Tumour Markers

oPatientPlus articles are written by UK doctors and are based on research evidence, UK and European Guidelines. They are designed for health professionals to use, so you may find the language more technical than the condition leaflets.

These are usually glycoproteins (soluble molecules) in the blood, which can be detected by monoclonal antibodies. Highly raised levels of a tumour marker can provide helpful information but inappropriate use can have economic implications, cause patients additional anxiety and distress, and unnecessary investigations may be associated with side-effects and may delay correct diagnosis and treatment.[1] Each tumour marker has a variable profile of uses:

Screening

Screening tests require high sensitivity to detect early-stage disease. No tumour marker has yet demonstrated a survival benefit in randomised controlled trials of screening in the general population.

Disease staging

For determining diagnosis and prognosis.

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Assessing response to therapy

  • Tumour marker values returning to normal may indicate cure despite radiographic evidence of persistent disease.[2] In this circumstance, the residual tumour is often non-viable.
  • Conversely, tumour marker levels may rise after effective treatment (possibly related to cell lysis), but the increase may not necessarily mean treatment failure. However, a consistent increase in tumour marker levels, coupled with lack of clinical improvement, may indicate treatment failure.
  • Residual elevation after definitive treatment usually indicates persistent disease.
  • Following tumour marker response is particularly useful when other evidence of disease is not readily accessible.

Monitoring for cancer recurrence

When monitoring these patients, tumour marker levels should be determined only when there is a potential for meaningful treatment.

Tumour marker Associated primary tumour Other conditions which may yield positive results
CA 27.29 Breast cancer. Colonic, gastric, hepatic, lung, pancreatic, ovarian and prostate cancers.
Breast, liver and kidney disorders, ovarian cysts.
CEA Colorectal cancer. Lung, gastric, pancreatic, breast, bladder cancers, medullary thyroid and other head and neck, cervical and hepatic cancers, lymphoma, melanoma. Cigarette smoking, peptic ulcers, inflammatory bowel disease, pancreatitis, hypothyroidism, cirrhosis, biliary obstruction.
CA 19-9 Pancreatic and biliary tract cancers. Colonic, oesophageal and hepatic cancers, pancreatitis, biliary disease, cirrhosis.
AFP Hepatocellular carcinoma, nonseminomatous germ cell tumours. Gastric, biliary and pancreatic cancers, cirrhosis, viral hepatitis, pregnancy.
b-hCG Nonseminomatous germ cell tumours, gestational trophoblastic disease. Rarely elevated in gastrointestinal cancers, hypogonadal states and marijuana use.
CA-125 Ovarian cancer. Endometrial, Fallopian tube, breast, lung, oesophageal, gastric, hepatic and pancreatic cancers, menstruation, pregnancy, fibroids, ovarian cysts, pelvic inflammation, cirrhosis, ascites, pleural and pericardial effusions, endometriosis.
PSA Prostate cancer. Prostatitis, benign prostatic hypertrophy, prostatic trauma, after ejaculation.

In certain situations, the use of a combination of tumour markers may be appropriate such as:[1]

  • Measurement of both human chorionic gonadotrophin (hCG) and alpha-fetoprotein (AFP) is mandatory in patients in whom testicular or other germ cell cancers are strongly suspected (these markers are not raised in all such patients).
  • Measurement of AFP and hCG is mandatory in the management of germ cell tumours.
  • In some high-risk patients, measurement of AFP, CA-125, or CA 19-9 may aid early detection of hepatocellular carcinoma, ovarian cancer or pancreatic cancer.

See separate article Prostate Specific Antigen (PSA).

  • The positive predictive value of PSA levels in prostate cancer greater than 4 ng/mL is 20-30%. This rises to 50% when PSA levels exceed 10 ng/mL.
  • Nevertheless, 20-30% of men with prostate cancer have PSA levels within normal ranges.[3]
  • Fewer than 2% of men with PSA levels below 20 ng/mL have bone metastases from prostate cancer.[2]

CA 15-3 and CA 27.29 are markers used in breast cancer therapy monitoring. Both may be superseded by the estimation of circulating tumour cells (CTCs).[4]

CA 15-3

CA 27.29

CA 27.29 has better sensitivity and specificity than CA 15-3.

