Tumor Markers: Definition, Classification, Uses, Techniques, Precision, Accuracy and Investigations

It is a biomarker found in blood, urine, or body tissues that can be elevated by the presence of one or more types of cancer.

There are many different tumor markers, each indicative of a particular disease process, and they are used in oncology to help detect the presence of cancer.

An elevated level of a tumor marker can indicate cancer; however, there may also be other causes of the elevation (false positive values).

Tumor markers can be produced directly by the tumor or by non-tumor cells in response to the presence of a tumor.

Although mammography, ultrasonography , computed tomography, magnetic resonance imaging, and tumor marker analysis aid in the staging and treatment of cancer, they are generally not definitive diagnostic tests. The diagnosis is mainly confirmed by biopsy.

Classification

Based on their chemical nature, tumor markers can be proteins, conjugated proteins, peptides, or carbohydrates. Proteins or conjugated proteins can be enzymes, hormones, or protein fragments.

Gene sequencing for diagnostic purposes is classified primarily under the heading of biomarker.

Applications

Tumor markers can be used for the following purposes:

  • Population-based detection of common cancers. Broad screening for all or most types of cancer was originally suggested, but has since been shown to be unrealistic.
  • Detecting specific types or sites of cancer requires a level of specificity and sensitivity that has so far only been achieved. Example: elevated prostate specific antigen suggests that it is used in some countries to detect prostate cancer.
  • Monitoring of cancer survivors after treatment, detection of recurrent disease. Example: elevated alpha-fetoprotein (AFP) in a child previously treated for teratoma suggests a relapse with endodermal sinus tumor.
  • Diagnosis of specific tumor types, particularly in certain brain tumors and other cases where biopsy is not feasible.
  • Confirmation of the diagnosis to verify characteristics such as the size and aggressiveness of a tumor and, therefore, to aid in the evaluation of an appropriate treatment program.
  • Staging: Some tumor markers are included in the staging procedures for some tumor sites.
  • Prognosis to plan treatment when pretreatment is used and to help patient plan for future when used after healing operation.
  • To check the effect of the treatment to change the treatment if it is ineffective. As an accompanying diagnosis to verify if the treatment is adequate for the type or subtype of tumor, particularly in personalized medicine.

As stated in the British Medical Journal in 2009, tumor markers should not generally be used for the diagnosis of cancers, as opposed to monitoring purposes in certain cancers or, in certain cases, for screening purposes.

Using these tests without understanding their usefulness has resulted in improper use of tumor marker blood tests, resulting in inappropriate over-screening for cancers.

Tumor markers were first developed to detect cancer in people without symptoms, but very few markers are effective in achieving this goal. Today, the most widely used tumor marker in the clinical setting is prostate specific antigen.

Furthermore, only a few markers that are available now have clinically useful predictive values ​​for cancer at an early stage, and only when screening high-risk patients.

Tumor markers are not the gold standard for diagnosing cancer. In most cases, a possible cancer can only be diagnosed by biopsy.

Alpha-fetoprotein is an example of a tumor marker that can be used to help diagnose cancer, especially hepatocellular carcinoma.

However, the level of alpha-fetoprotein can also increase in some liver diseases, although when it reaches a certain threshold it is usually indicative of hepatocellular carcinoma.

Some types of cancer grow and spread faster than others, while some cancers also respond well to various therapies. Sometimes the level of a tumor marker can be helpful in predicting the behavior and outcome of certain cancers.

For example, in testicular cancer, very high levels of a tumor marker such as human chorionic gonadotropin or alpha-fetoprotein can indicate an aggressive cancer with a poor survival outcome.

Patients with these high levels may require very aggressive therapy even at the beginning of cancer therapy. Certain markers found on cancer cells can be used to predict whether or not a treatment will produce a favorable outcome.

For example, in breast and stomach cancers, if the cells have too much protein called human epidermal growth factor receptor 2, drugs such as trastuzumab (Herceptin) may be helpful if used during chemotherapy.

However, with normal expression of human epidermal growth factor receptor 2, these drugs may not produce the expected therapeutic benefits. Tumor markers are also used to identify the recurrence of certain tumors after successful therapy.

Certain tumor markers may be useful for further evaluation of a patient after completion of treatment when there are no obvious signs of cancer in the body.

