tumour marker

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Dr. Anshuman Aashu 1 st year PGT, General Surgery IPGMER &SSKM Hospital TUMOUR MARKER

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Page 1: Tumour marker

Dr. Anshuman Aashu1st year PGT, General Surgery

IPGMER &SSKM Hospital

TUMOUR MARKER

Page 2: Tumour marker

WHAT ARE TUMOUR MARKERSBiological substances synthesized and

released by the tumour cells or by the host body in response to a tumour.

Detected in higher than normal levels in blood, serum, urine or other body fluids.

Indicators of cellular, biochemical, molecular, or genetic alterations whereby neoplasia can be recognised.

Found to be raised in certain benign conditions also and hence, elevated levels need to be interpreted with caution.

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HISTORICAL BACKGROUND1863 Bence Jones Protein1940 Acid Phosphatase1960 Immunoassay1963 -Fetoprotein1965 Carcinoembryonic Antigen1975 Monoclonal Antigens1980 CA 125, PSA, Carbohydrate

Antigens1970 Oncogenes1980 Tumour Suppressor Genes2001 Microarrays, Mass

Spectrometry, Neural Network, Multiparametric Analysis

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CLINICAL APPLICATIONScreening.Diagnosis.Staging.Prognosis.Therapy.Surveillance and monitoring.

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ScreeningBest example is the screening of prostate

cancer with serum PSA.Apart from PSA, no other tumour markers have

shown reliability for the purpose of screening.Major disadvantage being the overdiagnosis

and overtreatment of a certain tumour based on screening with tumour markers.

Some recent studies, like ERSPC and PLCO trials didn’t show any significant mortality benefit even in prostate cancer screened with PSA level. Only one in eight screen-detected cancers is likely to kill the patient.

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Diagnosis and StagingTumour markers doesn’t help in

establishing the diagnosis per se in most of the cases but corroborates it.

Helps in distinguishing benign from malignant cases in some tumours.

Correlates with amount of tumour present and hence, identifies the tumour burden.

Sometimes, allow subtype classification and hence helps in staging of the disease.

Page 7: Tumour marker

Prognosis, Therapy and MonitoringThe mere presence or absence of a tumor

marker or its quantification helps in determining the prognosis.

Predicts the response to therapy and hence guides the choice of therapy in many cases.

The newer modality of targeted therapy is based on the presence or absence of such markers.

Identifies the response to therapy with change in levels.

Helps in the monitoring for recurrences in follow-up.

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THE IDEAL TUMOUR MARKERHigh sensitivity and specificity.Level should correlate with the tumour

burden.Levels in healthy patient should be much

lower than that in a cancer patient.Predict recurrences before they are

clinically detectable.The tumour marker assay should be

reducible, rapid, and inexpensive.

Page 9: Tumour marker

AN IDEAL TUMOUR MARKER IS STILL AN

ENIGMA

Page 10: Tumour marker

CATEGORIES OF TUMOUR MARKERProtein:

o Oncofetal antigens – CEA, AFP.o Hormones – HCG, Calcitonin, Catecholamine

and its metabolites, Ectopic hormones.o Isoenzymes – Neuron specific enolase, Acid

phosphatase.o Mucin and other glycoprotiens – CA-19-9, CA-

125, CA-15-3.o Specific proteins – Immunoglobulins, PSA.

RNA based markers:o Overexpressed or underexpressed

transcripts.o Regulatory RNAs (e.g., micro-RNAs)

Page 11: Tumour marker

DNA-based markers:o Single nucleotide polymorphisms (SNPs).o Chromosomal translocation – bcr-abl

(Philadelphia).o Microsatellite instability.o Changes in DNA copy number.o Epigenetic changes(e.g., differential

promoter-region methylation)

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DETECTION OF TUMOUR MARKERSerological: Enzyme assays.Immunological:

Immunosorbent assay.ELISA.Radioimmuno assay.

Cytogenetic analysis:FISH.Spectral karyotyping.Comparative genomic hybridization.

Page 13: Tumour marker

Genetic analysis:Sequencing.Reverse transcription.Gel electrophoresis.DNA micro-array analysis.

Proteomics:Surface-enhanced laser desorption/ionization

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Recommendations for ordering testNever rely on result of a single test.Repeat tests while following up should be

ordered from the same lab using same kit.The half-life of the marker should be taken

into account before interpreting the result.Multiple markers should be considered to

improve the outcome of the test.Ectopic tumour markers should always be

kept in mind.

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CARCINOEMBRYONIC ANTIGENComplex glycoprotein that is associated with the

plasma membrane of tumor cells, from which it may be released in to the blood.

Mainly used for colorectal cancer but may be elevated in: Smokers Some benign conditions – IBD, pancreatitis, cirrhosis,

COPD etc Other malignant lesions – ovarian, breast, pulmonary.

Normal <2.5 ng/ml, Borderline 2.5-5.0 ng/ml, Elevated >5 ng/ml.

Upper limit of normal level in smokers considered to be 5 ng/ml.

