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Understanding Tumor Markers in Cancer Diagnosis and Treatment

Learn about the significance of tumor markers in cancer screening, diagnosis, and treatment monitoring. Discover different types of tumor markers and their role in predicting disease progression and patient survival.

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Understanding Tumor Markers in Cancer Diagnosis and Treatment

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  1. TUMOR MARKERS Michaela Králíková Department of Biochemistry Faculty of Medicine Masaryk University

  2. USE OF TUMOR MARKERS • Screening:calcitoninin families with MEN syndrome, AFPin patients with liver cirrhosis, PSA in men >50 years • Dg and diff. dgin symptomatic individuals • Clinical staging of cancer, is aided by quantitation of the marker, i. e. the serum level of the marker reflects the number of cancer cells present in the body • Monitoringof the disease and estimation of tumor value • Prognostic indicatorof disease progression and patient survival • Detection of cancer recurrence, permits early treatment or a change in therapy • Monitoring of responses to therapy

  3. Tu markerskinetics • Doublingtime = time to double its (serum/plasma) level. Theshorter, the more aggressive Tu growth. • biologicalhalf-life:

  4. CLASSIFICATION OF TUMOR MARKERS • According to proof: humoral, cellular • According to chemicalstructure(glykoproteins, glykolipids, polypeptides, imunoglobulins, polyamines) • According to visceral specificity • According to physiologicalfunction(oncofetalantigens, oncoplacentalantigens, enzymes, hormones, serumproteins, receptors and others)

  5. Visceral specificity • high:calcitonin - medullary carcinoma of the thyroid PSA - prostate cancer NSE - small cell lung cancer hCG - germ-cell tumors AFP- hepatocellularand germ-cell carcinoma • moderate:CA 19-9 - pancreatic cancer CA 125 - ovarian cancer CA 15-3 - breast cancer • low: CEA TPA

  6. Oncofetalantigens • substancesproducedduringfetallife(presentin highconcentrations in the sera offetuses, decrease to lowlevelsordisappearafterthebirth) • reappear in patientswithcancer • Theirproductiondemonstratesthatcertaingenes are reactivated as a resultofthemalignanttransformationofthe cell. SCC(squamous cell carcinoma) MCA (mucinouscarcinoma antigen) MSA (mammaryserum antigen) TATI (tumor associated trypsin inhibitor) • CEA • CA (carbohydrateantigens) • AFP

  7. CEA (carcinoembryonic antigen) • familyofrelatedoncofetal cell-surfaceglycoproteins • nonspecific • ↑:liver cirrhosis, pulmonaryemphysema, benignbreastcystsdisease, ulcerativecolitis, rectalpolypscolorectal, lung, ovarial, pancreatic, gastric and bileducts Ca • markerforcolorectaland breastcarcinoma, pancreatic, gastric and bileducts Ca • cutoffvalue< 5.0 ng/ml

  8. CEA – 1st choise marker of colorectal Ca (CRCA) • One of the most common malignancies in both sexes in economically developed countries • Incidence has increased more than 3 times during last 30 years. • Prevalence is increasing annually by 2−3%. • CR – newly diagnosed around 8 000 patients per year and about half of them die from CRCA. • CR – 3rd most common malignancy in ♂, 4th in ♀ • 25 % is diagnosed metastasized! 2017 data.

  9. Colorectal carcinoma • possibilities of prevention : Secondary Broadcastscreeningfrom 1.7.2000 (CR)-cyclicfecal occult blood testing in asymptomatic individuals from age 50 or screeningcolonoscopyfromage 55. Primary Lifestyle, nutrition

  10. CRCA – other possibilities of detection at an early stage • detectionof earlyadenomalesions or initial phasesof CRCA: • detectionofmutations (PCR, DNA biochips) in faeces and blood: • Detectionofnewbiomarkers: Point mutationsKRAS, APC; mutationsofinstabilitymarkersBAT 26, P53; DNA integrity test In faeces: CNRIP1, INA, MAL, SNCA, SPG20 In blood: matrix metaloproteinase 2 (MMP 2), tissue inhibitor ofmetaloproteinase2 (TIMP 2) Antibodiesagainst RPH3AL (rabphilin 3A-like protein) Monitoring ofserumcytokinesor HLA-G

  11. CA (carboydrateantigens) CA 19-9 CA 15-3 high-molecular-weight mucins or blood group antigens on the tumor cell surfaces or secreted by the tumor cells CA 72-4 CA 19-9, CA 125 CA 19-9, CA 72-4 CA 125

