CA 19-9, CA 72-4, CA 50, CA 15-3 and CA 125 tumor markers (cancer antigens)

CA 72-4 Tumor Marker

Indications:

• Monitoring disease course and treatment response in gastric (stomach) carcinoma.
• Monitoring disease course and treatment response in certain types of ovarian cancer, particularly mucinous subtypes.

Biology: CA 72-4 (Tumor-Associated Glycoprotein 72, TAG-72) is a high-molecular-weight mucin-like glycoprotein (~220-1000 kDa, 400 kDa often cited). It is expressed during fetal development but is found at very low levels in most healthy adult tissues.

Interpretation:

• Normal Range: Upper limit typically < 4.0 - 6.9 U/mL (highly assay-dependent).
• Elevated Levels:
  • Most commonly elevated in gastric cancer (adenocarcinoma). Sensitivity varies with stage (higher in advanced disease). Often used in combination with CEA for improved monitoring.
  • Also elevated in a significant proportion of mucinous ovarian cancers. May be elevated in other ovarian cancer types as well.
  • Can be elevated less frequently in colorectal, pancreatic, breast, and lung cancers.
  • Benign Conditions: Mild elevations (e.g., up to ~7 U/mL or slightly higher) can occur in benign gastrointestinal diseases (pancreatitis, gastritis, diverticulitis), liver disease (cirrhosis), benign ovarian conditions (cysts), rheumatic diseases, and benign lung diseases.

Use: Primarily for monitoring diagnosed gastric or ovarian cancer, particularly in combination with other markers (CEA for gastric, CA 125 for ovarian). Characterized by relatively high specificity for malignancy compared to some other CA markers.

CA 50 Tumor Marker

Indications:

• Historically investigated for pancreatic carcinoma monitoring, but generally considered less useful than CA 19-9.

Biology: CA 50 is a carbohydrate antigen, specifically a sialylated derivative of the Lewis(a) blood group antigen, similar but distinct from CA 19-9. It is a glycolipid.

Interpretation:

• Normal Range: Upper limit typically < 20 - 25 U/mL.
• Elevated Levels:
  • Can be elevated in pancreatic cancer, colorectal cancer, gastric cancer, lung cancer, and others.
  • Also frequently elevated in benign conditions, particularly liver cirrhosis and pancreatitis (reportedly up to 18% of patients, sometimes > 100 U/mL).

Use: Largely superseded by CA 19-9 for pancreatic cancer due to better performance characteristics. CA 50 offers no significant advantage and is less specific. It is rarely used in routine clinical practice today.

CA 15-3 Tumor Marker

Indications:

• Primarily used for monitoring therapy effectiveness and detecting recurrence in patients with diagnosed breast carcinoma, especially metastatic disease.

Biology: CA 15-3 measures epitopes on a large, transmembrane mucin glycoprotein called MUC1. This protein is normally expressed by various glandular epithelial cells, including breast ducts. In breast cancer, MUC1 is often overexpressed, aberrantly glycosylated, and shed into the circulation. CA 15-3 assays detect soluble forms of this altered MUC1 protein. Molecular weight is very high (~300-500 kDa).

Interpretation:

• Normal Range: Upper limit typically < 25 - 30 U/mL in healthy non-pregnant women.
• Elevated Levels:
  • Most commonly elevated in metastatic breast cancer. Sensitivity is low in early-stage disease (~10-30%) but increases with stage (~50-90% in metastatic disease). Levels often correlate with tumor burden and response to therapy. Rising levels strongly suggest recurrence or progression.
  • Can also be elevated in other cancers, including ovarian, lung, endometrial, pancreatic, liver, and colorectal cancer, particularly in advanced stages.
  • Benign Conditions: Moderate increases can occur in benign breast disease (mastopathy - though original text says usually not increased), benign liver disease (hepatitis, cirrhosis - up to ~50 U/mL reported), benign ovarian conditions, pelvic inflammatory disease, and endometriosis.
  • Pregnancy: Levels increase, especially during the third trimester (up to ~50 U/mL reported).

Use: Established marker for monitoring metastatic breast cancer alongside clinical and imaging assessment. Not useful for screening or initial diagnosis.

