Tumor Marker


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Tumor Marker

  1. 1. Tumor Markers Clinical Pathology Conference Noel C. Santos, M.D.
  2. 2. Definition • Tumor markers are oncoproteins or mutated forms of these proteins that can indicate the presence of a tumor. • Oncoproteins are products of mutated oncogenes – become permanently activated in stimulating cell growth and proliferation (i.e. ras gene) – become inactive in inhibiting cell proliferation (p53 protein)
  3. 3. Tumor Markers associated with Cell Proliferation • Hormones: hCG, serum proteins, ezymes (LDH, AP) and metabolites (VMA, HVA, 5-HIAA) • benign and nonmalignant diseases may also involve elevated levels - NOT SUITABLE FOR SCREENING OR CANCER DIAGNOSIS due to large number of FALSE- POSITIVE results • Useful in MONITORING during treatment
  4. 4. Tumor Markers related to Cell Differentiation • Carcinoembryonic proteins : seen in both fetal and tumor tissues but not in normal adult tissues • Measured by immunoassays due to small concentration (nanogram per milliliter)
  5. 5. Tumor Markers related to Cell Differentiation • Higher sensitivity and specificity than enzymes and metabolites • still not suitable for screening due to cross- reactivity of the protein with other normal proteins and does not appear early in the blood. • Useful in monitoring treatment and recurrence
  6. 6. Tumor Markers related to Metastasis • Cell products released and synthesized during the process of metastasis. • Indicate risk of occurrence of metastases or poor prognosis • Measurements are limited to tumor tissues and tumor tissue cytosols.
  7. 7. Related to other Tumor-Associated Events • Altered enzymatic activities such as: – Glycosyltransferases: CA 19-9 – Fucosyltransferase: AFP
  8. 8. Related to Malignant Transformation • Production of oncoproteins – lost the regulatory constraints on their activity – not dependent on external activation signals for them to promote cell proliferation • Production of c-erbB-2-protein (p185)
  9. 9. Inherited Mutations of Suppressor Genes • p53 - useful for screening and identification of families or individuals at high risk of developing various cancers • BRCA1 and BRCA2: breast cancer • BRCA1: also at risk for ovarian, colon and prostate cancer • BRCA2: risk of breast cancer in men
  10. 10. Monocolonal Antibody-Defined Tumor Markers • Hybridoma technology used to focus on only a small surface area, an EPITOPE or ANTIGENIC DETERMINANT using monoclonal antibodies. • There are no TUMOR-SPECIFIC EPITOPES, only TUMOR-ASSOCIATED EPITOPES
  11. 11. Monocolonal Antibody-Defined Tumor Markers • Much more specific and sensitive than polyclonal antibodies – Ex. CA 19-9, CA125 and CA15-3 are much more sensitive and specific than CEA for pancreatic, ovarian and breast CA, respectively. • Many tumor-associated epitopes are also shared by various tumor markers derived from different tumors – Ex. CA19-9, CA125 and CA15-3 are expressed by almost all carcinomas at VARYING DEGREES and vise-versa.
  12. 12. Pre-requisite in Using Tumor Markers • KNOW THE SENSITIVITY AND SPECIFICITY!
  13. 13. SENSITIVITY • 100% sensitivity means that the test can detect all patients with that disease • Measure of the true positivity % true positive Sensitivity = (%true-positive + %false- negative)
  14. 14. SPECIFICITY • 100% specificity means that it will identify only the patients with the specific type of disease and not those without the disease. • Measure of false-positivity % true negative Specificity = (%true-neg + %false-positive)
  16. 16. SCREENING • NONE of the tumor markers discovered had the specificity and sensitivity for screening. • Screening is not recommended especially to an asymptomatic population. – Exceptions: – Screening for primary hepatoma in China using AFP, due to high incidence – Screening for prostate CA with PSA and DRE due to tissue specificity of PSA and high incidence in men >50, African American.
  17. 17. DIAGNOSIS • The frequency of detecting elevated levels of tumor markers in nonmalignant diseases and the overlap observed between the normal concentrations and the concentrations of tumor markers in patients with proven cancer discourages their use in diagnosis • Measure Density (conc. Divided by the mass volume) and Velocity (rate of increase) to improve sensitivity and specificity.
