Supplementary Information to Chapter 57

RECENT TUMOR MARKERS

¾¾ Tumor markers are a group of proteins, hormones, enzymes, receptors, and other cellular products that are
overexpressed (produced in higher than normal amounts) by malignant cells.
¾¾ Tumor markers are usually normal cellular constituents that are present at normal or very low levels in the blood of
healthy persons.
¾¾ If the substance in question is produced by the tumor, its levels will be increased either in the blood or in the tissue
of origin.

PURPOSE
¾¾ The majority of tumor markers are used to monitor patients for recurrence of tumors following treatment.
¾¾ In addition, some markers are associated with a more aggressive course and higher relapse rate and have value in
staging and prognosis of the cancer.
¾¾ Most tumor markers are not useful for screening because levels found in early malignancy overlap the range of levels
found in healthy persons.
¾¾ The levels of most tumor markers are elevated in conditions other than malignancy, and are therefore not useful in
establishing a diagnosis.

PRECAUTIONS
¾¾ Tumor markers are sometimes elevated in nonmalignant conditions.
¾¾ Not every tumor will cause a rise in the level of its associated marker, especially in the early stages of some cancers.
¾¾ When a marker is used for cancer screening or diagnosis, the physician must confirm a positive test result by using
imaging studies, tissue biopsies, and other procedures.
¾¾ False positive results may occur in laboratory tests when the patient has cross-reacting antibodies that interfere with
the test.

DESCRIPTION
¾¾ Physicians use changes in tumor marker levels to follow the course of a patient’s disease, to measure the effect of
treatment, and to check for recurrence of certain cancers.
¾¾ Tumor markers have been identified in several types of cancer, including malignant melanoma; multiple myeloma;
and bone, breast, colon, gastric, liver, lung, ovarian, pancreatic, prostate, renal, and uterine cancers.
¾¾ Serial measurements of a tumor marker are often an effective means to monitor the course of therapy.
¾¾ Some tumor markers can provide physicians with information used in staging cancers, and some help predict the
response to treatment.
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¾¾ A decrease in the levels of the tumor marker during treatment indicates that the therapy is having a positive effect on
the cancer, while an increase indicates that the cancer is growing and not responding to the therapy.

TYPES OF TUMOR MARKERS

¾¾ There are five basic types of tumor markers.
• Enzymes
• Tissue Receptors
• Antigens
• Oncogenes
• Hormones

Enzymes
¾¾ Many enzymes that occur in certain tissues are found in blood plasma at higher levels when the cancer involves that
tissue.
¾¾ Enzymes are usually measured by determining the rate at which they convert a substrate to an end product, while
most tumor markers of other types are measured by a test called an immunoassay.
¾¾ Some examples of enzymes whose levels rise in cases of malignant diseases are acid phosphatase, alkaline phosphatase,
amylase, creatine kinase, gamma glutamyl transferase, lactate dehydrogenase, and terminal deoxynucleotidyl
transferase.

Tissue Receptors
¾¾ Tissue receptors, which are proteins associated with the cell membrane, are another type of tumor marker.
¾¾ These substances bind to hormones and growth factors, and therefore affect the rate of tumor growth.
¾¾ Some tissue receptors must be measured in tissue samples removed for a biopsy, while others are secreted into the
extracellular fluid (fluid outside the cells) and may be measured in the blood.
¾¾ Some important receptor tumor markers are estrogen receptor, progesterone receptor, interleukin-2 receptor, and
epidermal growth factor receptor.

ANTIGENS
¾¾ Oncofetal antigens are proteins made by genes that are very active during fetal development but function at a very
low level after birth.
¾¾ The genes become activated when a malignant tumor arises and produces large amounts of protein.
¾¾ Antigens comprise the largest class of tumor marker and include the tumor-associated glycoprotein antigens.
¾¾ Important tumor markers in this class are alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), prostate specific
antigen (PSA), cathespin-D, HER-2/neu, CA-125, CA-19-9, CA-15-3, nuclear matrix protein, and bladder tumor-
associated antigen.

Oncogenes
¾¾ Some tumor markers are the product of oncogenes, which are genes that are active in fetal development and trigger
the growth of tumors when they are activated in mature cells.
¾¾ Some important oncogenes are BRAC-1, myc, p53, RB (retinoblastoma) gene (RB), and Ph1 (Philadelphia
chromosome).
274 Textbook of Biochemistry— Case Studies

Hormones
¾¾ The fifth type of tumor marker consists of hormones.
¾¾ This group includes hormones that are normally secreted by the tissue in which the malignancy arises as well as those
produced by tissues that do not normally make the hormone (ectopic production).
¾¾ Some hormones associated with malignancy are adrenal corticotropic hormone (ACTH), calcitonin, catecholamines,
gastrin, human chorionic gonadotropin (hCG), and prolactin.

HOW ARE TUMOR MARKERS USED?

¾¾ Screening and early detection of cancer
¾¾ Diagnosing cancer
¾¾ Determining the prognosis (outlook) for certain cancers
¾¾ Determining the effectiveness of cancer treatment
¾¾ Detecting recurrent cancer