CA 125 Tumor Marker

Indications:

• Primarily used for monitoring therapy effectiveness and detecting recurrence in patients with diagnosed epithelial ovarian carcinoma (especially serous type).
• Sometimes used pre-operatively to help assess the likelihood of malignancy in women with a pelvic mass.
• Under investigation for ovarian cancer screening in high-risk women (e.g., BRCA mutation carriers), usually combined with transvaginal ultrasound, but not recommended for general population screening.

Biology: CA 125 (Cancer Antigen 125 or MUC16) is a very large glycoprotein (molecular weight > 200 kDa, can be millions) expressed during fetal development by tissues derived from the coelomic epithelium (lining body cavities like pleura, pericardium, peritoneum). In adults, it's found on the surface of cells lining these cavities, as well as fallopian tubes, endometrium, endocervix, and pancreas.

Interpretation:

• Normal Range: Upper limit typically < 35 U/mL. Some guidelines use a higher cutoff (e.g., 65 U/mL) to increase specificity when evaluating a pelvic mass.
• Elevated Levels:
  • Most significantly elevated in epithelial ovarian cancer (~80% overall, higher in later stages). Levels often correlate with tumor burden and response to treatment. Rising levels usually indicate recurrence.
  • Can also be elevated in other malignancies: Endometrial, fallopian tube, pancreatic, lung, breast, colorectal, gastric cancers.
  • Benign Conditions: Frequently elevated in various non-malignant conditions, limiting its diagnostic specificity. Causes include:
    • Gynecological: Endometriosis, uterine fibroids, pelvic inflammatory disease (PID), benign ovarian cysts, menstruation, pregnancy (especially first trimester).
    • Non-Gynecological: Peritonitis, pancreatitis, liver disease (hepatitis, cirrhosis), heart failure, renal failure, autoimmune diseases, recent surgery involving the peritoneum. Any condition causing irritation or inflammation of the peritoneum, pleura, or pericardium can raise CA 125.

Use: Standard marker for monitoring ovarian cancer treatment and recurrence. Use for diagnosis is limited by low specificity due to elevations in many benign conditions, especially in premenopausal women.

Testing Procedure (for CA markers)

• Sample Type: Blood serum.
• Preparation: No specific patient preparation like fasting is generally required. For CA 125, levels can fluctuate with the menstrual cycle, so consistent timing relative to the cycle might be considered for serial monitoring if relevant.
• Collection: Standard venipuncture (blood draw from a vein).
• Analysis: Measured in a clinical laboratory using specific immunoassays.

General Limitations

These Cancer Antigen markers share common limitations:

• Lack of Specificity: Can be elevated in various benign inflammatory or physiological conditions.
• Lack of Sensitivity: Often normal in early-stage cancers.
• Not for Screening: Generally unsuitable for screening asymptomatic populations (except potentially CA 125 in very high-risk women).
• Monitoring Focus: Most valuable for monitoring trends over time in diagnosed patients, not for single-point diagnosis.

References

1. National Cancer Institute (NCI). (n.d.). Tumor Markers. Retrieved from https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
2. American Cancer Society (ACS). (2023). Tumor Markers. Retrieved from https://www.cancer.org/cancer/diagnosis-staging/tests/tumor-markers.html
3. Duffy, M. J., Lamerz, R., Haglund, C., Nicolini, A., Topolcan, O., Sturgeon, C., & Hayes, D. F. (2014). Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report. *Annals of Oncology*, 25(3), 561–569. https://doi.org/10.1093/annonc/mdt594 (Focus on CA 19-9)
4. Duffy, M. J., Sturgeon, C. M., Soletormos, G., Barak, V., Bossuyt, P. M. M., Diamandis, E. P., ... & Hayes, D. F. (2015). Validation of new cancer biomarkers: a position statement from the European group on tumor markers. *Clinical Chemistry*, 61(6), 809–820. https://doi.org/10.1373/clinchem.2015.239861
5. Practice Committee of the American Society for Reproductive Medicine. (2012). Role of tubal surgery in the era of assisted reproductive technology: a committee opinion. *Fertility and Sterility*, 97(3), 539–545. https://doi.org/10.1016/j.fertnstert.2011.12.025 (Discusses CA 125 in endometriosis context)
6. Lab Tests Online. (Search for specific markers like CA 19-9, CA 125, CA 15-3). Retrieved from https://labtestsonline.org/