  • The CA 27.29 level is elevated in approximately 33% of women with early-stage breast cancer (stage I or II).
  • It is also elevated in 66% of women with late-stage disease (stage III or IV).[7]
  • CA 27.29 lacks predictive value in the earliest stages of breast cancer and so has no role in screening for or diagnosing the malignancy.
  • One trial has shown it may be possible to detect asymptomatic recurrence (in patients at high risk - stage II or III) after curative treatment.[8] CA 27.29 was highly specific and sensitive in detecting preclinical metastasis, and this may lead to prompt imaging of probable sites of metastasis, possibly decreasing morbidity because of earlier treatment.

See separate article Carcinoembryonic Antigen (CEA).

See separate article Cancer Antigen 125 (CA-125).

  • AFP elevations (see separate Alpha-fetoprotein (AFP) article) are associated with hepatocellular carcinoma and nonseminomatous germ cell tumours.
  • AFP levels are abnormal in 80% of patients with hepatocellular carcinoma and exceed 1,000 ng/mL in 40% of patients with this cancer.[9] In conjunction with abdominal ultrasonography, it is recommended that AFP be measured at six-monthly intervals in patients at high risk of hepatocellular carcinoma (especially those with liver cirrhosis related to hepatitis B or hepatitis C).[1]
  • Other gastrointestinal cancers occasionally cause elevations of AFP, but rarely to greater than 1,000 ng/mL.[9] AFP may also be raised in patients with lung cancer.
  • Patients with cirrhosis or viral hepatitis may have abnormal AFP values, although usually less than 500 ng/mL.
  • Pregnancy also is associated with elevated AFP levels, particularly if the pregnancy is complicated by a spinal cord defect or other abnormality.[9] Where AFP levels are elevated but no abnormality is found, there is a greater level of obstetric risk (also seen with hCG levels).[10]

This is normally produced by the placenta. Elevated b-hCG levels are most commonly associated with:

  • Pregnancy.
  • Germ cell tumours.
  • Gestational trophoblastic disease.
  • False-positive levels occur in lung cancer, chronic kidney disease, menopause, hypogonadal states and with marijuana use.[11]

Following AFP and b-hCG levels is imperative in monitoring response to treatment. Patients with AFP and b-hCG levels that do not decline as expected after treatment, have a significantly worse prognosis, and changes in therapy should be considered.[12] Tumour markers are followed every one to two months for one year after treatment, then quarterly for one year, and less frequently thereafter.[13] AFP or b-hCG elevation is frequently the first evidence of germ cell tumour recurrence.

Elevated levels of CA 19-9, an intracellular adhesion molecule, occur primarily in patients with pancreatic and biliary tract cancers, but may also be raised in colorectal, gastric, hepatocellular, oesophageal and ovarian cancers.

  • It has a sensitivity and specificity of 80-90% for pancreatic cancer.
  • It has a sensitivity of 60-70% for biliary tract cancer.
  • Benign conditions such as cirrhosis, cholestasis, cholangitis and pancreatitis also result in elevations, although values are usually less than 1,000 units per mL. May also be raised in diabetes mellitus and irritable bowel syndrome.
  • CA 19-9 levels above 1,000 units per mL predict the presence of metastatic disease.[14] Lack of sensitivity and specificity restrict the use of CA 19-9 measurement in the early diagnosis of pancreatic cancer but it may complement other diagnostic procedures, especially in the absence of cholestasis.[1]

Calcitonin has a role in diagnosis, detecting recurrence and monitoring treatment in patients with medullary thyroid cancer.

Can be used in detecting recurrence and monitoring treatment in patients with follicular or papillary thyroid cancer.

  • Paraproteins can also be measured in urine.
  • Can be used in the diagnosis, detecting recurrence and monitoring treatment in patients with B-cell proliferative disorders such as multiple myeloma.

