Cancer Antigen 125

Cancer antigen 125 (CA 125, MUC16) is a high-molecular-weight glycoprotein expressed by coelomic epithelium: the ovary, fallopian tube, endometrium, peritoneum, pleura and pericardium. It is measured in serum by immunoassay in U/mL (kU/L). It is raised in about 80% of epithelial ovarian cancers overall and in 50% of those confined to the ovary. It is neither sensitive nor specific for screening.

The test helps to triage women with a pelvic mass, supports the diagnosis of ovarian cancer, and monitors response to chemotherapy and recurrence. It is combined with ultrasound features and menopausal status in the risk of malignancy index, and in algorithms with HE4.

Ovarian cancer is the eighth commonest cancer in women, with about 300 000 new cases and 200 000 deaths a year worldwide. Most are diagnosed at stage III to IV because symptoms are vague, and five year survival is 30 to 45%. Lifetime risk is about 1.3% and rises to 40% or more with BRCA1 variants.

Indications. Persistent bloating, early satiety, abdominal or pelvic pain, urinary urgency, a pelvic mass, ascites in a woman over 50 years, monitoring during and after treatment of epithelial ovarian cancer, and assessment of high risk women (with imaging).

Specimen. Serum. No fasting is needed. Stable for days at 2 to 8 °C. Menstrual cycle phase and pregnancy affect the level, so record them.

Reference range. Under 35 U/mL (under 35 kU/L) in most assays. About 1% of healthy women have values over 35.

Risk of malignancy index. Ultrasound score (0, 1 or 3) multiplied by menopausal score (1 or 3) multiplied by CA 125. An index over 200 indicates high risk and needs referral to a gynaecological oncology team.

Ovarian cancer.

• Pelvic mass in a postmenopausal woman with CA 125 over 35 U/mL: raised risk of malignancy, with a positive predictive value of 80 to 95%.
• Premenopausal women: values over 35 U/mL are frequent with benign disease, and a value over 200 U/mL increases the chance of cancer.
• CA 125 is raised in 50 to 60% of stage I disease and over 90% of advanced disease. It is less often raised in mucinous and borderline tumours, and in clear cell cancers.
• HE4 added to CA 125 improves specificity (ROMA index), especially in premenopausal women and endometriosis.
• A level over 65 U/mL with ascites and a pelvic mass makes advanced ovarian cancer likely. A CA 125 to CEA ratio over 25 supports an ovarian rather than gastrointestinal primary.

Monitoring.

• Preoperative baseline and a fall to normal within 3 cycles of chemotherapy indicates response. A decline of at least 50% in 2 samples (or a half life under 20 days) is a favourable sign.
• A rise to twice the upper reference limit (or twice the nadir) on two samples indicates recurrence, often 3 to 5 months before clinical evidence. Early treatment on a CA 125 rise alone does not improve survival, so treatment decisions follow imaging and symptoms.

Other malignancies. Endometrial, fallopian tube and primary peritoneal cancers, adenocarcinoma of the lung, breast, pancreas, colon and stomach, and lymphoma.

Benign causes of raised CA 125.

• Gynaecological: menstruation, pregnancy (first trimester), endometriosis (often 50 to 200 U/mL), fibroids, adenomyosis, pelvic inflammatory disease, ovarian cysts, and ovarian hyperstimulation.
• Peritoneal and serosal: ascites from cirrhosis, heart failure, nephrotic syndrome, peritonitis, tuberculosis, pleural effusion, and pericarditis.
• Other: liver disease, pancreatitis, kidney failure, recent surgery or laparoscopy, sarcoidosis, systemic lupus erythematosus, and heart failure.

Critical values and findings needing immediate action.

• CA 125 over 200 U/mL with a pelvic mass or ascites: urgent referral to a gynaecological cancer service.
• A rising CA 125 in a woman after ovarian cancer treatment, with symptoms or imaging findings.
• Raised CA 125 with a suspected bowel obstruction, large ascites or breathlessness from pleural effusion.
• Persistent raised value in a woman with BRCA variants with symptoms.

Interferences and pitfalls.

• CA 125 is not a screening test for ovarian cancer in the general population, and screening has not reduced deaths.
• A normal value does not exclude ovarian cancer, particularly early stage, mucinous and borderline tumours.
• Raised values in a premenopausal woman are usually benign.
• Menstruation raises values transiently, and the test is best taken outside menstruation.
• Heterophile antibodies and human anti-mouse antibodies cause false positives, and biotin interferes with some assays.
• Different assay generations (OC125, M11) give different values, and serial measurements need the same method.
• Recent chemotherapy and surgery cause fluctuations, and a rise after surgery is expected for a few weeks.
• Ascites and serositis raise values without ovarian cancer.

Special groups.

• Postmenopausal women: the most informative group for CA 125, with ultrasound.
• Premenopausal women: poor specificity, and endometriosis and pregnancy are frequent causes.
• Pregnancy: first trimester levels may reach several hundred U/mL, and CA 125 is not used.
• Women with BRCA1 or BRCA2 variants: surveillance with CA 125 and ultrasound does not replace risk reducing salpingo oophorectomy.
• Regions: tuberculous peritonitis is a frequent cause of raised CA 125 and ascites in endemic areas.

Follow up tests. Pelvic ultrasound, CT or MRI of abdomen and pelvis, HE4 and ROMA index, CEA and CA 19-9, AFP, hCG and LDH in young women, liver function tests, ascitic fluid cytology and protein, tuberculosis tests, laparoscopy and histology, genetic testing (BRCA1, BRCA2, mismatch repair genes), and tumour tissue homologous recombination testing.