DR.PANKAJ GUPTA

tool for the management of cancer

Serum tumor markers

OBJECTIVES

• What are they?

• Why are they used?

• How are they used?

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

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.”

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

CLASSIFICATION

Tumour markers

Tumour associated proteins

Oncofeta

l antigens

Epithelial antigens

Enzymes

Hormones

Oncoproteins/ Oncogenes

Tumour suppressor genes

Adhesion molecules

CLINICAL IMPLICATION

Screening Diagnosis Staging Prognosis Monitoring treatment Recurrence

RECONMENDATIONS FOR ORDERING TUMORS MARKES

• Do serial testing

• Same lab

• While monitoring recurrence, make sure the tumour marker level was elevated before surgery

• Considering half life while interpreting the result

• Know the metabolism of the tumour marker

• Panel testing is better than testing a single marker

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

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

• 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

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

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

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

• 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

• 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

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

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

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

• 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

• 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

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

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

• 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

• 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.

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

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%.

• 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

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)

• 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

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

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

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)

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

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

NEXT SESSION• Beta 2 microglobulin• Calcitonin• CYFRA 21-1• Her 2 neu• Chromagranin A• PTHRP• p53

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