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Tumor Markers

Tumor Markers. Overview. Cancer remains the second leading cause of death in the USA, behind heart disease, with an estimated 1,437,180 new cases & 565,650 deaths in 2008 alone. It is expected that malignancies of prostate & breast origin will be

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Tumor Markers

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  1. Tumor Markers

  2. Overview Cancer remains the second leading cause of death in the USA, behind heart disease, with an estimated 1,437,180 new cases & 565,650 deaths in 2008 alone. It is expected that malignancies of prostate & breast origin will be the most common causes of new diagnoses in men & women, respectively, with tumors of the lung & bronchus the leading cause of cancer-related death in both genders

  3. Cancer A simple definition of cancer is: A relatively autonomous growth of tissue, that can develop into a solid mass or tumor & spread to other areas of the body Cancer cells : • Are not subject to regulatory system of cell growth • Infiltrate adjacent tissue (in contrast to benign tumours) • Form metastases due to lymphogenic or haematogenic spread The proliferation of normal cells is thought to be regulated by growth promoting oncogenes and counterbalanced by tumor-suppressor genes.

  4. Cell cycle Phases of cell activity divided into G, S & M (Growth, DNA synthesis & Mitosis respectively) Apoptosis Programmed cell death Development of new blood vessels to supply oxygen & nutrients to cells

  5. Proto-oncogenes • Proto-oncogenes are genes present in normal human cells & their products (proteins) may play important roles in normal cellular processes (as growth) • These proto-oncogenes may be activated to oncogenes • Oncogenesconvert normal cells into tumor (cancer) cells. • In cancer cells, oncogenes may be: Identical to normal genes but regulation of their expression in cancer cells is abnormal Or: Show very small structural differences from their counterparts in normal cells. These differences will produce agents that leads to transformation of normal cells to cancer cells.

  6. Tumour Suppressor Genes • Tumour suppressor genes are genes that encode for proteins (product) • Involved in protecting cells from unregulated growth • Their mutation may lead to cancer

  7. How to Diagnose Cancer? • A golden dream of an oncologist is to diagnose cancer at an early stage. • Diagnosis of carcinoma in the early stages is a difficult task due to several reasons including lack of symptoms at early stages. • On the other hand most diagnostic procedures (X ray, CT, MRI..etc) are not suitable for early diagnosis. • These methods only detect tumors of at least 1-2 cm in size (1x109cells) or more. • Tumor markers are considered as one of the highly valuable tools for detection and follow up of malignant tumors & their secondaries.

  8. Tumor Markers • Tumor Markers Are substances present in or produced by a tumor itself OR Are produced by host in response to a tumor • Can be used To determine the presence of a tumor OR To differentiate a tumor from normal tissue • Based on measurements in blood or secretions

  9. Tumor Markers Tumor markers include a variety of substances like: • Cell surface antigens • Cytoplasmic proteins • Enzymes • Hormones • Oncofetal antigens • Receptors • Oncogenes & their products (proteins)

  10. Characteristics of an Ideal Tumor Marker • Should be highly specific to a given tumor type • Should provide a lead-time over clinical diagnosis • Should be highly sensitive i.e. non-detectable in physiological or benign diseases • The levels of the marker should correlate reliably with the tumor burden • It is accurately reflecting any tumor progression or regression with ashort half-life • The test used for detection should be cheapfor screening at mass level • It should be of such nature as to be acceptable to the target population

  11. Applications of Tumor Markers 1- Diagnosis(D): to help to establish the diagnosis 2- Screening( S ): to identifypatients with early cancer 3- Prognosis( P ): to assess the aggressiveness 4- Monitoring (M) Evaluate the Response to Treatment (RT) Detection of Recurrence (R) 5- Determination of Risk

  12. 1- Screening Screening asymptomatic individuals Use of tumor markers, to date, has generally not been an effective strategy due to: • Most of the clinically used tumor markers are found in normal cells & benign conditions in addition to cancer cells. • The relatively low prevalence of individual cancer types. • The screening role is generally very useful if restricted to population at high risk because of: - Family history - Environmental exposure - Geographic prevalence - Clinical profile

  13. 1- Screening cont. High risk groups: Are individuals at increased risks for malignancy • Alpha fetoprotein (AFP) For patients with liver cirrhosis or chronic hepatitis who are at risk for development of hepatocelluar carcinoma • Prostate-specific antigen (PSA) For men older than 50 years in conjunction with a physical examination (clinical profile) for early detection of cancer prostate • Calcitonin For first degree relatives of a patient (family history) with medullary carcinoma

