Tumor markers tests (cancer biomarkers)
Tumor Markers Overview
Cancer remains a major global health challenge, being a leading cause of mortality after cardiovascular and cerebrovascular diseases. While advances in prevention and treatment are ongoing, early diagnosis is critical for improving outcomes. Unfortunately, many cancers are detected at later stages when they have already spread (generalized or metastasized), making successful treatment more difficult.
Detecting malignant tumors in their early stages significantly increases the likelihood of successful treatment, potentially leading to cure in up to 90% of cases. In oncology, laboratory tests that measure specific substances known as tumor markers (or cancer biomarkers) play an important role alongside imaging and pathology in the management of cancer patients.
These markers can aid in screening high-risk individuals, supporting diagnosis, determining prognosis, monitoring treatment effectiveness, and detecting cancer recurrence or metastasis earlier than might be possible with imaging or clinical symptoms alone.
What are Tumor Markers?
The terms "tumor markers" or "cancer biomarkers" encompass a broad and diverse group of biological substances that are produced either by cancer cells themselves or by the body in response to cancer. Their presence, or changes in their levels, can be correlated with the existence or progression of a malignant process.
These markers can have various biochemical characteristics, including:
- Oncofetal Antigens: Proteins normally produced during fetal development but re-expressed by some cancer cells (e.g., AFP, CEA).
- Oncoplacental Antigens: Proteins normally produced by the placenta (e.g., hCG).
- Tumor-Associated Antigens: Often glycoproteins or mucins overexpressed or altered on the surface of cancer cells (e.g., CA 15-3, CA 125, CA 19-9, MCA).
- Enzymes: Isoenzymes produced in higher amounts by certain tumors (e.g., NSE, LDH, PSA - prostatic acid phosphatase less used now).
- Hormones: Produced ectopically by non-endocrine tumors or excessively by endocrine tumors (e.g., Calcitonin in MTC, hCG).
- Oncogene Products or Related Proteins: Proteins related to cancer-causing genes (e.g., HER2 in tissue).
- Plasma Proteins: Specific proteins whose levels change significantly (e.g., Beta-2 Microglobulin in myeloma/lymphoma).
- Metabolic Products.
- Bioactive Peptides.
- Genetic Markers: Mutations or alterations in DNA/RNA found in tumor tissue or circulating in blood (liquid biopsy) - an expanding area.
These markers are typically measured in blood (serum or plasma), urine, or tumor tissue itself.
Clinical Uses of Tumor Markers
Tumor markers have several potential applications in oncology, although their utility varies greatly depending on the specific marker and cancer type:
- Screening: Detecting cancer in asymptomatic individuals. Only a few markers are suitable for screening specific high-risk populations (e.g., PSA for prostate cancer - controversial, AFP for HCC in cirrhosis patients, low-dose CT for lung cancer screening - not a blood marker). Most markers lack the specificity needed for general population screening.
- Diagnosis: Helping to establish a diagnosis, often in conjunction with imaging and biopsy. Few markers are diagnostic on their own, but some (like very high AFP/hCG for GCTs, high Calcitonin for MTC) can be highly suggestive. They can sometimes aid in differential diagnosis when the primary tumor site is unknown (e.g., NSE suggests neuroendocrine origin).
- Staging & Prognosis: The level of a tumor marker at diagnosis can sometimes correlate with the stage (extent) of the cancer and provide prognostic information (predicting likely outcome or aggressiveness).
- Monitoring Treatment Effectiveness: A significant decrease in an elevated marker level after treatment (surgery, chemotherapy, radiation) typically indicates a positive response. Failure to decline or subsequent increases suggest treatment resistance or failure.
- Detecting Recurrence: A rise in tumor marker levels during follow-up after initial remission can be the earliest sign of cancer recurrence or metastasis, often preceding clinical symptoms or imaging findings. This allows for earlier initiation of salvage therapy.
Characteristics of an Ideal Tumor Marker
The "ideal" tumor marker would possess several key characteristics, though no current marker meets all these criteria perfectly:
- High Specificity: Found only in patients with a specific type of cancer and not in healthy individuals or those with benign diseases (minimizing false positives).
- High Sensitivity: Detectable even when the tumor is very small (early stage) and present in almost all patients with that cancer (minimizing false negatives).
- Organ Specificity: Produced only by the tumor originating in a specific organ.
- Correlation with Tumor Burden: Levels should directly correlate with the amount of cancer present (tumor size, stage).
- Correlation with Treatment Response: Levels should accurately reflect the success or failure of treatment.
- Prognostic Value: Levels should help predict the likely course and outcome of the disease.
- Predictive Value: Levels might help predict whether a patient will respond to a specific therapy.
- Easy and Reliable Measurement: Test should be reproducible, readily available, and relatively inexpensive.
