Serum Tumor Markers for Malignancies - CAM 277

Description:
Tumor biomarkers are proteins detected in the blood, urine, or other body fluids that are either produced by the tumor itself or in response to its presence. These biomarkers are used to help detect, diagnose, stage, and manage some types of cancer (Hottinger & Hormigo, 2011).

Regulatory Status
There are numerous FDA-approved tests for the assessment of serum tumor markers. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). LDTs are not approved or cleared by the U.S. Food and Drug Administration; however, FDA clearance or approval is not currently required for clinical use.

Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

Note: Except for where otherwise specified in the coverage criteria below, quarterly measurement of designated serum tumor markers is permitted for follow-up, monitoring, and/or surveillance.

The use of the following serum tumor markers is considered MEDICALLY NECESSARY for the following indications:
1. Alpha fetoprotein (AFP) testing for:
  1. Epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer: initial diagnostic evaluation and in patients with newly diagnosed ovarian cancer after recent surgical procedure, during primary chemotherapy, and/or monitoring for complete response
    1. Ovarian low malignant potential tumors (Borderline Ovarian Epithelial Tumors): follow-up, monitoring, and/or surveillance; every visit if initially elevated
    2. Germ cell tumors: follow-up, monitoring, and/or surveillance no more than every 2 months for the first 2 years, every 4 months in years 3 – 5, and then annually after year 5
    3. Sex cord stromal tumors: follow-up, monitoring, and/or surveillance based on stage (i.e., 6 – 12 months if early-stage, low-risk disease; 4 – 6 months if high-risk disease)
  2. Hepatocellular carcinoma: screening, initial diagnostic evaluation, and/or surveillance (every 3 – 6 months for 2 years, then every 6 months up to 5 years)
  3. Intrahepatic cholangiocarcinoma: initial diagnostic evaluation
  4. Occult primary mass of the liver, mediastinum or retroperitoneum: initial diagnostic evaluation
  5. Testicular cancer:
    1. Nonseminoma: post-diagnostic evaluation, risk classification, post-treatment follow-up and/or surveillance
    2. Pure seminoma: initial and/or post-diagnostic evaluation, risk classification, post-treatment follow-up and/or surveillance
  6. Thymoma: initial diagnostic evaluation
  7. Saccrococcygeal teratoma: diagnostic evaluation and/or surveillance for up to 3 years
2. Alkaline Phosphatase (ALP) for:
  1. Metastatic and primary bone neoplasms: initial diagnostic evaluation and/or surveillance
  2. Systemic light chain amyloidosis: initial diagnostic evaluation
3. B-type natriuretic peptide (BNP) or N-terminal fragment of B-type natriuretic peptide (NT-proBNP)
  1. Systemic light chain amyloidosis: initial diagnostic evaluation
4. Beta human chorionic gonadotropin (beta-HCG) for:
  1. Epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer: initial diagnostic evaluation and in patients with newly diagnosed ovarian cancer after recent surgical procedure, during primary chemotherapy, and/or monitoring for complete response
    1. Ovarian low malignant potential tumors (borderline ovarian epithelial tumors): follow-up, monitoring, and/or surveillance; every visit if initially elevated
    2. Germ cell tumors: follow-up, monitoring, and/or surveillance no more than every 2 months for the first 2 years, every 4 months in years 3 – 5, and then annually after year 5
    3. Sex cord stromal tumors: follow-up, monitoring, and/or surveillance based on stage (i.e., 6 – 12 months if early-stage, low-risk disease; 4 – 6 months if high-risk disease)
  2. Occult primary mass of the mediastinum or retroperitoneum: initial diagnostic evaluation
  3. Saccrococcygeal teratoma: initial diagnostic evaluation
  4. Testicular cancer:
    1. Nonseminoma: post-diagnostic evaluation, risk classification, post-treatment follow-up and/or surveillance
    2. Pure seminoma: initial and/or post-diagnostic evaluation, risk classification, post-treatment follow-up and/or surveillance
  5. Thymoma: initial diagnostic evaluation
5. Beta-2 microglobulin (B2M) for:
  1. B-Cell lymphomas (including AIDS-related B-cell lymphomas, Castleman disease, diffuse large B-cell lymphoma, follicular lymphoma (grade 1 – 2), lymphoblastic lymphoma, and mantle cell lymphoma): initial diagnostic evaluation
  2. Chronic lymphocytic leukemia/small lymphocytic lymphoma: initial diagnostic evaluation
  3. Multiple myeloma: initial diagnostic evaluation and/or follow-up/surveillance as needed
  4. Systemic light chain amyloidosis: initial diagnostic evaluation
  5. Waldenström's macroglobulinemia/lymphoplasmacytic lymphoma: initial diagnostic evaluation and prognostication at the time of first-line treatment initiation
6. Cancer Antigen 15-3 and 27.29 (CA 15-3 and 27-29) for:
  1. Metastatic breast cancer: monitoring
7. Cancer Antigen 19-9 (CA 19-9) for:
  1. Epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer: initial diagnostic evaluation and in patients with newly diagnosed ovarian cancer after recent surgical procedure, during primary chemotherapy, and/or monitoring for complete response
    1. Mucinous carcinoma of the ovary: initial diagnostic evaluation
    2. Ovarian low malignant potential tumors (borderline ovarian epithelial tumors): follow-up, monitoring, and/or surveillance; every visit if initially elevated
    3. Germ cell tumors: follow-up, monitoring, and/or surveillance no more than every 2 months for the first 2 years, every 4 months in years 3-5, and then annually after year 5
    4. Sex cord stromal tumors: follow-up, monitoring, and/or surveillance based on stage (i.e., 6 – 12 months if early-stage, low-risk disease; 4 – 6 months if high-risk disease)
  2. Gallbladder cancer: initial diagnostic evaluation, monitoring, and/or surveillance
  3. Hepatocellular carcinoma: initial diagnostic evaluation
  4. Intrahepatic and extrahepatic cholangiocarcinoma: initial diagnostic evaluation and/or monitoring
  5. Pancreatic adenocarcinoma: initial diagnostic evaluation, risk classification, monitoring, and/or surveillance (every 3 – 6 months for 2 years, then every 6 – 12 months as clinically indicated)
  6. Small bowel adenocarcinoma: initial diagnostic evaluation and/or surveillance (every 3 – 6 months for 2 years, then every 6 months for a total of 5 years)
8. Cancer Antigen 125 (CA-125) for:
  1. BRCA mutation-positive individuals aged 30 and older who have not elected risk-reducing salpingo-oopherectomy (RRSO): ovarian cancer screening
  2. Endometrial cancer: initial diagnostic evaluation and/or surveillance
  3. Epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer: initial diagnostic evaluation, during primary chemotherapy, and/or monitoring for complete response
    1. Ovarian low malignant potential tumors (borderline ovarian epithelial tumors): follow-up, monitoring, and/or surveillance; every visit if initially elevated
    2. Germ cell tumors: follow-up, monitoring, and/or surveillance no more than every 2 months for the first 2 years, every 4 months in years 3 – 5, and then annually after year 5
    3. Sex cord stromal tumors: follow-up, monitoring, and/or surveillance based on stage (i.e., 6 – 12 months if early-stage, low-risk disease; 4 – 6 months if high-risk disease)
  4. Lynch syndrome: surveillance
  5. Malignant peritoneal mesothelioma: initial diagnostic evaluation
  6. Occult primary adenocarcinoma or carcinoma not otherwise specified: initial diagnostic evaluation
9. Carcinoembryonic Antigen (CEA) for:
  1. Colon cancer: initial diagnostic evaluation, monitoring, and/or surveillance every 3 – 6 months for 2 years, then every 6 months for a total of 5 years
  2. Epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer: initial diagnostic evaluation and in patients with newly diagnosed ovarian cancer after recent surgical procedure, during primary chemotherapy, and/or monitoring for complete response
    1. Less common ovarian cancers: initial diagnostic evaluation
    2. Mucinous carcinoma of the ovary: initial diagnostic evaluation
    3. Ovarian low malignant potential tumors (borderline ovarian epithelial tumors): follow-up, monitoring, and/or surveillance; every visit if initially elevated
    4. Germ cell tumors: follow-up, monitoring, and/or surveillance no more than every 2 months for the first 2 years, every 4 months in years 3 – 5, and then annually after year 5
    5. Sex cord stromal tumors: follow-up, monitoring, and/or surveillance based on stage (i.e., 6 – 12 months if early-stage, low-risk disease; 4 – 6 months if high-risk disease)
  3. Hepatobiliary cancers including:
    1. Intrahepatic cholangiocarcinoma: initial diagnostic evaluation and/or monitoring
    2. Extrahepatic cholangiocarcinoma: initial diagnostic evaluation and/or monitoring
    3. Gallbladder cancer: initial diagnostic evaluation, monitoring, and/or surveillance
  4. Malignant pleural or peritoneal mesothelioma: initial diagnostic evaluation
  5. Metastatic breast cancer: monitoring metastatic disease
  6. Neuroendocrine and adrenal tumors - multiple endocrine neoplasia, type 2: initial diagnostic evaluation and/or surveillance
  7. Non-small cell lung cancer: initial diagnostic evaluation
  8. Occult primary adenocarcinoma or carcinoma not otherwise specified: initial diagnostic evaluation
  9. Rectal cancer: initial diagnostic evaluation, monitoring, and/or surveillance every 3 – 6 months for 2 years, then every 6 months for a total of 5 years
  10. Small bowel adenocarcinoma: initial diagnostic evaluation and/or surveillance every 3 – 6 months for 2 years, then every 6 months for a total of 5 years
  11. Thyroid carcinoma - medullary carcinoma: initial diagnostic evaluation, monitoring, and/or surveillance 2 – 3 months postoperative, then every 6 – 12 months
10. Calcitonin (CALCA) expression for:
  1. Cervical cancer: initial diagnostic evaluation
  2. Neuroendocrine and adrenal tumors - multiple endocrine neoplasia, type 2: initial diagnostic evaluation
  3. Occult primary adenocarcinoma or anaplastic/undifferentiated tumors of the head and neck, or otherwise unspecified: initial diagnostic evaluation
  4. Thyroid carcinoma - medullary carcinoma: initial diagnostic evaluation, monitoring, and/or, surveillance 2 – 3 months postoperative, then every 6 – 12 months
11. Free light chain (circulating serum kappa or lambda chains) for:
  1. B-cell lymphoma – Castleman disease: initial diagnostic evaluation
  2. Multiple myeloma: initial diagnostic evaluation and/or surveillance as needed
  3. Systemic light chain amyloidosis: initial diagnostic evaluation
  4. Waldenström's macroglobulinemia / lymphoplasmacytic lymphoma: initial diagnostic evaluation
12. Inhibin (INHA) expression for:
  1. Epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer: initial diagnostic evaluation, in patients with newly diagnosed ovarian cancer after recent surgical procedure, during primary chemotherapy, and/or monitoring for complete response
    1. Ovarian low malignant potential tumors (borderline ovarian epithelial tumors): follow-up, monitoring, and/or surveillance; every visit if initially elevated
    2. Germ cell tumors: follow-up, monitoring, and/or surveillance no more than every 2 months for the first 2 years, every 4 months in years 3 – 5, and then annually after year 5
    3. Sex cord stromal tumors: follow-up, monitoring, and/or surveillance based on stage (i.e., 6 – 12 months if early-stage, low-risk disease; 4 – 6 months if high-risk disease)
  2. Occult primary adenocarcinoma or carcinoma not otherwise specified: initial diagnostic evaluation
  3. Undiagnosed pelvic mass: initial diagnostic evaluation for clinical indication to assess for LCOC (Less Common Ovarian Cancers) and pregnancy
  4. Uterine neoplasms - uterine sarcoma: initial diagnostic evaluation
13. Lactate dehydrogenase (LDH) for:
  1. Acute lymphoblastic leukemia (ALL) and pediatric acute lymphoblastic leukemia (PED-ALL): initial diagnostic evaluation
  2. Acute myeloid leukemia (AML) initial diagnostic evaluation
  3. B-cell lymphomas (including AIDS-related B-cell lymphomas, Burkitt lymphoma, Castleman disease, diffuse large B-cell lymphoma, follicular lymphoma (grade 1 – 2), gastric MALT lymphoma, lymphoblastic lymphoma, mantle cell lymphoma, nodal marginal zone lymphoma, nongastric MALT lymphoma, post-transplant lymphoproliferative disorders, and splenic marginal zone lymphoma): initial diagnostic evaluation and/or surveillance every 3-6 months for 5 years then annually, or as clinically indicated
  4. Bone cancer: initial diagnostic evaluation and/or surveillance
  5. Chronic lymphocytic leukemia/small lymphocytic lymphoma and Richter's syndrome: initial diagnostic evaluation
  6. Cutaneous melanoma: initial diagnostic evaluation for metastatic or recurrent disease
  7. Epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer: initial diagnostic evaluation, in patients with newly diagnosed ovarian cancer after recent surgical procedure, during primary chemotherapy, and/or monitoring for complete response
    1. Ovarian low malignant potential tumors (borderline ovarian epithelial tumors): follow-up, monitoring, and/or surveillance; every visit if initially elevated
    2. Germ cell tumors: follow-up, monitoring, and/or surveillance no more than every 2 months for the first 2 years, every 4 months in years 3 – 5, and then annually after year 5
    3. Sex cord stromal tumors: follow-up, monitoring, and/or surveillance based on stage (i.e., 6 – 12 months if early-stage, low-risk disease; 4 – 6 months if high-risk disease
  8. Hairy cell leukemia: initial diagnostic evaluation
  9. Hodgkin lymphoma: initial diagnostic evaluation
  10. Kidney cancer: initial diagnostic evaluation
  11. Multiple myeloma: initial diagnostic evaluation, staging, and/or follow-up/surveillance as needed
  12. Myelodysplastic syndromes: initial diagnostic evaluation
  13. Myeloproliferative neoplasms: initial diagnostic evaluation and/or monitoring while on and after therapy
  14. Pediatric aggressive mature B-cell lymphomas: initial diagnostic evaluation
  15. Primary cutaneous lymphomas (including primary cutaneous B-cell Lymphoma, cutaneous T-cell lymphoma, mycosis fungoides/ Sezary syndrome, primary cutaneous CD30+ T-cell lymphoproliferative disorders): initial diagnostic evaluation
  16. Small cell lung cancer: prognosis
  17. Systemic light chain amyloidosis: initial diagnostic evaluation
  18. Testicular cancer:
    1. Nonseminoma: post-treatment follow-up and/or surveillance
    2. Pure seminoma: initial and/or post-diagnostic evaluation, risk-classification, post-treatment follow-up and/or surveillance
  19. T-cell lymphomas (including adult T-cell leukemia/lymphoma, breast implant-associated anaplastic large cell lymphoma, extranodal NK/T-cell lymphomas, hepatosplenic T-cell lymphoma, peripheral T-cell lymphoma, and T-cell prolymphocytic leukemia): initial diagnostic evaluation and prognosis (except breast implant-associated ALCL). May be used in staging breast implant-associated ALCL
  20. Waldenström's macroglobulinemia / lymphoplasmacytic lymphoma: initial diagnostic evaluation
14. Troponin T for:
  1. Systemic light chain amyloidosis: initial diagnostic evaluation and/or staging
15. Tryptase for:
  1. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes: initial diagnostic evaluation
  2. Systemic mastocytosis: initial diagnostic evaluation, monitoring response to therapy, and/or risk classification
The use of urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type 1 (PAI-1) to guide decisions on adjuvant systemic therapy is considered MEDICALLY NECESSARY in patients with estrogen receptor (ER)- or progesterone receptor (PgR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (node-negative) breast cancer.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

