Tumour Markers

These are usually glycoproteins (soluble molecules) in the blood, which can be detected by monoclonal antibodies. Each tumour marker has a variable profile of uses:

Screening

Screening tests require high sensitivity to detect early-stage disease. These tests also must have sufficient specificity to protect patients with false-positive results from unwarranted diagnostic evaluations. 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.

Assessing response to therapy

Tumour marker values returning to normal may indicate cure despite radiographic evidence of persistent disease.¹ In this circumstance, the residual tumour is frequently nonviable. 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.

This is a glycoprotein produced by prostatic epithelium. Various isoforms can be assayed, but their value is not yet certain.² The PSA level (see our dedicated record) can be elevated in:³

• Prostate cancer
• Prostatitis
• Benign prostatic hypertrophy
• Prostatic trauma
• After ejaculation

The positive predictive value of PSA levels in prostate cancer greater than 4 ng per mL is 20 to 30%. This rises to 50% when PSA levels exceed 10 ng per mL. Nevertheless 20 - 30% men with prostate cancer have PSA levels within normal ranges.³ Fewer than 2% men with PSA levels below 20 ng per mL have bone metastases from prostate cancer.¹

These markers are used in breast cancer therapy monitoring. CA15-3 is useful in prognosis.^4,5 CA 27.29 has better sensitivity and specificity than CA 15-3.

• The CA 27.29 level is elevated in approximately 33% women with early-stage breast cancer (stage I or II).
• It is also elevated in 66% women with late-stage disease (stage III or IV).⁶
• 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.⁷ 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.

Both may be superseded by the estimation of circulating tumour cells (CTC).⁸

CEA is an oncofetal glycoprotein, which is expressed in normal mucosal cells and overexpressed in adenocarcinoma, especially colorectal cancer. Mesenteric blood levels are more sensitive than peripheral.⁹ Levels exceeding 10 ng per mL are rarely due to benign disease.¹⁰

• ≤ 25 percent of patients with disease purely within the colon have an elevated CEA level. Sensitivity increases with advancing tumour stage.
• CEA values (see our dedicated record) are elevated in approximately 50 percent of patients with tumour extension to lymph nodes.
• They are elevated in 75 percent of patients with distant metastasis.¹¹

The major role for CEA levels is in following patients for relapse after intended curative treatment of colorectal cancer.

See our dedicated record on CA 125. This is a glycoprotein normally expressed in coelomic epithelium during fetal development. This epithelium lines body cavities and envelopes the ovaries. Elevated CA 125 values most often are associated with epithelial ovarian cancer, although levels also can be increased in other malignancies.¹²

• Levels are elevated in about 85% women with ovarian cancer, but in only 50% those with stage I disease. Low sensitivity limits its usefulness in ovarian cancer screening. The positive predictive value is only 20 percent, translating to five exploratory laparotomies for each ovarian cancer diagnosed. Also, survival was not improved in the women who were found through CA 125 screening to have ovarian cancer.
• Higher levels are associated with increasing bulk of disease and are highest in tumours with nonmucinous histology.¹²
• Multiple benign disorders also are associated with CA 125 elevations, presumably by stimulation of the serosal surfaces.¹³
• In postmenopausal women with asymptomatic palpable pelvic masses, CA 125 levels higher than 65 units per mL have a positive predictive value of 98 percent for ovarian cancer.¹

Levels can also be used in assessing function in chronic heart failure.¹⁴

This is the major protein of fetal serum, but it is usually undetectable after birth.

• AFP elevations (see dedicated record) are associated with hepatocellular carcinoma and nonseminomatous germ cell tumours.
• AFP levels are abnormal in 80% patients with hepatocellular carcinoma and exceed 1,000 ng per mL in 40% patients with this cancer.¹⁵
• Other gastrointestinal cancers occasionally cause elevations of AFP, but rarely to greater than 1,000 ng per mL.¹⁵
• Patients with cirrhosis or viral hepatitis may have abnormal AFP values, although usually less than 500 ng per mL.
• Pregnancy also is associated with elevated AFP levels, particularly if the pregnancy is complicated by a spinal cord defect or other abnormality.¹⁵ Where AFP levels are elevated but no abnormality is found, there is a greater level of obstetric risk (also seen with hCG levels).¹⁶

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

• Pregnancy
• Germ cell tumours
• Gestational trophoblastic disease (a rare neoplastic complication of pregnancy)

False-positive levels occur in hypogonadal states and with marijuana use.¹⁷
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.¹⁸ Tumour markers are followed every one to two months for one year after treatment, then quarterly for one year, and less frequently thereafter.¹⁹ 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 also have been reported in patients with other malignancies.

• It has a sensitivity and specificity of 80 to 90 percent for pancreatic cancer
• It has a sensitivity of 60 to 70 percent 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.
• CA 19-9 levels above 1,000 units per mL predict the presence of metastatic disease.²⁰

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.²¹

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.²²

1. Perkins GL, Slater ED, Sanders GK, et al; Serum tumor markers. Am Fam Physician. 2003 Sep 15;68(6):1075-82. [abstract]
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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. [abstract]
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7. 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. [abstract]
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9. Ivankovics IG, Fernandes LC, Saad SS, et al; Peripheral and mesenteric serum levels of CEA and cytokeratins, staging and histopathological variables in colorectal adenocarcinoma. World J Gastroenterol. 2008 Nov 21;14(43):6699-703. [abstract]
10. Fletcher RH; Carcinoembryonic antigen. Ann Intern Med. 1986 Jan;104(1):66-73. [abstract]
11. No authors listed; Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology. J Clin Oncol. 1996 Oct;14(10):2843-77. [abstract]
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14. Vizzardi E, Nodari S, D'Aloia A, et al; CA 125 tumoral marker plasma levels relate to systolic and diastolic ventricular function and to the clinical status of patients with chronic heart failure. Echocardiography. 2008 Oct;25(9):955-60. Epub 2008 Sep 2. [abstract]
15. 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. [abstract]
16. 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. [abstract]
17. 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. [abstract]
18. 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. [abstract]
19. 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.
20. Steinberg W; The clinical utility of the CA 19-9 tumor-associated antigen. Am J Gastroenterol. 1990 Apr;85(4):350-5. [abstract]
21. 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. [abstract]
22. Widschwendter M, Menon U; Circulating Methylated DNA: A New Generation of Tumor Markers. Clin Cancer Res. 2006 Dec 15;12(24):7205-8.

• 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.
• Cancer Research UK