TUMOUR MARKERS: LEARNING OUTCOME

Learning Outcomes
Students will be able to:

  • Identify the characteristics of an ideal tumour marker.

  • Explain the application of tumour markers in cancer diagnosis.

  • Employ various tumour markers in the diagnosis of colon and prostate cancers.

WHAT IS CANCER?

  • Definition of Cancer: Cancer is identified as a malignant tumour.

  • Types of Cancers:

    • Carcinoma: Cancer arising in tissues lining the skin or internal organs (epithelial tissue).

    • Sarcoma: Cancer originating in connective tissues like bone, muscle, or fat.

  • Tumour Definition: A mass of tissue caused by uncontrolled cell division; tumours can be either benign (non-cancerous) or malignant (cancerous).

    • Benign Tumour: Growth does not invade nearby tissues.

    • Malignant Tumour: Growth invades surrounding tissues and can metastasize (spread to other parts of the body).

DIAGNOSIS AND STAGING OF CANCER

  • Differentiation of Cancer Cells:

    • Well-Differentiated: Cancer cells appear similar to normal cells and generally grow and spread more slowly.

    • Poorly Differentiated: Cancer cells look less like normal cells and tend to grow and spread more aggressively.

  • Degree of Differentiation: Evaluated through histopathological examination of cancer cells, categorized from G1 (well-differentiated) to G4 (poorly differentiated).

  • Cancer Grading: Helps predict the likely behavior of cancer based on the differentiation of cancer cells.

  • Cancer Staging: Determined by imaging, surgery, and histopathological examination; involves TNM staging to describe the extent of cancer, including tumor size and spread to lymph nodes or distant organs.

TUMOUR MARKERS

  • Definition: Tumour markers are biological substances produced either by cancer cells or by the body in response to cancer.

  • Importance: Testing for tumour markers can assist in diagnosing, staging, evaluating treatment responses, or detecting recurrent disease.

  • Limitations: Most tumour marker tests lack the sensitivity and specificity required for general population screening.

  • Historical Note: The first tumour marker identified was Bence Jones protein, associated with Multiple Myeloma, discovered in 1846.

PROPERTIES OF STANDARD TUMOUR MARKERS

  • Production: Produced in response to a tumour, usually in the form of proteins.

  • Nonspecific Nature: Tumour markers may not be exclusive to cancer and can indicate other non-cancerous conditions.

  • Screening Limitations: Most tumour markers are not viable for screening; an exception is prostate-specific antigen (PSA), used for prostate cancer screening.

APPLICATION OF TUMOUR MARKERS

  • Used for:

    • Monitoring and Detecting Recurrence: A decrease in tumour marker values typically indicates a positive response to treatment.

    • Medical and Surgical Information: Tumour markers are often combined with other medical/surgical data and usually cannot serve as standalone diagnostic tools.

IDEAL CHARACTERISTICS OF TUMOUR MARKERS

  • Clinical Accuracy: Must accurately detect disease presence (clinical sensitivity) and correctly report negative results (clinical specificity) to minimize false negatives and false positives.

  • High Precision: Consistent test results across multiple uses.

  • Cost-Effective: Should be reasonably priced for widespread use.

  • Rapid Results: Results should be delivered in a timely manner.

ANALYTICAL ACCURACY

  • Definition: Refers to how close test results are to the true or universally accepted value of the analyte measured.

  • Analytical Sensitivity: The ability of a test to detect very low amounts of the target substance (analyte), typically expressed as the limit of detection (LOD), the smallest concentration identifiable with 95% confidence.

  • Analytical Specificity: The ability of a test to measure only the intended analyte without interference from other substances, indicating how well a test distinguishes the target marker from similar molecules.

TYPES OF TUMOUR MARKERS

  • Oncofetal Antigens:

    • Used to diagnose colorectal cancer; also elevated in smokers, breast, lung, and gastrointestinal cancers.

    • Example: Carcinoembryonic Antigen (CEA), for monitoring recurrence and treatment effectiveness.

  • Carbohydrate Antigens:

    • CA-125: Elevated in primary ovarian cancer; may also appear elevated in benign cysts and pregnancy.

    • CA 19-9: Elevated in colorectal, gastric, pancreatic, and biliary cancers; also found elevated in pancreatitis and cholangitis.

  • Enzymes:

    • Prostate-Specific Antigen (PSA): Serine protease elevated in prostate cancer but also in benign prostatic hyperplasia (BPH).

    • Alkaline Phosphatase (ALP): Isoenzyme that rises in metastatic bone cancer, also elevated in Paget’s disease.

    • TdT (Terminal deoxynucleotidyl transferase): Elevated in Acute Lymphoblastic Leukemia (ALL) and certain viral infections.

  • Hormones:

    • Eutopic Hormones: Normally produced by healthy tissues but can be overproduced in certain cancers (e.g., excessive adrenaline in pheochromocytoma).

