Role of Tumor Markers in Cancer

What is a tumor biomarker?

It is a molecular or tissue based process requiring a special assay that is beyond routine clinical, radiographic, or pathologic examination, that provide future behavior of a cancer.

So by definition, biomarker is a property of a cancer associated with a clinical or biologic outcome. Substances /molecular changes detected in abnormal amounts in the blood, urine or  body tissues of patients with cancer, produced either by tumor or by the other cells in the body in response to the disease and related to the presence or progress of a tumor. They can be measured at multiple levels; DNA, RNA, protein, cell and tissue.

Various types of tumor biomarkers

Structurally

• Circulating
• Enzymes
• Hormones
• Oncofetal Antigens
• Proteins
• Tissue
• Receptors
• Genetic Markers

Functionally

• Diagnostic markers
• Prognostic markers
• Therapy selection & response markers
• Recurrence and metastasis markers

What are Ideal criterion for Tumor Biomarkers?

• Detectable early in malignant disease
• Specific for type & site
• Production by all pts with a specific malignancy
• Correlates quantitatively with the tumor load, biological behavior, progression
• Responds rapidly to a change in size
• Standardized reproducible quantitative assay

Presently no tumor marker fulfils all of the above criteria

What are the Types of Tumor Markers?

Prostate Specific Antigen

It is specific for prostate cancer. Level of more than 4 ng/ml is seen in around 70% of the cases of prostate cancer. But some non-malignant prostate abnormalities could cause PSA elevation. Levels of PSA between 4 to 10 ng/ml could be overlapping for benign and malignant causes. In such cases, PSA velocity and Percent-Free PSA may be helpful to differentiate between the two.

PSA velocity

It is the change in PSA values over time. It increases the specificity of a single PSA measurement for early cancer detection. Normal levels are around 0.75ng/ml/year. Current recommendation include collection of PSA velocity over not less than 18 months and the use of three values to calculate PSA velocity.

Percent Free PSA

It is free PSA, expressed as a ratio with total PSA. Percentage of Free PSA is significantly lower in men with Ca prostate. US FDA approved it for early detection in patients with PSA between 4 & 10 ng/ml.

Benign conditions that may cause false positive PSA elevation

• BPH
• Lower tract endoscope manipulation
• Transrectal & transperineal prostate Bx
• Acute urinary retention
• Digital rectal examination
• Prostate massage
• Acute prostatitis 

Clinical applications of PSA

Screening – Along with other investigations, it is a part of screening workup for prostate cancer in high risk individuals.

Monitoring treatment- It helps in monitoring the response to treatment in prostate cancer. If it is well controlled on a particular therapy, it is an indicator of response to treatment.

Detection of early recurrence – If the PSA values start rising after a particular treatment, it may indicate recurrence, and requires imaging for confirmation of the same.

Human Chorionic Gonadotrophin (hCG)

It has two subunits, Alpha & Beta Chain. Alpha chain is identical to alpha chain of TSH,FSH, & LH. Serum half-life is 18 to 36 hours. Normal reference range is 0 to 5 IU/L. 

Its levels may increase in following malignancies-

• GTN (complete/ partial molar pregnancy, choriocarcinoma
• NSGCT - Seminoma
• Ca of ovary, liver, stomach, lung & pancreas.

Sometimes, it may be elevated in non-malignant conditions, giving false positive results. Such non-malignant causes are follows-

• Ectopic pregnancy
• Pituitary adenoma
• Pregnancy
• After termination of pregnancy
• Hypogonadal state
• Marijuana use

Clinical applications of beta-HCG

To monitor the response to treatment and in follow-up for-

• Gestational trophoblastic tumor
• With AFP in Non Seminomatous germ cell tumors (NSGCT) of testis, ovary, &  other sites

Alfa Fetoprotein (AFP)

It is a major protein in fetus and is undetectable after birth. Half life of AFP is 5 to 7 days. Normal values is less than 15 ng/mL.

It may be elevated in-

• NSGCT – Testis, ovary, other sites
• Hepatocellular Carcinoma (HCC)
• Hepatoblastoma

Sometimes, non-malignant conditions may also cause AFP elevation. Such false positive causes of elevation are as follows-

• Pregnancy, Infants
• Hepatitis
• Cirrhosis
• Biliary tract obstruction
• Alcoholic liver disease
• Ataxia telangiectasia
• Hereditary tyrosinaemia
• Wiscott – Aldrich syndrome

Clinical Applications of AFP are as follows-

Screening

• HCC – High risk population (eg; China)
• HCC – High risk disease groups (eg; Hemochromatosis, Hepatitis)

Diagnosis

• HCC
• Hepatoblastoma

Staging & Prognosis

• NSGCT

Carcinoembryonic Antigen (CEA)

It is a 200 kDa. Glycoprotein with physiological function of role in cell adhesion and initiation of apoptosis. It’s half life is 3 days and normal values range from 0-3.5 ng/mL to 0-5.0 ng/mL. It is mainly used in colorectal cancer.