  14. 1- Screening cont. Sensitivity & Specificity of Screening Tumor Markers: Ideal tumor marker for screening asymptomatic population should be: 100% sensitive: Always positive in patients with the disease 100% specific: Always negative in individuals who do not have the disease For examples: If a test gives positive results in 99 patients out of 100 patients: Its sensitivity is 99% If a test gives negative results in 90 normal individuals out of 100 normal individ. Its specificity is 90%

  15. 1- Screening cont. In reality, an ideal tumor marker which gives 100% specificity & 100 % sensitivity does notexist. To increase sensitivity & specificity of a tumor marker • Combination of multiple tumor markers • Combination of tumor markers with other procedures e.g. combination of Carbohydrate Antigen 125 (CA 125) with ultrasonography for early detection of ovarian malignancy

  16. 2- Prognosis • For cancer patients, determination of prognosis is based on determination of aggressiveness of tumor, which , in turn determines how a patient should be treated. • As the serum concentrations of tumor markers increases with progression and usually reaches the highest levels when tumors become metastasized, the serum levels at diagnosis are likely to reflect the aggressiveness of the tumor and predict the outcome. • High levels of serum tumor marker measured during diagnosis would indicate the presence of a malignant or metastatic tumor associated with poor prognosis.

  17. 4- Monitoring of Disease, Response of Treatment &Detection of Recurrence • Constitutes the most common clinical use of serum tumor markers. • Markers usually increase with progressive disease, decrease with remission & do not change significantly with stable disease. • After treatment (surgical resection, radiation or chemotherapy), tumor markers are routinely followed serially (to monitor the response to treatment & recurrence). • It is desirable to monitor the patient using a highly sensitive tumor marker test to detect recurrence as early as possible • The appearance of most of the circulating tumor markers have a lead time of several month (3-6 months) prior to the stage at which many of the physical procedures can be used for detection of the cancer • So, rising tumor marker levels may detect recurrence of disease before any clinical or radiological evidence of disease is apparent (biochemical recurrence)

  18. 5- Determination of Risk • Usually involves genetic probes that evaluate any specific genetic abnormality or mutation noted to indicate an increased risk of a particular malignancy. • Examples of such abnormalities would include: - Carriers of Philadelphia chromosome for hematological malignancies - Carriers of BRCA 1 or 2 genes, which confer a higher risk of breast or ovarian malignancies

  19. Samples used for tumor marker estimations 1- Tissue (tissue tumor marker) • Solid tumors • Lymph nodes • Bone marrow • Circulating tumor cells in the blood 2- Body fluids (serological tumor markers) • Ascitic fluid • Pleural fluid • Serum • Urine

  20. Factors that affect serum concentrations of tumor markers • False positive results occur with: • Inflammatory conditions • Benign conditions • Presence of liver diseases: Causes disturbances in metabolism and excretion of some tumor markers as AFP, TPA, CEA, CA 19-9, CA 15-3.. • Disturbances of renal function: affects levels of some tumor markers as beta-2-microglobulin, calcitonin, PSA, CEA, CA 19-9, CA 15-3… • As a consequence of diagnostic and therapeutic procedures: digito-rectal examination, mamography, surgery, radio and chemotherapy • As a consequence of different physiological conditions: as in pregnancy may affect ßHCG, AFP…..).

  21. AFP: alpha fetoprotein B-hCG: beta human chorionc gonadotrpin CEA: carcinembrionic antigen CA 125: carbohydrate antigen 125

  22. Factors that affect serum concentrations of tumor markers False negative results occur with: • Insufficient expression of a certain antigenic determinant or production in only some of tumor cells • Insufficient blood circulation in the tumor • Production of immune complexes with autoantibodies • Rapid degradation & clearance of antigens

  23. Frequency of Ordering • As a general guideline, the time interval between serial determinations should be 3 months. • But in case of an abnormal value, a repeat estimate can be ordered within 2 to 4 weeks irrespective of the initial reading. • The success of surgical removal of a tumor as determined by tumor marker concentrations is ideally ascertained after a period not less than 5-6 half-lives, to allow tumor marker levels to make a plateau or fall to normal. • This period may be even longer in case of treatment with chemotherapy or radiotherapy, wherein the therapeutic effects themselves are manifested after a lag period.

