CLINICAL CHEMISTRY TUMOR MARKERS OUTLINE • Tumor Markers o Tumor Markers in Recurrent Conditions o Specific Tumor Markers • TUMOR MARKERS • Tumor markers are substances that can be found in the body when cancer is present • Malignancies increase tumor marker levels • Tumor marker elevation is only seen in advance/terminal/ end stages of cancers, they are not elevated in early stages • Early detection of cancer is important for cancer mgmt o Tumor markers are not useful in early detection o During early stages of cancer, biopsy examination is used for detection o Histopathologic examination of biopsy - gold standard in early detection of cancer • Found in blood, urine, and other body fluids, tissues, tumors • Types : o Specific - seen in single type of cancer ▪ Ex. Prostate specific antigen (PSA) - for prostatic carcinoma/cancer o Nonspecific - Seen in many types of cancer ▪ Ex. Carcinoembryonic antigen (CEA) - seen in various types of cancers • Uses : o Diagnosing cancer ▪ Ex.: CA 12-5 (ovarian cancer), Alpha fetoprotein (AFP; hepatocellular carcinoma) o Determining how well treatment is working o Seeing if certain treatments are likely to work ▪ Useful in clinical trials ▪ Ex. HER2, drugs such as Trastuzumab (Herceptin®) o Detecting recurrent cancer ▪ Patients are tested for tumor markers annually or biannually to check reoccurrence of cancer/presence of hidden cancer TUMOR MARKERS IN RECURRENT CONDITIONS • Prostate specific antigen (PSA) for prostate cancer • Human chorionic gonadotropin (HCG) for gestational trophoblastic tumors and some germ cell cancers • Alpha fetoprotein (AFP) for certain germ cell cancers and liver cancer • CA 125 for ovarian cancer • Carcinoembryonic antigen (CEA) for colon and rectal cancers; some women who have been treated for breast cancer have blood tests for levels of tumor marker CA 15-3 • CA 15-3 for WHEN TO CHECK FOR TUMOR MARKERS • At the time of diagnosis • Before, during, and after treatment • Regularly for many years to see if cancer has come back REASONS WHY MOST TUMOR MARKERS CAN’T BE USED TO DETECT EARLY CANCER • Almost everyone has a small amount of these markers in their blood, so 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, it doesn't always mean that cancer is present. o Other tests to detect cancer: imaging studies, physical exams, histopathologic bipsy SPECIFIC TUMOR MARKERS ALPHA-FETOPROTEIN (AFP) • Most common tumor marker for hepatoma (liver cancer) • Help diagnose and guide the treatment of liver cancer (hepatocellular carcinoma/hepatoma) • Normal levels of AFP are usually less than 10 ng/mL o Normally high among fetus • Also elevated in acute and chronic hepatitis o Uncontrolled hepatitis B can progress to hepatoma o Hepatoma - Infectious cancer • Useful in following response to treatment for liver cancer • Also higher in certain germ cell tumors, such as some testicular cancers (those containing embryonal cell and endodermal sinus types) certain rare types of ovarian cancer (yolk sac tumor or mixed germ cell cancer) o Non specific for liver cancer but commonly used for hepatocellular carcinoma • Germ cell tumors that start in the chest (mediastinal germ cell tumors) Bcr-abl • Abnormal gene used as marker for Chronic Myeloid Leukemia (CML) • Presence is associated with certain leukemia (CML) • The detection is through polymerase chain reaction (PCR) o Amplification of gene segments • Use: the level of the gene can be measured and used to guide treatment among leukemia patients
BETA-2-MICROGLOBULIN (B2M) • Elevated in multiple myeloma (cancer of the plasma cells), chronic lymphocytic leukemia (CLL), and some lymphomas (lymphatic cancer) • Levels may also be higher in some non-cancerous conditions such as kidney disease and hepatitis • Nonspecific to cancers, can be higher in other conditions • Normal levels are usually below 2.5 mg/L • Uses: to help predict the long-term outlook (prognosis) • Checked during treatment of multiple myeloma to see how well the treatment is working. BETA HCG • Or human chorionic gonadotropin (HCG) • Hormone tumor marker • Physiologically elevated among pregnant women especially in first trimester o Used as marker for detecting pregnancy • Blood levels are elevated in patients with some types of testicular and ovarian cancers (germ cell tumors) • Also increased in