Methods: We examined 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 associations of serum calcium with incident ovarian cancer in a second prospective cohort, the NHANES Epidemiological Follow-up Study (NHEFS). Results: In NHANES III, eleven deaths from ovarian cancer occurred over 95,556 person-years of follow-up. After adjustment for age, height, body mass index, and cigarette smoking, the risk for fatal ovarian cancer increased 52% for each 0.1 mmol/L increase in total serum calcium (RH = 1.52, 95% CI 1.06–2.19) and 144% per each 0.1 mmol/L increase in ionized serum calcium (RH = 2.44, 95% CI = 1.45–4.09). Significant associations persisted after adjustment for established ovarian cancer risk factors including nulliparity and the never use of oral contraceptives. In the NHEFS, 8 incident ovarian cancers occurred over 31,089 person-years of follow-up. After adjusting for covariates, there was a 63% increase in the risk for ovarian cancer for 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: These findings suggest that 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. These findings require confirmation in other cohorts.