Any of the tumor markers listed above for any cancer indication not otherwise listed and all other applications of serum tumor markers is considered NOT MEDICALLY NECESSARY including but not limited to:
1. A2-PAG (pregnancy associated alpha2 glycoprotein)
2. AFP-L3 (Lens culinaris agglutinin reactive AFP)
3. BCM (breast cancer mucin)
4. CA-50 (cancer antigen 50)
5. CA 72-4 (cancer antigen 72-4)
6. CA-242 (cancer antigen 242)
7. CA-195 (cancer antigen 195)
8. CA-549 (cancer antigen 549)
9. CAM 17-1 (antimucin monoclonal antibody)
10. CAM-26 (carcinoma associated mucin antigen)
11. CAM-29 (carcinoma associated mucin antigen)
12. CA-SCC (squamous cell carcinoma antigen)
13. CAR-3 (antigenic determinant recognized by monoclonal antibody AR-3)
14. Circulating extracellular domain of HER2 (human epidermal growth factor receptor 2)
15. DCP (Des-Gamma-Carboxy Prothrombin)
16. DMSA (pentavalent technetium-99mm dimercaptosuccinic acid)
17. Du-PAN-2 (sialylated carbohydrate antigen)
18. Human epididymis protein (HE4)
19. Ki-67 antigen for esophageal or breast cancer
20. MCA (mucinous carcinoma associated antigen)
21. MSA (mammary serum antigen)
22. NSE (neuron specific enolase)
23. P-LAP (placental alkaline phosphatase)
24. PNA-ELLA (peanut lectin bonding assay)
25. P53 (monocolonal antibody)
26. SLEX (sialylated Lewis-X antigen)
27. SLX (sialylated SSEA-1 antigen)
28. SPAN-1 (sialylated carbonated antigen SPAN-1)
29. ST-439 (sialylated carbohydrate antigen ST-439)
30. TAG-12 (tumor associated glycoprotein 12)
31. TAG 72 (tumor associated glycoprotein 72)
32. TAG-72-3 (tumor associated glycoprotein 72-3)
33. TNF-alpha (TNF-a) (tumor necrosis factor alpha)
34. TATI (tumor associated trypsin inhibitor)
35. TPA (tissue polypeptide antigen)
36. TPS (tissue polypeptide specific antigen)
The following tests is considered NOT MEDICALLY NECESSARY for all indications, as there is insufficient evidence to support the use of these tests.
1. Apifiny®
2. BeScreened™ (BeScreened™ -CRC)
3. Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) for predicting the risk of breast cancer.
4. Carcinoembryonic antigen cellular adhesion molecule-7 (CEACAM-7) expression as a predictive marker for rectal cancer recurrence
5. Cofilin (CFL1) as a prognostic and drug resistance marker in non-small cell lung cancer.
6. ColonSentry test for screening of colorectal cancer.
7. CIMP, LINE-1 hypomethylation, and Immune cells for colon cancer.
8. Colorectal Cancer DSA (Almac Diagnostics, Craigavon, UK)
9. EarlyCDT-Lung test
10. HE4 immunoassay
11. HERmark®
12. Mucin 4 expression as a predictor of survival in colorectal cancer.
13. OVA1™
14. OvaCheck™
15. Overa (OVA1 Next Generation)
16. Panexia test
17. PreOvar test for the KRAS-variant to determine ovarian cancer risk.
18. REVEAL Lung Nodule Characterization
19. ROMA™
20. VeriStrat^®
21. Xpresys Lung Test
Analysis of proteomic patterns in serum for screening and detection of cancer is considered NOT MEDICALLY NECESSARY.