HISTORY OF TUMOR MARKERS

¾¾ The first modern tumor marker used to detect cancer was human chorionic gonadotropin (hCG) the substance doctors
look for in pregnancy tests.
¾¾ Women who have ended a pregnancy but still have an enlarged uterus are tested for hCG.
¾¾ A high level of hCG in the blood may be a sign of a cancer of the placenta called gestational trophoblastic disease
(GTD).
¾¾ This cancer continues to produce hCG.
¾¾ Some testicular and ovarian cancers look a lot like GTD because they start in reproductive cells called germ cells.
¾¾ These cancers also make hCG, so this marker is also used to help diagnose them and watch their response to treatment.
¾¾ The hope in the search for tumor markers was that all cancers could some day be detected by a single blood test.
¾¾ Both GTD and germ cell tumors of the ovaries and testicles are too rare to look for these cancers by testing everyone.
¾¾ But other cancers, such as colon, breast, and lung are much more common.
¾¾ A simple blood test that could detect these cancers in their earliest stages could prevent the deaths of millions of
people.
¾¾ And so, many scientists began working toward this goal.
¾¾ The first success in developing a blood test for a common cancer was in 1965, when carcinoembryonic antigen (CEA)
was found in the blood of some patients with colon cancer.
¾¾ By the end of the 1970s, several other blood tests had been developed for different cancers.
¾¾ The new markers were often given numeric labels.
¾¾ There was CA 19-9 for colorectal and pancreatic cancer, CA15-3 for breast cancer, and CA 125 for ovarian cancer.
¾¾ Many others were also found, but because they did not show an advantage over the already discovered markers, they
were not studied any further.
¾¾ None of these tumor markers, including CEA, mets the original goal of being able to find cancer at a very early stage.
¾¾ There were a few reasons for this:
• Almost everyone has a small amount of these markers in his blood, and it is very hard to spot early cancers by
using these tests.
• The levels of these markers tend to get higher than normal only when there is a large amount of cancer present.
• Some people with cancer never have higher levels of these markers.
• Even when levels of these markers are high, they are often not specific enough. For example, the level of the tumor
marker CA 125 can be high in women with gynecologic conditions other than ovarian cancer.
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• The only tumor marker widely used in screening today is the prostate-specific antigen (PSA) test.
• It was discovered around the same time as the others, but it’s been in widespread use for screening since the early
1990s because it has certain advantages.
• First, it is made only by prostate cells, so a rise in PSA is most likely a sign of a prostate problem.
• Also, the PSA level usually rises even in early cancers, so most prostate cancers can be found at an early stage,
when they are most likely to be curable.
• But the test is not perfect.
• Some men may have an elevated PSA because of other prostate conditions.
• In others, the high PSA is from a prostate cancer that would never have needed treatment.
• Also, some men with prostate cancer may not have an elevated PSA.
• This is why doctors and medical organizations do not agree about whether all men should be tested.

SPECIFIC TUMOR MARKERS

ALPHA-FETOPROTEIN (AFP)
¾¾ AFP can be helpful in the diagnosis and treatment of liver cancer (hepatocellular carcinoma).
¾¾ Normal levels of AFP are usually less than 10 ng/mL (nanograms per milliliter). (A nanogram is one-billionth of a
gram.)
¾¾ AFP levels are increased in most patients with liver cancer.
¾¾ AFP is also elevated in acute and chronic hepatitis, but it seldom gets above 100 ng/mL in these diseases.
¾¾ In someone with a liver tumor, an AFP level over a certain value means that the person has liver cancer.
¾¾ In people without liver problems, that value is 400 ng/mL.
¾¾ But in a person with chronic hepatitis who has a liver tumor, AFP levels of over 4,000 ng/mL are a sign of liver cancer.
¾¾ AFP is also useful in following the response to treatment for liver cancer.
¾¾ If the cancer is completely removed with surgery, the AFP level should go down to normal.
¾¾ If the level goes back up again, it often means that the cancer has come back.
¾¾ AFP is also higher in certain testicular cancers (those containing embryonal cell and endodermal sinus types) and is
used for follow-up of these cancers.
¾¾ Elevated AFP levels are also seen in certain rare types of ovarian cancer called yolk sac tumor or mixed germ cell
cancer.

BETA-2-MICROGLOBULIN (B2M)
¾¾ B2M blood levels are elevated in multiple myeloma, chronic lymphocytic leukemia (CLL), and some lymphomas.
¾¾ Levels may also be higher in some non-cancerous conditions, such as kidney disease.
¾¾ Normal levels are usually below 2.5 mg/L (milligrams per liter).
¾¾ B2M is useful to help predict the long-term outlook (prognosis) in some of these cancers.
¾¾ Patients with higher levels of B2M usually have a poorer prognosis.
¾¾ B2M is also checked during treatment of multiple myeloma to see how well the treatment is working.

BLADDER TUMOR ANTIGEN (BTA)

¾¾ BTA is found in the urine of many patients with bladder cancer.
¾¾ It may be a sign of some non-cancerous conditions, too, such as kidney stones or urinary tract infections.
¾¾ The results of the test are reported as either positive (BTA is present) or negative (BTA is not present).
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¾¾ It is sometimes used along with NMP22 (see below) to test patients for the return (recurrence) of bladder cancer.
¾¾ This test is not often used but is still being studied.
¾¾ It is not as good as cystoscopy (looking into the bladder through a thin, lighted tube) for finding bladder cancer, but it
may be helpful in allowing cystoscopy to be done less often during bladder cancer follow-up.
¾¾ Most experts still consider cystoscopy the standard for diagnosis and follow-up of bladder cancer.

CA 15-3
¾¾ CA 15-3 is mainly used to watch patients with breast cancer.
¾¾ Elevated blood levels are found in less than 10% of patients with early disease and in about 70% of patients with
advanced disease.
¾¾ Levels usually drop after effective treatment, but they may go up in the first few weeks after treatment is started.
¾¾ This rise is caused when dying cancer cells spill their contents into the bloodstream.
¾¾ The normal level is usually less than 30 U/mL (units/milliliter), depending on the lab.
¾¾ But levels as high as 100 U/mL can sometimes be seen in women who do not have cancer.
¾¾ Levels of this marker can also be higher in other cancers and in some non-cancerous conditions, such as benign breast
conditions and hepatitis.

