Tumor Markers PDF

TUMOR MARKERS Presented by Dr. Sahar Gamal Elbager Assistant Professor of Molecular Haematology Dean of MLS Head of Haematology Department University of Medical Sciences and Technology (UMST) What are the tumor markers? Tumor...

TUMOR MARKERS Presented by Dr. Sahar Gamal Elbager Assistant Professor of Molecular Haematology Dean of MLS Head of Haematology Department University of Medical Sciences and Technology (UMST) What are the tumor markers? Tumor markers are defined as a biochemical substance (e.g. hormone, enzymes or proteins) synthesized and released by cancer cells or produced in the host in response to cancerous substance. They are used to monitor or identify the presence of cancerous growth. They are different from substances produced by normal cell in quantity and quality. Tumor marker may be present in Blood circulation Body cavity fluids Cell membranes Cell cytoplasm DNA Dr.Sahar Elbager 3 A good tumor maker should have those properties: 1. A tumor marker should be present in or produced by tumor itself. 2. A tumor marker should not be present in healthy tissues. 3. Plasma level of a tumor marker should be at a minimum level in healthy subjects and in benign conditions. Dr.Sahar Elbager 4 4. A tumor marker should be specific for a tissue, it should have different immunological properties when it is synthesized in other tissues. 5. Plasma level of the tumor marker should be in proportion to the both size of tumor and activity of tumor. 6. Half life of a tumor marker should not be very long Dr.Sahar Elbager 5  7. A tumor marker should be present in plasma at a detectable level, eventhough tumor size is very small 8. The tumor marker is useful both for the prediction of the presence of the tumor and recurrence of the tumor. Dr.Sahar Elbager 6 Tumor markers can be classified as respect with the type of the molecule: 1. Enzymes or isoenzymes (ALP, PAP) 2. Hormones (calcitonin) 3. Oncofetal antigens (AFP, CEA) 4. Carbonhydrate epitopes recognised by monoclonal antibodies (CA 15-3,CA 19-9, CA125) 5. Receptors (Estrogen, progesterone) Dr.Sahar Elbager 7  6. Genetic changes (mutations in some oncogenes and tumor suppressor genes. Some mutations in BRCA1 and 2 have been linked to hereditary breast and overian cancer) Dr.Sahar Elbager 8 Potential uses of tumor markers Screening in general population Differential diagnosis of symptomatic patients Clinical staging of cancer Estimating tumor volume As a prognostic indicator for disease progression Evaluating the success of treatment Dr.Sahar Elbager 9  Detecting the recurrence of cancer Monitoring reponse to therapy Radioimmunolocalization of tumor masses Dr.Sahar Elbager 10  In order to use a tumor marker for screening in the presence of cancer in asymptomatic individuals in general population, the marker should be produced by tumor cells and not be present in healthy people. However, most tumor markers are present in normal, benign and cancer tissues and are not spesific enough to be used for screening cancer. Dr.Sahar Elbager 11  Few markers are specific for a single individual tumor, most are found with different tumors of the same tissue type. They are present in higher quantities in blood from cancer patients than in blood from both healthy subjects and patients with benign diseases. Dr.Sahar Elbager 12  Some tumor markers have a plasma level in proportion to the size of tumor while some tumor markers have a plasma level in proportion to the activity of tumor. The clinical staging of cancer is aidded by quantitiation of the marker. Dr.Sahar Elbager 13  Serum level of marker reflects tumor burden. The level of the marker at the time of diagnosis may be used as a prognostic indicator for disease progression and patient survival. After successful initial treatment, such as surgery, the marker value should decrease. The rate of the decrease can be predicted by using the half life of the marker. Dr.Sahar Elbager 14  The magnitude of marker reduction may reflect the degree of success of the treatment. In the case of recurrence of cancer, marker increases again. Most tumor marker values correlate with the effectiveness of treatment. Dr.Sahar Elbager 15  ENZYMES Alkaline Phosphatase (ALP) Increased alkaline phosphatase activities are seen in primary or secondary liver cancer. Its level may be helpful in evaluating metastatic cancer with bone or liver involvement. Dr.Sahar Elbager 16  Prostatic acid phosphatase (PAP) It is used for staging prostate cancer and for monitoring therapy. Increased