Tumour markers

What are tumour markers?

Tumour markers 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 and cause patients additional anxiety and distress. Additionally, unnecessary investigations may be associated with side-effects and may delay correct diagnosis and treatment.¹

Tumour markers can be categorised according to various criteria, including their nature (eg, protein, nucleic acid, metabolite, and radiographic biomarker), their function (eg, receptor and mutation), the type of sample in which they are measured (eg, blood-derived), their clinical purpose (eg, screening, early detection, and recurrence monitoring), or the techniques employed for detecting them (eg, immunoassays and molecular methods).² Each tumour marker has a variable profile of uses.

An ideal tumour marker should exhibit high specificity and sensitivity, enable minimally invasive or non-invasive testing, and be consistently and accurately measurable across different laboratory settings, using a simple, cost-effective method. Additionally, it should be related to tumour biology, have a clear biological association with tumour characteristics and/or treatment response mechanisms.³

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.

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 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.¹

Monitoring for cancer recurrence

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

In certain situations, the use of a combination of tumour markers may be appropriate such as:⁸

• 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.

Prostate specific antigen

See also the separate Prostate specific antigen (PSA) article.

• 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.⁹

• A personalised strategy can reduce the harms effects of screening, maintaining the reduction of metastases and death, according the European Randomized Study of Screening for Prostate Cancer.¹⁰ The algorithm proposed by EAU is applied to well-informed subjects and starts with a baseline PSA that will determine the periodicity of subsequent measurements.

Cancer antigens 15-3 and 27.29

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).¹¹

CA 15-3

• CA15-3 is useful in prognosis¹²¹³.

• CA 15-3 may also be raised in acute hepatitis, chronic liver diseases (eg, cirrhosis, chronic active hepatitis, chronic kidney disease, colitis and some skin conditions⁸.

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 increases in women with late-stage disease (stage III or IV).¹⁴

• 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.

• It may be possible to detect asymptomatic recurrence (in patients at high risk - stage II or III) after curative treatment.¹⁵ CA 27.29 is specific and sensitive in detecting pre-clinical metastasis and this may lead to prompt imaging of probable sites of metastasis, possibly decreasing morbidity because of earlier treatment.

Carcinoembryonic antigen

See the separate Carcinoembryonic antigen (CEA) article.

Cancer antigen 125

See the separate Cancer antigen 125 (CA 125) article.

Alpha-fetoprotein

See the separate Alpha-fetoprotein (AFP) article.

• AFP elevations are associated with hepatocellular carcinoma and nonseminomatous germ cell tumours.

• The utility of AFP is limited because of both low sensitivity and specificity, and discrepancies among the different methods of measurements. Moreover, its accuracy varies according to patient characteristics and the AFP cut-off values used. Combination of AFP with novel biomarkers such as AFP-L3, Golgi specific membrane protein (GP73) and des-gamma-carboxyprothrombin significantly improved its accuracy in detecting HCC.¹⁶

• Pregnancy also is associated with elevated AFP levels, particularly if the pregnancy is complicated by a spinal cord defect or other abnormality.¹⁷ Where AFP levels are elevated but no abnormality is found, there is a greater level of obstetric risk (also seen with hCG levels).¹⁸

Beta subunit of human chorionic gonadotrophin

This is normally produced by the placenta. Elevated beta-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.¹⁹

  • Hypogonadal states.

  • Marijuana use.

Following AFP and beta-hCG levels is imperative in monitoring response to treatment. Patients with AFP and beta-hCG levels that do not decline as expected after treatment have a significantly worse prognosis and changes in therapy should be considered.²⁰ Tumour markers are followed every one to two months for one year after treatment, then quarterly for one year and less frequently thereafter. AFP or beta-hCG elevation is frequently the first evidence of germ cell tumour recurrence.

Cancer antigen 19-9

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.

• Elevated preoperative serum levels of CA 19-9 have been associated with both the intraoperative detection of occult metastases and worse disease-free survival, even in resectable PDAC patients.²¹ Therefore CA 19.9 has become the main biological parameter to be used to assess biological resectability.

s100 protein ⁴²²

S100 is a family of calcium-binding proteins that can be used as a diagnostic tumour marker, particularly for malignant melanoma as it is present in approximately 99% of cases. It is sensitive but not very specific, as it is also found in nerve sheath tumours (schwannomas, neurofibromas), and glial tumours. It is also a sensitive, non-specific marker for Langerhans cells, chondrocytes, and adipocytes.

Calcitonin ²³

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

Thyroglobulin ²⁴

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

Paraproteins (M protein/Bence Jones' protein) ²⁵

• 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 myeloma.

Microphthalmia transcription factor

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.²⁶

Circulating methylated DNA

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.²⁷

The above mentioned classical tumour markers remain standard clinical practice in oncology. However, there have been significant advances in techniques, such as immunohistochemistry, flow cytometry, polymerase chain reaction, and in situ hybridisation, that have introduced a molecular component to diagnosis. These advances offer new methods of determining the origin of a tumour, facilitating differential diagnosis, and improving prediction and prognosis. ²