SERUM TUMOR MARKERS
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DR.PANKAJ GUPTA
tool for the management of cancer
Serum tumor markers
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OBJECTIVES
• What are they?
• Why are they used?
• How are they used?
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A BREIF HISTORY OF TUMOR MARKERS
• In 1875, H. Bence Jones described and named Multiple Myeloma and Bence Jones Proteinuria
• In 1960, immunoassay techniques were developed
• In 1975, monoclonal antibodies were developed by hybridoma technique
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TUMOUR MARKERS: A DEFINITION
“Tumour markers are molecules that can be detected in blood, body fluids or tissue of the host and which are produced either as a response to cancer or by cancer cells themselves.”
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WHAT MAKES AN IDEAL TUMOR MARKER ?
• 100% sensitive and specific
• Having a short half life
• Easily measurable and easily reproducible
• Proportionate to the size of the tumour
• Cost-effective
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CLASSIFICATION
Tumour markers
Tumour associated proteins
Oncofeta
l antigens
Epithelial antigens
Enzymes
Hormones
Oncoproteins/ Oncogenes
Tumour suppressor genes
Adhesion molecules
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CLINICAL IMPLICATION
Screening Diagnosis Staging Prognosis Monitoring treatment Recurrence
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RECONMENDATIONS FOR ORDERING TUMORS MARKES
• Do serial testing
• Same lab
• While monitoring recurrence, make sure the tumour marker level was elevated before surgery
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• Considering half life while interpreting the result
• Know the metabolism of the tumour marker
• Panel testing is better than testing a single marker
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α- FETO PROTEIN (AFP)
• Glycoprotein
• Secreted from fetal yolk sac, liver and gastrointestinal tract
• Normal levels are <15 ng/ml (HL= 3-5 days)
• Resembles, structurally as well as genetically to albumin
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INTERPRETATION
1. Hepatocellular carcinoma
• Screening tool in high prevalence areas
• Levels > 500 ng/ml in adults
• Markedly increased levels (>1000 ng/ml) s/o tumors size > 3cm
• High initial concentrations correlate with poor prognosis
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• Failure to return normal after surgery indicates incomplete resection or presence of mets
• Post operative decrease in concentration followed by increase suggest recurrence
• Short doubling time usually is predictor of occult metastasis
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2. Tumor marker for germ cell tumors of ovary and testis• Embryonal carcinoma• Malignant teratoma
3. Can also be increased in • Pancreatic, gastric, bronchogenic and colon cancer• Benign disease like hepatitis, post necrotic cirrhosis, primary biliary
cirrhosis.
4. Neonatal hepatitis and neonatal biliary atresia.
5. Screening for fetal defects and placental diseases
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CARCINOMA EMBRYONIC ANTIGEN (CEA)
• High molecular weight glycoprotein
• Normal value is <2.5ng/ml
• Half life 3-13 days
• Has a diagnostic and prognostic importance in colorectal cancer
• Lacks high sensitivity and specificty
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INTERPRETATION
In Colon cancer• After complete removal of colon cancer, the levels should fall to
normal in 6-12 weeks.
• CEA has sensitivity of 97% in detecting recurrence in patients with preoperative elevated levels
• Increase concentration indicates poor prognosis within a given stage
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• High level correlate with metastasis (80% patient of colon cancer with level > 20 ng/ml have recurrence in 14 months)
• Concentrations < 5ng/ml before therapy correlate with localized disease and good prognosis
• Uninterrupted increase denote failure to response
• Immediate sustained decrease followed by increase indicate, lack of response
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• Undifferentiated or poorly differentiated tumors do not produce CEA
• Levels <2.5 ng/ml do not rule out primary, metastatic or recurrent cancer
• Surge in CEA for weeks followed by decrease indicate response
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Increased in • Cancers of Stomach, Pancreas, Lung, Breast, Head and neck and
ovary
• Effusion fluids due to these cancers
• Active non malignant inflammatory diseases like UC, peptic ulcers, regional enteritis, chronic pancreatitis
• Liver diseases, Renal failure, Heavy smokers
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CA-125• A mucin-like glycoprotein with a molecular weight of 200kDa
recognized by monoclonal antibody OC 125
• Normal value <35 U/ml
• Has a half -life of 3-5days
• Elevated in more than 80% of non-mucinous ovarian cancer
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INTERPREATION• Normal concentrations does not exclude tumor
• Not useful in distinguish benign and malignant pelvic mass
• Not recommended for screening women for serous carcinomas of ovary
• May be useful for screening in hereditary cancer syndrome
• Correlates with poorer prognosis if elevated 3-6 weeks after surgery
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• Concentration of > 35 U/ml detects residual tumor in 95 % patients but normal levels do not exclude
