In this lecture In this lecture Cancer Biochemistry and Cancer Biochemistry and Cancer basics Tumour Markers Tumour Markers Definition of Tumour Marker (TM) What is the perfect TM? History of TMs Clinical Biochemistry Department Examples of TMs currently in use City Hospital Appropriate use of TMs Analytical aspects of TM analysis Cancer Cancer – – Signs and symptoms Signs and symptoms Cancer (tumour) Cancer (tumour) - - Introduction Introduction • Appear when the tumour starts growing and invading • Malignant neoplasm – uncontrolled growth and healthy tissues invasion of healthy tissues (metastasis) • Local effects (specific) • Lung – blockage of bronchus – cough or pneumonia Lung blockage of bronchus cough or pneumonia • Not all cancers all malignant ll ll li • Esophageal – narrowing of esophagus – painful / difficult to swallow • Over 200 known cancers that affect humans • Colorectal – narrowing or blockage in the bowel – change in bowel habits • Bleeding (eg cough up blood, rectal bleeding, blood in the • Environmental and genetic factors urine, vaginal bleeding) 1
Cancer Cancer – – Signs and symptoms Signs and symptoms What is a Tumour Marker? What is a Tumour Marker? • Systemic effects (general) ‘A Tumour Marker (TM) is any substance which can be • Unexplained weight loss related to the presence or the progress of a tumour’ • Unexplained fever A TM can be ‘tumour specific’ – only produced by the tumour - not normal tissue or • Fatigue A TM can be produced in relatively larger amounts by malignant cells than non-malignant cells – usual • Back pain scenario. ?Perfect Tumour Marker ?Perfect Tumour Marker Tumour Marker History Tumour Marker History • Total negativity in healthy subjects (ie 100% • Urine Bence Jones Protein, 1847: Patients with specific) multiple myeloma. Monoclonal light chain. • 1928 – 1968: Study of hormones, enzymes, • Total positivity for a single tumour type (ie 100% 100% sensitive) iti ) isoenzymes and proteins isoenzymes and proteins • 1975 : monoclonal antibody techniques and use in • There is a close correlation between the blood oncofoetal antigens TM concentration and the tumour size. • 1990s: Molecular techniques, oncogenes, suppressor & DNA repair genes. • THE PERFECT TM DOES NOT EXIST 2
Metabolic Effects of Tumours Metabolic Effects of Tumours Types of Tumour Markers Types of Tumour Markers Hypercalcaemia - often seen, PTHrelated peptide. Structural molecules – carbohydrate antigens: Haematological - erthyrocytosis, anaemia. CEA, CA-19-9, CA15-3, CA 125 CEA, CA 19 9, CA15 3, CA 125 Carbohydrate metabolism hypoglycaemia lactic Carbohydrate metabolism, hypoglycaemia, lactic acidosis. Secretion products, enzymes, hormones: Protein Metabolism - increased catabolism/decreased AFP, hCG, PSA, catecholamines synthesis. Hormone Production - can be appropriate to cell line Cell turnover markers or ectopic. Colorectal Cancer & CEA Colorectal Cancer & CEA Classical Tumour Marker Use Classical Tumour Marker Use Carcinoembryonic antigen: Normally present in small concentrations. Elevated in cancer but also some benign conditions. Myeloma : Paraprotein band detection. y p Primary use is in monitoring colorectal cancer to check for Phaeochromocytoma : Urine and serum recurrence. catecholamines. Other cancers that give CEA elevations: melanoma, lymphoma, breast, lung, pancreas, stomach, bladder, GI Tract. Carcinoid: 5HIAA, Chromogranin A Non cancer Conditions that give elevations: smoking, inflammatory bowel, liver disease. 3
