Cancer Antigen 15-3

Cancer antigen 15-3 (CA 15-3) is a soluble form of MUC1, a high-molecular-weight transmembrane mucin expressed on the surface of glandular epithelial cells and overexpressed and shed by breast cancer cells. It is measured in serum by immunoassay in U/mL (kU/L). A related assay, CA 27.29, detects a similar epitope and has similar performance. The marker is not used for screening or diagnosis because it is insensitive in early disease and raised in many benign conditions.

The test is used to monitor response to treatment in metastatic breast cancer, together with symptoms, examination and imaging, and as an adjunct in finding recurrence. Its role in routine follow up of early breast cancer is limited, since earlier treatment on a rising marker alone has not improved survival.

Breast cancer is the commonest cancer in women worldwide, with over 2.3 million new cases and about 670 000 deaths a year. About 5 to 10% of cases present with metastases, and 20 to 30% of women with early disease later develop them. Bone is the commonest site of metastasis, followed by liver, lung and brain.

Indications. Monitoring of treatment response in metastatic breast cancer, especially in disease that is bone only or not measurable on imaging, a baseline at the start of systemic treatment, and a rising value prompting imaging when recurrence is suspected clinically.

Specimen. Serum. No fasting is needed. Stable for days at 2 to 8 °C. A baseline is taken before treatment starts, and the same assay is used for serial results.

Reference range. Under 30 U/mL (some assays under 25 or under 31.3 U/mL). About 5% of healthy women exceed 30 U/mL.

Metastatic breast cancer.

• Sensitivity is about 60 to 80% in metastatic disease and only 5 to 30% in stage I and II disease, so a normal value does not exclude cancer.
• A value over 100 U/mL in a woman with breast cancer is highly suggestive of metastases. Levels over 400 U/mL are associated with a large tumour burden, and liver and bone metastases give the highest values.
• A fall of 50% or more over 2 to 3 months suggests response, while a rise of 25% or more on two measurements 2 to 4 weeks apart suggests progression. Imaging confirms.
• A transient rise in the first 4 to 6 weeks of chemotherapy or endocrine therapy (the flare phenomenon) is not progression and is excluded before changing treatment.
• High baseline values predict a poorer prognosis.

After curative treatment. A rise may precede clinical recurrence by 5 to 6 months, but routine measurement in asymptomatic women has not improved survival and causes anxiety and extra imaging. It is used in selected cases only.

Other malignancies. Ovarian, lung, pancreatic, colorectal, liver and prostate cancers, and lymphoma.

Benign causes of raised CA 15-3. Benign breast disease, chronic liver disease and cirrhosis, hepatitis, sarcoidosis, tuberculosis, systemic lupus erythematosus, rheumatoid arthritis, kidney failure, pregnancy and lactation (mild), and ovarian cysts. Most benign values stay under 50 U/mL.

Critical values and findings needing immediate action.

• A rising CA 15-3 with new bone pain, breathlessness, jaundice, headache or neurological signs in a woman with breast cancer.
• A marked rise (over 100 U/mL) in a woman with a history of breast cancer, even without symptoms, which needs restaging.
• Hypercalcaemia or cord compression symptoms in a woman with breast cancer.

Interferences and pitfalls.

• It is not a screening or stand alone diagnostic test.
• It is normal in about 20 to 40% of women with metastatic disease, and a normal result does not mean response.
• Assays differ in range, and CA 15-3 and CA 27.29 values cannot be exchanged.
• Heterophile antibodies and human anti-mouse antibodies cause false elevation, and biotin interferes with some assays.
• The marker may rise transiently with the start of treatment, and rise with hepatic dysfunction.
• Use is limited in HER2-positive and triple negative disease when other markers or imaging are better.
• Do not treat a number alone. Imaging, examination and symptoms decide.

Special groups.

• Men with breast cancer: the same range and use.
• Pregnancy and lactation: mild rise, and the test is not used.
• Postmenopausal women with bone only disease: the marker has most value.
• Older adults with kidney or liver disease: baseline may be raised.
• Regions: where imaging is limited, the marker may help follow response, with caution about false rises.

Follow up tests. CEA, CA 125 and alkaline phosphatase, calcium, liver function tests, bone scan or PET-CT, contrast CT of chest, abdomen and pelvis, MRI of brain or spine when indicated, circulating tumour DNA, and tumour receptor status (oestrogen, progesterone, HER2) on a new biopsy of a metastasis.