Limitations and Considerations
It is crucial to understand the limitations when using tumor markers:
- Lack of Specificity: Many tumor markers can be elevated in benign (non-cancerous) conditions (e.g., inflammation, infection, liver or kidney disease), leading to false-positive results and unnecessary anxiety or further testing.
- Lack of Sensitivity: Not all cancers of a specific type produce the associated marker, and levels may not be elevated in early-stage disease, leading to false-negative results. A normal tumor marker level does not rule out cancer or recurrence.
- Lead-Time Bias: Detecting recurrence earlier with a marker might not always translate into improved survival if effective salvage therapy is not available.
- Heterogeneity: Tumors can be diverse, and not all cells within a tumor may produce the marker consistently.
- Combination Testing: Due to the limitations of single markers, using a panel of several different markers is sometimes employed to improve sensitivity or specificity for certain cancers (e.g., AFP + hCG for germ cell tumors).
Therefore, tumor marker results must always be interpreted in the context of the patient's overall clinical picture, including history, physical examination, imaging studies, and pathology results.
Tumor Markers in Monitoring
One of the most valuable applications of tumor markers is in monitoring patients already diagnosed with cancer.
- Baseline Level: Establishing a baseline level before starting treatment is important.
- Post-Treatment Decline: The rate at which a marker level decreases after surgery or during chemo/radiotherapy can indicate treatment effectiveness and predict prognosis. The time it takes for the marker to return to normal (its half-life) is relevant.
- Surveillance for Recurrence: Serial measurements during follow-up can detect a rise in marker levels, often signalling recurrence before it becomes clinically apparent. This requires consistent testing intervals and careful interpretation of trends rather than single values.
- Reliability for Action: Ideally, a rising marker indicative of relapse should be reliable enough to prompt further investigation (e.g., imaging) or even treatment decisions, sometimes even before definitive radiological or cytological confirmation (though this depends heavily on the specific marker and clinical context).
Examples of Common Tumor Markers
Below are Tumor Markers Table commonly used in clinical practice:
Tumor Marker | Associated Cancers/Conditions | Normal Adult / Pregnancy Levels | Interpretation and Notes |
---|---|---|---|
Alpha-fetoprotein (AFP) | Liver cancer (hepatocellular carcinoma), germ cell tumors (e.g., testicular, ovarian), yolk sac tumors | Normal: <10 ng/mL Pregnancy: Elevated (10–150 ng/mL in second trimester) |
Notes: Also elevated in non-cancerous conditions like hepatitis or pregnancy. |
Human chorionic gonadotrophin (hCG) | Germ cell tumors (e.g., testicular, ovarian), gestational trophoblastic disease (e.g., choriocarcinoma, molar pregnancy) | Normal: <5 mIU/mL (non-pregnant) Pregnancy: Highly elevated (e.g., 10,000–200,000 mIU/mL) |
Notes: Useful for monitoring treatment response in these cancers. |
Carcinoembryonic antigen (CEA) | Colorectal cancer, lung cancer, breast cancer, pancreatic cancer, gastric cancer | Normal: <5 ng/mL (non-smokers); <10 ng/mL (smokers) Pregnancy: Not significantly elevated |
Notes: Non-specific; also elevated in benign conditions like smoking or inflammatory bowel disease. |
CA 15-3 / CA 27.29 / CA 549 | Breast cancer | Normal: <30 U/mL (CA 15-3); <40 U/mL (CA 27.29); <10 U/mL (CA 549) Pregnancy: Not significantly elevated |
Notes: Primarily used for monitoring advanced breast cancer and treatment response. |
CA 19-9 | Pancreatic cancer, biliary tract cancer (cholangiocarcinoma), gastric cancer, colorectal cancer | Normal: <37 U/mL Pregnancy: Not significantly elevated |
Notes: Limited specificity; can be elevated in benign pancreatic or biliary diseases. |
CA 125 | Ovarian cancer, endometrial cancer | Normal: <35 U/mL Pregnancy: May be mildly elevated |
Notes: Also elevated in benign conditions like endometriosis or pelvic inflammatory disease. |
Prostate-specific antigen (PSA) | Prostate cancer | Normal: <4 ng/mL (age-dependent) Pregnancy: Not applicable (male-specific) |
Notes: Used for screening, diagnosis, and monitoring; elevated in benign prostatic hyperplasia (BPH) or prostatitis. |
Calcitonin | Medullary thyroid cancer | Normal: <10 pg/mL (men); <5 pg/mL (women) Pregnancy: Not significantly elevated |
Notes: Highly specific; also used to monitor recurrence post-treatment. |
Thyroglobulin (Tg) | Differentiated thyroid cancer (post-thyroidectomy) | Normal: <1 ng/mL (post-thyroidectomy) Pregnancy: Not significantly elevated |
Notes: Used to monitor for recurrence; requires absence of thyroid tissue. |