Rationale
Actionable molecular assays for tumor biomarkers may guide treatment decisions for common malignancies (Febbo et al., 2011). Tumor biomarkers are proteins detected in blood, urine or body fluids that serve as surrogate indicators to increase or decrease the clinician’s suspicion of future clinically important events. These can be used to determine risk, screen for early cancers, establish diagnosis, estimate prognosis, predict that a specific therapy will work, and/or monitor for disease recurrence or progression (Catharine M. Sturgeon et al., 2008). The NCCN task force guidelines recommend that tumor markers be classified by indication as diagnostic, prognostic, predictive and companion tests. An individual marker may serve more than one purpose and thus can fall into more than one category of biomarker. Biomarkers may also have different categorization across different stages of disease or different types of tumor (Febbo et al., 2011). Some of these categories are listed below:

Diagnostic biomarkers – Tumor biomarkers that aid in the diagnosis or subclassification of a particular disease state. Detection of diagnostic biomarkers may result in different management of the disease, but the marker is used primarily to establish that a particular disease is present in the patient sample. An example of a diagnostic biomarker is the Philadelphia chromosome in chronic myelogenous leukemia.
Prognostic – Tumor biomarkers that have an association with some clinical outcomes, such as overall survival or recurrence-free survival, independent of the treatment rendered. An example is the p53 gene, whose presence may indicate a more aggressive type of cancer.
Predictive - Tumor biomarkers predict the activity of a specific class or type of therapy and are used to help make more specific treatment decisions. An example is human epidermal growth factor 2 (HER2), which is assessed in breast cancer patients. Patients who are negative for this biomarker do not respond as well to trastuzumab.
Companion - Biomarkers may be diagnostic, prognostic, or predictive, but are used to identify a subgroup of patients for whom a therapy has shown benefit. This category of biomarker is similar to the predictive category, but these biomarkers do not usually have independent prognostic or predictive strength (Febbo et al., 2011).

Alpha-fetoprotein (AFP)
AFP is a commonly assessed biomarker in cancer patients. AFP is a protein that is normally produced by the fetal yolk sac, and its concentration stabilizes at approximately < 10 µg/L shortly after birth (Schefer et al., 1998). Many tissues produce this protein if they become malignant, and AFP is elevated in a variety of cancers, such as hepatocellular carcinomas . False positives may occur due to liver damage or a rare hereditary syndrome (Gilligan et al., 2010).

AFP can be fractionated into three different isoforms based on reactivity with Lens culinaris agglutinin (LCA), and the three types are as follows: L1 (no reactivity), L2 (low reactivity), L3 (high reactivity). AFP-L3 is theorized to associate with HCC because the dedifferentiation of HCC tissues correlates with the production of the enzyme that produces AFP-L3. This means that AFP-L3 may be closely related to cancer-specific events and are at least more specific to more malignant cancers (M. Wu et al., 2018).

Beta-human chorionic gonadotropin (beta-HCG)
beta-HCG is the beta subunit of the normal hCG hormone produced during pregnancy. Some malignancies express the gene for the beta subunit of hCG, thereby producing this protein outside of pregnancy (Goff, 2016; Harvey, 2019). The beta subunit is responsible for providing the biological and immunological specificity to each hormone (Marcillac et al., 1992) This biomarker is typically associated with aggressive disease in nontrophoblastic tumors. This biomarker may be seen in ovarian cancers, testicular cancers, and more (Hotakainen et al., 2002).

Beta-2 microglobulin (B2M)
B2M is the light chain component of the MHC-1 molecule and is present in most cells of the body (Berrebi et al., 2009). This protein may aggregate and eventually form insoluble amyloid fibrils, which cause numerous conditions such as bone and joint damage (Katou et al., 2002; Marcinko et al., 2017). Elevated serum levels of B2M have been associated with cancers such as multiple myeloma or chronic leukocytic leukemia (Berrebi et al., 2009).

Calcitonin
Serum calcitonin is the primary tumor marker for medullary thyroid carcinoma (MTC). MTC is a neuroendocrine tumor of the parafollicular or C cells of the thyroid gland, and production of calcitonin is a signifying characteristic of this tumor. The concentration of calcitonin tends to correlate with tumor mass (Tuttle, 2018; Tuttle, 2020). However, the ATA has noted this biomarker to have significant uncertainties (Haugen et al., 2016; Wells et al., 2015)

Cancer antigens (CA)
Cancer antigens (CA) refer to any substance produced by the body in response to a tumor. Various cancer antigens have been proposed as biomarkers for numerous types of cancer, such as CA 19-9, CA 125, and CA 15-3. CA 19-9 (also called carbohydrate antigen) refers to a specific antibody that binds a sialyl compound produced by cancer tissue (Sialyl Lewis A). CA 19-9 is elevated in several different types of cancer, such as adenocarcinomas or colorectal cancer (Magnani, 2004). CA 125 is a glycoprotein produced in fetal tissue as well as mesothelial cells in adults (Isaksson et al., 2017). Its function is thought to assist with cell adhesion, metastasis, and immunosuppression (Dorigo & Berek, 2011).

Carcinoembryonic antigen (CEA)
CEA is a protein normally produced by fetal tissue, and as with AFP, stabilizes soon after birth. CEA is often elevated in malignancies such as breast or pancreatic cancer, although other conditions such as liver damage or cigarette smoking may affect CEA levels as well (Ueland, 2017; Ueland, 2020). The gene encoding CEA encompasses certain genes encoding for cell adhesion, as well as MHC antigens (Duffy, 2001).

Chromogranin A (CgA)
Chromogranins are proteins contained in neurosecretory vesicles of NET cells and are typically elevated in neuroendocrine neoplasms. CgA is the most sensitive of the three chromogranins, and as such as the primary marker used to evaluate neoplasms. However, this biomarker is highly variable (Strosberg, 2017, 2019).

Lactate Dehydrogenase (LDH)
LDH is an enzyme that catalyzes the interconversion between lactate and pyruvate. LDH is often found to be upregulated in tumors, and a key feature of cancer sites is the accumulation of lactate or lactic acid. This is thought to be caused by increased glycolysis and this increase in lactate causes an elevated concentration of LDH (Pucino et al., 2017). Increased LDH is found in several different cancers, such as B-cell lymphomas and osteosarcomas (NCCN, 2022p).

