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Tumor markers tests (cancer biomarkers)

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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.

Tumour markers serve as indispensable tools in the realm of cancer detection and diagnosis, offering valuable insights into disease progression and treatment response.

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)
  • Very high levels (>400–500 ng/mL) are highly suggestive of HCC or AFP-producing GCTs.
  • Moderately elevated levels (e.g., 20–400 ng/mL) can be seen in HCC or GCTs, but also in non-cancerous liver conditions.
  • Slight elevations may occur in various situations and need careful interpretation.

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)
  • Very high levels (>10,000 mIU/mL) are highly suggestive of gestational trophoblastic disease or GCTs.
  • Moderately elevated levels (e.g., 5–10,000 mIU/mL) may indicate GCTs or early pregnancy-related conditions.
  • Slight elevations may occur in non-cancerous conditions and require further evaluation.

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
  • Very high levels (>20 ng/mL) are highly suggestive of colorectal or other adenocarcinomas.
  • Moderately elevated levels (e.g., 10–20 ng/mL) may indicate cancer or benign conditions like colitis.
  • Slight elevations may occur in smoking or inflammatory conditions and need careful interpretation.

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
  • Very high levels (>100 U/mL for CA 15-3; >120 U/mL for CA 27.29) are highly suggestive of advanced breast cancer.
  • Moderately elevated levels (e.g., 30–100 U/mL for CA 15-3) may indicate breast cancer progression or recurrence.
  • Slight elevations may occur in benign breast conditions and require further evaluation.

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
  • Very high levels (>1,000 U/mL) are highly suggestive of pancreatic or biliary tract cancer.
  • Moderately elevated levels (e.g., 37–1,000 U/mL) may indicate pancreatic cancer or benign biliary conditions.
  • Slight elevations may occur in non-cancerous conditions like pancreatitis and need careful interpretation.

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
  • Very high levels (>200 U/mL) are highly suggestive of ovarian cancer.
  • Moderately elevated levels (e.g., 35–200 U/mL) may indicate ovarian or endometrial cancer or benign gynecologic conditions.
  • Slight elevations may occur in endometriosis or infections and require further evaluation.

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)
  • Very high levels (>10 ng/mL) are highly suggestive of prostate cancer.
  • Moderately elevated levels (e.g., 4–10 ng/mL) may indicate prostate cancer, BPH, or prostatitis.
  • Slight elevations may occur in benign conditions and need careful interpretation.

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
  • Very high levels (>100 pg/mL) are highly suggestive of medullary thyroid cancer.
  • Moderately elevated levels (e.g., 10–100 pg/mL for men) may indicate early medullary thyroid cancer or C-cell hyperplasia.
  • Slight elevations may occur in rare non-cancerous conditions and require further evaluation.

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
  • Very high levels (>10 ng/mL post-thyroidectomy) are highly suggestive of thyroid cancer recurrence.
  • Moderately elevated levels (e.g., 1–10 ng/mL) may indicate residual thyroid tissue or early recurrence.
  • Slight elevations may require further imaging or clinical correlation.

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
  • Very high levels (>100 ng/mL) are highly suggestive of small cell lung cancer or neuroblastoma.
  • Moderately elevated levels (e.g., 13–100 ng/mL) may indicate neuroendocrine tumors or disease progression.
  • Slight elevations may occur in non-cancerous conditions and need careful interpretation.

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
  • Very high levels (>10 ng/mL) are highly suggestive of non-small cell lung cancer or advanced bladder cancer.
  • Moderately elevated levels (e.g., 3.3–10 ng/mL) may indicate cancer progression or recurrence.
  • Slight elevations may occur in benign lung conditions and require further evaluation.

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
  • Very high levels (>5 ng/mL) are highly suggestive of advanced squamous cell carcinomas.
  • Moderately elevated levels (e.g., 1.5–5 ng/mL) may indicate squamous cell cancers or recurrence.
  • Slight elevations may occur in benign skin or lung conditions and need careful interpretation.

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
  • Very high levels (>5 mg/L) are highly suggestive of multiple myeloma or lymphoma.
  • Moderately elevated levels (e.g., 2.5–5 mg/L) may indicate hematologic malignancies or renal dysfunction.
  • Slight elevations may occur in chronic inflammation and require further evaluation.

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
  • Very high levels (>30 U/mL) are highly suggestive of advanced breast cancer.
  • Moderately elevated levels (e.g., 11–30 U/mL) may indicate breast cancer progression or recurrence.
  • Slight elevations may occur in benign conditions and need careful interpretation.

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
  • Very high levels (>1 µg/L) are highly suggestive of melanoma or sarcomas.
  • Moderately elevated levels (e.g., 0.15–1 µg/L) may indicate melanoma progression.
  • Slight elevations may occur in non-cancerous conditions and require tissue correlation.