CA 27.29
¾¾ CA 27.29 is another marker that can be used to follow patients with breast cancer during or after treatment.
¾¾ This test measures the same marker as the CA 15-3 test, but in a different way.
¾¾ Although it is a newer test than CA 15-3, it is not any better in detecting either early or advanced disease.
¾¾ It may be less likely to be positive in people without cancer.
¾¾ The normal level is usually less than 40 U/mL (units/milliliter), depending on the testing lab.
¾¾ This marker can also be elevated in other cancers and in some non-cancerous conditions, but it is not elevated in all
patients with breast cancer.

CA 125
¾¾ CA 125 is the standard tumor marker used to follow women during or after treatment for epithelial ovarian cancer (the
most common type of ovarian cancer).
¾¾ Normal blood levels are usually less than 35 U/mL (units/milliliter).
¾¾ More than 90% of women have high levels of CA 125 when the cancer is advanced.
¾¾ And changes in CA 125 levels are often watched during treatment to get an idea of how well it's working.
¾¾ Levels are also elevated in about half of women whose cancer has not spread outside of the ovary.
¾¾ This is why CA 125 has been studied as a screening test.
¾¾ The trouble with using it as a screening test is that it would still miss many early cancers, and problems other than
ovarian cancer can cause an elevated CA 125 level.
¾¾ For example, it is also often higher in women with uterine fibroids or endometriosis (having uterine cells in abnormal
locations).
¾¾ It may also be higher in men and women with lung, pancreatic, breast, and colon cancer, and in people who have had
cancer in the past.
¾¾ Because ovarian cancer is a rather rare disease, an increased CA 125 level is more likely to be caused by something
other than ovarian cancer.
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CA 72-4
¾¾ CA 72-4 is a newer test being studied in ovarian and pancreatic cancer and cancers starting in the digestive tract,
especially stomach cancer.
¾¾ There is no evidence that it is better than the tumor markers currently in use, but it may be valuable when used along
with other tests.
¾¾ Studies of this marker are still in progress.

CA 19-9
¾¾ The CA 19-9 test was first developed to detect colorectal cancer, but it is more often used in patients with pancreatic
cancer.
¾¾ In very early disease the level is often normal, so it is not good as a screening test.
¾¾ Still, it is the best tumor marker for following patients with cancer of the pancreas.
¾¾ Normal blood levels of CA 19-9 are below 37 U/mL (units/milliliter).
¾¾ A high CA 19-9 level in a newly diagnosed patient usually means the disease is advanced.
¾¾ CA 19-9 can also be used to watch colorectal cancer, but the CEA test is preferred for this type of cancer.
¾¾ CA 19-9 can also be elevated in other forms of digestive tract cancer, especially cancers of the stomach and bile ducts,
and in some non­cancerous conditions such as thyroid disease and pancreatitis (inflammation of the pancreas).

CALCITONIN
¾¾ Calcitonin is a hormone produced by cells called parafollicular C cells of the thyroid gland.
¾¾ It normally helps regulate blood calcium levels.
¾¾ Normal calcitonin levels are below 5 to 12 pg/ml (picograms per milliliter). (A picogram is one trillionth of a gram.)
¾¾ In medullary thyroid carcinoma (MTC), a rare cancer that starts in the parafollicular C cells, blood levels of this
hormone are often greater than 100 pg/ml.
¾¾ This is one of the rare tumor markers that can be used to help detect early cancer.
¾¾ Because MTC is often inherited, blood calcitonin can be measured to detect the cancer in its very earliest stages in
family members who are known to be at risk.
¾¾ Other cancers, such as lung cancers and leukemias, can also cause calcitonin levels to be elevated, but calcitonin
blood levels are not usually used to follow these cancers.

CARCINOEMBRYONIC ANTIGEN (CEA)

¾¾ CEA is not used to diagnose or screen for colorectal cancer, but it is the preferred tumor marker to help predict
outlook in patients with colorectal cancer.
¾¾ The normal range of blood levels varies from lab to lab, but levels higher than 3 ng/mL (nanograms per milliliter) are
not normal.
¾¾ The higher the CEA level at the time colorectal cancer is detected, the more likely it is that the cancer is advanced.
¾¾ CEA is also the standard marker used to follow patients with colorectal cancer during and after treatment.
¾¾ In this way CEA levels are used to see if the cancer is responding to treatment or to see if it has come back (recurred)
after treatment.
¾¾ This marker can be high in some other cancers, too.
¾¾ If the CEA level is high at diagnosis, it can be used to follow the response to treatment.
¾¾ It is often used for cancers of the lung and breast.
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¾¾ CEA levels are also elevated in many other cancers such as those of the thyroid, pancreas, liver, stomach, prostate,
ovary, and bladder.
¾¾ They are elevated in some non-cancerous diseases and in otherwise healthy smokers too.

CHROMOGRANIN A
¾¾ Chromogranin A (CgA) is made by neuroendocrine tumors, which include carcinoid tumors, neuroblastoma, and
small cell lung cancer.
¾¾ The blood level of CgA is often elevated in people with these diseases.
¾¾ It is probably the most sensitive tumor marker for carcinoid tumors.
¾¾ It is abnormal in 1 out of 3 people with localized disease and 2 out of 3 of those with cancer that has spread (metastatic
cancer).
¾¾ Levels can also be elevated in some advanced forms of prostate cancer that have neuroendocrine features.
¾¾ The range of normal blood levels varies between testing centers, but is commonly less than 50 ng/mL (nanograms
per milliliter).

HORMONE RECEPTORS
¾¾ Breast tumor samples—not blood samples—from all cases of breast cancer are tested for estrogen and progesterone
receptors.
¾¾ Breast cancers that contain estrogen receptors are often referred to as “ER-positive”; those with progesterone receptors
are “PR-positive”.
¾¾ About 2 out of 3 breast cancers test positive for at least one of these markers.
¾¾ These cancers tend to grow more slowly and have a better outlook than cancers without these receptors.
¾¾ Cancers that have these receptors can be treated with hormone therapy such as tamoxifen or aromatase inhibitors.