Inhibins
The primary function of inhibins is to inhibit hormones such as follicle stimulating hormone. However, since this protein is restricted to ovarian granulosa cells in women, unusual levels of inhibins may signal tumors in this region (Walentowicz et al., 2014). This marker exists as two different isoforms, inhibin A and B. Either form can be measured, although an active tumor may over-secrete one or both forms (Gershenson, 2017, 2020). Inhibin B is generally considered to be more accurate than inhibin A, with sensitivities ranging from 0.88 to 1.00 whereas inhibin A’s sensitivity ranges from 0.67-0.77. However, inhibin B has limitations of its own such as fluctuations with the menstrual cycle (Farkkila et al., 2015).

Urokinase plasminogen activator
Urokinase plasminogen activator (uPA) is a serine protease with an important role in cancer invasion and metastases (Stephens et al., 1998). When bound to its receptor (uPAR), uPA converts plasminogen into plasmin and mediates degradation of the extracellular matrix during tumor cell invasion. High levels have been associated with shorter survival in women with breast cancer (Chappuis et al., 2001; Foekens et al., 2000; Malmstrom et al., 2001; Stephens et al., 1998). ASCO guidelines include the option for using uPA and PAI-1 to guide decisions on adjuvant systemic therapy for patients with node-negative, hormone-positive/HER2-negative disease, but not for patients with HER2-positive or triple-negative disease (L. N. Harris et al., 2016; Theodoros & Bergh, 2019).

Serum free light chains
Light chains are proteins produced by plasma cells that, along with heavy chains, collectively make up an immunoglobulin macromolecule. There are a total of 5 heavy chain protein classes (IgG, IgE, IgA, IgD, and IgM), and 2 light chain protein classes (kappa and lambda). Healthy plasma cells produce polyclonal immunoglobulins that are capable of binding to antigens and inducing an immune response; unhealthy plasma cells produce monoclonal immunoglobulins that do not effectively engage antigens (Kyrtsonis MC, 2012). In the case of certain plasma cell disorders, an abundance of monoclonal immunoglobulin or free light chains (kappa and/or lambda), may accumulate in the serum and serve as useful diagnostic markers.

Multiple myeloma
Multiple myeloma is an uncontrolled growth of plasma cells (ACS, 2018a). In most cases, the cancerous clonal cells secrete an intact monoclonal immunoglobulin, and the gold standard for diagnosis is serum protein electrophoresis and immunofixation (Tosi et al., 2013). Less commonly, however, myeloma clones will secrete only light chains; in these instances, a serum free light chain assay can be employed to quantify the ratio of kappa and lambda chains in the serum. It has been demonstrated that in healthy individuals, the kappa/lambda ratio in the serum is approximately 0.58 (Katzmann et al., 2002). In the case of plasma cell neoplasms, free light chains are overproduced and the kidneys are unable to completely clear them, resulting in accumulation in the serum and a change in the kappa/lambda ratio. This ratio is often used to aid in the diagnosis, prognosis, and monitoring of plasma cell disorders (Tosi et al., 2013).

Waldenström's Macroglobulinemia / Lymphoplasmacytic Lymphoma
Waldenström's Macroglobulinemia (WM) is a type of cancer that is similar to multiple myeloma and non-Hodgkin lymphoma. WM cells are called “lymphoplasmacytoid” because they have features of both plasma cells and lymphocytes (ACS, 2018b). WM cells are distinguished by the production of immunoglobulin M (IgM) serum monoclonal protein, also referred to as a “macroglobulin” (Cautha et al., 2022). While serum IgM level is useful for diagnostic purposes, it does not correlate with prognosis. The addition of a serum free light chain assay to the care of patients with suspected Waldenström's Macroglobulinemia has been shown to improve overall care, as it may help differentiate patients with another, potentially benign disorder called monoclonal gammopathy of undetermined significance (MGUS), as well as influence prognosis (Moreau AS, 2006).

Castleman disease
Castleman disease represents a group of B-cell lymphoproliferative disorders characterized by distinct pathogenesis and clinical outcomes (Oyaert et al., 2014; D. Wu et al., 2018). Patients with suspected Castleman disease have been reported to present with abnormal levels or kappa or lambda light chains, making the serum free light chain assay a potentially useful tool in the management of this disease (Oyaert et al., 2014; D. Wu et al., 2018). Utilization of a serum free light chain assay has been shown to be clinically useful in the workup of Castleman disease, though an important caveat is that changes in the absolute values of both kappa and lambda free light chain in the serum can occur with preservation of a ratio within the normal reference range (Stankowski-Drengler et al., 2010); hence, both the free light chain ratio as well as the absolute values of each light chain protein should be considered.

Light chain amyloidosis
Immunoglobulin light chain amyloidosis is a disorder that results from the accumulation of amyloid fibrils due to the production of fragments of monoclonal light chains (Dispenzieri, 2022; Merlini et al., 2013). As amyloid fibrils continue to accumulate, they begin to interfere with the biological function of various organs, eventually resulting in organ damage and potentially organ failure. Due to the involvement of light chains in the pathogenesis of amyloidosis, serum free light chain measurement may hold diagnostic and prognostic value, and be a viable response marker following therapy (Akar et al., 2005; Bhole et al., 2014; Kumar et al., 2010).

Importantly, Bhole and colleagues highlighted key challenges with serum free light chain assays that include but are not limited to over or under-estimation of the monoclonal protein, and performance differences between available tests. Therefore, despite the demonstrated utility of these assays, clinicians should be aware of their limitations.

Proteomics
Proteomics is a qualitative and quantitative assessment of the protein constituents in a given biological sample. This is typically performed with modification of polyacrylamide gel electrophoresis (PAGE) or matrix-assisted laser desorption/ionization (MALDI). However, this method is still under investigation (Raby, 2020, 2021).

Clinical Validity and Utility
Most biomarkers are not specific for tumors or organs, and their levels may rise in other diseases. The diagnostic value of a tumor marker will depend on the prevalence of the disease and on the specificity and sensitivity of the marker (Hottinger & Hormigo, 2011). The analytic and clinical validity as well as the clinical utility of each biomarker should be taken into account before its use for screening and or management of malignancies (Catharine M. Sturgeon et al., 2008). Establishing a biomarker’s ability to associate with a given outcome of interest (diagnostic, prognostic, et al.) and ability to improve clinical outcomes and decision-making is critical (Febbo et al., 2011).

With respect to biomarker acquisition, growing evidence continues to support the utility of liquid biopsy. Compared to the “gold standard” tissue biopsy, serum can be obtained in a relatively non-invasive manner, without the need for surgery and the associated risks and recovery time. Further, serum is generally always available; tumor tissue, conversely, may not always be accessible or present in a clinically useful quantity (Pinzani et al., 2021).

Kim et al. performed a study assessing the association of serum CA 19-9 and CEA with colorectal neoplasia. A total of 124509 measurements of serum CEA level and 115833 measurements of serum CA 19-9 were taken. All subjects were asymptomatic and underwent a colonoscopy. Elevated serum levels of CEA were found to be associated with any adenoma and elevated CA 19-9 was found to be associated with high-risk or advanced adenoma, CRC, and advanced colorectal neoplasia (Kim et al., 2017).

A review by O’Neill and Stoita expands upon the use of CA 19-9 obtained from serum in the diagnostic workup of pancreatic cancer, while also highlighting that several biomarkers lack the necessary sensitivity and/or specificity to be used as a new gold standard. Dozens of biomarkers other than CA 19-9 were examined in this review with respect to potential utility in the management of pancreatic cancer; but interestingly, no particular marker has yet emerged as an outstanding candidate. The authors postulate that diagnostic panels (as opposed to single markers) may hold future promise (O'Neill & Stoita, 2021).

Li et al. performed a study assessing the association between CA 15-3 and CEA with breast cancer. 36 studies with 12933 subjects were included in the meta-analysis, and elevated levels of both markers were associated with poorer disease-free survival (DFS) and overall survival (OS) rates. The hazard ratio of CA 15-3 in OS rates was 2.03 and 1.79 for CEA. The hazard ratio for CA 15-3 in DFS rates was 1.56 and 1.77 for CEA (X. Li et al., 2018).

Liu et al. performed a study evaluating the OS rates of an extremely high concentration of LDH (> 1,000 IU/L, considered by the study to be four times the upper normal limit). A total of 311 patients with >1000 U/L were examined, and the OS rate of this cohort was 1.7 months with 163 perishing within 2 months. However, 51 patients’ LDH decreased to normal following chemotherapy, and the OS rate of this group was 22.6 months. The cohort who survived at 2 months but did not see their LDH decrease had an OS rate of 4 months. There was no positive association found between OS and type of cancer, although there were different OS rates for patients at different stages of lymphoma (Liu et al., 2016).

