Tumor
Markers
· What are tumor markers?
Tumor markers are substances that are
produced by cancer or by other cells of the body in response to cancer or
certain benign (noncancerous) conditions. Most tumor markers are made by normal
cells as well as by cancer cells; however, they are produced at much higher
levels in cancerous conditions. These substances can be found in the blood,
urine, stool, tumor tissue, or other tissues or bodily fluids of some patients
with cancer. Most tumor markers are proteins. However, more recently, patterns
of gene expression and changes to DNA have also begun to be used
as tumor markers. Markers of the latter type are assessed in tumor tissue
specifically.
Thus far, more than 20 different tumor
markers have been characterized and are in clinical use. Some are associated
with only one type of cancer, whereas others are associated with two or more
cancer types. There is no “universal” tumor marker that can detect any type of
cancer.
There are some limitations to the use of
tumor markers. Sometimes, noncancerous conditions can cause the levels of
certain tumor markers to increase. In addition, not everyone with a particular
type of cancer will have a higher level of a tumor marker associated with that
cancer. Moreover, tumor markers have not been identified for every type of
cancer.
· How are tumor markers used in cancer care?
Tumor markers are used to help detect,
diagnose, and manage some types of cancer. Although an elevated level of a
tumor marker may suggest the presence of cancer, this alone is not enough to
diagnose cancer. Therefore, measurements of tumor markers are usually combined
with other tests, such as biopsies, to diagnose cancer.
Tumor marker levels may be measured before
treatment to help doctors plan the appropriate therapy. In some types of
cancer, the level of a tumor marker reflects the stage (extent) of the disease
and/or the patient’s prognosis (likely outcome or course of disease).
Tumor markers may also be measured periodically
during cancer therapy. A decrease in the level of a tumor marker or a return to
the marker’s normal level may indicate that the cancer is responding to
treatment, whereas no change or an increase may indicate that the cancer is not
responding.
Tumor markers may also be measured after
treatment has ended to check for recurrence (the return of cancer).
· How are tumor markers measured?
A doctor takes a sample of tumor tissue or
bodily fluid and sends it to a laboratory, where various methods are used to
measure the level of the tumor marker.
If the tumor marker is being used to
determine whether treatment is working or whether there is a recurrence, the marker’s level will be measured in multiple
samples taken over time. Usually these “serial measurements,” which show
whether the level of a marker is increasing, staying the same, or decreasing,
are more meaningful than a single measurement.
· What
tumor markers are currently being used, and for which cancer types?
A number of tumor markers are currently being
used for a wide range of cancer types. Although most of these can be tested in
laboratories that meet standards set by the Clinical Laboratory Improvement
Amendments, some cannot be and may therefore be considered experimental. Tumor
markers that are currently in common use are listed below.
- Cancer
types: Liver cancer and germ cell tumors
- Tissue
analyzed: Blood
- How used: To help diagnose liver cancer and follow
response to treatment; to assess stage, prognosis, and response to
treatment of germ cell tumors
- Cancer
types: Choriocarcinoma and testicular cancer
- Tissue
analyzed: Urine or blood
- How
used: To assess stage, prognosis, and response to treatment
- Cancer
type: Chronic myeloid leukemia
- Tissue
analyzed: Blood and/or bone marrow
- How
used: To confirm diagnosis and monitor disease status
- Cancer
types: Cutaneous melanoma and colorectal cancer
- Tissue
analyzed: Tumor
- How
used: To predict response to targeted therapies
CA15-3/CA27.29
- Cancer
type: Breast cancer
- Tissue
analyzed: Blood
- How
used: To assess whether treatment is working or disease has recurred
CA19-9
- Cancer
types: Pancreatic cancer, gallbladder cancer, bile duct cancer, and gastric cancer
- Tissue
analyzed: Blood
- How
used: To assess whether treatment is working
- Cancer
type: Ovarian cancer
- Tissue
analyzed: Blood
- How used: To help in diagnosis, assessment of response
to treatment, and evaluation of recurrence
- Cancer
type: Medullary thyroid cancer
- Tissue
analyzed: Blood
- How used: To aid in diagnosis, check whether treatment
is working, and assess recurrence
- Cancer
types: Colorectal cancer and breast cancer
- Tissue
analyzed: Blood
- How used: To check whether colorectal cancer has
spread; to look for breast cancer recurrence and assess response to
treatment
- Cancer
type: Non-Hodgkin lymphoma
- Tissue
analyzed: Blood
- How
used: To determine whether treatment with a targeted therapy is
appropriate
- Cancer
type: Neuroendocrine tumors
- Tissue
analyzed: Blood
- How used: To help in diagnosis, assessment of treatment
response, and evaluation of recurrence
Chromosomes
3, 7, 17, and 9p21
- Cancer
type: Bladder cancer
- Tissue
analyzed: Urine
- How
used: To help in monitoring for tumor recurrence
- Cancer
type: Lung cancer
- Tissue
analyzed: Blood
- How
used: To help in monitoring for recurrence
- Cancer
type: Non-small cell lung cancer
- Tissue
analyzed: Tumor
- How
used: To help determine treatment and prognosis
- Cancer
type: Breast cancer
- Tissue
analyzed: Tumor
- How used: To determine whether treatment with hormonal therapy (such as tamoxifen) is appropriate
Fibrin/fibrinogen
- Cancer
type: Bladder cancer
- Tissue
analyzed: Urine
- How
used: To monitor progression and response to treatment
HE4
- Cancer
type: Ovarian cancer
- Tissue
analyzed: Blood
- How
used: To assess disease progression and monitor for recurrence
- Cancer
types: Breast cancer, gastric cancer, and esophageal cancer
- Tissue
analyzed: Tumor
- How
used: To determine whether treatment with trastuzumab is appropriate