Some conditions may cause false positive elevation of CEA, i.e., causes other than colorectal cancer. They include other malignancies and benign conditions as follows-

Malignant Conditions

• Gastric
• Breast
• Lung
• Melanoma, pancreas

Benign Conditions

• Hepatitis
• Cirrhosis
• Alcoholic liver disease
• Obstructive jaundice
• Ulcerative colitis
• Crohn’s disease
• Pancreatitis
• Renal disease & Chronic smokers  

Clinical Application of CEA

1. Screening - Due to it’s low sensitivity, it has a limited role in screening of colorectal cancer.
2. Diagnosis – It may sometimes be normal in cases of colorectal cancer (false negative) and sometimes be elevated in conditions other than colorectal cancer (false positive), as listed above. So these factors limit it’s use as a diagnostic test.
3. Prognosis – High preoperative CEA value is an indicator of poor prognosis.
4. Monitoring response to treatment
5. Detection of early recurrence 

CA-125

It is a mucin like molecule produced by mesothelial cells of peritoneum and tissues of mullerian origin. It is not found in normal ovary and it’s physiological function is unknown.

It may be elevated in-

Gynaecological Conditions

• Endometriosis
• Pelvic inflammatory disease
• Adenomyosis
• Benign ovarian neoplasm
• Functional ovarian cyst
• Menstruation
• Uterine Myomata
• Ovarian carcinoma
• Primary peritoneal carcinoma
• Endometrial carcinoma

Non-gynaecological Conditions

• Acute hepatitis
• Acute pancreatitis
• Chronic liver disease
• Cirrhosis
• Congestive heart failure
• Diverticulitis
• Pericarditis
• Systemic lupus erythematosus
• Sarcoidosis
• Ca pancreas
• Hepatocellular carcinoma

Clinical Application of CA-125

1. Screening - Due to it’s low sensitivity, it has a limited role in screening of ovarian cancer.
2. Diagnosis - It may sometimes be normal in cases of ovarian cancer (false negative) and sometimes be elevated in conditions other than ovarian cancer (false positive), as listed above. So these factors limit it’s use as a diagnostic test.
3. Prognosis - High preoperative CAA-125 value is an indicator of poor prognosis and an independent prediction of survival
4. Monitoring response to treatment
5. Detection of early recurrence 

CA 19-9

It’s half life is 1 to 3 days and normal  range is  0.37 to 0-100 U/L. It is mainly elevated in pancreaticobiliary tumors.

Some other malignancies and benign conditions that may cause CA19-9 elevation are as follows-

• Pancreatic Cancer - 70-100% cases
• Hepatocellular Carcinoma
• Gastric Cancer
• Colorectal Cancer
• Acute and chronic pancreatitis
• Hepatocellular jaundice
• Cirrhosis
• Acute cholecystitis
• Cystic Fibrosis

Clinical Application of CA 19-9

1. Screening - Due to it’s low sensitivity, it has a limited role in screening of pancreatic cancer.
2. Diagnosis - It may sometimes be normal in cases of pancreatic cancer (false negative) and sometimes be elevated in conditions other than pancreatic cancer (false positive), as listed above. So these factors limit it’s use as a diagnostic test.
3. Monitoring response to treatment
4. Detection of early recurrence 

ER, PR, Her-2 neu

These are the biomarkers for breast cancer, based on which breast cancer may be classified as-

• Hormone Receptor positive – ER+ and/or PR+
• HER-2 Neu positive
• Triple negative

Clinical Applications 

1. Prognosis – These markers are important for prognostication of breast cancer, with hormone positive ones having the best prognosis, and triple negative being the worst.
2. Deciding the Treatment – Based on these markers, hormone therapy and targeted therapy are added to treatment protocol for breast cancer.

Beta 2 microglobulin

It is a light chain of class 1 histocompatibility antigen, expressed on the surface of all nucleated cells. Normal level is less than 2.5 ug/mL. It may be elevated in multiple myeloma, CLL, or lymphoma. In MM, it reflects tumor load & renal function and is an important prognostic factor.

Miscellaneous

Alkaline Phosphatase is secreted from Liver, Bone, and Placenta. Levels may be elevated in Bone metastases or Liver involvement.

LDH is an enzyme in glycolytic pathway. It is a nonspecific marker and an indicator of tumor load in Lymphoma, Acute Leukemia, and NSGCT.

Neuron Specific Enolase is found in neural tissue and may be elevated in SCLC, carcinoid, and Neuroblastoma.