HER2 (ALSO KNOWN AS HER2/NEU, ERBB­-2, OR EGFR2)

¾¾ HER2 is a protein that tells breast cancer cells to grow.
¾¾ It is elevated in some breast cancers.
¾¾ Higher than normal levels can be found in some other cancers, too.
¾¾ The HER2 level is usually found by testing a sample of the cancer tissue itself, not the blood.
¾¾ About 1 in 5 breast cancers test positive for HER2.
¾¾ These cancers tend to grow and spread more aggressively than other breast cancers.
¾¾ All newly diagnosed breast cancers should be tested for HER2.
¾¾ HER2-positive cancers are more likely to respond to certain treatments such as trastuzumab (Herceptin®) and lapatinib
(Tykerb®), which work against the HER2 receptor on breast cancer cells.

HUMAN CHORIONIC GONADOTROPIN (HCG)

¾¾ hCG (also known as beta-hCG) blood levels are elevated in patients with some types of testicular and ovarian cancers
(germ cell tumors) and in gestational trophoblastic disease, mainly choriocarcinoma.
¾¾ They are also higher in some people with mediastinal germ cell tumors—cancers in the middle of the chest (the
mediastinum) that start in the same cells as germ cell tumors of the testicles and ovaries.
¾¾ Levels of hCG can be used to help diagnose these conditions and can be followed over time to see how well treatment
is working.
¾¾ They can also be used to look for cancer that has come back after treatment has ended (recurrence).
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¾¾ An elevated blood level of hCG will also raise suspicions of cancer in certain situations.
¾¾ For example, in a woman who still has a large uterus after pregnancy has ended, a high blood level of this marker is
a possible sign of a cancer.
¾¾ This is also true of men with an enlarged testicle or anyone with a tumor in their chest.
¾¾ It is hard to define the hCG normal level because there are different ways to test for this marker and each has its own
normal value.

IMMUNOGLOBULINS
¾¾ Immunoglobulins are not really tumor markers but antibodies, which are blood proteins normally made by immune
system cells to help fight germs.
¾¾ There are many types of immunoglobulins, including IgA, IgG, IgD, and IgM. Bone marrow cancers such as multiple
myeloma and Waldenstrom macroglobulinemia often cause a person to have too much of 1 type of immunoglobulin
in the blood.
¾¾ These cancers can also cause pieces of immunoglobulin to be found in the urine.
¾¾ A high level of immunoglobulins may be a sign of one of these diseases.
¾¾ There are normally many different immunoglobulins in the blood, with each one differing very slightly from the
others.
¾¾ A classic sign in patients with myeloma or macroglobulinemia is a very high level of a certain monoclonal
immunoglobulin.
¾¾ This can be seen on a test called serum protein electrophoresis (also called SPEP).
¾¾ In this test, the blood proteins are separated by an electrical current.
¾¾ With myeloma or macroglobulinemia, the monoclonal immunoglobulin forms a monoclonal “spike” on the SPEP.
¾¾ This is often called the M spike, monoclonal protein, or M protein.
¾¾ The level of the spike is important, because some people may show low levels of a spike without having myeloma or
macroglobulinemia.
¾¾ Still, the diagnosis of multiple myeloma or Waldenstrom macroglobulinemia must be confirmed by a biopsy of the
bone marrow.
¾¾ Immunoglobulin levels can also be followed over time to help see how well treatment is working.

LIPID ASSOCIATED SIALIC ACID IN PLASMA (LASA-P)

¾¾ LASA-P has been studied as a marker for ovarian cancer as well as some other cancers.
¾¾ For the most part it has not proven valuable, and has been replaced by more specific marker tests.
¾¾ It is not specific for any one cancer or even for cancer in general, as it can also be elevated in some non-cancerous
conditions.
¾¾ Still, it is sometimes used along with other tumor markers to follow response to treatment.

NEURON-SPECIFIC ENOLASE (NSE)

¾¾ NSE, like chromogranin A, is a marker for neuroendocrine tumors such as small cell lung cancer, neuroblastoma, and
carcinoid tumors.
¾¾ It is not used as a screening test.
¾¾ It is most useful in the follow-up of patients with small cell lung cancer or neuroblastoma.
¾¾ Chromogranin A seems to be a better marker for carcinoid tumors.
¾¾ Elevated levels of NSE may also be found in some non­neuroendocrine cancers.
¾¾ Abnormal levels are usually higher than 9 ug/mL (micrograms per milliliter).
280 Textbook of Biochemistry— Case Studies

NMP22
¾¾ NMP22 is a protein found in the nucleus (control center) of cells.
¾¾ Levels of NMP22 are often elevated (more than 10 U/mL or units/milliliter) in the urine of people with bladder cancer.
¾¾ So far it hasn't been found to be sensitive enough to be used as a screening tool.
¾¾ It is most often used to look for cancer that has come back after treatment.
¾¾ This is a less invasive way to look for cancer than cystoscopy (looking into the bladder with a thin, lighted tube), but
it's not always as accurate.
¾¾ NMP22 testing can't take the place of cystoscopy completely, but it can permit this procedure to be done less often.
¾¾ NMP22 levels can also be higher than normal with some non­cancerous conditions or due to recent treatment with
chemotherapy.