Immunoglobulins
- Cancer
types: Multiple myeloma and Waldenström macroglobulinemia
- Tissue
analyzed: Blood and urine
- How used: To help diagnose disease, assess response to
treatment, and look for recurrence
KIT
KRAS
mutation analysis
- Cancer
types: Colorectal cancer and non-small cell lung cancer
- Tissue
analyzed: Tumor
- How used: To determine whether treatment with a
particular type of targeted therapy is appropriate
- Cancer
type: Germ cell tumors
- Tissue
analyzed: Blood
- How
used: To assess stage, prognosis, and response to treatment
Nuclear
matrix protein 22
- Cancer
type: Bladder cancer
- Tissue
analyzed: Urine
- How
used: To monitor response to treatment
- Cancer
type: Prostate cancer
- Tissue
analyzed: Blood
- How
used: To help in diagnosis, assess response to treatment, and look for
recurrence
- Cancer
type: Thyroid cancer
- Tissue
analyzed: Tumor
- How
used: To evaluate response to treatment and look for recurrence
Urokinase plasminogen activator (uPA) and plasminogen
activator inhibitor (PAI-1)
- Cancer
type: Breast cancer
- Tissue
analyzed: Tumor
- How
used: To determine aggressiveness of cancer and guide treatment
5-Protein
signature (Ova1)
- Cancer
type: Ovarian cancer
- Tissue
analyzed: Blood
- How
used: To pre-operatively assess pelvic mass for suspected ovarian cancer
21-Gene
signature (Oncotype DX)
- Cancer
type: Breast cancer
- Tissue
analyzed: Tumor
- How
used: To evaluate risk of recurrence
70-Gene
signature (Mammaprint)
- Cancer
type: Breast cancer
- Tissue
analyzed: Tumor
- How
used: To evaluate risk of recurrence
· Can tumor markers be used in cancer
screening?
Because tumor markers can be used to assess
the response of a tumor to treatment and for prognosis, researchers have hoped
that they might also be useful in screening tests that aim to detect cancer
early, before there are any symptoms. For a screening test to be useful, it
should have very high sensitivity (ability to correctly identify people who
have the disease) and specificity (ability to correctly identify people who do not
have the disease). If a test is highly sensitive, it will identify most people
with the disease—that is, it will result in very few false-negative results. If
a test is highly specific, only a small number of people will test positive for
the disease who do not have it—in other words, it will result in very few
false-positive results.
Although tumor markers are extremely useful
in determining whether a tumor is responding to treatment or assessing whether
it has recurred, no tumor marker identified to date is sufficiently sensitive
or specific to be used on its own to screen for cancer.
For example, the prostate-specific antigen (PSA) test, which measures the level
of PSA in the blood, is often used to screen men for prostate cancer. However,
an increased PSA level can be caused by benign prostate conditions as well as
by prostate cancer, and most men with an elevated PSA level do not have
prostate cancer. Initial results from two large randomized controlled trials, the NCI-conducted Prostate, Lung,
Colorectal, and Ovarian Cancer Screening Trial, or PLCO, and the European
Randomized Study of Screening for Prostate Cancer, showed that PSA testing at
best leads to only a small reduction in the number of prostate cancer deaths.
Moreover, it is not clear whether the benefits of PSA screening outweigh the
harms of follow-up diagnostic tests and treatments for cancers that in many
cases would never have threatened a man’s life.
Similarly, results from the PLCO trial showed
that CA-125, a tumor marker that is sometimes elevated in the blood
of women with ovarian cancer but can also be elevated in women with benign
conditions, is not sufficiently sensitive or specific to be used together with transvaginal ultrasound to screen for ovarian cancer in women
at average risk of the disease. An analysis of 28 potential markers for ovarian
cancer in blood from women who later went on to develop ovarian cancer found
that none of these markers performed even as well as CA-125 at detecting the
disease in women at average risk.
· What kind of research is under way to
develop more accurate tumor markers?
Cancer researchers are turning to proteomics
(the study of protein structure, function, and patterns of expression) in hopes
of developing new biomarkers that can be used to identify disease in its early
stages, to predict the effectiveness of treatment, or to predict the chance of
cancer recurrence after treatment has ended.
Scientists are also evaluating patterns of gene expression for their ability to help determine a
patient’s prognosis or response to therapy. For example, the NCI-sponsored TAILORx trial assigned women with lymph node-negative, hormone
receptor–positive breast cancer who have undergone surgery to different
treatments based on their recurrence scores in the Oncotype DX test. One of the
goals of the trial is to determine whether women whose score indicates that
they have an intermediate risk of recurrence will benefit from the addition of
chemotherapy to hormonal therapy or whether such women can safely avoid chemotherapy.
The trial has accrued its required number of subjects and these subjects will
be followed for several years before results are available.
The Program for the Assessment of Clinical Cancer Tests (PACCT),
an initiative of the Cancer Diagnosis Program of NCI’s Division of Cancer Diagnosis
and Treatment, has been developed to ensure that development of the next
generation of laboratory tests is efficient and effective. The PACCT strategy
group, which includes scientists from academia, industry, and NCI, is
developing criteria for assessing which markers are ready for further
development. PACCT also aims to improve access to human specimens, make
standardized reagents and control materials, and support validation studies. A
new program, the Clinical Assay Development Program, allows NCI to assist in
the development of promising assays that may predict which treatment may be
better or that will help indicate a particular cancer’s aggressiveness.