Techniques

Tumor markers can be determined in serum or rarely in urine or other body fluids, often by immunoassay, but other techniques are sometimes used, such as determination of enzyme activity.

Microscopic visualization in tissue by immunohistochemistry does not provide quantitative results and is not considered here.

For many assays, different assay techniques are available. For monitoring it is important that the same assay is used as the results of different assays are generally not comparable.

For example, for alpha-fetoprotein there are many different commercial test kits, based on different technologies, and for thymidine kinase there are tests for enzyme activity or amount of substance.

If repeat tumor marker measurements are needed, some clinical testing labs provide a special reporting mechanism, a serial monitor that links test results and other data pertaining to the person being tested.

Interlaboratory proficiency tests for tumor marker tests and for clinical trials in general are routine in Europe and in an emerging field. in the U.S. New York State is prominent in defending such an investigation.

Precision and accuracy

The precision and accuracy required for different analytes varies:

Some analytes give small or moderate changes in concentration or activity, thus requiring high precision and accuracy to be useful, while others that show large differences between normal and pathological values ​​may be useful even if the precision and accuracy is lower.

Therefore, the precision and accuracy required for a given assay may be different for different applications, such as in different diagnostics or for different uses.

This also influences the useful working range for a given assay for different diagnoses or uses. Each laboratory must verify the precision and precision of the tests with the instruments and personnel used.

The high hook dose effect is an artifact of immunoassay kits that causes the reported amount to be incorrectly low when the amount is high. An undetected hook effect can cause delayed recognition of a tumor.

The hook effect can be detected by analyzing serial dilutions. The hook effect is absent if the reported amounts of tumor marker in a serial dilution are proportional to the dilution.

Multiple tumor marker test

As with other diagnostic tests, tumor markers have a few test characteristics that influence their usability:

Imperfect sensitivity, which would lead to false negative tests, meaning the test result is reassuring but the cancer is present or has come back or progressed.

Imperfect specificity, resulting in false positive tests, meaning no cancer, but the test result indicates otherwise, resulting in unnecessary testing or additional anxiety.

As with other tests, the predictive value (the probability that a positive or negative result represents the truth) is highly dependent on the pre-test probability.

The predictive value can be increased if two or more tests are performed in parallel. The condition is that the tests themselves have similar predictive values. The test combinations that will give the most accurate results are, for example:

Colorectal : M2-PK; If M2-PK is not available, it can test for carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125.

Breast : carcinoembryonic antigen, carcinoma antigen 15-3, Cyfra 21-1.

Ovary : carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125, alpha fetoprotein, beta human chorionic adotropin.

Uterine : carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125, Cyfra 21-1, squamous cell carcinoma.

Prostate : prostate specific antigen, free prostate specific antigen and ratio.

Testis : alpha fetoprotein, beta human chorionic gonadotropin.

Pancreas / stomach : carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 72-4.

Liver : carcinoembryonic antigen, alpha-fetoprotein.

Esophagus : carcinoembryonic antigen, Cyfra 21-1.

Thyroid : carcinoembryonic antigen, neuronal specific enolase.

Lung : carcinoembryonic antigen, carbohydrate antigen 19-9, cancer antigen 125, neuronal-specific enolase, Cyfra 21-1 (the 95 percentile sensitivity for Cyfra 21-1 is 79 percent, while for squamous carcinoma and carcinoembryonic antigen are 41 and 31 percent, respectively).

Bladder : carcinoembryonic antigen, Cyfra 21-1, tissue polypeptide antigen.

Can tumor markers be used in cancer screening?

For a screening test to be useful, it must have very high sensitivity (the ability to correctly identify people who have the disease) and specificity (the ability to correctly identify people who do not have the disease).

If a test is very sensitive, it will identify most people with the disease, that is, it will give very few false negative results.

For example, the prostate specific antigen (PSA) test, which measures the level of prostate specific antigen in the blood, is often used to detect prostate cancer in men.

The initial results of two large randomized controlled trials:

The National Cancer Institute-sponsored Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the European Randomized Prostate Cancer Screening Study.

They showed that prostate-specific antigen testing only leads to a small reduction in the number of prostate cancer deaths at best.

Results from the prostate, lung, colorectal, and ovarian assay showed cancer antigen 125, a tumor marker that is sometimes elevated in the blood of women with ovarian cancer.

What kind of research is being done to develop more accurate tumor markers?