PAP activity may be seen in osteogenic sarcoma, multiple myeloma and bone metastasis of other cancers and in some benign conditions such as hyperparathyroidism. Dr.Sahar Elbager 17  Prostate Specific Antigen (PSA) The clinical use of PAP has been replaced by PSA. PSA is much more specific for screening or for detection early cancer. It is found in mainly prostatic tissue. PSA exists in two major forms in blood circulation. The majority of PSA is complexed with some proteins. A minor component of PSA is free. Dr.Sahar Elbager 18  PSA testing itself is not effective in detecting early prostate cancer. Other prostatic diseases, urinary bladder cateterization and digital rectal examination may lead an increased PSA level in serum. The ratio between free and total PSA is an reliable marker for differentiation of prostatic cancer from benign prostatic hyperplasia. Dr.Sahar Elbager 19  The greatest clinical use of PSA is in the monitoring of treatment. The PSA level should fall below the detection limit. This may require 2-3 weeks. If it is still at a high level after 2-3 weeks, it must me assumed that residual tumor is present. Dr.Sahar Elbager 20  HORMONES Calcitonin Calcitonin is a hormone which decreases blood calcium concentration. Its elevated level is usually associated with medullary thyroid cancer. Calcitonin levels appear to correlate with tumor volume and metastasis. Calsitonin is also useful for monitoring treatment and detecting the recurrence of cancer. Dr.Sahar Elbager 21  Human Chorionic Gonadotropin (hCG) It is a glycolprotein appears in pregnancy. Its high levels is a useful marker for tumors of placenta and some tumors of testes. hCG is also at a high level in patients with primary testes insufficiency. hCG does not cross the blood-brain barier. Higher levels in CSF may indicate metastase to brain. Dr.Sahar Elbager 22  ONCOFETAL ANTIGENS Oncofetal antigens are proteins which are typically present only during fetal development but are found in adults with certain kinds of cancer Most reliable markers in this group are 1. α-fetoprotein 2. carcinoembryonic antigen (CEA) Dr.Sahar Elbager 23  α-Fetoprotein (AFP) AFP is a protein normaly produced by the liver and yolk sac of a fetus α-fetoprotein is a marker for hepatocellular and germ cell carcinoma. It is also increased in pregnancy and chronic liver diseases. AFP is useful for screening (AFP levels greater than 1000 µg/L are indicative for cancer except pregnancy), determining prognosis and monitoring therapy of liver cancers. Dr.Sahar Elbager 24  α-Fetoprotein (AFP) AFP is also a prognostic indicator of survival. Serum AFP levels is less than 10 µg/L in healthy adults. Elevated AFP levels are associated with shorter survival time. AFP and hCG combined are useful in classifying and staging germ cell tumors.One or both markers are increased in those tumors. Dr.Sahar Elbager 25 Carcinoembryonic antigen (CEA) A carcinoembryonic antigen (CEA) a specific blood protein. Usually, people are born with high CEA levels that decrease as they get older. CEA elevated in various malignancies such a colorectal, gastrointestinal, lung and breast carcinoma. CEA levels are also elevated in smokers and some patients having benign conditions such as cirrhosis, rectal polips, ulcerative colitis and benign breast disease. It is a cell-surface protein and a well defined tumor marker. CEA is a marker for CEA testing should not be used for screening. It is useful for staging and monitoring therapy. Dr.Sahar Elbager 26  Carbohydrate Markers These markers either are antigens on the tumor cell surface or are secreted by tumor cells. The carbohydrate tumor markers are further classified as 1. High-molecular weight mucins and 2. Blood group antigen-related markers. Monoclonal antibodies have been developed against these antigens. Most reliable markers in this group are CA 15-3, CA 125 and CA19-9. Dr.Sahar Elbager 27  CA 15-3 CA 15-3 is a marker for breast carcinoma. Elevated CA 15-3 levels are also found in patients with pancreatic, lung, ovarian, colorectal and liver cancer and in some benign breast and liver diseases. It is not useful for diagnosis. It is most useful for monitoring therapy. Dr.Sahar Elbager 28  CA 125 Although CA 125 is a marker for ovarian and endometrial carcinomas, it is not specific. CA 125 elevates in pancreatic, lung, breast, colorectal and gastrointestinal cancer, and in benign conditions such as cirrhosis, hepatitis, endometriosis, pericarditis and early pregnancy. It is useful in