    • Ectopic Hormones: Secreted by malignant tissues not typically producing these hormones (e.g., beta-hCG in testicular carcinoma).

  • Genetic Markers:

    • Treatment Response Prediction: Patients with KRAS/NRAS mutations typically have low response to anti-EGFR therapy in colorectal cancer.

    • Prognosis: BRCA1/BRCA2 mutations significantly increase breast cancer risk.

    • Circulating Tumour DNA (ctDNA): Useful for monitoring minimal residual disease (MRD), detecting recurrence, and molecular profiling.

ANALYTICAL METHODS

  • Types of Analytical Techniques:

    • Enzyme Assay: Commonly used for measuring specific enzyme levels.

    • Immunoassay: Techniques such as Sandwich ELISA for specific antigen detection.

    • Chromatography: High-Performance Liquid Chromatography (HPLC) used for analyzing catecholamines and metabolites.

    • Genetic Profiling: Tools like polymerase chain reaction (PCR) and microarrays for detecting mutations (bcr-abl1, KRAS & BRAF).

PSA: PROSTATE-SPECIFIC ANTIGEN

  • Definition: PSA is a serine protease produced in the prostate gland; it regulates semen viscosity and dissolves cervical mucus.

  • Forms of PSA:

    • Free PSA: Comprised of approximately 20% of total PSA; elevated levels associate with benign conditions like BPH.

    • Complexed PSA: Roughly 80% of PSA; complexed with alpha-1-antichymotrypsin; elevated levels are indicative of prostate cancer.

MEASUREMENT OF PSA

  • Components Measured:

    • Total PSA: Overall measurement used to assess prostate health.

    • Free PSA: Important for evaluating risk of prostate cancer.

    • Complexed PSA: Less common measure; provides additional diagnostic information.

    • PSA Velocity: Change in PSA levels over time; monitored through 3 or more measurements over an 18-24 month period.

TOTAL PSA: CLINICAL SIGNIFICANCE

  • PSA levels above 4 ng/mL often lead to follow-up procedures such as digital rectal exams and/or biopsies.

  • Benign prostatic hyperplasia (BPH) can also contribute to elevated total PSA levels.

FREE PSA INTERPRETATION

  • Risk Stratification:

    • <10%: Indicates a high risk of prostate cancer.

    • 10-25%: Indicates an intermediate risk.

    • >25%: Suggests a low risk.

PSA VELOCITY (PSAV)

  • A PSA velocity greater than 0.75 ng/mL/year is an indicator that prostate cancer might be present.

TUMOUR MARKER: CLINICAL SIGNIFICANCE IN COLORECTAL CANCER

  • Screening:

    • Purpose: Designed to detect early-stage colorectal cancer with high sensitivity and specificity.

    • Method: Fecal occult blood testing (FOBT) is commonly used.

    • Benefit: Early intervention can significantly improve patient outcomes.

  • Diagnosis: Current tumour markers for diagnosis are not specified.

  • Treatment Response Prediction:

    • Purpose: To assess the likelihood that treatment will be effective.

    • Evidence indicates that KRAS and NRAS mutations correlate with low responses to anti-EGFR therapy.

  • Monitoring Response to Treatment:

    • This involves evaluating patients' responses during or immediately after treatment to make necessary adjustments or withdrawals.

    • The Carcinoembryonic Antigen (CEA) serves as a key monitoring marker.

  • Post-Treatment Monitoring and Recurrence Detection: CEA is used to monitor malignancy progression before clinical symptoms emerge.

PHYSIOLOGICAL FUNCTION OF CEA

  • CEA is an oncofetal glycoprotein that is normally produced by fetal gut tissue, gets suppressed after birth, and is re-expressed in colorectal cancer cells that lose their ability to differentiate and participate in cell adhesion.

CEA CUTOFF VALUES

  • Cutoff Levels: Vary between smokers and non-smokers;

    • Smokers: <5 ng/mL

    • Non-smokers: <3 ng/mL

    • Note: Values may vary between different commercial kits.

  • Other Causes of Increased CEA Levels:

    • Conditions like cirrhosis, cholecystitis, tobacco use, inflammatory bowel diseases, lung infections, and pancreatitis can also elevate CEA levels.

MODERN TUMOUR MARKER: SEPT9 METHYLATION TEST

  • Gene Function: The SEPT9 promoter controls the expression of the SEPT9 gene producing septin-9, a cytoskeletal protein necessary for cell division and apoptosis.

  • Hypermethylation: The promoter hypermethylation silences the gene's expression.

  • Association with Fusobacterium nucleatum: This oral anaerobe linked to periodontal disease is associated with SEPT9 promoter hypermethylation and its potential role in early colorectal cancer.

  • Application: The SEPT9 test is a blood-based screening test for circulating tumour DNA (ctDNA), FDA-approved for colorectal cancer screening in adults aged 50 and older who decline colonoscopy and fecal tests.