A meta-analysis performed by Yang et al. assessed the association of CgA with neuroendocrine tumors. 13 studies totaling 1260 patients (967 healthy controls) were included in the analysis, and the pooled sensitivity was found to be 0.73. The pooled specificity was found to be 0.95. However, the study stressed that further research needs to be undertaken (Yang et al., 2015). Another study by Tian et al found that although median CgA levels were significantly higher than healthy controls (93.8 ng/mL compared to 37.1 ng/mL), only a weak correlation was found between changes in serum CgA levels and clinical regimen. The CgA cutoff value for this study was 46.2 ng/mL, which led to a sensitivity of 78.8% and specificity of 73.8% (Tian et al., 2016).

Isaakson et al. performed a study of tumor markers’ association with resectable lung adenocarcinomas. The study evaluated blood samples from 107 patients with stages I-III lung adenocarcinoma and examined the following markers: CEA, CA 19-9, CA 125, human epididymis protein 4 (HE4), and neuron-specific enolase (NSE). When the authors calculated the disease-free survival rate, CA 19-9 and CA 125 were found to be significantly associated with recurrent disease with a combined hazard ratio of 2.8. The authors stated that “high pre-operative serum CA 19–9 and/or CA 125 might indicate an increased incidence of recurrent disease in resectable lung adenocarcinomas” (Isaksson et al., 2017).

A study was performed by Feng et al. that focused on the diagnostic and prognostic value of CEA, CA 19-9, AFP, and CA125 for early gastric cancer. 587 patients were evaluated, and the positive rate for all markers combined was 10.4%. CEA’s positive rate was 4.3%, CA 19-9’s was 4.8%, AFP’s was 1.5%, and CA125’s was 1.9%. The authors noted that elevated CEA was correlated with lymph node metastasis and concluded that CEA was an independent risk factor for poor prognosis of early gastric cancer (Feng et al., 2017).

A study by Santos Schraiber et al. assessed the ability to predict recurrence of hepatocellular carcinoma (HCC) after liver transplant using AFP. 206 patients were analyzed, and the recurrence frequency was found to be 15.5%. However, the authors’ multivariate analysis found that the only risk factor for recurrence was an AFP level of > 200 ng/mL, which was associated with a 3.32 times higher increase in the probably of HCC recurrence. The authors noted that recurrence was also associated with lower survival rate (Santos Schraiber et al., 2016).

Pre-treatment serum AFP-L3% predicts tumor progression, recurrence and poor clinical outcome (Saito et al., 2012; Song et al., 2002; Zhang et al., 2011), and it has superior prognostic accuracy as a tumor marker compared with AFP or DCP (des-γ-carboxy prothrombin) (Beppu et al., 2010; Kobayashi et al., 2007). Nevertheless, conflicting data have emerged regarding the ability of pre-treatment serum AFP-L3% to predict disease-free survival (DFS) and overall survival (OS) in HCC. Yi et al performed a meta-analysis of AFP-L3’s accuracy for detection of HCC. 12 studies were evaluated, and the pooled sensitivity was found to be 0.483, the pooled specificity was found to be 0.929, the diagnostic odds ratio was found to be 12.33, and the area under the curve was found to be 0.7564 (Yi et al., 2013).

Cheng at al. conducted a meta-analysis of fifteen studies (4465 patients) to evaluate the association between high pre-treatment serum AFP-L3% and overall survival (OS) and disease-free survival (DFS) in HCC patients. The authors found that high pre-treatment serum AFP-L3% implied poor OS (Hazard Ratio [HR]: 1.65, and DFS (HR: 1.80) of HCC. The authors found an association between pre-treatment serum AFP-L3% and OS and DFS in low AFP concentration HCC patients (HR: 1.96 and 2.53 respectively). The authors concluded that “high pre-treatment serum AFP-L3% levels indicated a poor prognosis for patients with HCC (Cheng et al., 2014).”

Abdel-Aziz et al. performed a study comparing AFP-L3% to AFP as serum markers for HCC. 86 patients with chronic liver diseases were included along with 20 healthy controls. Serum concentrations of AFP, AFP-L3, and p53 protein were measured and correlations were determined. The authors found that AFP-L3% and p53 levels were significantly higher in HCC than non-HCC patients. “ROC curve analysis showed that the highest specificity and sensitivity of the studied parameters are gained at cutoffs of 15%, 120.5 ng/mL, and 0.14 ng/mL for AFP-L3, AFP, and p53; respectively. Combining AFP-L3 and p53 improved sensitivity to 95.4% with a specificity of 85%.” However, the authors concluded: “No significant correlation was found between AFP, AFP-L3%, and p53; however, the simultaneous determination of the three tumor markers yielded a better diagnostic accuracy and sensitivity in the detection of HCCs than each biomarker alone (Abdel-Aziz et al., 2016).”

Park et al. compared the diagnostic values of AFP, AFP-L3, and PIVKA-II individually and in combination to find the best biomarker or biomarker panel. 79 patients with newly diagnosed HCC and 77 control patients with liver cirrhosis were enrolled. When the three biomarkers were analyzed individually, AFP showed the largest area under the receiver-operating characteristic curve (AUC) (0.751). For combinations of the biomarkers, the AUC was highest (0.765) for PIVKA-II > 40 mAU/mL and AFP > 10 ng/mL. Adding AFP-L3 > 10% led to worse sensitivity and lower AUC. The authors concluded that “the diagnostic value of AFP was improved by combining it with PIVKA-II, but adding AFP-L3 did not contribute to the ability to distinguish between HCC and non-HCC liver cirrhosis” and that “AFP showed the best diagnostic performance as a single biomarker for HCC (Park et al., 2017).”

Ryu et al. investigated the prognostic implications of the expression patterns of three tumor markers, alpha-fetoprotein (AFP), the Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des-γ-carboxy prothrombin (DCP). 1182 consecutive patients underwent hepatic resection and surgical microwave ablation for HCC. This study analyzed 475 patients within the Milan criteria and Child-Pugh class A. Cumulative overall survival (OS) and disease-free survival (DFS) rates were analyzed relative to the number of positive tumor markers. OS and DFS at 5 years postoperatively were 85.3 and 44.2% in triple-negative patients, 79.4 and 48.0% in single-positive patients, 56.2 and 32.9% in double-positive patients, and 61.7 and 35.7% in triple-positive patients. OS in triple-negative or single-positive patients was 85.3%, and that in all double- or triple-positive patients was 58.0%; DFS at 5 years postoperatively in these two groups was 45.9 and 34.0%, respectively. The authors concluded that “both double- and triple-positive tumor markers are associated with early recurrence and poor survival in HCC patients within the Milan criteria and Child-Pugh class A (Ryu et al., 2017).”

Yamao et al. performed a study assessing the significance of high AFP-L3 with low AFP in HCC patients. 283 patients were divided into high AFP-L3 (> 10%, n = 24) and low (≤ 10%, n = 249). Overall survival (OS) and 2-year recurrence rates were compared. The OS and recurrence rates were both found to be significantly worse than the low AFP-L3 group (Yamao et al., 2019).

Caviglia et al. conducted a study evaluating AFP, AFP-L3, and DCP as detection tools for HCC. 98 patients were enrolled (44 without HCC, 54 with), and the FDA-approved uTASWako was used to measure these biomarkers. AFP-L3 had an area under the curve of 0.867, a sensitivity of 0.849, a specificity of 0.886, a negative predictive value of 0.830, and a positive predictive value of 0.900. The combination of all three biomarkers had an accuracy of 87.6%. The overall accuracy of uTASWako was 84.5%. The authors concluded that the uTASWako had a “high analytical performance” and that the biomarker combination was superior to any of them alone (Caviglia et al., 2016).

Lucarelli et al. evaluated CA 15-3, CA125, and B2M as biomarkers for renal cell carcinoma (RCC). 332 patients undergoing nephrectomy for RCC were analyzed. 35.2% (117/332) of patients had abnormal levels of CA 15-3, 9.6% (32/332) had abnormal levels of CA125, and 30.4% (101/332) had abnormal B2M. Cancer specific survival (CSS) rates significantly decreased for high levels of any of the three biomarkers, and at a multivariate analysis found high levels of CA 15-3 to be an independent adverse prognostic risk factor for CSS (Lucarelli et al., 2014).

J. Li et al. evaluated beta-HCG as a marker for colorectal cancer (CRC). 50 patients out of 136 patients expressed beta-HCG at the “invasive front.” The authors found that higher expression of beta-HCG to be associated with worse prognosis than those with low beta-HCG expression and that beta-HCG “promoted the migration and invasion of CRC in vitro and in vivo but had no effect on the proliferation of tumor cells”. A correlation was also found between beta-HCG expression level and tumor invasion in early-stage CRC patients (J. Li et al., 2018).