Cancer researchers are turning to studying protein structure, function, and expression patterns in the hope of developing new biomarkers.

That can be used to identify disease in its early stages, predict the effectiveness of treatment, or predict the possibility of cancer recurrence after treatment has ended.

Scientists are also evaluating gene expression patterns to determine your prognosis or response to treatment.

For example, results from the National Cancer Institute-sponsored Trial Assigning Individual Treatment Options (TAXORx) showed that women newly diagnosed with:

Negative lymph nodes, positive hormone receptors, HER2 negative breast cancer that had undergone surgery, those with the lowest recurrence scores of 21 genes.

The trial is ongoing to see if women at intermediate risk of recurrence, based on the 21-gene test, do better with chemotherapy in addition to hormone therapy than with hormone therapy alone.

What tumor markers are currently used and for what type of cancer?

Currently, several tumor markers are used for a wide variety of cancers.

Alpha-fetus protein (AFP):

  • Liver, germ cell cancer, ovarian or testicular cancer.
  • Also elevated during pregnancy.
  • Helps diagnose, monitor treatment, and determine recurrence.

CA 15-3 (cancer antigen 15-3):

  • Breast and other cancers, including lung and ovary.
  • Also elevated in benign breast conditions.
  • Stage disease, monitor treatment and determine recurrence.

CA 19-9 (cancer antigen 19-9):

  • Pancreas, sometimes intestines and bile ducts.
  • Also elevated in pancreatitis and inflammatory bowel disease.
  • Stage disease, monitor treatment and determine recurrence.

CA-125 (cancer antigen 125):

  • Ovarian cancer
  • Also elevated with endometriosis, some other benign diseases and conditions; not recommended as a general display.
  • Helps diagnose, monitor treatment, and determine recurrence.

Calcitonin:

  • Medullary thyroid carcinoma.
  • Also elevated in pernicious anemia and thyroiditis.
  • Helps diagnose, monitor treatment, and determine recurrence.

Carcino-embryonic antigen (CEA):

  • Cancer of the intestine, lung, breast, thyroid, pancreas, liver, cervix and bladder.
  • Elevated in other conditions such as hepatitis, chronic obstructive pulmonary disease, colitis, pancreatitis, and in cigarette smokers.
  • Monitor treatment and determine recurrence.

Human chorionic gonadotropin (hCG):

  • Testicular and trophoblastic disease.
  • Elevated in pregnancy, testicular failure.
  • Helps diagnose, monitor treatment, and determine recurrence.

Human epidermal growth factor receptor 2 (Her-2 / neu):

  • Breast cancer.
  • Oncogene that is present in multiple copies in 20-30% of invasive breast cancer.
  • Determine prognosis and guide treatment.

Monoclonal immunoglobulins:

  • Multiple myeloma and Waldenstrom’s macroglobulinemia.
  • Overproduction of an immunoglobulin or antibody, usually detected by protein electrophoresis.
  • Helps diagnose, monitor treatment, and determine recurrence.

Estrogen receptors:

  • Breast cancer.
  • Increase in hormone-dependent cancer.
  • Determine prognosis and guide treatment.

Progesterone receptors:

  • Breast cancer.
  • Increase in hormone-dependent cancer.
  • Determine prognosis and guide treatment.

Prostate specific antigen (PSA):

  • Prostate cancer.
  • Elevated benign prostatic hyperplasia, prostatitis and with age.
  • Find and help diagnose, monitor treatment, and determine recurrence.

Tiroglobulina:

  • Thyroid cancer.
  • It is used after the thyroid is removed to evaluate treatment.
  • Determine recurrence.

Other less widely used tumor markers:

B2M (Beta-2 microglobulina):

  • Multiple myeloma and lymphomas.
  • Present in many other conditions, including Crohn’s disease and hepatitis.
  • Determine the forecast.

Neuron specific enolase (NSE):

  • Neuroblastoma, small cell lung cancer.
  • It may be better than carcinoembryonic antigen (CEA) to track this particular type of lung cancer.
  • Monitor treatment.

Soluble Mesothelin-Related Peptides (SMRP):

  • Mesothelioma.
  • It is often used in conjunction with imaging tests.
  • To monitor progression or recurrence.

Although most of these can be tested in laboratories that meet the standards set by the Clinical Laboratory Improvement Amendments, some cannot be, and therefore can be considered, experimental.