gestational trophoblastic disease mainly choriocarcinoma • Also higher in some people with mediastinal germ cell tumors - cancers in the middle of the chest (mediastinum) • Uses: Levels of HCG can be used to help diagnose these conditions and can be followed over time to see how well treatment is working • Can be used to assess suspected cancer in some situations o Woman with enlarged uterus after pregnancy o Man with enlarged testicles BLADDER TUMOR ANTIGEN (BTA) • Found in the urine of many patients diagnosed with urinary bladder cancer • Also used as a sign of other non-cancerous conditions o Non-specific marker • Test is reported as either positive or negative • Used along with NMP22 to test patients for the return (recurrence) of bladder cancer • Not as good as cystoscopy (imaging for bladder) CA 15-3 • Commonly used for detecting breast cancer • Used to watch patients with breast cancer o Commonly used tumor marker • The normal level is usually less than 30 U/mL • This marker can also be higher in other cancers such as lung and ovarian • Also elevated in some non-cancerous conditions like benign breast conditions and hepatitis • Elevated blood levels are found in: o Less than 10% of patients with early disease o About 70% of patients with advanced disease • Fine Needle Aspiration Biopsy (FNAB) - modern technique used for histopathological studies CA 27.29 • Used to follow patients with breast cancer during or after treatment ( determining patients’ response to treatment) • Measurement same with CA15-3 • Normal level is usually less than 40 U/L • Can also be elevated in other cancers and in some non-cancerous conditions • It is not elevated in all patients with breast cancer CA 125 • Standard tumor marker used to follow women with epithelial ovarian cancer • Normal blood levels are usually less than 35 U/mL • >90% of woman with high levels have advanced cancer • Increased level during diagnosis is used for treatment assessment • Elevated in about half of women whose cancer has not spread outside of the ovary (metastasis) • Disadvantages : o Can miss early stage of cancer o Can be seen elevated in other conditions other than Ovarian cancer such as: uterine fibroids or endometriosis lung, pancreatic, breast, and colon cancer and people who have had cancer in the past CA 72-4 • Newer test to detect the ff : o Ovarian and pancreatic cancer o Cancers starting in the digestive tract, especially stomach cancer CA 19-9 • Developed to detect colorectal cancer (large intestine & rectum) • Now used to detect pancreatic cancer • Normal blood levels of CA 19-9 are below 37 U/mL • Increased levels in newly diagnosed patient indicates that the cancer is in advanced stage • CA 19-9 can also be elevated in the ff : o Other forms of digestive tract cancer, especially cancers of the stomach and bile ducts. o And in some non-cancerous conditions such as thyroid disease, inflammatory bowel disease, and pancreatitis (inflammation of pancreas) • W/ elevated enzyme AMY can be used to detect pancreatitis CALCITONIN • Hormone tumor marker • Produced by cells called parafollicular C cells in thyroid gland • It normally helps regulate blood calcium levels • Normal calcitonin levels are below 5-12 pg/mL • In diagnosing medullary thyroid carcinoma (MTC), blood levels of this hormone are often greater than 100 pg/ml. • Uses: o Can detect early cancer o Since MTC is often inherited, Calcitonin can be used to detect early cancer to family members at risk o Other cancers, like lung cancers and leukemias, can also cause calcitonin levels to be elevated
CARCINOEMBRYONIC ANTIGEN (CEA) • CEA is used to diagnose or screen for colorectal cancer • Physiologically high among fetus/newborns • Higher than 3 ng/mL (nanograms per milliliter) are not normal level • The higher the level of CEA when diagnosed, the more advance the cancer is • Standard marker used to follow patients with colorectal cancer during and after treatment • Other conditions where CEA is elevated: o Lung and Breast cancer. o Cancers of the thyroid, pancreas, liver, stomach, prostate, ovary, cervix, and bladder o Non-cancerous conditions such as like hepatitis, chronic obstructive pulmonary disease (COPD), colitis (inflammation of colon), and pancreatitis, and in otherwise healthy smokers. • If the CEA level is high at