PROSTATE-SPECIFIC ANTIGEN (PSA)

¾¾ PSA is a tumor marker for prostate cancer.
¾¾ It is the only marker used to screen for a common type of cancer, although some medical groups do not recommend
its use.
¾¾ PSA is a protein made by cells of the prostate gland.
¾¾ The prostate gland is found only in men. It makes some of the liquid in semen.
¾¾ The level of PSA in the blood can be elevated in prostate cancer, but PSA levels can be affected by other factors, too.
¾¾ Men with benign prostatic hyperplasia (BPH), a non-cancerous growth of the prostate, often have higher levels.
¾¾ The PSA level also tends to be higher in older men and those with infected or inflamed prostates.
¾¾ It can also be elevated for a day or 2 after ejaculation.
¾¾ When the PSA test is used for screening, it should be done along with a digital rectal exam.
¾¾ For this test the doctor puts a gloved, lubricated finger into the rectum to feel the prostate gland for any bumps or
hard areas.
¾¾ PSA is measured in nanograms per milliliter (ng/mL).
¾¾ Most doctors feel that a blood PSA level below 4 ng/mL means cancer is unlikely.
¾¾ Levels greater than 10 ng/mL mean cancer is likely.
¾¾ The area between 4 and 10 is a gray zone.
¾¾ Men with PSA levels in this borderline range have about a 1 in 4 chance of having prostate cancer.
¾¾ Doctors often recommend a prostate biopsy (getting samples of prostate tissue to look for cancer) for men with a PSA
level above 4 ng/mL.
¾¾ But not all doctors agree with these cutoff points.
¾¾ This is because some men with prostate cancer do not have an elevated PSA level, while some others with a borderline
or elevated level will not have cancer.
¾¾ Some doctors believe it is more useful to follow the PSA level over time because an increase from one year to the next
may mean prostate cancer is more likely.
¾¾ This is called PSA velocity.
¾¾ Most doctors believe that PSA levels should be measured at least 3 times over a period of at least 18 months in order
to get an accurate PSA velocity.
¾¾ Doctors are also looking at the PSA level in other ways to see if it might be more useful.
¾¾ A helpful test when a PSA value is in the borderline range (between 4 and 10 ng/mL) is to measure the free PSA (or
percent-free PSA).
¾¾ PSA is in the blood in 2 forms—some is bound to a protein and some is free.
¾¾ The percent-free PSA (fPSA) is the ratio of how much PSA circulates free compared to the total PSA level.
¾¾ As the amount of free PSA goes up, the less likely it is that there is prostate cancer.
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¾¾ When the free PSA makes up more than 25% of the total PSA, prostate cancer is unlikely.
¾¾ If the free PSA is below 10%, the chance of prostate cancer is much higher and a biopsy should be done.
¾¾ The PSA test is very valuable in the follow-up of men with prostate cancer.
¾¾ For those who have been treated with surgery meant to cure the disease, the PSA should fall to an undetectable level.
¾¾ Those treated with radiation therapy should also have the PSA go down after treatment.
¾¾ A rise in the PSA level may be a sign the cancer is coming back.
¾¾ The PSA can also be used to follow the response to treatment.

PROSTATIC ACID PHOSPHATASE (PAP)

¾¾ PAP (not to be confused with the Pap test for women) is another test for prostate cancer.
¾¾ It was used before the PSA test was developed but is seldom used now because the PSA test is better.

PROSTATE-SPECIFIC MEMBRANE ANTIGEN (PSMA)

¾¾ PSMA is a substance found in all prostate cells.
¾¾ Blood levels increase with age and with prostate cancer.
¾¾ PSMA is a very sensitive marker, but so far it has not proven to be better than PSA.
¾¾ Its use in finding or following cancer is still being studied.
¾¾ Its current use is limited to being part of a nuclear scan (a type of imaging test) to look for the spread of prostate
cancer in the body.
¾¾ Some potential immunotherapy treatments for prostate cancer based on PSMA are now under study.

S-100
¾¾ S-100 is a protein found in most melanoma cells.
¾¾ Tissue samples of suspected melanomas are often tested for this marker to help in diagnosis.
¾¾ Some studies have shown that blood levels of S­-100 are elevated in most patients with metastatic melanoma.
¾¾ The test is sometimes used to look for melanoma spread before, during, or after treatment.

TA-90
¾¾ TA-90 is a protein found on the outer surface of melanoma cells.
¾¾ Like S-100, TA-90 can be used to look for the spread of melanoma. Its value in following melanoma is still being
studied, and it is not widely used at this time.
¾¾ It is also being studied for use in other cancers such as colon and breast cancer.

THYROGLOBULIN
¾¾ Thyroglobulin is a protein made by the thyroid gland.
¾¾ Normal blood levels depend on a person's age and gender.
¾¾ Thyroglobulin levels are elevated in many thyroid diseases, including some common forms of thyroid cancer.
¾¾ Treatment for thyroid cancer often involves removal of the entire thyroid gland, sometimes along with radiation
therapy.
¾¾ Thyroglobulin levels in the blood should fall to undetectable levels after treatment.
¾¾ A rise in the thyroglobulin level may mean the cancer has come back.
¾¾ In people with thyroid cancer that has spread, thyroglobulin levels can be followed over time to evaluate the results
of treatment.
282 Textbook of Biochemistry— Case Studies

¾¾ Some people’s immune systems make antibodies against thyroglobulin, which can affect test results.
¾¾ This is why levels of anti-thyroglobulin antibodies are often measured at the same time.

TISSUE POLYPEPTIDE ANTIGEN (TPA)

¾¾ TPA is a protein marker that is found in high levels when there are many rapidly dividing cells (such as cancer cells).
¾¾ The TPA blood test is sometimes used along with other tumor markers to help follow patients being treated for lung,
bladder, and many other cancers.
¾¾ TPA levels are also elevated in some non­cancerous conditions.