  24. GUIDELINES FOR ORDERING/ INTERPRETING TUMOR MARKER TESTS • Never rely on the result of a single test • Order every test from the same laboratory • Consider half-life of the tumor when interpreting the result • Consider how the Tumor Marker is removed or metabolized • Consider presence of HeterophileAntibodiesInterfere with testing due to the presence of circulating antibodies against animal immunoglobulin (in the test materials)

  25. METHODS FOR DETECTION Immunoassay is the most common measurement method Challenges • Markers often above linearity • Lipemia, hemolysis and antibody cross reactivity cause interferences

  26. Examples of Frequently Ordered Tumor Markers • Alpha-fetoprotein • CA-125 • CEA • hCG • PSA • Her-2/neu • p53 • BrCa1 • BrAa2 • CA-15.3 • CS-19.9 • Estrogen & progesterone receptor • VMA

  27. Suggested Recommended Markers for diagnosis/prognosis

  28. Suggested Recommended Markers for diagnosis/prognosis

  29. Oncofetal Proteins

  30. Oncofetal Proteins • These are proteins produced during fetal life. • They are present in high concentrations in the sera of fetuses & decrease to low levels or disappear after birth. • They reappear in individuals with cancer. • This demonstrates that certain genes are reactivated as a result of the malignant transformation of cells. • There are several oncofetal antigens as AFP & CEA

  31. Alfa-feto Protein (AFP) • AFP is a glycoprotein. • It is one of the major proteins in the fetal circulation • The fetal AFP reaches the peak at 14 weeks of gestation and declines at term. • The maternal AFP level increase from 12 weeks to peak during the third trimester • It is a marker of hepatocellular carcinoma & germ cell ( non-seminoma ) carcinoma. • Other causes of increased AFP due to non-malignant causes: - Pregnancy - Non- cancerous liver diseases : hepatitis & cirrhosis • Except in pregnancy , AFP level greater than 1000ug/L indicates cancer

  32. Alfa-fetoprotein (AFP) cont. • Clinical Application of AFP: • Diagnosis, prognosis & monitoring of hepatocellular carcinoma (i.e. hepatoma). • Used with ultrasound imaging every 6 months in patients at high risk of developing HCC (e.g. patients with hepatitis B virus & hepatitis C virus-induced liver cirrhosis). AFP is used for early detection (in the lead period) which is ~ 3 - 6 months before clinical manifestations of the cancer appear. • AFP is not completely specific for HCC • AFP may be increased in pregnancy & benign liver disease. • AFP is used as a tumor marker for nonseminomatous testicular cancer in combination with another tumor marker: -human chorionic gonadotropin (-hCG)

  33. Carcinoembryonic Antigen (CEA) It is the most widely used tumor marker for colorectal cancer. The main clinical use of CEA is as a tumor marker for colorectalcancer for: Prognosis Postsurgery surveillance Monitorresponse to chemotherapy

  34. Hormones as Tumor marker The production of hormone in cancer involves 2 separate routes: 1.The endocrine tissue that normally produces the hormone can produce excessive amounts e.g. pheochromcytoma tumor of adrenal medulla ( TM VMA) - 2. A hormone can be produced by non endocrine tissue that normally does not produce the hormone e.g. ectopic production of ACTH

  35. Human Chorionic Gonadotropin (hCG) • hCG is a hormone normally secreted by trophoblasts in the placenta during pregnancy. It is a glycoprotein consisting of  and  subunits. • It is the most useful marker for detection of gestational trophoblastic diseases (GTDs) that include: • Hydatiform mole (vesicular mole) • Choriocarcinoma • It is alsoelevated in nonseminomas tumors of the testis.

  36. Enzymes as Tumor Markers Generally, an increase in enzymes is not specific or sensitive to identify type of cancer. PSA is an exception

  37. Prostate Specific Antigen (PSA) • PSA is a glycoprotein produced only in the epithelial cells of the acini & ducts of the prostate. There are 2 major forms of PSA that are found in the blood: Free & Complexed: to 1-antichymotrypsin or 2-macroglobulin. • Total PSA isused in screening & in monitoring of prostate cancer • Free PSA can help to differentiate levels of PSA that are in the grey zone: i.e. not high enough to diagnose cancer prostate, but not low enough to rule out the diagnosis of cancer prostate: Patient with cancer prostate have a lower % of free PSA.