diagnosis, it can be used to follow the response to treatment o Gradual decrease - good indication of response to chemotherapy or cancer treatment. CHROMOGRANIN-A • Made by neuroendocrine tumors • The most sensitive tumor marker for carcinoid tumors • 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) • Can also be elevated in some advanced forms of prostate cancer that have neuroendocrine features • Normal level is less than 50 ng/mL EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) • Also known as HER1 • A receptor found on cells that helps them grow • Use to assess growth of cancer cells • Used to guide treatment and predict outcomes of non-small cell lung, head, and neck, colon, pancreas, or breast cancers • Results are reported as a percentage based on the number of cells tested. • Some lung cancers have defects (mutations) in EGFR gene • These gene defects are most common among lung cancer patients that are: Women, Non-smokers, Asians HORMONE RECEPTORS • Estrogen and Progesterone receptors o Important in breast cancer tumor o Fuel the growth of breast cancer cells o RESULTS: “ERpositive” “PR-positive” HER2 • Also known as HER2/neu, erbB-2, or EGFR2 • Protein that tells some cancer cells to grow • Elevated in about 1 out of 5 breast cancers and can also be elevated in some stomach cancers • Sample used is tumor (surgically removed cancer tissues) • Cancers that are HER2-positive tend to grow and spread faster than other cancers IMMUNOGLOBULINS (Ig) • Blood proteins normally made by immune system cells to help combat infection • Bone marrow cancers such as multiple myeloma (MM) and Waldenstrom macroglobulinemia (WM) o MM - increased level of IgG o WM - increased level of IgM (largest ig) • Serum Protein Electrophoresis (SPEP): o M spike, monoclonal protein or M protein; almost same peak as albumin (most abundant protein) KRAS • Gene used in assessing colorectal cancer • Used as guide in administering treatment to Colorectal CA • Cetuximab (Erbitux®), Panitumumab (Vectibix®), Erlotinib (Tarceva®), or Gefitinib (Iressa®) LACTATE DEHYDROGENASE (LDH ) • LDH1 - isoenzyme elevated in conditions involving cancer or malignancies • Marker for testicular cancer and other germ cell tumors • Level can be up with many other things besides cancer, including blood and liver problems • Used to monitor the effect of treatment and to watch for recurrent disease. NEURON-SPECIFIC ENOLASE (NSE) • A marker for neuroendocrine tumors • It is not used as a screening test. • It is most useful in the follow-up of patients with small cell lung cancer or neuroblastoma • Abnormal levels are usually higher than 9 ug/mL NMP22 • Protein found in the nucleus (control center) of the cells • Elevated (more than 10 U/mL) in the urine of people with bladder cancer is diagnostic of cancer • Not as invasive as cystoscopy PROSTATE-SPECIFIC ANTIGEN (PSA) • At present, best tumor marker discovered o Because they are cancer-specific (prostate CA), gender-specific (among male) • Tumor marker for prostate cancer • The only marker used to screen for a common type of cancer o Prostate cancer - common among male geriatrics • A protein made by cells of the prostate gland, which is found only in men • PSA also elevates in the ff. : o Benign prostatic hyperplasia (BPH) o Older men o Infected/inflamed prostate o After ejaculation • For slight elevation, it is attributed to non-cancerous conditions of the prostate • PSA is only specific to the conditions of prostate gland • Level below 4 ng/mL means cancer is unlikely. • Levels greater than 10 ng/mL mean cancer is likely.
• The area between 4 and 10 is a gray zone. Caused by some physiologic conditions • Men with PSA levels in this borderline range have about a 1 in 4 chance of having prostate cancer • Parameters measured o PSA velocity o Percent-free PSA (fPSA) S-100 • A protein tumor marker found in most melanoma cells • Tissue samples of suspected melanomas may be tested for this marker to help in diagnosis • Elevated in most patients with metastatic melanoma • Used to look for melanoma spread before, during, or after treatment THYROGLOBULIN • Protein made by the thyroid gland • Elevated in many thyroid diseases, including some common forms of thyroid cancer • Thyroid CA treatment involves: o Surgical removal of entire thyroid o Radiation therapy •