AFP AFP HCG HCG • Alpha-foetal protein normally produced by developing foetus. 70 kDa glycoprotein • Dimer composed of alpha and beta chains. Alpha chain almost identical to that of TSH, FSH, LH. Beta chain distinct but 75% • Increase in hepatocellular carcinoma, germ cell cancer - ovary or testis, hepatoblastoma. homology with LH. • Found in several forms in blood - intact, free and fragments. • Often normal in stage I testicular cancer. Oft l i t I t ti l Uses of HCG • Elevated in non-cancer conditions include liver disease, pregnancy and first year of life. • Monitor gestational trophoblastic disease. • With AFP to monitor cancer of testis and ovary. Clinical Use • Raised in pregnancy and marijuana use. • With HCG to monitor non-seminomatous germ cell tumours. • Diagnostic aid for hepatocellular carcinoma and hepatoblastoma • Hepatocellular carcinoma screening in high risk population - China. Ovarian Cancer & CA 125 Ovarian Cancer & CA 125 Ovarian Cancer & CA 125 Ovarian Cancer & CA 125 New NICE Guidelines (April 2011) GPs should measure CA125 in women with FREQUENT symptoms that suggest ovarian cancer Ovarian cancer 5 th most common cancer in women with overall 5-year Persistent abdominal bloating or distention survival rate < 35% Feeling full and/or loss of appetite F li f ll d/ l f tit Most women present with advanced disease having had symptoms for Pelvic or abdominal pain months before presentation Increased urinary urgency and/or frequency Additional delays often occur before specialist referral Symptoms suggestive of IBS in women >50yrs If CA125 >35kU/L, GP should arrange U/S of abdomen & pelvis If U/S suggestive of cancer refer urgently to specialist team 4
Ovarian Cancer & CA 125 Ovarian Cancer & CA 125 Other Routine Tumour Markers Other Routine Tumour Markers CA 199: In pancreatic cancer higher levels associated with CA125 elevations in other cancers such as uterus, cervix, pancreas, liver, advanced disease. Originally found in colorectal cancer and also intestine. increased in hepatobiliary disease. Increased in non-cancer disease such as liver disease, pancreatitis, and any CA 153: Used in following breast cancer treatment Rarely raised CA 153: Used in following breast cancer treatment. Rarely raised condition that inflames the pleura. diti th t i fl th l in early disease. Can also see elevated CA 153 in benign breast CA125 can also be increased in menstruation and pregnancy. or ovarian disease and range of other diseases. LDH: Ubiquitous enzyme. Can be useful in monitoring treatment, CA125 results within reference range DO NOT exclude ovarian or other for example non-Hodgkin’s lymphoma and some types of malignancies leukaemia. Molecular Biology & Tumour Molecular Biology & Tumour Tumour Markers Basics Tumour Markers Basics Markers Markers • Normal levels do not exclude underlying • Role in specific therapeutic interventions. For neoplasm. example her-2/neu oncogene overexpression in • High levels are not necessarily diagnostic breast cancer. Herceptin is a monoclonal antibody targeted to the gene product. • Different methods not always comparable. Follow-up by different lab can mislead. • BRCA 1 & 2 in family screening for breast cancer. • “Shotgun” requesting approach: You will end up trying to explain lots of raised results! 5
Audit of Tumour Marker Use in a Audit of Tumour Marker Use in a Large Hospital Large Hospital Hull Royal Infirmary: McGinley PJ, Kilpatrick ES. Annals Clin Biochem 2003; 40: 643-7 1997/8 - 2001/02 saw 125% increase in tumour marker requesting. Looked at 12 months requesting = 27,000 tests - CA125 (ovarian)– 612/3616 on male subjects. - CA 15/3 (breast follow-up) 98/374 on men PSA (Ca prostate) 12/11,585 were on women. Conclusion: Inappropriate screening, use before a diagnosis and poor understanding of use of tumour markers. WHO 10 Principles of Screening WHO 10 Principles of Screening NHS Cancer Screening NHS Cancer Screening • Condition is an important health problem • Natural history well understood • Recognisable at an early stage • Treatment is better at an early stage • www.cancerscreening.nhs.uk www.cancerscreening.nhs.uk • • Suitable test exists Suitable test exists • Acceptable test exists • Adequate facilities exist to cope with abnormalities detected • Screening is done at repeated intervals when the onset is insidious • The chance of harm is less than the chance of benefit • The cost is balanced against benefit 6
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