  38. Prostate Specific Antigen (PSA) • Annual PSA testing for screening of prostate cancer is indicated for: • In men over 50 years old • In younger men at high risk: e.g. Those with a family history of prostate cancer. • To increase the accuracy of the PSA testing, it is essential to use age-adjusted cutoff values of PSA • The best clinical use & first clinical applications of PSA testing was to monitor for the progression of prostate cancer after therapy (e.g. radical prostatectomy) • Causes other than prostate cancer that can  elevated PSA: • Prostate infection • Prostate irritation • Benign prostatic hyperplasia (enlargement)

  39. Carbohydrate Markers Carbohydrate relate tumor markers: are either: Antigens on tumor cells Or: Secreted by the tumor cells ( CA = carbohydrate antigens)

  40. Carbohydrate Antigen-125 (CA-125) CA-125 may be useful for detecting ovarian tumors: Only clinically accepted serologic marker of ovarian cancer Diagnoseovarian tumors at early stages Distinguish benign masses from ovarian cancer Monitoring treatments CA-125 is notconsidered specific enough for ovarian cancer, as it may be elevated in patients with Endometriosis During the first trimester of pregnancy During menstruation.

  41. Carbohydrate Antigen 15.3 (CA 15-3) • These are large glycoproteins e.g. mucins that are normally found on a variety of epithelial cell types, including breast, • It is most useful in used in disease monitoring of metastatic breast cancer

  42. Receptors as Tumor Markers

  43. Estrogen/Progesterone Receptors (ER/PR) • These steroid receptors can play a role in breast carcinogenesis and similar to HER-2, assessment of ER/PR status is crucial for optimal treatment planning • Decreased recurrence rates & disease-related mortality have been demonstrated with tamoxifen for ER+ cancers, which are not seen when the tumors are ER–. • Receptor status also has significant prognostic implications, with best to poorest survival ranging from ER+/PR+ to ER−/PR–.

  44. Genetic Markers Two classes are involved in the development of cancer Oncogenes: as HER-2/neu Suppressor genes: as BRCA1 , BRCA2, p53

  45. Human Epidermal Growth Factor Receptor 2 (Her-2/neu) • HER-2 gene productis a transmembrane protein normally involved in cell growth and differentiation through its interaction with circulating growth factors • It is identified as an oncogeneas its amplification results in protein over expression that supports rapid cellular proliferation (tumorogenesis) • Her-2/neu is a marker for breast & ovarian cancers • It is now routinely measured in breast cancer to determine the type of therapy: • Breast cancer positive for Her-2/neu is responsive to treatment (Herceptin) • Breast cancer negative for Her-2/neu is NOT responsive to treatment

  46. Tumor suppressor genes (e.g. p53) Tumour suppressor genes are genes that encode for proteins that are: • Involved in protecting cells from unregulated growth • If mutated may lead to cancer • An example is p53 • P53 gene is located on chromosome 17 (together with the genes of • BRCA1 & Her-2/neu • Encodes a protein of 53 kDa that normally result in cell cycle arrest & • induces apoptosis • Upon mutation: loss of function mutation  cancer

  47. p53 • Mutations in p53 gene Transition mutations : Purine is substituted by a purine i.e. adenine by guanine or pyrimidine by pyrimidine i.e. cytosine by thymine. Occurs in: C - G dinucleotide (hot spot) Cancer colon & Brain cancer Transversionmutations: Purine is substituted by pyrimidine i.e. guanine by thymine or pyrimidine by purine i.e. cytosine by adenine. Occurs in: G to T mutations at codon 249 of the gene. Cancer lung & cancer liver

  48. p53 • Aflatoxin B Potent hepatocarcinogen to which many individuals are exposed to it in China & Africa. It causes transversion mutations of p53 gene leading to cancer liver • Smoking & exposure to agent benz (a) pyrene: cause transversion mutations in p53 gene leading to lung cancer So, detection of specific type of mutation in genes from human tumours may reveal the cause of cancer

  49. BRCA1 & BRCA2 • It is inherited as autosomal dominant trait. • Two genetic loci : BRCA1 on chromosome 17 & BRAC2 on chromosome 13 BRCA 1 encodes for a protein that act as a trancription factor • Carriers of BRCA1 gene mutation: have an 85% risk of developing breast cancer & 45%risk of developing ovarian cancer

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