  18. 18. MONITORING TREATMENT • One of the two most useful applications of tumor markers • The serum level of tumor markers reflects well the success of surgery or the efficacy of chemotherapy
  19. 19. DETECTION OF RECURRENCE • Second most useful application • The appearance of most of the circulating tumor markers has a “lead time” of several months (3-6 months) prior to the stage at which many of the physical procedures could be used for the detection of the cancer • The specificity of tumor markers does not present a problem for this application.
  20. 20. FOR PROGNOSIS • The risk factors associated with the process of tumor metastases such as proteases and adhesion molecules are usually better markers for predicting prognosis. • Most of these are measured in tumor tissues and cytosols.
  22. 22. 1. Never rely on the result of a single test
  23. 23. 2. When ordering serial testing, be certain to order every test from the same laboratory using the same assay kit
  24. 24. 3. Be certain that the tumor marker selected for monitoring recurrence was elevated in the patient prior to surgery – BASELINE!!!!
  25. 25. 4. Consider the half-life of the tumor marker when interpreting the test result
  26. 26. 5. Consider how the tumor marker is removed or metabolized from the blood circulation – KIDNEY AND LIVER
  27. 27. 6. Consider ordering multiple markers to improve the sensitivity and specificity for diagnosis
  28. 28. 7. Order the nonspecific markers for cost-saving and for their high sensitivity.
  29. 29. 8. Be aware of the presence of ectopic tumor markers
  30. 30. AFP • A major fetal serum protein and is also one of the major carcinoembryonic proteins • Resembles albumin in physicochemal properties • Majority is synthesized in fetal yolk sac and hepatocytes, and to a lesser extent, GIT and kidney • Found in patients with primary hepatoma and yolk- sac derived germ cell tumors. • Most useful marker in HCC
  31. 31. AFP • Transiently elevated during pregnancy and in many benign liver diseases. • Screening for hepatoma in China • AFP & hCG, reduces clinical staging errors in patients with some testicular tumors • Increase in fucosylation (lentil lectin reactivity) differentiates between hepatoma and benign liver disease, signals development of hepatoma
  32. 32. CA 19-9, CA 50, AND CA 19-5 • Defined by monoclonal antibodies • Assay for CA 19-9 measures a CHO antigenic determinant expressed on a HMW mucin. It appears as a mucin in the sera of cancer patients and as a ganglioside in tumor cells. • CA 19-9 is related to Lewis blood group substances and only serum antigen of cancer patients belonging to Le(a-b+) and (a+b-) will be positive
  33. 33. CA 19-9, CA 50, AND CA 19-5 • CA 50 is found in Lewis negative individuals • CA 19-9 used for gastric and pancreatic CA, in monitoring and recurrence • CA 19-9 and CA 50 complement each other in pancreatic and other carcinomas, used simultaneously, improves sensitivity. • Elevated levels are found in colon, pancreatic, and HCC.
  34. 34. CA 125 • Associated with a HMW mucin-like glycoprotein • Expressed by greater than 80% of nonmucinous epithelial ovarian carcinomas. • Serous, endometrioid and clear cell carcinomas of ovary • Patients undergoing chemotx may show a false decline and a negative result does not always rule out tumor recurrence. • Also used for follow-up on uterine tumors and in endometriosis
  35. 35. CA 15-3 • Circulating breast cancer-associated antigen • Present in a variety of adenocarcinomas including breast, colon, lung, ovary, and pancreas • More sensitive and specific marker for monitoring the clinical course of patients with metastatic breast CA • More patients have elevated circulating levels of CA 15-3 than CEA • better correlates with disease progression, regression, or stability • Also elevated in chronic hepatitis, cirrhosis, sarcoidosis, TB, and SLE
  36. 36. Calcitonin • One of the circulating peptide hormones elevated with increased bone turnover rate associated with skeletal metastases • Ectopically elevated in bronchogenic carcinomas and medullary carcinoma of thyroid – PARANEOPLASTIC SYNDROMES
  37. 37. Carcinoembryonic Antigen • First of the carcinoembryonic proteins discovered • Still the most widely used tumor marker for GI cancer • Initially thought to be a specific marker for colorectal CA but is now used to follow patient during therapy and to detect recurrence • Metabolized in the liver, hence liver damage impairs CEA clearance • May be increased in patients following radiation tx and chemotx
  38. 38. C-erbB-2 (Her-2/neu) Oncoprotein • Member of the class of oncogenes associated with tyrosine protein kinase • This gene is amplified in 25 to 30% of human breast and ovarian CA • An independent predictor of both disease relapse and overall survival • superior to all known prognostic factors (with exception of lymph nodes) when tested positive
  39. 39. C-erbB-2 (Her-2/neu) Oncoprotein • Useful marker to identify patients with breast Ca who are most likely to benefit from high dose adjuvant chemotx • Associated with poor prognosis and with short survival and recurrence in various carcinomas • Herceptin is a monoclonal antibody against its receptor, used as treatment for metastatic breast CA.