COMMON CANCERS AND THE TUMOR MARKERS LINKED TO THEM

BLADDER CANCER
¾¾ No tumor markers in urine are recommended for bladder cancer screening.
¾¾ But the bladder tumor antigen (BTA) and the NMP22 tests can be used along with cystoscopy (using a thin, lighted
tube to look in the bladder) in diagnosing it in patients with symptoms.
¾¾ These tests are also being used to follow some patients after treatment, though cystoscopy and urine cytology (using a
microscope to look for cancer cells in the urine) are still recommended as the standard tests for diagnosis and follow-
up.
¾¾ BTA and NMP22 tests are often used between cystoscopies.
¾¾ Normal values may allow cystoscopy to be done less often.
¾¾ These tests do not take the place of urine cytology and cystoscopy.
¾¾ Other tumor markers are also being studied in this setting.
¾¾ For advanced bladder cancer, some of the markers used for other cancers such as CEA, CA 125, CA 19-9, and TPA
may be elevated and can be used to follow patients during and after treatment.

BREAST CANCER
¾¾ No tumor marker has been found to be useful for screening or diagnosing early stage breast cancer.
¾¾ At the time of diagnosis, breast cancer tissue should be tested for estrogen and progesterone receptors, as well as the
HER2/neu antigen.
¾¾ These markers give information on how aggressive the cancer may be and how likely it is to respond to certain
treatments.
¾¾ The markers most often used to follow patients with advanced cancer or to look for the return of the cancer after
treatment (recurrence) are CA 15-3 and CEA.
¾¾ The CA 27.29 test is also used by some doctors. The CA 15-3 and CA 27.29 are probably equally sensitive, while the
CEA is less sensitive.
¾¾ These markers are most useful in measuring the results of treatment for patients with advanced disease.
¾¾ In most cases, blood levels go down if the cancer responds to treatment and rise if the cancer progresses.
¾¾ Some doctors use these tests to look for signs of recurrence in women who have no symptoms of cancer after their
first treatment.
¾¾ But most professional groups do not recommend using these markers to follow women already treated for early stage
disease.
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COLORECTAL CANCER
¾¾ The markers most often elevated in advanced colorectal cancer are CEA and CA 19-9, but neither of these is useful as
a screening test for colorectal cancer.
¾¾ An elevated CEA before surgery may be a sign of a poorer outcome.
¾¾ If it is high before surgery, the CEA should go to normal levels in about 4 to 6 weeks if all of the cancer has been
removed.
¾¾ Many doctors follow patients after surgery with CEA tests every 3 to 6 months or so to look for the return of the
cancer (recurrence).
¾¾ Finding a recurrence early is good because it may then be removed by surgery.
¾¾ But for most patients the recurrence is likely to be too widespread to be removed.
¾¾ CEA is also used to follow patients who are being treated for advanced or recurrent disease.
¾¾ The CEA level will go down if the treatment is working and will rise if the cancer progresses.
¾¾ If the CEA is not elevated in patients with advanced or recurrent cancer, sometimes the CA 19-9 can be used to follow
the disease.

GESTATIONAL TROPHOBLASTIC DISEASE

¾¾ Trophoblastic tumors include molar pregnancies (a pregnancy that results in a tumor of the placenta) and the more
aggressive choriocarcinoma.
¾¾ Human chorionic gonadotropin (hCG) is elevated in these tumors.
¾¾ hCG testing can be used to find these cancers in women who are no longer pregnant but still have an enlarged uterus.
¾¾ Measurements of hCG during treatment for trophoblastic disease are very useful in looking at response to treatment.

LIVER CANCER
¾¾ Cancer that starts in the liver (known as hepatocellular carcinoma) is linked with chronic infections caused by hepatitis
B and C viruses and with cirrhosis from various causes.
¾¾ This is a common type of cancer in Southeast Asia.\
¾¾ Liver cancers can cause elevated levels of alpha fetoprotein (AFP).\
¾¾ Higher AFP levels occur in most patients with liver cancer.
¾¾ An elevated AFP in someone with chronic hepatitis may suggest the diagnosis of this cancer and lead to testing to see
if the liver contains a tumor.
¾¾ Liver cancer is not very common in the United States, so AFP testing is not used to test the general population for
this type of cancer.
¾¾ Screening with AFP has been successful in parts of Asia where liver cancer is common.
¾¾ Sometimes the cancer is found early enough so that the patient can be cured with surgery.
¾¾ Because of this success, some doctors in the United States may screen their patients with cirrhosis of the liver due to
hepatitis B or C.
¾¾ A rising AFP level might be a sign of cancer.
¾¾ AFP can be used to help figure out the best treatment for liver cancer and to follow patients after curative surgery or
other treatment.

LUNG CANCER
¾¾ No tumor markers have proven useful as screening tests for lung cancer.
¾¾ Some of the tumor markers that may be elevated in lung cancer are the carcinoembryonic antigen (CEA) in non-small
cell lung cancer and the neuron-specific enolase (NSE) in small cell lung cancer.
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¾¾ Sometimes doctors will follow these markers to evaluate treatment results.

¾¾ There are many other markers that can also be followed.
¾¾ But because lung cancer is fairly easily seen on chest X-rays or other imaging tests, tumor markers play a less
important role.

MELANOMA SKIN CANCER

¾¾ No tumor marker is of value in finding this disease early.
¾¾ The markers TA-90, S-100, and some other markers can be used to test tissue samples to help see if a tumor is
melanoma.
¾¾ Blood levels of TA-90 have been used to help find out if the melanoma has spread (metastasized).
¾¾ If the blood TA-90 level is high, there is a good chance the melanoma is metastatic.
¾¾ But TA-90 can sometimes be elevated in the absence of metastatic melanoma. Because of this, it has not yet been used
to plan treatment or predict prognosis.
¾¾ S-100 is also elevated in the blood when the disease is widespread. This marker can also be used to look for progression
of the melanoma.