detecting residual disease in cancer patients following initial therapy. Dr.Sahar Elbager 29  CA 125 The reference range of CA 125 is 0-35 kU/L. A preoperative CA 125 level of less than 65 kU/L is associated with a greater 5 y survival rate than is a level greater 65 kU/L. It is also useful in differentiating benign from malignant disease in patients with ovarian masses. In the detection of recurrence, use of CA 125 level as an indicator is about 75 % accurate. Dr.Sahar Elbager 30  CA 19-9 CA 19-9 is a marker for both colorectal and pancreatic carcinoma. However elevated levels were seen in patients with hepatobiliary, gastric, hepatocellular and breast cancer and in benign conditions such as pancreatitis and benign gastrointestinal diseases. CA 19-9 levels correlate with pancreatic cancer staging. It is useful in monitoring pancreatic and colorectal cancer. Dr.Sahar Elbager 31  CA 19-9 Elevated levels of CA 19-9 can indicate recurrence before detected by radiography or clinical findings in pancreatic and colorectal cancer. Dr.Sahar Elbager 32  Protein Markers Most reliable markers in this group are β2- microglobulin, ferritin, thyroglobulin and immunoglobulin. β2-microglobulin β2-microglobulin is a marker for multiple myeloma, Hodgkin lymphoma. It also increases in chronic inflammation and viral hepatitis. Dr.Sahar Elbager 33  Ferritin Ferritin is a marker for Hodgkin lymphoma, leukemia, liver, lung and breast cancer. Thyroglobulin It is a useful marker for detection of differentiated thyroid cancer. Dr.Sahar Elbager 34  Immunoglobulin: Monoclonal immunoglobulin has been used as marker for multiple myeloma for more than 100 years. Monoclonal paraproteins appear as sharp bands in the globulin area of the serum protein electrophoresis. Bence-Jones protein is a free monoclonal immunoglobulin light chain in the urine and it is a reliable marker for multiple myeloma. Dr.Sahar Elbager 35  Receptor Markers Estrogen and progesterone receptors are used in breast cancer as indicators for hormonal therapy. Patients with positive estrogen and progesterone receptors tend to respond to hormonal treatment. Those with negative receptors will be treated by other therapies. Dr.Sahar Elbager 36  Hormone receptors also serve as a prognostic factors in breast cancer. Patients with positive receptor levels tend to survive longer. Dr.Sahar Elbager 37  Cytoplasmic estrogen receptors are now routinely measured in samples of breast tissue after surgial removal of a tumor. Of patients with breast cancer, 60 % have tumors with estrogen receptor. Approximately two thirds of patients with estrogen receptor (+) tumors respond to the hormonal therapy. 5% of patients with estrogen receptor (-) tumors respond to the hormonal therapy. Dr.Sahar Elbager 38  Progesterone receptor testing is a useful adjunt to the estrogen receptor testing. Because progesterone receptor synthesis appears to be dependent on estrogen action. Measurement of progesterone receptors provides a confirmation that all the steps of estrogen action are intact. Indeed breast cancer patients with both progesterone and estrogen receptor (+) tumors have a higher response rate to hormonal therapy. Dr.Sahar Elbager 39  C-erbB2 (HER-2) It is receptor for epidermal growth factor (EGF) but it doesn’t contain EGF binding domain. It serves as a co-receptor in EGF action In the case of increased expression of HER-2 leads the aut -activation and increased signal transduction Dr.Sahar Elbager 40  Genetıc Changes 4 classes of genes are implicated in development of cancer: 1) Proto-oncogenes which are responsible for normal cell growth and differentiation 2) Tumor suppressor genes Alterations on these genes may lead tumor development. 3)Apoptosis-related genes are responsible for regulation of apoptosis 4)DNA repair genes which are involved in recognition and repair of damaged DNA. Dr.Sahar Elbager 41  DNA repair genes: BRCA1 and BRCA2 are specific genes in inherited predisposition for developing breast and over cancer, and mutations. Mismatch-repair genes are mutated in some colon cancers Dr.Sahar Elbager 42  Tumor suppressor genes: Retinoblastoma gene P53 gene P21 gene Those genetic markers are very new and not routinely measured in laboratories. Dr.Sahar Elbager 43  Chromosomal translocation In chronic myeloid leukemia, there is a translocation between chromosomes 9 and 22. New gene encodes a DNA-binding protein which stimulates cell dividing. Dr.Sahar Elbager 44 Dr.Sahar Elbager 45 Dr.Sahar Elbager 46 Thank you Dr.Sahar Elbager 47