  40. 40. Chromogranin A • Major soluble protein of the chromaffin granule • Released from the adrenal medulla together with catecholamines upon stimulation of the splanchnic nerve • Also present in various neuroendocrine tissues • It can be detected in pheochromocytoma and small-cell carcinoma
  41. 41. Estrogen and progesterone receptors • Measurement in breast tumor cytosol is used to identify patients who are most likely to benefit from endocrine therapy • Positivity indicates good prognosis, longer disease-free interval and longer overall survival. • 55-60% of those positive for ER and 85% positive for both will respond to endocrine therapy
  42. 42. Human Chorionic Gonadotropin • Synthesized and secreted by trophoblast cells of the placenta • Elevated hCG can be found in trophoblastic tumor, choriocarcinoma and testicular tumors • 60% patients with nonseminomas and 10-30% with seminomas have elevated free β-hCG. β-hCG is useful for detection of recurrence of metastasis for chorio when the intact hCG may remain normal.
  43. 43. Human Chorionic Gonadotropin • Seminomatous testicular cancer contains both intact hCG, β-hCG, and α subunit in equal amounts; only one assay is needed for monitoring • Only intact hCG and β-hCG may be found in patients with nonseminomatous cancers; measuring both intact and free subunit increase sensitivity.
  44. 44. Human Chorionic Gonadotropin • Ectopic free β-hCG found in urothelial cancer • Ectopic α-hCG is a marker of malignancy in pancreatic endocrine tumors
  45. 45. Neuron-specific Enolase • Found in tumors originating from the neuroendocrine cell system. • A relatively specific marker for small cell lung cancer (85%) • Useful marker for monitoring the treatment and predicting relapse in patients with SCLC
  46. 46. p53 • A nuclear phosphoprotein that is a negative regulator of cell growth - tumor suppressor • Found to be mutated in about half of almost all types of cancer arising from a wide spectrum of tissues. • Can be measured in either tissue, fibroblast, white cell, or serum.
  47. 47. pS2 protein • A cysteine-rich peptide, secreted from breast cells, induced by estrogen • Capable of predicting response to endocrine therapy • Associated with longer overall and disease-free survival • Negative pS2 associated with earlier recurrence and death • ER-PR + / pS2+ , 85% to 97% good prognosis • ER-PR+/ pS2- , 50 to 54% good prognosis
  48. 48. Parathyroid Hormone-related peptide • Secreted by tumors associated with hypercalcemia • Binds and activates receptors that also bind PTH • Useful in differential diagnosis of hypercalcemia related to malignancy and associated either with primary hyperthyroidism, sarcoidosis, Vit. D toxicity, or various malignancies (including SCCA, renal, bladder and ovarian CAs) • Impaired renal function increases plasma concentration
  49. 49. Prostate-Specific Antigen • The best tumor marker discovered thus far due to its tissue specificity • Useful for screening and for management of prostate CA • Lack of cancer specificity is the only drawback; also elevated in BPH, prostatitis, and infarction • Useful in monitoring success of surgical prostatectomy
  50. 50. Prostate-Specific Antigen • A transient and modest increase may occur during radiation therapy and should not be misinterpreted as disease progression • Useful in detecting recurrence • In combination with DRE or UTZ, is a good screening tool
  51. 51. Free PSA • Measurement of free PSA and calculation of %fPSA has been used to help differentiate between BPH from prostatic CA. • %fPSA = (fPSA / PSA) x 100 • >23% associated with BPH • <6% associated with prostatic CA
  52. 52. Squamous Cell Carcinoma antigen • More than 70% of patients with advanced cervical cancer have elevated SCC. • Useful for following patients with cervical cancer during therapy. • Also useful for monitoring SCCA of the head and neck, lung, esophagus, and anal canal • Highest in patients with metastases • Renal clearance
  53. 53. Thank you
  54. 54. Tumor Markers Clinical Pathology Conference Noel C. Santos, M.D.