MULTIPLE MYELOMA
¾¾ There are no tumor markers commonly used to screen for this disease, but tests for immunoglobulins can be used to
help detect it or make a diagnosis.
¾¾ Protein electrophoresis and immunofixation can find these immune system proteins in the blood or urine of most
patients with myeloma.
¾¾ Pieces of immunoglobulins in the urine, called Bence Jones proteins, are found in some patients with multiple
myeloma.
¾¾ Most people with myeloma also have detectable levels of a certain immunoglobulin, called a monoclonal protein or
M-protein, in their blood.
¾¾ This protein leads to a monoclonal spike, or M spike, on a protein electrophoresis.
¾¾ These proteins can help diagnose the disease, but a bone marrow biopsy may be needed to confirm the diagnosis.
¾¾ These markers are also helpful in tracking the course of the disease and its response to treatment.
¾¾ Many patients with multiple myeloma also have higher blood levels of beta-2-microglobulin, which can also give
information on outlook and the response to treatment.

OVARIAN CANCER
¾¾ Epithelial ovarian cancer (the most common form of ovarian cancer) is linked with elevated levels of CA 125.
¾¾ Other markers that are sometimes measured are CA 72-4 and LASA-P. CA 125, which is elevated in most women with
advanced disease, is the standard marker that most doctors use.
¾¾ Ovarian cancer, even when advanced, is often confined to the abdomen and pelvis and hard to find through X-ray
testing.
¾¾ This is why the CA 125 is often the easiest and best way to measure the response to treatment or to find a cancer that
has come back.
¾¾ CA 125 has been studied as a screening tool in women who have no family history of ovarian cancer.
¾¾ At the present time, most medical groups do not recommend CA 125 testing for ovarian cancer screening because it
doesn’t seem to find the cancer early enough to help women live longer.
¾¾ Another problem with this test is that ovarian cancer is not common, and the CA 125 level can be elevated in other
cancers and other conditions.
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¾¾ So an elevated CA 125 is more likely to be due to some other cause, and more tests, including surgery, are often
needed to rule out ovarian cancer.
¾¾ CA 125 is used by some doctors to screen for ovarian cancer in women with a strong family history of ovarian cancers.
¾¾ Such women usually get regular ultrasounds for early detection along with CA 125 tests.
¾¾ Still, even in women with a high risk of ovarian cancer, this testing has not yet been found to diagnose the cancers
early or help women live longer.
¾¾ The second most common group of ovarian cancers is the germ cell tumors.
¾¾ Patients with these cancers often have elevated levels of hCG and/or AFP, which are useful in diagnosis and follow-
up.

PANCREATIC CANCER
¾¾ No markers have been found to be helpful in screening for pancreatic cancer.
¾¾ The CA 19-9 marker is the most useful marker for pancreatic cancer.
¾¾ Most people with pancreatic cancer have elevated levels of CA 19-9 in their blood.
¾¾ The higher the level, the more likely the disease has spread.
¾¾ CA 19-9 levels give information about the outlook for people with pancreatic cancer but cannot be used to diagnose
the disease.
¾¾ It can be useful in patient follow-up.
¾¾ Patients whose CA 19-9 levels drop to normal after surgery have a much better outlook than those people whose CA
19-9 remains elevated after surgery.
¾¾ This marker can also be used to follow the effects of treatment on more advanced disease.
¾¾ Some doctors also follow the level of CEA in the blood, but it may not be as helpful as the CA 19-9 level.

PROSTATE CANCER
¾¾ The marker most often used to detect prostate cancer is the prostate-specific antigen (PSA).
¾¾ Prostate cancer can often be found in its early stages by measuring blood levels of PSA.
¾¾ Levels above 4 (ng/mL) suggest cancer may be present, while levels above 10 (ng/mL) strongly suggest cancer.
¾¾ Doctors usually advise that men with elevated PSA levels have their prostate gland biopsied to find out if there is
cancer.
¾¾ Prostate cancer is often a slow growing cancer that is found in older men.
¾¾ This is why it is not clear if screening with PSA really saves lives or helps people live longer.
¾¾ Some doctors believe that screening may cause more harm than good.
¾¾ It may lead some men to get treated for cancers that would never have caused them problems, and the treatment itself
can have major side effects.
¾¾ PSA is very useful in finding cancer that has come back after treatment (recurrent disease).
¾¾ After surgery, the PSA level should be undetectable or near undetectable (0 or very close to 0).
¾¾ Those treated with radiation therapy should also have a huge drop in PSA after treatment, but it can take years before
it goes back to normal.
¾¾ A rise in PSA after treatment could mean the disease is coming back and that more treatment should be considered.
¾¾ The PSA can also be used to follow the response to treatment for more advanced disease.
¾¾ Another marker being studied for following prostate cancer is the prostate-specific membrane antigen (PSMA). It’s
not yet clear how useful it will be.
¾¾ A rare type of prostate cancer, small cell, has neuroendocrine features. It often does not cause abnormal blood PSA
levels or responds well to hormone therapy.
286 Textbook of Biochemistry— Case Studies

¾¾ Men with these cancers may have higher than normal levels of chromogranin A. These cancers are more likely to
respond to certain chemotherapy drugs.
¾¾ Prostatic acid phosphatase (PAP) is an older, less sensitive marker which is no longer used very much.

STOMACH (GASTRIC) CANCER

¾¾ No marker has been developed for this cancer.
¾¾ Some other digestive cancer markers may be elevated, such as CEA, CA 72-4, and/or CA 19­-9.
¾¾ If the levels of these markers are elevated at the time of diagnosis, the levels can be followed while the cancer is being
treated.