Microphthalmia transcription factor (Mitf) is important in melanocyte development and melanoma growth. It has been investigated regarding its expression as a marker for circulating melanoma cells in blood and to determine the correlation with disease stage and survival in melanoma patients. It can detect subclinical metastatic disease and predict treatment outcome in melanoma patients.[15]

Circulating nucleic acids may be biomarkers that could be used in the early detection of cancer. They could also be used to follow the progression of patients with cancer. Methylated DNA is one such nucleic acid-based marker. DNA is a very stable molecule and can be detected using simple polymerase chain reaction-based approaches.[16]

Further reading & references

  1. Sturgeon CM, Lai LC, Duffy MJ; Serum tumour markers: how to order and interpret them. BMJ. 2009 Sep 22;339:b3527. doi: 10.1136/bmj.b3527.
  2. Perkins GL, Slater ED, Sanders GK, et al; Serum tumor markers. Am Fam Physician. 2003 Sep 15;68(6):1075-82.
  3. No authors listed; Prostate-specific antigen (PSA) best practice policy. American Urological Association (AUA). Oncology (Williston Park). 2000 Feb;14(2):267-72, 277-8, 280 passim.
  4. Saad A, Abraham J; Role of tumor markers and circulating tumors cells in the management of breast cancer. Oncology (Williston Park). 2008 Jun;22(7):726-31; discussion 734, 739, 743-4.
  5. Martin A, Corte MD, Alvarez AM, et al; Prognostic value of pre-operative serum CA 15.3 levels in breast cancer. Anticancer Res. 2006 Sep-Oct;26(5B):3965-71.
  6. Velaiutham S, Taib NA, Ng KL, et al; Does the pre-operative value of serum CA15-3 correlate with survival in breast cancer? Asian Pac J Cancer Prev. 2008 Jul-Sep;9(3):445-8.
  7. Gion M, Mione R, Leon AE, et al; Comparison of the diagnostic accuracy of CA27.29 and CA15.3 in primary breast cancer. Clin Chem. 1999 May;45(5):630-7.
  8. Chan DW, Beveridge RA, Muss H, et al; Use of Truquant BR radioimmunoassay for early detection of breast cancer recurrence in patients with stage II and stage III disease. J Clin Oncol. 1997 Jun;15(6):2322-8.
  9. Johnson PJ; The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis. 2001 Feb;5(1):145-59.
  10. Chandra S, Scott H, Dodds L, et al; Unexplained elevated maternal serum alpha-fetoprotein and/or human chorionic gonadotropin and the risk of adverse outcomes. Am J Obstet Gynecol. 2003 Sep;189(3):775-81.
  11. Fowler JE Jr, Platoff GE, Kubrock CA, et al; Commercial radioimmunoassay for beta subunit of human chorionic gonadotropin: falsely positive determinations due to elevated serum luteinizing hormone. Cancer. 1982 Jan 1;49(1):136-9.
  12. Mazumdar M, Bajorin DF, Bacik J, et al; Predicting outcome to chemotherapy in patients with germ cell tumors: the value of the rate of decline of human chorionic gonadotrophin and alpha-fetoprotein during therapy. J Clin Oncol. 2001 May 1;19(9):2534-41.
  13. Bosl GJ, Bajorin DF, Sheinfeld J, Motzer RJ, Chaganti RS. Cancer of the testis. In: DeVita VT, Hellman S, Rosenberg SA, et al., eds. Cancer, principles and practice of oncology. 6th ed. Philadelphia: Lippincott, Williams & Wilkins, 2001:1491-518.
  14. Steinberg W; The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990 Apr;85(4):350-5.
  15. Koyanagi K, O'Day SJ, Gonzalez R, et al; Microphthalmia transcription factor as a molecular marker for circulating tumor cell detection in blood of melanoma patients. Clin Cancer Res. 2006 Feb 15;12(4):1137-43.
  16. Widschwendter M, Menon U; Circulating Methylated DNA: A New Generation of Tumor Markers. Clin Cancer Res. 2006 Dec 15;12(24):7205-8.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. EMIS has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions. For details see our conditions.

Original Author:
Dr Hayley Willacy
Current Version:
Last Checked:
22/06/2011
Document ID:
3178 (v23)
© EMIS