Ovarian cancer is the most fatal of the gynecologic cancers because it is so often diagnosed at an advanced stage; only 15% of ovarian tumors are detected while still localized, and for the 60% of cases that go undetected until they are metastatic, 5-year survival is only 27%.1

Early detection by monitoring biomarkers has potential to improve the survival rate, but CA-125, the most extensively studied serum marker for ovarian cancer, is elevated in only 50% of women with localized disease. A recent study led by researchers at the Wake Forest School of Medicine suggests that monitoring total serum calcium and ionized serum calcium may provide a better means to identify women with ovarian cancer at a preclinical phase.2

Many ovarian cancers express high levels of parathyroid hormone-related protein, which increases serum calcium by accelerating the release of calcium from the bone and suppressing renal calcium excretion. Although few ovarian cancers are associated with hypercalcemia, the researchers postulated that, serum calcium may rise gradually from normal to the upper limit of normal range before reaching hypercalcemic levels in women with ovarian cancer.

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“Everyone has calcium and the body regulates it very tightly,” said Halcyon G. Skinner, PhD, one of the study authors. “We know that some rare forms of ovarian cancer are associated with very high calcium, so it’s worth considering whether more common ovarian cancers are associated with moderately high calcium.”

To test their hypothesis, the investigators examined data on serum calcium from two prospective cohorts: the Third National Health and Nutrition Examination Survey (NHANES 3) and the NHANES Epidemiological Follow-up Study (NHEFS).

In NHANES 3, there were 11 deaths from ovarian cancer over 95,556 person-years of follow-up; the risk rose 52% for each 0.1 mmol/L increase in total serum calcium and 144% for each 0.1 mmol/L increase in ionized serum calcium.

In NHEFS, there were eight ovarian cancer cases over 31,089 person-years of follow-up, with a 63% higher risk with each 0.1 mmol/L increase in total serum calcium. This study must be considered preliminary because of the small number of cases. Moreover, it is possible that ovarian cancers of a hypercalcemic type were over-represented in the sample; this cancer type tends to occur in younger women, yet the median age at death in NHANES 3 was 68 years.

The key question is, do high serum calcium levels cause or result from ovarian cancer? The long latency period of ovarian cancer—estimated at 15 to 20 years—is consistent with the idea that preclinical cancer causes a gradual rise in serum calcium, rather than the other way around. The following lists possible biomarkers for ovarian cancer are currently under investigation3:

  • CA-125 has a sensitivity of 50% to 60% and specificity of 90% for early-stage ovarian cancer in postmenopausal women and is useful in evaluating response to therapy. However, CA-125 is not expressed in approximately 20% of ovarian cancers and may fluctuate with the menstrual cycle and pregnancy. It may be also elevated in benign conditions such as liver cirrhosis, endometriosis, and peritonitis. Therefore, monitoring CA-125 is not recommended for the general population.
  • Human epididymis protein 4 (HE4) is overexpressed in ovarian carcinoma and has been approved by the US Food and Drug Administration for monitoring relapse or progression of epithelial ovarian carcinoma. Monitoring HE4 in conjunction with CA-125 may have greater sensitivity than either biomarker used alone.
  • Mesothelin is overexpressed in most epithelial ovarian cancers and is present in urine in 42% of women with early-stage ovarian cancer. High levels of mesothelin predict poor survival following surgery.
  • Human prostasin is overexpressed in malignant ovarian epithelial cells and stroma with sensitivity of 92% and specificity of 94%.


1) American Cancer Society. Cancer Facts & Figures 2013. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf. Accessed March 6, 2013.

2) Schwartz GG, Skinner HG. Prospective studies of total and ionized serum calcium in relation to incident and fatal ovarian cancer. Gynecol Oncol. 2013 Jan 9. pii: S0090-8258(13)00005-X

3) Sarojini S, Tamir A, Lim H, et al. Early detection biomarkers for ovarian cancer. J Oncol. 2012;2012:709049.