Seo et al. examined the prognostic value of B2M for diffuse large B-cell lymphoma. 833 patients at a ≥2.5 mg/L cutoff were analyzed, and both five-year survival and overall survival rates were found to be significantly worse in patients with elevated B2M (290 patients or 34.8%). The elevated B2M cohort was calculated to have a 41% five-year survival rate and a 49.2% overall survival rate, compared to 76.1% five year survival and 83.8% overall survival for the remaining 543 patients (Seo et al., 2016).
Farkkila et al. evaluated anti-Müllerian hormone (AMH) and inhibin B in the context of ovarian adult-type granulosa cell tumors (AGCTs). 560 samples were taken from 123 patients, and both markers were significantly elevated in AGCTs. The area under the curve for inhibin B was 0.94, but measurement of both markers was noted to be a better method than measuring either marker individually (Farkkila et al., 2015).

Tormey et al. evaluated measurement of serum calcitonin in patients presenting with thyroid nodules. 44 patients were evaluated, and 33 of the patients did not have a “detectable serum calcitonin”, noting that three patients had an initially elevated serum concentration that became undetectable. The authors also note that out of the 2070 patients in their sample, only 7 cases of medullary thyroid cancer (MTC) were diagnosed. The authors recommended not screening routinely for MTC (Tormey et al., 2017).

Chen et al. analyzed four serum tumor markers in patients with ovarian tumors. HE4, CA-125, CA19-9, and CEA were all studied. 386 healthy controls, 262 patients with benign ovarian tumors, and 196 patients with malignant ovarian tumors were evaluated. The authors found that the serum marker levels were significantly higher in patients with malignant tumors than the two other groups. HE4 was found to have a high specificity (96.56%) in malignant tumors. HE4, CA125, CA19-9, and CEA had sensitivities of 63.78%, 62.75%, 35.71%, and 38.78%, respectively. HE4 and CA125 combined was found to have the highest diagnostic sensitivity at 80.10%, as well as a specificity of 69.08%. Although adding markers to the HE4-CA125 combination increased diagnostic sensitivity (to 88.52%), this difference was not considered significant (Chen et al., 2018).

Feng et al. investigated the clinical significance of serum EGFR mutation as well as other markers in predicting tyrosine kinase inhibitor (TKI) efficacy in patients with lung adenocarcinoma. 90 patients were included, with 51 receiving an EGFR-TKI drug (oral gefitinib). The authors found serum CA19-9, CA24-2, and CEA levels to be significantly correlated with serum EGFR mutation. After receiving gefitinib, the progression-free survivals of patients with high serum level of CEA, CA19-9, or EGFR mutation was higher than those of other patients (Feng et al., 2019).

Bind et al. evaluated the diagnostic ability of CA19-9 and CA 125 for gallbladder cancers. A total of 118 patients were included, 91 benign cases and 27 malignant. The mean value of CA19-9 was found to be 12.86 U/mL in benign cases and 625.35 U/mL in malignant cases. For CA 125, the mean value for benign cases was found to 17.98 U/mL, and for malignant cases, 239.63 U/mL. The authors examined a theoretical diagnostic cut-off value of 252.31 U/mL for CA19-9 and 92.19 U/mL for CA 125. At this cutoff, sensitivity and specificity for CA19-9 was 100% and 98.9% respectively, and for CA 125, 100% and 94.5%. The authors concluded that “… both serum CA 19-9 and serum CA 125 may act as a good adjunct for diagnosis of cases of carcinoma gallbladder along with imaging studies. However, changes in CA19-9 are more significant than CA 125.” (Bind et al., 2021)

Proteomic analyses have been performed in cancer patients to assess unusual levels of protein regulation. A study by Chen et al evaluated the proteomes of patients with CRC and healthy controls. Chen et al found 36 proteins that were upregulated in cancer patients as well as 22 proteins that were downregulated compared to healthy controls. The proteins that were upregulated tended to be processes that regulated the “pretumorigenic microenvironment for metastasis” and the downregulated proteins tended to be ones that controlled tumor growth and cell survival (Chen et al., 2017).

Qin et al. performed a “serological proteome analysis” to explore the association between an identified protein marker and gastric cancer (GC). Proteomic analysis was used to identify the protein marker of interest, an autoantibody called “anti-GRP78” (along with its corresponding antigen, the 78-kDa glucose-regulated protein [GRP78]). Two cohorts were included, a test group of 266 patients (133 GC patients, 133 controls) and a validation group of 600 patients (300 GC, 300 control). The authors found that the levels of anti-GRP78 was higher in both cohorts. The receiver operating characteristic (ROC) curve analysis found similar values for both groups to identify GC patients among control patients. The area under curve (AUC) ranged from 0.676 to 0.773 in the test group and 0.645 to 0.707 in the validation group. The authors noted this marker’s potential use as a diagnostic marker (Qin et al., 2020).

Regarding prostate cancer, it is generally well accepted that there is a strong need for easily obtained biomarkers other than prostate-specific antigen (PSA) to aid in the workup and management of this disease. A review of liquid biopsy-obtained biomarkers for diagnosis and prognosis of prostate cancer was recently published, in which the authors evaluated the utility of several potentially useful candidates. Compared to PSA, it was determined that several commercially available tests (including PHI and 4Kscore) that measure a variety of biomarkers demonstrated better specificity. Other markers like prostate cancer antigen 3 gene (PCA3) may help reduce unnecessary additional biopsies, though a consensus is still lacking on a clinically useful cutoff value. Overall, the authors advocate for the use of a multifaceted approach that involves “molecular biomarkers, clinical and histopathological features and diagnostic imaging” in the future management of prostate cancer (Matuszczak et al., 2021).

National Academy of Clinical Biochemistry (NACB) now known as the American Association for Clinical Chemistry (AACC) Academy
The National Academy of Clinical Biochemistry published practice Guidelines for the use of major tumor markers for Liver, Bladder, Cervical, and Gastric Cancers (Sturgeon et al., 2010).

The NACB recommends use of AFP measurements when managing hepatocellular carcinoma (HCC). For screening, the NACB recommends AFP be measured at 6-month intervals in patients at high risk of HCC, noting that concentrations above 20 μg/L should “prompt further investigation even if an ultrasound is negative”. Sustained increases of serum AFP may be used with in combination with ultrasound to inform detection and management and AFP concentrations may provide prognostic information in untreated patients. Monitoring of disease should include measurement of AFP. However, other liver biomarkers such as Glypican-3 cannot be recommended at this time without further research.

The NACB did not recommend any biomarkers for the management of bladder cancer (such as NMP22, UroVysion, etc), stating that further research is required to assess their utility. The NACB did not recommend any biomarkers for screening, monitoring, prognosis, or diagnosis of cervical cancer. While pretreatment measurements of squamous cell carcinoma antigen (SCC) were acknowledged to provide information, their routine use could not be recommended. The NACB did not recommend any biomarkers for screening, diagnosis, or prognosis of gastric cancer. Routine measurement of CEA or CA 19-9 was also not recommended (Sturgeon et al., 2010).

The NACB also published guidelines on use of major tumor markers for Testicular, Prostate, Colorectal, Breast, and Ovarian Cancers (C. M. Sturgeon et al., 2008). For testicular cancer, the NACB stated that pretreatment determination of AFP, lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG) was mandatory if testicular cancer was suspected or if risk stratification and staging was done. These three biomarkers were also recommended for monitoring. NACB notes that measurement of the hCGβ component is essential when measuring hCG. For prostate cancer, PSA assessment is required during all stages of the disease, with NACB recommending against age-specific intervals. PSA measuring is recommended to monitor disease status after treatment. However, the NACB also did not make any recommendations on PSA screening for prostate cancer.

For colorectal cancer (CRC), carcinoembryonic antigen (CEA) measurement is recommended every 3 months in stage II or III CRC if “patient is a candidate for surgery or systemic therapy of metastatic disease”. Pre-operative CEA measurements may be used in conjunction with other factors to plan surgery. Regular CEA measurements should be done in patients with advanced CRC that are undergoing systemic therapy. However, CEA is not recommended for screening in healthy individuals. Routine measurement of other biomarkers such as CA 19-9, TIMP-1, or CA 242 is not recommended, for prognosis or predicting response to treatment. The NACB recommends individuals older than 50 be screened for CRC. Fecal DNA is also recommended for CRC screening, as joint guidelines from other societies such as the American Cancer Society have recommended its use. Finally, the NACB supports guidelines such as the NCCN and AGA regarding genetic testing for CRC (C. M. Sturgeon et al., 2008).