  12. CA 72-4 (carbohydrate antigen 72-4) • glycoproteinproduced by oesophageal, gastric and pancreaticepithelium • in adults↑:liver diseases, acutepancreatitis, gastriculcer, inflammationsof GITCa ofstomach, colon, uterus, lung(NSCLC) • markerformonitoring ofgastric Ca (1st choicemarker), pancreatic, oesophageal and ovarianCa • cutoff≤ 7 IU/ml

  13. CA 19-9 (carbohydrate antigen 19-9) • glycoproteinoffetal GIT, pancreas and liver epithelium; in adultsitisproduced by GIT and bronchialepithelium. • markerforpancreatic, colorectal and gastriccarcinoma • cutoffvalue≤ 40 IU/ml

  14. CA 19-9 • Sensitivity in selectedTu(Klinická biochemie a metabolismus, 2009)

  15. CA 125 (carbohydrate antigen 125) • glycoproteinofairways and digestive tractepitheliumofbothfetuses and adults • ↑:*ovarial, colorectal Ca *endometrial, breast, pancreatic, liver and pulmonaryCa * pregnancy, breastmilk* benigndiseasesofovaries and endometrium, hepatitis, icterus, pancreatitis • markerfordg and monitoring oftherapyof non-mucinousovarianCa; additionalmarkerforpancreaticand colorectalCa • cutoff≤ 35 IU/ml

  16. CA 15-3 (carbohydrate antigen 15-3) • glycoprotein of fetal bronchial and hepatic cells, adult mammary cells • in adults ↑: pregnancy rheumatic dis., chronic dis. of liver, stomach, pancreas, ovaries, uterus, prostatic gland, AIDS Ca of organs mentioned above • marker for breast Ca monitoring • cut off ≤ 35 IU/ml

  17. CA 15-3 and CEA – 1st choicemarkersforbreastcarcinoma • The 2nd most commonCa in females • Incidence – 1 million of womanworldwide • 90 - 95% sporadic • 5 – 10% inherited - BCRA1 and2 genemutations – possibility of DNA testing from peripheral lymphocytes • The lifetime risk of developing cancer for BRCA1/2 is 87%, in women without mutation 8-10%. • Secondaryprevention –mammography orultrasoundexamination from 45 years of age

  18. AFP (a1-fetoprotein) • glycoproteinsynthesized in largequantities by thefetalyolksac and liver • oneofthe major proteins in thefetalcirculation • in adults AFP /S ↑: pregnancy liver diseases • markerforhepatocellular and germ-cell carcinoma • cutoffvalue < 10mg/l

  19. AFP (a1-fetoprotein) • Sensitivity in selected Tu(Klinická biochemie a metabolismus, 2009)

  20. Oncoplacentalantigens • Substancesproduced by thetrophoblasticcellsofthe placenta in bothpregnancy and pathologicalconditions and also by germinativetumors as a markofmalignantdedifferentiation • ↑ levels show evidence of ↑ malignancy and metastaticpotencyofthegiven tumor SP-1 • hCG

  21. hCG (humanchorionic gonadotropin) • glycoproteinsecreted by thesyncytiotrophoblasticcellsofthe placenta • consistsoftwosubunits:a-subunit (common to severalotherhormones, e. g. FSH, LH or TSH)b-subunit(unique to hCG) • ↑:pregnantwomenhydatidiformmole • markerfortumorsof placenta (trophoblastictumors, particularlychoriocarcinoma), and germ-cell tumorsofthetestis and ovary • cutoffvalue < 2.00 IU/l males, < 10.00 IU/l females(bhCG)

  22. Enzymes NSE (neuron specificenolase) TK (thymidinkinase) LD kathepsins • present in much higherconcentrationsinsidecells • releasedintocirculation as theresultof tumor necrosisor a change in themembrane permeability ofthecancercells→ • elevated enzyme levelsmaysignalthe presence ofmalignancy but usually are not specificenough to identify a cancer type or organ involvement • PSA • ALP

  23. Prostate carcinoma • 2nd most common malignancy in men, CR • 7 049 new cases in 2015 (136 new cases/ 100 000 males) • Risk factors: age, life style, genetic factors Year

