What are they?
Tumour markers are substances, usually proteins, produced by the body in response to cancer growth or by cancer tissue itself. Their detection and measurement in blood plasma, urine or tissue can help to detect and aid diagnosis of some types of cancer, predict and monitor response to treatment and detect recurrence. Recently advances have allowed mutations in cell genetic material (DNA, RNA) to be used as tumour markers to help diagnosis and to determine the prognosis and guide targeted treatment of a few cancers. Research in progress on tumour markers includes analysis of cell-free RNA released into the circulation by cancers and on methods of trapping circulating intact cancer cells for genetic investigation.
Some limitations of tumour markers are that
- none has sufficiently high sensitivity and specificity to be used to screen the general population
- few are specific for one type of cancer
- many are raised in non-cancerous conditions
- not all patients with a cancer of one type have raised concentrations in the bloodstream of its specific tumour marker
- some cancers have no associated tumour marker
Consequently, they cannot be used alone to diagnose cancer but must be considered in conjunction with a patient's medical history, physical examination and other laboratory and imaging tests. A definitive diagnosis of cancer is made by examining a biopsy specimen under a microscope.
Why are they done?
Tumour markers often have more than one purpose. Examples of tumour markers found on this web site are listed below in three groups according to their primary purpose, with comments on associated cancers and non-cancerous conditions that can cause abnormal values. More details about each individual tumour marker can be found by clicking on its name.
1. To monitor
Some blood tumour markers are used to monitor the success of treatment by a falling concentrations and to detect recurrence by an increase, but are not used for diagnosis. They include:
CA 15-3 (cancer antigen 15-3) is rarely raised when breast cancer is localised but is raised in about three-quarters of those in whom it has spread to other organs. CA 15-3 may also be raised in bowel cancer, lung cancer, cirrhosis, hepatitis and benign breast disease.
CA 19-9 (cancer antigen 19-9) is raised in most patients with advanced pancreatic cancer but may also be raised in bowel cancer, lung cancer, gall bladder cancer and such benign diseases as gall stones, pancreatitis, cystic fibrosis and liver disease.
CEA (carcinoembryonic antigen) is not normally present in the bloodstream but may appear in many kinds of cancer. It is commonly measured in bowel cancer, but has been used to monitor patients with cancers of the lung, breast, liver, pancreas, stomach and ovary. It can also appear in benign conditions such as liver disease and inflammatory bowel disease.
SMRP (soluble mesothelin-related peptides) concentrations are raised in malignant mesothelioma, a rare cancer of the membranes that cover the outside of internal organs and line the body cavities including the chest, the abdomen and the heart. The test is used to monitor rather than to diagnose the condition.
Thyroglobulin is made only in the thyroid gland. Following treatment of thyroid cancer by complete removal or destruction of the gland, plasma thyroglobulin concentration usually drops to very low or undetectable. It is monitored to assess the completeness of removal and to detect recurrence of disease.
2. To help diagnose and to monitor
Some tumour markers help to suggest a diagnosis as well as to monitor the success of treatment and to detect recurrence. They include:
AFP (alpha-fetoprotein) concentration is raised in most patients with cancer of the liver, some patients with cancer of the testis and occasionally in other cancers. It is also increased in chronic hepatitis and cirrhosis of the liver, conditions which can go on to develop liver cancer. Patients with cirrhosis may be monitored for a further increase in AFP as an indication for an ultrasound, CT or MRI scan to detect the development of liver cancer.
BCR-ABL mutation detection in blood cells or bone marrow cells is used to supplement microscopic and chromosomal examination of the cells to diagnose chronic myeloid leukaemia (CML) and a type of acute lymphoblastic leukaemia (ALL). It is also used to monitor response to treatment, to check for the development of treatment-resistant mutations and, in patients in remission, to monitor for recurrence.
CA 125 (cancer antigen 125) is raised in plasma in about 80% of women with ovarian cancer but can also be raised in pregnancy, during menstruation, endometriosis and pelvic inflammatory disease. It can help with the diagnosis of ovarian cancer: Raised CA 125 concentrations in women with suggestive symptoms are an indication for ultrasound examination of the abdomen and pelvis.
Calcitonin is raised in plasma in medullary cancer of the thyroid gland and usually in its non-cancerous precursor, C-cell hyperplasia. Concentrations may also occasionally be raised with lung, breast and pancreatic cancers, insulinomas and leukaemias. Raised concentrations support the diagnosis in patients with suspected thyroid cancer and are an indication for ultrasound or CT scans and confirmation by thyroid biopsy.
CgA (chromogranin A) is raised in plasma in benign and malignant tumours of the neuroendocrine system such as carcinoid tumour and phaeochromocytoma. In a patient with characteristic symptoms, a raised concentration indicates the presence of a tumour but not its type or location. CgA concentrations may be raised in liver disease, inflammatory bowel disease and renal disease, but patients with these conditions do not have characteristic neuroendocrine symptoms.
Gastrin concentration is increased by hyperplasia of gastrin-producing cells and by gastrin-producing tumours (gastrinomas) in the pancreas or duodenum, but rarely in other parts of the body. More than 50% of gastrinomas are malignant. Gastrin concentrations normally rise as a response to low gastric (stomach) acid, for example after taking antacids. The combination of a high fasting gastrin concentrations with high gastric acidity is diagnostic of gastrinoma. A variety of imaging techniques may be necessary to locate tumours which are often very small.
hCG (human chorionic gonadotropin) is produced in pregnancy by the placenta, and its presence/absence in urine is used as a pregnancy test. Concentrations in plasma peak about the tenth week of pregnancy then fall gradually. Plasma and urine hCG concentrations increase in placental cell disorders ranging from benign molar pregnancies to malignant conditions such as choriocarcinoma.
Monoclonal immunoglobulins are not normally present in plasma or urine. In multiple myeloma and Waldenström’s macroglobulinaemia a single plasma cell becomes malignant and its clone of daughter cells secretes immunoglobulin (antibody) of a single chemical structure. This marker is recognised by serum protein electrophoresis as a single band. Sometimes the smaller light chain part of the immunoglobulin is produced in excess and is detected in the urine as Bence Jones protein.
PSA (prostate-specific antigen) is often raised in plasma in prostate cancer, but is also raised in BPH, a benign increase in size (hypertrophy) of the gland, and in gland inflammation (prostatitis). Diagnosis requires prostate ultrasound and biopsy.
3. To assess prognosis and guide treatment
A few tumour markers are used to assess the likely course and outcome of a cancer and to indicate the probability of response to a specific treatment. They include:
HER-2 (human epidermal growth factor receptor-2) testing is carried out on breast cancer tissue obtained by biopsy or during surgery. The positive results obtained in 25-30% of tumours are associated with faster growth, failure to respond to some treatments and a poorer outlook. However, a proportion of positive tumours respond to HER-2 targeted treatment with drugs such as trastuzumab (Herceptin®).
Hormone receptor status (oestrogen and progesterone receptors) is determined on breast cancer tissue obtained by biopsy or at operation. An oestrogen and progesterone receptor positive cancer is likely to respond to anti-hormone treatment with drugs such as tamoxifen, but response is less likely if the tumour is also HER-2 positive.
RAS gene mutations (KRAS and NRAS mutations) are tested for on colon cancer tissue obtained by biopsy. Patients with metastases whose tumour shows no RAS mutations benefit from treatment with anti-epithelial growth factor receptor antibodies such as cetuximab which improve their response to chemotherapy.