Page 16: Tumour marker

CEA Distribution In Healthy Individuals and Patients with Non-Malignant Conditions

% Distribution of CEA

ng/mL ng/mLng/mL

Healthy Subjects 0-3.0 3.1-10 >10.0

Non Smokers 96 4 0

Smokers 80 19 1Non-Malignant DiseasesCirrhosis 53 42

5Ulcerative Colitis 65 26

9Rectal polyps 78 19

3Pulmonary 52 39

9Gastrointestinal 76 21

3

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CEA Distribution In Patients With Malignant Disease

% Distribution of CEA 0-3 3.1-10

>10 ng/mL ng/mL ng/mL

Colorectal 28 20 52Breast 50 27

23Ovarian 80 16

4 Pulmonary 39 29

32

Page 18: Tumour marker

CEA (contd)Not useful for screening purposes as higher

rate of false positive results seen and low sensitivity in early cases.

Elevated level reflects tumour burden.More the concentration:

Worse the prognosis.Higher the chances of recurrence.

More sensitive for hepatic and retroperitoneal metastases. Relatively insensitive for local recurrences and pulmonary or peritoneal metastases.

Monitors response to chemotherapy in metastatic disease.

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-FetoproteinUsed for Hepatocellular carcinoma and non-

seminomatous testicular tumour.Elevated in benign conditions like cirrhosis, acute

and chronic hepatitis, 2nd and 3rd semester of pregnancy, IBD etc.

Other malignant conditions show elevation and include pancreatic, gastric, colorectal or lung cancer.

Upper limit of normal value in non-pregnant adult is <25ng/ml.

No detectable level in upto 20% of HCC cases.Level correlates with tumour burden, staging and

hence prognosis.

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AFP (contd)Prognosis not only depend on the initial

concentration but also the rate of its rise called the AFP doubling time.

Level decreases with resection or ablation and hence marks response to the therapy. Level should decrease and remain below 10 ng/ml.

Maintenance of a higher level after treatment predicts early recurrence.

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Carbohydrate Antigen 19-9Serum marker for pancreatic cancer.Lewis a negative blood group patients don’t

produce this antigen and hence can’t be used in this group that consists of 10% of population.

Also elevated in benign biliary tract diseases, acute and chronic pancreatitis.

Elevated in malignant lesions of biliary tract (95%), stomach, liver, colon and lung.

For above reasons, use is limited to monitoring of response to therapy, not as a diagnostic marker.

Level correlates with tumour burden and hence marks prognosis.

Page 22: Tumour marker

Prostate Specific AntigenFormed in prostatic epithelium and secreted in

prostatic ducts.Highly specific tissue marker for prostate but not a

specific cancer marker as level is elevated in benign prostatic diseases.

Not only the level but the rate of increase of the level (PSA velocity) and its concentration per unit volume of prostatic tissue (PSA density) is also imoportant.

Normal upper limit varies with the age of the patient.Only tumour marker widely used for screening

purposes.Monitors the response of therapy as elevated levels

predict recurrence.

Page 23: Tumour marker

Carbohydrate Antigen 125Normally present in the fetus as a

derivative of coelomic epithelium.In healthy adults, detected in epithelium of

fallopian tubes, endometrium and endocervix.

Upper limit of normal 35 U/mlElevated in benign conditions like PID,

endometriosis, adenomyosis, fibroids, cirrhosis and ascites.

Elevated in ovarian carcinoma and cancer of fallopian tube, endometrium and cervix. Non gynaec malignancies including pancreas, colon, lung and liver also have elevated level.

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CA-125 (contd)Not useful for screening due to low

specificity.Marks worse prognosis with elevated levels.Monitors disease course with decreasing

levels following therapy and increasing level predicting recurrence.

Peritoneal fluid level of CA 125 found to be more sensitive than serum level.

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-HCGGlycoprotein synthesized from the

syncytiotrophoblastic cells of normal placenta.

Level is elevated in early pregnancy with peak in the first trimester.

Elevated in gestational trophoblastic neoplasia- choriocarcinoma.

Elevated in non-seminomatous testicular germ cell tumours and constitute an important tumour marker for testicular malignancies alongwith AFP, LDH and PLAP.

Page 26: Tumour marker

Breast Cancer and EREstrogen Receptor (ER) 2 isoforms: ERa and ERb ERa → better prognosis, predictor of relapse useful when deciding on adjuvant hormone

treatment As diagnostic marker when it is a primary

unknown tumor ERb → Good prognostic factor, correlates with

low grade and negative axillary LN status tumours.

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HER-2/neu oncogene (using monoclonal antibody) - over expression related to poor prognosis in breast cancer

Oncogene c-erbB-2 gene: over expressed in 30% of breast cancers, correlation between c-erbB-2 gene positivity, positive axillary node status, reduced time to relapse and reduced overall survival.

BRCA1 gene on chromosome 17q:familial breast-ovarian cancer syndrome, and breast cancer in early-onset breast cancer families → high risk screening

Breast Cancer Oncogenes

Page 28: Tumour marker

Breast Cancer and CA15-3- To monitor Rx. & to detect recurrence BR

Ca ↑ in 20% with localized breast cancer, ~80% with

metastatic disease, esp. if with bone involvement Specificity of 86%, sensitivity of 30% Also ↑ in gastric, pancreatic, cervical & lung

cancer.

Page 29: Tumour marker

Other common tumour markersNeuron specific enolase – neuroendocrine

tumours like small cell carcinoma of lung, neuroblastoma, pheochromocytoma etc.

Calcitonin – medullary carcinoma of thyroid.Thyroglobulin – follicular carcinoma of

thyroid.S-100, Tyrosinase – Malignant melanoma.Other DNA and RNA based markers.

Page 30: Tumour marker

Thank You