Neuron-specific enolase (NSE) | Small cell lung cancer, neuroblastoma, neuroendocrine tumors | Normal: <13 ng/mL Pregnancy: Not significantly elevated |
Notes: Useful for prognosis and monitoring treatment response. |
Cytokeratin-19 fragment (CYFRA 21-1) | Non-small cell lung cancer, bladder cancer, head and neck cancers | Normal: <3.3 ng/mL Pregnancy: Not significantly elevated |
Notes: Useful for prognosis in lung cancer. |
Squamous cell carcinoma antigen (SCC) | Cervical cancer, squamous cell lung cancer, head and neck squamous cell carcinoma, esophageal cancer | Normal: <1.5 ng/mL Pregnancy: Not significantly elevated |
Notes: Limited sensitivity for early-stage disease. |
β-2 microglobulin (B2M) | Multiple myeloma, lymphoma, chronic lymphocytic leukemia | Normal: <2.5 mg/L Pregnancy: Not significantly elevated |
Notes: Also used to assess kidney function and prognosis in hematologic malignancies. |
Mucin-like carcinoma-associated antigen (MCA) | Breast cancer | Normal: <11 U/mL Pregnancy: Not significantly elevated |
Notes: Less commonly used; often combined with other markers like CA 15-3. |
S100 protein | Melanoma, schwannomas, some sarcomas | Normal: <0.15 µg/L Pregnancy: Not significantly elevated |
Notes: Less common as a blood marker now; more often used in tissue staining. |
Tissue polypeptide antigens (TPA, TPS) | Various cancers (measure cell proliferation; non-specific) | Normal: <80 U/L (TPA); <3 U/L (TPS) Pregnancy: Not significantly elevated |
Notes: Limited specificity; used in combination with other markers. |
*Lactate dehydrogenase (LDH)* | Lymphoma, leukemia, germ cell tumors, melanoma, neuroblastoma | Normal: 140–280 U/L (varies by lab) Pregnancy: Not significantly elevated |
Notes: Non-specific; elevated in many cancers and non-cancerous conditions (e.g., hemolysis, tissue damage). |
*Chromogranin A (CgA)* | Neuroendocrine tumors (e.g., carcinoid tumors, pheochromocytoma, pancreatic NETs) | Normal: <100 ng/mL Pregnancy: Not significantly elevated |
Notes: Highly sensitive for neuroendocrine tumors; used for diagnosis and monitoring. |
*BRCA1/BRCA2 mutation-associated markers (ctDNA)* | Breast cancer, ovarian cancer, pancreatic cancer, prostate cancer | Normal: Not detectable in healthy individuals Pregnancy: Not applicable |
Notes: Emerging use in liquid biopsies to detect mutations for targeted therapies. |
*KRAS mutation (ctDNA)* | Colorectal cancer, pancreatic cancer, non-small cell lung cancer | Normal: Not detectable in healthy individuals Pregnancy: Not applicable |
Notes: Used in liquid biopsies for prognosis and guiding targeted therapy (e.g., anti-EGFR therapies). |
*HER2/neu (serum)* | Breast cancer, gastric cancer | Normal: <15 ng/mL Pregnancy: Not significantly elevated |
Notes: Measures soluble HER2 protein; used for monitoring HER2-positive cancers. |
*Estrogen receptor (ER) / Progesterone receptor (PR) (CTCs)* | Breast cancer | Normal: Not detectable in healthy individuals Pregnancy: Not applicable |
Notes: Emerging in liquid biopsies to assess hormone receptor status for treatment planning. |
*HE4 (Human Epididymis Protein 4)* | Ovarian cancer | Normal: <150 pmol/L Pregnancy: Not significantly elevated |
Notes: Often used with CA 125 for improved specificity in ovarian cancer diagnosis. |
*ProGRP (Pro-gastrin-releasing peptide)* | Small cell lung cancer, neuroendocrine tumors | Normal: <50 pg/mL Pregnancy: Not significantly elevated |
Notes: More specific than NSE for small cell lung cancer. |
*BRAF mutation (ctDNA)* | Melanoma, colorectal cancer, papillary thyroid cancer | Normal: Not detectable in healthy individuals Pregnancy: Not applicable |
Notes: Used in liquid biopsies to guide targeted therapies (e.g., BRAF inhibitors). |
*ALK rearrangement (ctDNA)* | Non-small cell lung cancer, anaplastic large cell lymphoma | Normal: Not detectable in healthy individuals Pregnancy: Not applicable |
Notes: Guides use of ALK inhibitors in targeted therapy. |
*PD-L1 expression (CTCs or serum)* | Non-small cell lung cancer, melanoma, bladder cancer | Normal: Varies by assay Pregnancy: Not applicable |
Notes: Emerging marker for predicting response to immunotherapy (e.g., checkpoint inhibitors). |
*Gastrin-releasing peptide (GRP)* | Small cell lung cancer, neuroendocrine tumors | Normal: <50 pg/mL Pregnancy: Not significantly elevated |
Notes: Less commonly used than ProGRP but relevant in specific contexts. |
*Osteopontin* | Lung cancer, mesothelioma, breast cancer | Normal: <50 ng/mL Pregnancy: Not significantly elevated |
Notes: Investigational; may indicate tumor progression or metastasis. |
*Mesothelin* | Mesothelioma, pancreatic cancer, ovarian cancer | Normal: <2.5 nmol/L Pregnancy: Not significantly elevated |
Notes: Emerging marker, especially for mesothelioma diagnosis and monitoring. |
Additional Notes
- Normal Adult Levels: Values are approximate and may vary by laboratory standards or assay used. Always consult lab-specific reference ranges.