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
  • Very high levels (>200 U/L for TPA) are suggestive of high proliferative cancers.
  • Moderately elevated levels (e.g., 80–200 U/L for TPA) may indicate cancer or benign conditions.
  • Slight elevations may occur in non-cancerous proliferative states and need careful interpretation.

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
  • Very high levels (>1,000 U/L) are highly suggestive of aggressive lymphoma or germ cell tumors.
  • Moderately elevated levels (e.g., 280–1,000 U/L) may indicate cancer or non-cancerous tissue damage.
  • Slight elevations may occur in hemolysis or inflammation and need careful interpretation.

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
  • Very high levels (>500 ng/mL) are highly suggestive of neuroendocrine tumors.
  • Moderately elevated levels (e.g., 100–500 ng/mL) may indicate early neuroendocrine tumors or recurrence.
  • Slight elevations may occur in benign conditions and require further evaluation.

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
  • Detectable mutations are highly suggestive of BRCA-associated cancers.
  • Presence in ctDNA may indicate tumor progression or recurrence.
  • Non-detectable levels do not rule out cancer; requires genetic testing correlation.

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
  • Detectable KRAS mutations are highly suggestive of colorectal or pancreatic cancer.
  • Presence in ctDNA may indicate resistance to anti-EGFR therapies.
  • Non-detectable levels do not rule out cancer; requires molecular testing.

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
  • Very high levels (>50 ng/mL) are highly suggestive of HER2-positive breast or gastric cancer.
  • Moderately elevated levels (e.g., 15–50 ng/mL) may indicate HER2-positive cancer progression.
  • Slight elevations may occur in non-cancerous conditions and need careful interpretation.

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
  • Detectable ER/PR in CTCs is highly suggestive of hormone receptor-positive breast cancer.
  • Presence may indicate suitability for hormone therapy.
  • Non-detectable levels do not rule out breast cancer; requires tissue correlation.

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
  • Very high levels (>400 pmol/L) are highly suggestive of ovarian cancer.
  • Moderately elevated levels (e.g., 150–400 pmol/L) may indicate ovarian cancer or benign gynecologic conditions.
  • Slight elevations may occur in non-cancerous conditions and need careful interpretation.

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
  • Very high levels (>200 pg/mL) are highly suggestive of small cell lung cancer.
  • Moderately elevated levels (e.g., 50–200 pg/mL) may indicate neuroendocrine tumors or early SCLC.
  • Slight elevations may occur in benign conditions and require further evaluation.

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
  • Detectable BRAF mutations are highly suggestive of melanoma or colorectal cancer.
  • Presence in ctDNA may indicate suitability for BRAF inhibitors.
  • Non-detectable levels do not rule out cancer; requires molecular testing.

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
  • Detectable ALK rearrangements are highly suggestive of NSCLC or lymphoma.
  • Presence in ctDNA may indicate suitability for ALK inhibitors.
  • Non-detectable levels do not rule out cancer; requires molecular testing.

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
  • High PD-L1 expression is suggestive of potential response to immunotherapy.
  • Moderate expression may indicate variable immunotherapy response.
  • Low or absent expression does not rule out cancer; requires clinical correlation.

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
  • Very high levels (>200 pg/mL) are highly suggestive of small cell lung cancer or NETs.
  • Moderately elevated levels (e.g., 50–200 pg/mL) may indicate early neuroendocrine tumors.
  • Slight elevations may occur in benign conditions and need careful interpretation.

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
  • Very high levels (>150 ng/mL) are suggestive of lung cancer or mesothelioma.
  • Moderately elevated levels (e.g., 50–150 ng/mL) may indicate cancer progression.
  • Slight elevations may occur in benign conditions and need careful interpretation.

Notes: Investigational; may indicate tumor progression or metastasis.
*Mesothelin* Mesothelioma, pancreatic cancer, ovarian cancer Normal: <2.5 nmol/L
Pregnancy: Not significantly elevated
  • Very high levels (>10 nmol/L) are highly suggestive of mesothelioma or pancreatic cancer.
  • Moderately elevated levels (e.g., 2.5–10 nmol/L) may indicate cancer or benign pleural conditions.
  • Slight elevations may occur in non-cancerous conditions and need careful interpretation.

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

  1. National Cancer Institute (NCI). (n.d.). Tumor Markers. Retrieved from https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-markers-fact-sheet
  2. American Cancer Society (ACS). (2023). Tumor Markers. Retrieved from https://www.cancer.org/cancer/diagnosis-staging/tests/tumor-markers.html
  3. 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
  4. 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
  5. 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
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