CA 15-3

Cancer antigen 15-3 (CA 15-3) is used to monitor response to breast cancer treatment and disease recurrence.

The reference range of serum CA 15-3 is less than 30 U/mL. The upper limit of the range varies depending on the laboratory and kit used for the test. Values obtained with different assay kits, methods, or laboratories cannot be used interchangeably.

CA 15-3 levels are most commonly used to monitor metastatic breast cancer during active therapy. Tumor marker levels must be used in conjunction with the history, physical examination, and diagnostic imaging. A decrease in marker levels during treatment can indicate tumor response, whereas stable or increasing levels despite adequate treatment can indicate that the tumor is not responding to treatment or that the tumor is recurring.

CA 15-3 measurement can also be used to survey disease recurrence after treatment of metastatic breast cancer. In the absence of measurable disease, an increase in CA 15-3 levels could indicate treatment failure. However, CA 15-3 levels can rise during the initial 4-6 weeks of starting therapy. This transient rise does not usually correlate with disease progression.

Higher CA 15-3 levels have been correlated with more advanced stages of breast cancer ^[1] or with larger tumor burden. If the tumor produces CA 15-3, marker levels will increase as the tumor grows. The highest levels may be seen in metastatic breast cancer, particularly when metastases to the liver or bones exist. However, CA 15-3 can be low or absent in all of these settings, since not all breast cancers produce CA 15-3 or early stage breast cancers may not produce detectable CA 15-3 levels. Thus, normal levels do not ensure the absence of localized or metastatic breast cancer.

Nonetheless, a retrospective study by De Cock et al found that in 62% of patients treated for early breast cancer in whom metastases were found, CA 15-3 levels were above 30 U/mL at the time that the metastases were discovered. Moreover, in 37% of patients, the higher CA 15-3 level was the first sign that resulted in diagnosis of the metastases; these CA 15-3–associated diagnoses occurred most often for liver and bone metastases (45% and 41%, respectively). ^[2]

Elevation of CA 15-3 levels can also be seen in healthy individuals, in benign conditions, and in other malignant conditions. However, CA 15-3 levels tend to remain relatively stable over time in benign conditions; thus, elevated levels need to be interpreted within the context of the patient’s history and physical examination, diagnostic imaging, and laboratory workup.

Benign causes of elevated CA 15-3 levels are as follows ^[3] :

• Chronic hepatitis

• Liver cirrhosis

• Tuberculosis

• Sarcoidosis

• Benign breast disease

• Pelvic inflammatory disease

• Endometriosis

• Systemic lupus erythematosus

• Lactation and pregnancy

Malignant causes of elevated CA 15-3 levels are as follows:

• Small cell lung cancer

• Non-small cell lung cancer

• Liver cancer

• Colon cancer

• Ovarian cancer

• Endometrial cancer

• Pancreatic cancer

Collection

Specimen: Serum

Container: Red-top tube (see the first image below), tiger-top tube (see the second image below), or gold-top tube (see the third image below). Discuss collection methods with your laboratory prior to collecting the specimen.

Collection method: Venipuncture

Panels

Serum CA 15-3 is not typically part of a panel.

CA 15-3 may also be ordered with other tests such as estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2)/neu, or other genetic expression tests.

Consideration may be given to ordering multiple tumor markers due to the heterogeneity in cell composition of each tumor. Other tumor markers for epithelial-derived carcinomas include carcinoembryogenic antigen (CEA), CA 19-9, and CA 125. ^[4]

Cancer antigen 27.29 (CA 27.29) measures the same antigen in the blood as CA 15-3. One or the other tumor marker is ordered, typically not both.

Description

Cancer antigen 15-3, or CA 15-3, is an epitope of a large transmembrane glycoprotein named MUC1 that is derived from the MUC1 gene. The MUC1 protein, also known as polymorphic epithelial mucin or epithelial membrane antigen, has a large extracellular region, a transmembrane sequence, and a cytosolic domain. This protein is frequently overexpressed and aberrantly glycosylated on its extracellular region in breast cancer. ^[5]

Physiologically, the MUC1 protein may be involved in cell adhesion by decreasing the degree of cell-to-extracellular matrix and cell-to-cell interactions. ^[5] It has been suggested that the MUC1 protein and its overexpression may be causally related to cancer invasion and metastasis.

The CA 15-3 antigen (also known as MUC1) represents sequences of mucins that are often overexpressed in malignant glandular cells, such as breast cancer. ^[6] These carbohydrate epitopes may be antigenically different than those in normal breast cells. As tumor cells shed this MUC1 antigen into the bloodstream, it is recognized by 2 monoclonal antibodies in a radioimmunoassay. These 2 antibodies target epitopes located on the peptide core of the extracellular domain of MUC1. Early stage breast cancers have a low incidence of elevated CA 15-3 levels, while higher-stage breast cancers have an increased incidence of elevated levels as well as higher absolute levels. However, not all breast cancers express the CA 15-3 antigen, so this assay cannot detect all breast cancers. The MUC1 protein can also be measured in the peripheral blood by a related test, CA 27-29.