- Pregnancy Levels: Most tumor markers are not significantly elevated in pregnancy except AFP and hCG, which are naturally elevated due to fetal/placental production.
- Tumor Marker Interpretation: Markers are primarily used for monitoring treatment response, detecting recurrence, or assessing prognosis rather than primary diagnosis, except in specific cases (e.g., PSA, calcitonin). Elevated levels in non-cancerous conditions reduce specificity. The interpretation follows the AFP example with very high, moderately elevated, and slight elevation categories.
- Highlighted Markers: Markers with an asterisk (*) are the additional ones not in the original list, reflecting emerging or less commonly used markers in clinical practice.
- Emerging Markers: Liquid biopsies (e.g., ctDNA, CTCs) are increasingly used for genetic mutations (e.g., KRAS, BRAF, ALK) to guide personalized therapies.
How Tumor Marker Tests are Performed
- Sample Type: Most commonly blood (serum or plasma). Can also be urine, other body fluids (like CSF, pleural fluid), or tumor tissue itself (e.g., for hormone receptors, HER2, genetic mutations).
- Preparation: Usually no special preparation (like fasting) is needed for most blood-based tumor marker tests. Follow specific instructions from your doctor or the laboratory.
- Collection: Standard venipuncture (blood draw), urine collection, or biopsy procedure.
- Analysis: Performed in a clinical laboratory using various techniques, most often immunoassays (like ELISA, CLIA) that use antibodies to detect and quantify the marker.
References
- National Cancer Institute (NCI). (n.d.). Tumor Markers. Retrieved from https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
- American Cancer Society (ACS). (2023). Tumor Markers. Retrieved from https://www.cancer.org/cancer/diagnosis-staging/tests/tumor-markers.html
- Mayo Clinic Staff. (n.d.). Tumor markers: Used to help diagnose cancer. Mayo Clinic Patient Care & Health Information. Retrieved from https://www.mayoclinic.org/diseases-conditions/cancer/in-depth/tumor-markers/art-20045438
- Sturgeon, C. M., Hoffman, B. R., Chan, D. W., Ch'ng, S. L., Hammond, E., Hayes, D. F., ... & Diamandis, E. P. (2008). National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in clinical practice: quality requirements. *Clinical Chemistry*, 54(8), e1–e10. https://doi.org/10.1373/clinchem.2007.094144
- Duffy, M. J. (2007). Role of tumor markers in patients with solid cancers: A critical review. *European Journal of Internal Medicine*, 18(3), 175–184. https://doi.org/10.1016/j.ejim.2006.12.001
See also
- Complete blood count (CBC):
- Urinalysis:
- Cerebrospinal fluid (CSF) analysis
- Biochemical markers of bone remodeling and diseases
- Markers of autoimmune connective tissue diseases (CTDs)
- Antiphospholipid syndrome (APS)
- Lipoprotein(a), Lp(a)
- Semen analysis (sperm count test)
- Tumor markers tests (cancer biomarkers):
- β-2 microglobulin (beta-2)
- Alpha-fetoprotein (AFP)
- Squamous cell carcinoma antigen (SCC)
- S100 protein tumormarker
- Calcitonin
- Mucin-like carcinoma-associated antigen (MCA)
- Neuron-specific enolase (NSE)
- Prostate-specific antigen (PSA) test
- Cancer associated antigen 549 (CA 549)
- CA 19-9, CA 72-4, CA 50, CA 15-3 and CA 125 tumor markers (cancer antigens)
- Carcinoembryonic antigen (CEA)
- Thyroglobulin (Tg)
- Tissue polypeptide antigens (ТРА, TPS)
- Cytokeratin-19 fragment (CYFRA 21-1)
- Human chorionic gonadotrophin (hCG)