For breast cancer, the NACB states estrogen receptor (ER) and progesterone receptor (PR) measurements should be done in all patients with breast cancer. HER-2 should be measured in all patients with invasive breast cancer, while urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1) may be used to identify “lymph node–negative breast cancer patients who do not need or are unlikely to benefit from adjuvant chemotherapy”. CA 15-3, CEA, and BR 27.29 should not routinely be used for early detection in asymptomatic patients with diagnosed breast cancer. BRCA1 and BRCA2 mutation testing may be used to identify women at high risk of developing breast or ovarian cancer, while OncoType DX may be used to predict recurrence in “lymph node–negative, ER-positive patients receiving adjuvant tamoxifen”. NACB does recommend that microarray-based gene signatures should be routinely used for predicting patient outcome (C. M. Sturgeon et al., 2008).

For ovarian cancer, CA125 screening is not recommended for asymptomatic women but is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women with hereditary syndromes. CA125 is also recommended for distinguishing benign from malignant masses and may be used to monitor response to chemotherapeutic response. Measurement of CA125 during follow-up visits is recommended if the patient’s initial values were increased. CA125 measurement is also recommended during primary therapy. Other biomarkers such as inhibin and hCG cannot be recommended at this time (C. M. Sturgeon et al., 2008).

American Society of Clinical Oncology (ASCO) (Allison et al., 2020; Gilligan et al., 2010; L. N. Harris et al., 2016; Kindler et al., 2018; Krop et al., 2017; Sepulveda et al., 2017; Stoffel et al., 2018; Van Poznak et al., 2015)
The ASCO released Clinical Practice Guideline on Uses of Serum Tumor Markers (STMs) in Adult Males With Germ Cell Tumors (GCTs) in 2010 (Gilligan et al., 2010). ASCO recommends against any STMs to screen for GCTs. While ASCO recommends assessment of serum AFP and hCG before orchiectomy to establish a diagnosis and baseline levels, it recommends against its use to decide whether to perform an orchiectomy. The society also recommends against using these biomarkers to “guide treatment of patients with CUP and indeterminate histology”. However, substantially elevated serum AFP and/or hCG may be considered sufficient for a diagnosis in unusual cases such as patients presenting with a retroperitoneal or anterior mediastinal primary tumor. Their recommendations also include measuring serum AFP, hCG, and LDH for “all patients with testicular nonseminomatous germ cell tumors (NSGCTs) shortly after orchiectomy and before any subsequent treatment”, “before chemotherapy begins for those with mediastinal or retroperitoneal NSGCTs to stratify risk and select treatment”, and “immediately prior to chemotherapy for stage II/III testicular NSGC” (Gilligan et al., 2010).

ASCO recommends measuring AFP and hCG before retroperitoneal lymph node dissection in patients with stage 1 or II NSGCT and recommends measuring serum AFP and hCG at the start of each chemotherapy cycle and when chemotherapy concludes. These biomarkers are also recommended to be measured during surveillance after “definitive therapy for NGSCT” and this surveillance should continue for 10 years after therapy concludes (Gilligan et al., 2010).

ASCO recommends measuring “postorchiectomy serum concentrations of hCG and/or LDH for patients with testicular pure seminoma and preorchiectomy elevations” but recommends against using these concentrations for staging or prognosis. No markers are recommended to guide treatment decisions, monitor response, or progression for seminomas. However, serum hCG and AFP should be measured both when treatment concludes as well as during post-treatment surveillance. ASCO recommends these intervals: every 2 to 4 months in the first year, every 3 to 4 months in the second year, every 4 to 6 months in the third and fourth years, and annually thereafter. Surveillance should last for at least 10 years following the conclusion of therapy (Gilligan et al., 2010).

ASCO also published joint guidelines with the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology regarding biomarkers for colorectal cancer. In it, they do not mention any serum tumor markers for testing (Sepulveda et al., 2017).

In 2007, ASCO released an update of recommendations for the use of tumor markers in breast cancer (Harris et al., 2007).

CA 15-3 and CA 27.29 have insufficient data to recommend for screening, staging, monitoring, or diagnosis. These biomarkers, along with CEA, may be used in conjunction with other assessments for monitoring patients with metastatic disease during active therapy, but not alone. Increasing CA 15-3 or CA 27.39 may indicate treatment failure. CEA is not recommended for screening, diagnosis, staging, or routine surveillance after primary therapy (Harris et al., 2007).

ER, HER2 expression or amplification, PgR should be measured on “every primary invasive breast cancer and may be measured on metastatic lesions if the results would influence treatment planning”. HER2 should be used to identify good candidates for trastuzumab but should not be used to guide use of taxane chemotherapy in the adjuvant setting. HER2 should not be used to select endocrine therapy. Finally, measuring the extracellular domain of HER2 is not recommended (Harris et al., 2007).

Measurement of circulating tumor cells (CTCs) is not recommended. Insufficient data to recommend the use of flow cytometry-based markers, p53, cathepsin D, cyclin E, proteomic analysis, bone marrow micrometastases and immunohistochemically based markers of proliferation. uPA/PAI-1 measurement with ELISA may be used for prognosis determination. IHC for these biomarkers is not accurate (Harris et al., 2007)

In newly diagnosed patients with node-negative, estrogen-receptor positive breast cancer, the Oncotype DX assay can be used to predict the risk of recurrence in patients treated with tamoxifen.

ASCO also released guidelines on use of biomarkers to inform treatment decisions on systemic therapy for women with metastatic breast cancer. “Patients with accessible, newly diagnosed metastases from primary breast cancer should be offered biopsy for confirmation of disease process and testing of ER, PR, and HER2 status. With discordance of results between primary and metastatic tissues, the panel consensus is to preferentially use the ER, PR, and HER2 status from the metastasis to direct therapy if supported by the clinical scenario and the patient’s goals for care.” Decisions on changing to a new drug or regimen, initiating, or discontinuing treatment should be based on the patient’s goals for care and clinical evaluation and judgment of disease progression or response. There is no evidence at this time that changing therapy solely on the basis of tissue or circulating biomarker results beyond ER, PR, and HER2 improves health outcomes, quality of life, or cost-effectiveness. To date, clinical utility has not been demonstrated for any additional biomarkers. “CEA, CA 15-3, and CA 27.29 may be used as adjunctive assessments to contribute to decisions regarding therapy for metastatic breast cancer. Data are insufficient to recommend use of CEA, CA 15-3, and CA 27.29 alone for monitoring response to treatment” (Van Poznak et al., 2015).

ASCO released a focused update for women with early-stage invasive breast cancer, which is as follows (Krop et al., 2017).

If a patient has ER/PgR-positive, HER2-negative, node-negative, breast cancer, the MammaPrint assay may be used in those with high clinical risk, but not low clinical risk per MINDACT categorization to inform decisions on withholding adjuvant systemic chemotherapy.

If a patient has ER/PgR-positive, HER2-negative, node-positive, breast cancer, the MammaPrint assay may be used in patients with 1-3 positive nodes and at high clinical risk, but not for patients at low clinical risk.

If a patient has HER2-positive breast cancer or ER/PgR negative and HER2-negative breast cancer (triple negative the clinician should not use the MammaPrint assay.

The following recommendations were unchanged from the 2016 version:

If a patient has ER/PgR-positive, HER2-negative (node-positive or node-negative) breast cancer, the clinician should not use tumor-infiltrating lymphocytes (TILs), the five-protein assay (Mammostrat), and the immunohistochemistry 4 (IHC4) assay, to guide decisions on adjuvant systemic therapy.

If a patient has ER/PgR-positive, HER2-negative (node-positive) breast cancer, the clinician should not use the Breast Cancer Index, the PAM50-ROR, the 12-gene risk score, or the 21-gene RS, (EndoPredict), to guide decisions on adjuvant systemic therapy.

If a patient has ER/PgR-positive, HER2-negative (node-negative) breast cancer, the clinician may use urokinase plasminogen activator (uPA), plasminogen activator inhibitor type 1 (PAI-1), the Breast Cancer Index, the PAM50 risk of recurrence (ROR) score, the 12-gene risk score (EndoPredict), and the 21-gene recurrence score (Oncotype DX) to guide decisions on adjuvant systemic therapy. If the patient has had 5 years of endocrine therapy without evidence of recurrence, the clinician should not use multiparameter gene expression or protein assays (Oncotype DX, EndoPredict, PAM50, Breast Cancer Index, or IHC4) to guide decisions on extended endocrine therapy.

If a patient has HER2-positive breast cancer or TN breast cancer, the clinician should not use uPA, IHC4, the 12-gene risk score (EndoPredict), PAI-1, the 21-gene RS (Oncotype DX), the five-protein assay (Mammostrat), the Breast Cancer Index or TILs to guide decisions on adjuvant systemic therapy. The clinician should not use circulating tumor cells (CTCs) to guide decisions on adjuvant systemic therapy.