• Rising levels during chemotherapy is associated with tumor progression and fall to normal is associated with response
• Rising concentration may precede clinical recurrence by many months but normal levels does not indicate absence of persistent or recurrent tumor
• Values > 65 U/ml correlate with peritoneal involvement
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• Prognosis may be better if
1. 50% decline within 5 days of surgery
2. Ratio of postoperative and preoperative concentrations (4 weeks)
3. Ratio >0.1 to <0.5 may benefit from chemotherapy
4. Ratio > 0.8 should consider alternative therapy
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Increased in• Non mucinous epithelial ovarian carcinoma (85%) and Tumors of
Fallopian tube (100%)
• Cervical adenocarcinoma, Endometrial adenocarcinoma, Trophoblastic tumors, liver, lung and pancreas
• Non hodgkin lymphomas representing pleuropericardial or peritoneal involvement
• Cirrhosis, Renal failure, Menstruation, Endometriosis, disorders of GI tract
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HUMAN CHORIONIC GONADOTROPHIN (hCG)
• A glycoprotein hormone synthesized by placenta
• Has alpha and beta subunits
• Normal value of beta hCG is<5mIU/ml
• Normal half-life of 12-20hrs
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• Used as a routine pregnancy test
• Diagnosis and monitor course and evaluate prognosis of gestational
trophoblastic tumors (with AFP)
• Differentiation of ectopic pregnancy from other causes of acute abdomen
• Prenatal screening of Down syndrome
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• Increased levels after 12 weeks of pregnancy >500,000 IU/24 hours usually are associated with moles and level >1,000,000 IU are alsmot always associated with moles.
• In choriocarcinoma failure to fall to an undetectable level or a rise after initial fall, signals residual tumor
• Also increased in non seminomatous germ cell tumors of testis, some non trophoblastic cancer like ovary, GI tract, lung and breast.
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PROSTATE SPECIFIC ANTIGEN (PSA)
• Also known as human kallikrein 3
• Serine protease produced by prostatic acinar cells
• Also by periurethral glands and breast in women, pancreas and salivary glands in both sex
• Reference rang <4ng/ml with half life of 4 days
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INTERPRETATION• Recommended for screening along with DRE
• Used in staging of prostate cancer
- < 4ng/ml, organ confined disease
- < 10ng/ml, bone metastasis is rare
- > 10ng/ml, >50% have extracapsular disease
- > 50ng/ml, most have positive lymphnodes
- >100ng/ml, predicts bone mets with 90% accuracy, S/S=66%/96% with a PPV = 79%.
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• Failure of radiation to decrease PSA to < 1ng/ml means likelihood of recurrence
• After radical prostatectomy doubling time reflects aggressiveness of original cancer
• Free PSA and complex PSA help in differentiating cancer from BPH and prostatitis
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PSA velocity and density• More rapid rate of increase of velocity (>0.75 ng/ml/year or
>20%/year) correlates with cancer. Requires min. 3 tests/18 months.
• Specially useful when PSA levels are between 4-10ng/ml
• Low density is unlikely to be cancer (<0.15)
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• DRE increases PSA significantly if initial value is >20ng/ml
• PSA has no circadian rhythm but variation can occur between specimens collected on same day
• Ejaculation causes transient increase < 1.0 ng/ml for 48 hrs
• Slight increase may be associated with cancer of salivary gland, sweat glands, breast, colon, lung and ovary and in conditions like ARF and MI
• Indwelling catheters, vigorous bicycle exercise, Treadmill stress test
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CA 19-9• Blood group carbohydrate
• Sialylated derivative of Lewis antigen, and is denoted a Lexa
• Synthesized by normal human pancreatic and biliary ductal cells
• Also by gastric, colonic, endometrial and salivary epithelia
• Normal value <37 U/ml
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INTERPRETATION• Used in detection, diagnosis and prognosis of pancreatic cancer
• To determine preoperative resectability
• Only 5 % of patient with levels >1000 U/ml are surgically resectable
• Post surgical increase concentration correlates with recurrence
• May indicate development of Cholangiocarcinoma in PSC
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CA 15-3
• Glycoprotein expressed by various adenocarcinoma especially breast
• Half life of around 7 days
• Only to detect breast carcinoma recurrence and to monitor response to treatment (FDA)
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INTERPRETATION• Increases directly related to stage of disease
• Increases in 75% with progressive disease
• Decreases in 38% responding to therapy
• >30 U/L indicates shorter survival
• Also increased in benign breast disease and liver disease
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CA 72-4• A high molecular weight (>106 Da) mucin-like complex
• Marker for carcinomas of the GI tract and of the ovary
• Also used in multivariate analysis of colorectal cancer with βhcg and CEA for prognosis
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NEXT SESSION• Beta 2 microglobulin• Calcitonin• CYFRA 21-1• Her 2 neu• Chromagranin A• PTHRP• p53
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THANK YOU