Indications/Applications

CA 15-3 testing to screen, diagnose, and stage breast cancer

Currently, insufficient data exists to recommend the use of CA 15-3 measurement for screening, diagnosing, or staging breast cancer. ^{[7, 8]} CA 15-3 levels are elevated infrequently in early stage breast cancer or completely absent from other breast cancers, making it difficult to detect early stage cancers or those tumors that do not express this antigen. However, several studies report prognostic value of the CA 15-3 marker in early stage breast cancer. ^{[7, 9, 10]} Presence of this tumor marker may predict a worse outcome, but the implication on management of early stage breast cancer remains unclear. This marker has no clinical value in breast cancers that do not produce the CA 15-3 marker.

CA 15-3 levels may also be increased in several benign and malignant conditions. This results in low sensitivity, specificity, and positive predictive values, making it difficult to reliably screen, diagnose, or stage breast cancers. The CA 27.29 assay is slightly more sensitive for breast cancer, but its indications and limitations are identical to the CA 15-3 assay. ^[7]

CA 15-3 testing to detect recurrent disease after treatment of primary breast cancer

Currently, insufficient data exists to recommend the use of CA 15-3 testing for monitoring the recurrence of breast cancer after primary and/or adjuvant treatment of a primary breast cancer. Several studies have shown that an increase in CA 15-3 levels may predict recurrence approximately 5–6 months prior to the onset of signs or symptoms, or positivity of other tests. ^{[7, 11, 12]} However, no randomized clinical trials have shown that early detection and treatment of these asymptomatic or occult recurrences improve overall survival, disease-free survival, and quality of life. ^[7] Additionally, the cost-effectiveness and impact of increased treatment toxicity with early detection is unclear.

CA 15-3 testing for clinical management of metastatic breast cancer

The overall sensitivity and specificity of CA 15-3 for all breast cancers is low. However, the sensitivity and specificity is higher for advanced (metastatic) or recurrent disease. Studies have shown that CA 15-3 levels may increase in larger tumors and higher-stage breast cancers, which is consistent with its putative role in anti-adhesion, cancer cell invasion, and metastases. ^[5] CA 15-3 testing, in conjunction with the history, physical examination, and diagnostic imaging, can be used to monitor response of metastatic breast cancer to active therapy. ^[7]

CA 15-3 measurement, however, should not be used alone to monitor treatment response in this setting. Additionally, if no other indication of measurable disease exists (ie, via history, physical examination, or imaging), an increase in CA 15-3 levels can represent a failure of treatment. False rises in CA 15-3 levels may occur in the first 4-6 weeks of therapy, and caution should be used when interpreting these results. ^{[7, 13, 14]}

A study by Nicolini et al indicated that as a means of predicting distant metastases in asymptomatic women who have undergone curative breast cancer surgery, a marker panel combining CEA, tissue polypeptide antigen (TPA), and CA 15-3 has a sensitivity, specificity, and accuracy of 95.2%, 97.8%, and 97.9%, respectively. The analysis was carried out using an individual reference limit to define critical changes in marker levels. ^[15]

CA 15-3 testing for surgical prognosis

A study by Lasham et al reported that plasma levels of microRNA (miR)-923 and CA 15-3 at the time that patients undergo breast cancer surgery are independent prognostic markers. They may therefore help to suggest, along with standard clinicopathologic predictors, which patients require more aggressive management or closer postsurgical surveillance. ^[16]

Considerations

Breast cancer is one of several conditions that may cause elevated levels of CA 15-3. Elevated levels can be seen in healthy individuals, in benign conditions, and in other malignant conditions. Thus, elevated CA 15-3 levels could be due to conditions other than breast cancer, making interpretation and accurate diagnosis difficult.

CA 15-3 levels may be absent or low in early stage breast cancer, which precludes widespread use of this marker in screening. On the other hand, high levels of CA 15-3 can indicate metastatic disease, but currently, insufficient evidence exists to incorporate marker levels into the staging system.

A retrospective, single-center cohort study by Heylen et al indicated that 38% of patients with newly diagnosed breast cancer who have a baseline elevated CA 15-3 level of more than 30 kU/L present with primary metastatic disease, while secondary metastatic disease develops in 15% by median 74-month follow-up. In study patients, the greatest proportion of primary metastatic disease occurred with luminal-HER2–positive tumors (48%), while the largest proportion of secondary metastatic disease occurred with triple-negative tumors (24%). ^[17]

Studies have shown that early recurrence of disease can be predicted by an average of 5-6 months prior to other signs or symptoms. However, the benefit of this post-treatment monitoring is controversial since no studies have shown that measurement of this tumor marker leads to more effective therapy and an improvement in patient outcome.

Low sensitivity in early stage breast cancer, low overall specificity, and lack of effective treatment when recurrences are detected are important limitations of the CA 15-3 assay. ^[18] Prospective, randomized trials will be needed to further clarify the clinical utility and impact on patient outcome of CA 15-3 measurement.