TESTICULAR CANCER
¾¾ Tumor markers are very important in this cancer and are used by doctors to follow its course.
¾¾ Human chorionic gonadotropin (hCG) and alpha fetoprotein (AFP) are usually elevated in the blood of men with
testicular cancer.
¾¾ There are different kinds of testicular cancers, and they differ in the level and kind of marker that is elevated.
¾¾ Seminoma: About 10% of men with seminoma, a type of testicular cancer, will have elevated hCG. None will have
elevated AFP.
¾¾ Non-seminoma: More than half of men with early stage disease will have elevated hCG or AFP or both. The amount
of the marker found in the blood at the time of diagnosis does not often help in predicting outcome. These markers
are elevated in most men with advanced disease. Very high levels of these markers can be a sign of a poorer outlook.
¾¾ hCG is almost always elevated and AFP is never elevated in choriocarcinoma, a subtype of non-seminoma.
¾¾ In contrast AFP, but not hCG, is elevated in another subtype known as yolk sac tumor or endodermal sinus tumor.
¾¾ Many tumors are made up of a mixture of different types of non-seminoma.

GENOMICS
¾¾ Researchers are starting to focus on genetic markers to detect cancer.
¾¾ We know that most cancers have changes in their DNA, the molecules that direct the functions of all cells.
¾¾ By looking for DNA changes in blood, stool, or urine, scientists may be able to find cancers very early.
¾¾ The study of patterns of DNA changes (known as genomics) is likely to prove more useful than looking for single
DNA changes.

NEW DEVELOPMENTS AND AREAS OF RESEARCH FOR SOME COMMON CANCERS

BLADDER CANCER
¾¾ Doctors have been looking for ways to find bladder cancer that has come back (recurrence) by testing the urine.
¾¾ Looking at DNA in the urine has been very successful so far.
¾¾ In fact, the urine tests can find cancer recurrence before doctors can see it by looking directly into the bladder with
cystoscopy.
¾¾ Breast cancer cells likely spill into the blood, even in early stages of the disease.
¾¾ Researchers have found abnormal DNA from these cells in the blood of patients with breast cancer.
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¾¾ About half of patients with even early stage breast cancer have cancer cells in their blood.
¾¾ Researchers are still trying to figure out if the presence of these cells can help predict a person's outlook.
¾¾ New genetic tests may help find out if women are likely to have cancer come back (recurrence) after initial treatment,
and whether they might benefit from additional (adjuvant) hormone therapy or chemotherapy.
¾¾ Tests such as Oncotype DX™ and MammaPrint®, which look at a number of specific genes in a breast tumor sample,
are now being used by some doctors for this purpose, and other tests are being studied.
¾¾ Some other markers in the tumor tissue may also help to predict outlook and help guide treatment decisions.
¾¾ The levels of 2 proteins, urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) may be
helpful for this.
¾¾ Higher-than-normal levels of these tumor markers in the cancer tissue may mean that the cancer is more aggressive
(faster growing).
¾¾ These tumor markers may be used to guide the use of chemotherapy after surgery for patients with node-negative
breast cancer (meaning there is no cancer found in the lymph nodes).
¾¾ The problem with these markers is that they have to be checked on tumor tissue that is not preserved (It must be fresh
or frozen).
¾¾ This makes these tests harder to do (and less available) than other tumor marker tests for breast cancer.

COLORECTAL CANCER
¾¾ Most colorectal cancers contain changes in genes such as APC, k-ras, and p53.
¾¾ New studies have found pieces of abnormal DNA in the stools of people with early colorectal cancer.
¾¾ Testing stool samples for these DNA changes can be used to screen for this disease.
¾¾ Other studies have found changes in DNA in the blood of patients with early colorectal cancer.
¾¾ Looking at the number of repeated sequences in DNA (known as microsatellite instability) may give doctors clues as
to how well treatment might work.

LUNG CANCER
¾¾ Studies have found elevated levels of DNA in the blood of patients with lung cancer, while more sensitive tests have
been able to detect abnormal DNA in their blood.
¾¾ These abnormal DNA changes have also been found in the sputum of patients with early lung cancer.
¾¾ Doctors think that this may some day be a good way of finding lung cancer early in patients who have a high risk of
developing the disease.

LIVER CANCER
¾¾ The gene called p53 is often abnormal in liver cancers.
¾¾ Blood tests can find this abnormality in DNA in the blood of some patients with this cancer.
¾¾ It's not yet clear how useful this will be.

MELANOMA
¾¾ In patients with advanced melanoma, small numbers of melanoma cells are found in the blood.
¾¾ This may prove to be a good way of finding out how advanced a person’s melanoma is and whether it is responding
to treatment.
¾¾ More study is needed.
288 Textbook of Biochemistry— Case Studies

ORAL CAVITY CANCERS

¾¾ Abnormal DNA can be found in saliva samples of people with these cancers.
¾¾ It may be a good way to detect them early in people at high risk or who have been treated for these cancers.
¾¾ Research on this is under way.

OVARIAN CANCER
¾¾ Several different blood tests are being studied for early detection of this cancer.
¾¾ The most successful appears to be the use of protein patterns in patients' blood.
¾¾ This method, called proteomics, has shown some promising early results.
¾¾ This type of test still needs to be studied to see if it can find this cancer at an early stage in women with no symptoms.
¾¾ The use of CA 125, along with imaging tests such as ultrasound, as a screening test for ovarian cancer is still being
studied.

PROSTATE CANCER
¾¾ There is a major clinical trial in progress to determine the value of PSA screening for prostate cancer.
¾¾ There are also newer versions of this test that look at certain fractions of PSA, such as free PSA or complexed PSA,
which may give more useful information.
¾¾ Doctors are also studying the usefulness of watching the change in PSA levels over time, as opposed to focusing on
a single test result (PSA velocity).
¾¾ There are also attempts to look at protein patterns in the blood as a way of finding the disease in the early stages.
¾¾ Other new tests are looking at certain proteins or genes to try to find out which prostate cancers are likely to be
aggressive (and need treatment) and which are likely to grow more slowly (and can probably just be watched carefully).
¾¾ Most of these new methods of detecting cancer are still in the experimental stage.
¾¾ Many studies are in progress to try to figure out how useful they will be.