  24. Epidemiology of prostate cancer

  25. PSA (prostate-specific antigen) • glykoprotein protease (237 AA, Mr = 33 000) produced exlusively by the epitelial cells of the prostate gland, secreted into seminal fluid (liquefaction). • Produced as inactive proPSA → PSA. • In serum, it occurs as free fPSA anda1-antichymotrypsinora2-macroglobulinbound (55-95%). • ↑: benign prostatic hyperplasia BPH, prostate infammation, urological manipulations • marker for screening (men > 50y, urinating difficulties),dg and monitoring of course and treatment of prostate cancer • cut off value <4.0 µg/l(= ng/ml) (> 50 y), 2.5µg/l(< 50 y, see more in age specific levels)

  26. Increased levels of total PSA in plasma / serum • agespecificlevels: cutoff 40-49 y. 2,5 ng/ml, 50-59 y. 3,5 ng/ml, 60-69 y. 4,5 ng/ml, 70 and more y.6,5 ng/ml • tPSA> 10 ng/ml: suspiciousPCa, weperformanotherexaminations • tPSA4 – 10 ng/ml: PCax BHP???, weperformanotherexaminations

  27. Derived parameters • index f/t PSA – free/total PSA:fPSA<15%: probablePCa, fPSA> 20% probablebenigncondition • tPSAD (tPSAdensity): • ratio [tPSA]/UTSprostatevolume in cm3 • adjustmentof BPH and PCa: cutoff0.15 ng/ml • PSAV (tPSAvelocity): • increaseof[tPSA] / year • healthy0.04 ng/ml/y, BPH 0.07-0.27 ng/ml/y, PCa≥ 0.75 ng/ml/y • tPSAdoublingtime: • time to double [tPSA] • tPSA-TZ: • [tPSA] / transitionzonevolume

  28. Other derived parameters

  29. Other causes of PSA increase in blood • Otherprostatediseases:benignprostatehyperplasia, prostaticinflammation • Mechanicalstimulation(fPSAis more susceptible): biopsy, cystoscopy, catetrization, per rectumexamination • Ejaculation • PSA is a prostate-specific biochemical marker but is not specific for cancer.

  30. ALP (alkalinephosphatase) • Zn2+glycoprotein, in alkalineenvironment (pH= 8-10) itcatalysesthehydrolysisof H3PO4monoesters and transphosphorylation • bone isoenzyme (b-ALP) • ↑: osteoSa, bone metastasesotherbone affections; growth • liver isoenzyme (l-ALP) • ↑:liver metastasesotherliver diseases • ref.values : adults 0.5-2.15 mkat/l, 1 month - 15 years 1.35-7.5 mkat/l, newborns1.2-6.3 mkat/l

  31. Hormones ACTH ADH • Theproductionofhormones in cancerinvolvestwoseparateroutes: • theendocrinetissuethatnormallyproducesthegiven hormone canproduceitsexcessamounts • ectopic syndrome - hormone produced by a distantnonendocrinetissuethatnormallydoes not producethishormone (forinstance: ACTH normallyproduced by thepituitarygland,ectopicalyproduced by thelungsmallcells) • elevationof a hormone is not specific← itmaybeproduced by a variety ofcancers • prolactin • calcitonin • PTH 1. 2.

  32. Serumproteins producedeither by tumor cellsor by anorganism in the presence of tumor ferritin β2-microglobulin • paraproteins

  33. Monoclonalimmunoglobulins(paraproteins) • thefirstdescribed tumor markersproduced by neoplastic plasma cells in monoclonalgammopathies. In serum, wecanidentifywholeIg, heavychains (IgG, M, A; D, E) andk, l lightchains (Bence Jones proteins) -these are smallenough (22 kD) to passthroughthekidneyintothe urine→prerenal „over-flow“proteinuria. • ↑: multiplemyeloma and othermonoclonalgammapathies, lymphomas and leukemias, osteogenicsarcoma, bone metastases • markerformultiplemyeloma and othermonoclonalgammapathies • ref. values: FLC (free lightchains)/S:k = 3.3-19.4 mg/l,l = 5.7-26.3 mg/l, indexk/l= 0.26-1.65;polyclonal FLC/U = 1-10 mg/24h;k/U = 1.25-5.5 mg/l,l/U= 0.51-3.2 mg/l, indexk/l= 0.82-3.0; paraprotein/U - obsolete

  34. Receptors Cellular (tissue) markersused in hormone-producingtumors Growthfactorsreceptors (HER1, HER2/neu) DNA aneuploidy • Estrogen rec. • Progesterone rec. Themainusage: breast Ca, colorectal Ca; brain tumors

