CA-125, or cancer antigen 125, is an epitope (antigen) on the transmembrane glycoprotein MUC16, or mucin 16. This protein is expressed on the surface of tissue derived from embryonic coelomic and Müllerian epithelium including the reproductive tract. CA-125 is also expressed in other tissue such as the pleura, lungs, pericardium, intestines, and kidneys. MUC16 plays an important role in tumor proliferation, invasiveness, and cell motility.1 In patients with epithelial ovarian cancer (EOC), CA-125 may be found on the surface of ovarian cancer cells. It is shed in the bloodstream and can be quantified using a serum test.
There are a number of CA-125 assays in commercial use, and although none have been deemed to be clinically superior, there can be some differences between assays. It is important, if possible, to use the same assay when following serial CA-125 values. Most frequently, this will mean getting the test through the same laboratory.
Dr. Katherine Tucker
CA-125 has Food and Drug Administration approval for use in patients with a current or prior diagnosis of ovarian cancer to monitor treatment response, progression of disease, or disease recurrence.
It is frequently used off label in the workup of adnexal masses, while not FDA approved. CA-125 and other serum biomarkers may help determine the etiology of an adnexal mass; however, they are not diagnostic and should be used thoughtfully. It is important to have conversations with patients before ordering a CA-125 (or other serum biomarkers) about potential results and their effect on diagnosis and treatment. This will lessen some patient anxiety when tests results become available, especially in the setting of autoreleasing results under the Cures Act.
One of the reasons that CA-125 can be difficult to interpret when used as a diagnostic tool is the number of nonmalignant disease processes that can result in CA-125 elevations. CA-125 can be elevated in inflammatory and infectious disease states, including but not limited to, chronic obstructive pulmonary disease, pelvic inflammatory disease, diverticulitis, and pneumonia. Severe/critical COVID-19 infection has recently been found to be associated with increased levels of CA-125.2 It is important to obtain a complete medical history and to take specific note of any current or recent flares in inflammatory or infectious processes that could contribute to CA-125 elevations.
Special caution should be taken in premenopausal patients. The sensitivity and specificity of CA-125 are lower in this cohort of patients compared to postmenopausal women. This is multifactorial but in part due to gynecologic conditions that can increase CA-125, such as uterine fibroids and endometriosis, and the higher incidence of nonepithelial ovarian cancers (which frequently have different serum biomarkers) in younger patients. A patient’s gynecologic history, her age, and ultrasound or other imaging findings should help determine what, if any, serum biomarkers are appropriate for workup of an adnexal mass rather than the default ordering of CA-125 to determine need for referral to gynecologic oncology. If the decision has been made to take the patient to the operating room, CA-125 is not approved as a triage tool to guide who best to perform the surgery. In this case, one of two serum tumor marker panel tests that has received FDA approval for triage after the decision for surgery has been made (the multivariate index assay or the risk of ovarian malignancy algorithm) should be used.
When considering its ability to serve as a diagnostic test for ovarian cancer, the sensitivity of CA-125 is affected by the number of patients with epithelial ovarian cancer who have a test result that falls within the normal range (up to 50% of patients with stage I disease).3 The specificity of CA-125 is affected by the large number of nonmalignant conditions that can cause its elevation. Depending on the age of the patient, her menopausal status, comorbid conditions, and reason for obtaining serum biomarkers (e.g., decision for surgery has already been made), CA-125 (or CA-125 alone) may not be the best tool to use in the workup of an adnexal mass and can cause significant patient anxiety. In the setting of acute disease, such as COVID-19 infection, it may be better to delay obtaining serum biomarkers for the work-up of an adnexal mass. If delay is not feasible, then repeat serum biomarkers once the acute phase of illness has passed.
Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill.
References
1. Thériault C et al. Gynecol Oncol. 2011 Jun 1;121(3):434-43.
2. Wei X et al. J Med Virol. 2020;92(10):2036-41.
3. Zurawski VR Jr et al. Int J Cancer. 1988;42:677-80.