  35. Estrogen and progesterone receptors • The most important prognostic markers for breast Ca;detected in tumor tissue. • positivity = ↑ cell diferentiation, ↓ invasivity, better prognosis; = antiestrogen therapy indication • immunohistochemical determination: positivity % value • ELISA: cut off < 15 fmol/mg of protein

  36. Growthfactorsreceptors • Transmembrane receptors with tyrosinkinase activity – phosphorylation of Tyr fosforylují tyr residues of protein substrates • The binding of substrate to the extracellular domain causes a conformational change of the receptor,its autophosphorylation and activation of downstream signaling pathways → influence of cel. proliferation, inhibition of apoptosis • HER1 (EGFR), HER/2neu, HER3, HER4

  37. Growthfactorsreceptors * Nomenclature: HER 2 in humans, neu in rodents

  38. Breast carcinoma markers - summary • Basic markers: CEA and CA 15-3 • Receptor markers: • Growth factors receptors • Estrogene receptor • Progesterone receptor • Markers of metastasis and proliferation - see further

  39. Other tumor markers tissues - producedsubstances, whichwecannotclasswiththepreviouslymentionedgroups Chromogranin A Neuropeptide Y S-100 b 5-hydroxyindolacetic acid • TPA, TPS • Mesotelin

  40. TPA (tissue polypeptide antigen) • non-specificcytokeratinsfragmentsproduced by bothnormal and tumor cells • ↑levelsseen in increased cell proliferation→itsestimationisusefulfor monitoring ofthedisease • ↑:liver dis., DM, rheumatoid dis. breastand GIT tumors • markerforurinarybladdercarcinoma • cutoffvalue≤ 140 IU/l

  41. Tumor markers – lungs, bronchi, trachea Non-parvicellular Ca (NSCLC) CEA CYFRA 21-1 Parvicellular Ca (SCLC) NSE CYFRA 21 -1

  42. CYFRA 21-1 (cytokeratin fragment) • Cytokeratin 19 fragment present in lung, uterine and GIT cells. Markerofdegradationofmalignanttissues and necrosis. • ↑:cirrhosis, asthma, respiratoryinfections, renalfailure • markerforcervical and pulmonary (NSCLC) carcinoma • cutoffvalue≤ 3.3 mg/l

  43. NSE (neuron-specific enolase) • enolase - enzyme ofglycolysis(2-phosphoglycerate → phosphoenolpyruvate) • NSE - formofenolasefound in neuronal and neuroendocrinetissues • ↑: lung and liver dis., renalfailure • markerforsmall-cell lungcancer (SCLC), pheochromocytoma, neuroblastoma, medullarycarcinomaofthethyroid, melanoma, and pancreaticendocrinetumors • cutoffvalue < 15 mg/l

  44. Markersfor dg and monitoring of bone metastasis Bone metastases: tumors of lungs, prostate, breast Monoclonal gamapathies New bone formationmarkersUsage: monitoring the effect of treatment on osteoblastic metastases Bone resorption markers Usage: dg bone mass distribution of solid tumors (PCa), monitoring the effect of antiresorptive treatment

  45. Markers in bone metastases Bone formationmarkers • PINP (N-terminalpropeptideof type I procollagen) tropocollagen → collagenmaturation PINP, PICP • Osteocalcin - serum levels are proportional to its formation in osteoblasts. • Bone ALP – bone izoenzyme of ALP, serum levels are proportional to osteoblastsactivity procollagen

  46. Markers in bone metastases Bone resorptionmarkers • ICTP (C-telopeptideof type I collagen): marker of collagendegradationby action of MMP 9 • CTX-I (b-CTX b-Cross Laps, C-terminaltelopeptideof type I collagen):marker of collagendegradationby action of enzymesfromosteoclasts osteoclast cathepsin K MMP 9 tumor cell collagen I CTX-I ICTP NTX-I

  47. Proliferative antigen Ki-67 • The non-histone nuclear protein expressed during active cell cycle phases (max at the G2 interface and mitosis, is absent in the G0 phase). • It affects the spatial layout of chromatin - gene expression control. • Immunohistochemistry detection in biopsy tissue - Anti-Ki-67 antibody. • Ki-67 expression = proliferative tumor activity. • Proliferative activity in cancer correlates with grade and prognosis. = prognostic marker determined in tumor tissue of solid tumors

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