The clinician should not use CYP2D6 polymorphisms, p27 expression, Ki-67 labeling index, microtubule-associated protein (MAP)-Tau mRNA expression or mRNA expression, HER1/epidermal growth factor receptor (EGFR) expression, TOP2A gene amplification or TOP2A protein expression, HER2 and TOP2A gene coamplification; CEP17 duplication; or TIMP-1, FOXP3, or p53 protein expression (all by IHC) to guide adjuvant endocrine therapy selection. If a patient has HER2-positive breast cancer, the clinician should not use PTEN or soluble HER2 levels to guide adjuvant therapy selection.

If a patient has HER2-positive breast cancer, the clinician should not use the PAM50-ROR to guide decisions on adjuvant systemic therapy.

If a patient has TN breast cancer, the clinician should not use the PAM50-ROR to guide decisions on adjuvant systemic therapy.

ASCO released a provisional clinical opinion on evaluating susceptibility to pancreatic cancer, stating that “there are currently no proven biomarkers using noninvasively obtained biospecimens (eg, blood, urine, stool) for early detection of pancreatic cancer in asymptomatic individuals”. ASCO states that further validation of biomarkers is needed (Stoffel et al., 2018).

ASCO also released a guideline on treatment of malignant pleural mesothelioma, stating that calretinin, keratins 5 and 6, and nuclear WT-1 are expected to be positive while CEA, EPCAM, Claudin 4, and TTF-1 should be negative. Non-tissue based biomarkers are currently not recommended due to their unvalidated statistical accuracy (Kindler et al., 2018).

ASCO remarks that “If a patient has ER/PgR-positive, HER2-negative (node-negative) breast cancer, the clinician may use urokinase plasminogen activator and plasminogen activator inhibitor type 1 to guide decisions on adjuvant systemic therapy”. The guidelines also recommend against using IHC4 to guide decisions on adjuvant systemic therapy (Lyndsay N. Harris et al., 2016).

ASCO released an update on ER / PgR testing for breast cancer. In it, they continue to recommend ER testing for predicting success of endocrine therapy. They remark that similar principles apply to PgR testing, which provides prognostic information for ER+ cancer. ASCO also recommends testing ER for patients with ductal carcinoma in situ (DCIS) to determine benefit of endocrine therapies (Allison et al., 2020).

American College of Chest Physicians (ACCP) (Detterbeck et al., 2013)
In 2013, the ACCP published evidence-based clinical practice guidelines for diagnosis and management of lung cancer. The guidelines did not mention proteomic markers as a potential diagnostic or screening tool (Detterbeck et al., 2013).

National Institute for Health and Clinical Excellence (NICE, 2011, 2018)
The National Institute for Health and Clinical Excellence (NICE) issued guidelines in 2011 on the recognition and initial management of ovarian cancer. It stated that the routine use of CA-125 is recommended; the data on other serum markers is not substantial enough to recommend their use. It included the following recommendations:

Measure serum CA-125 in primary care in women with symptoms that suggest ovarian cancer.
If serum CA-125 is 35 IU/mL or greater, arrange an ultrasound scan of the abdomen and pelvis.
If the ultrasound suggests ovarian cancer, refer the woman urgently for further investigation.
For any woman who has normal serum CA-125 (less than 35 IU/mL), or CA-125 of 35 IU/mL or greater but a normal ultrasound: 1) assess her carefully for other clinical causes of her symptoms and investigate if appropriate; 2) if no other clinical cause is apparent, advise.
Calculate a risk of malignancy index I (RMI I) score (after performing an ultrasound). (The RMI 1 combines CA-125, menopausal status and the ultrasound score).

The NICE guidelines also suggested to measure AFP, beta-hCG and serum CA125 in women under 40 with suspected ovarian cancer (NICE, 2011).

NICE also recommends using a serum free-light chain assay to “confirm the presence of a paraprotein indicating possible myeloma or monoclonal gammopathy of undetermined significance (MGUS).” Serum immunofixation is recommended if serum protein electrophoresis is abnormal. Finally, serum free light-chain ratio is recommended for prognosis (NICE, 2018).

National Comprehensive Cancer Network (NCCN, 2022p)

Marker	Recommendation	Source
AFP	Hepatocellular workup (HCC). AFP for surveillance and screening is optional	NCCN Hepatobiliary Cancers Version 1.2022 (NCCN, 2022k)
AFP	Consider for intrahepatic cholangiocarcinoma workup	NCCN Hepatobiliary Cancers Version 1.2022 (NCCN, 2022k)
AFP	Women under 35 years with a pelvic mass. AFP measurement may be clinically indicated in the workup and management of epithelial ovarian, fallopian tube, primary peritoneal, and less common ovarian cancers.	NCCN Ovarian Cancer Version 1.2022 (NCCN, 2022r)
AFP	Thymomas and thymic carcinoma initial evaluation	NCCN Thymomas and Thymic Carcinomas Version 1.2020 (NCCN, 2022z)
AFP	Both seminoma and nonseminoma, serum prognostic factor and contribute to diagnosis and staging. Also indicated for “suspicious testicular mass” workup	NCCN Testicular Cancer Version 2.2022 (NCCN, 2022y)
AFP	Workup for occult primary mass of the liver, mediastinum, or retroperitoneum	NCCN Occult Primary Version 1.2022 (NCCN, 2021f)
Alkaline Phosphatase (ALP)	Should be assessed prior to treatment for bone cancers	NCCN Bone cancers Version 2.2022 (NCCN, 2021a)
Alkaline Phosphatase (ALP)	Part of the initial diagnostic workup for systemic light chain amyloidosis	NCCN Systemic Light Chain Amyloidosis Version 1.2022 (NCCN, 2021i)
Beta-HCG	Testicular cancer workup for a “suspicious testicular mass”, beta-hCG needs to be assessed as it is a prognostic factor and contributes to diagnosis and staging. Assessed pre- and post-orchiectomy.	NCCN Testicular Cancer Version 2.2022 (NCCN, 2022y)
Beta-HCG	May be clinically indicated in the workup and management of epithelial ovarian, fallopian tube, primary peritoneal, and less common ovarian cancers.	NCCN Ovarian Cancer Version 1.2022 (NCCN, 2022r)
Beta-HCG	Thymomas and thymic carcinoma initial evaluation	NCCN Thymomas and Thymic Carcinomas Version 2.2022 (NCCN, 2022z)
Beta-HCG	Workup for occult primary mass of the mediastinum or retroperitoneum	NCCN Occult Primary Version 1.2022 (NCCN, 2021f)
Beta-2 microglobulin (B2M)	Multiple myeloma initial workup and follow-up/surveillance	NCCN Multiple Myeloma Version 5.2022 (NCCN, 2022m)
Beta-2 microglobulin (B2M)	Workup for: follicular lymphoma (grades 1-2), mantle cell lymphoma, diffuse B-cell Lymphoma (useful in selected cases), AIDS-related B-cell lymphoma (useful in selected cases), lymphoblastic lymphoma workup (useful in selected cases), Castleman’s disease	NCCN B-cell Lymphomas Version 3.2022 (NCCN, 2022b)
Beta-2 microglobulin (B2M)	Waldenström's Macroglobulinemia/ Lymphoplasmacytic Lymphoma essential workup, prognostic factor	NCCN Waldenström's Macroglobulinemia/ Lymphoplasmacytic Lymphoma Version 3.2022 (NCCN, 2022ab)
Beta-2 microglobulin (B2M)	Workup and prognostic information (“useful under certain circumstances”)	NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Version 2.2022 (NCCN, 2022d)
Beta-2 microglobulin (B2M)	Initial diagnostic Workup	Systemic Light Chain Amyloidosis Version 1.2022 (NCCN, 2021i)
BNP/NT-BNP	Initial diagnostic Workup (may be considered)	Systemic Light Chain Amyloidosis Version 1.2022 (NCCN, 2021i)
Cancer Antigen 15-3 and 27.29	Cancer Antigen 15-3 and 27.29 as part of findings for identification of disease progression. An isolated increase in tumor marker should not be used as the only indicator of disease progression as these two biomarkers may also increase if metastatic disease is responding to treatment.	NCCN Breast Cancer Version 3.2022 (NCCN, 2022c)
Cancer Antigen 19-9	Pancreatic adenocarcinoma pre-op workup, post treatment, and surveillance, differential diagnosis, screening, staging, determining resectability, et al. Levels may be elevated up to 2 years before pancreatic CA diagnosis.	NCCN Pancreatic Adenocarcinoma Version 1.2022 (NCCN, 2022s)
Cancer Antigen 19-9	Workup and surveillance for small bowel adenocarcinoma	NCCN Small Bowel Adenocarcinoma Version 1.2022 (NCCN, 2022v)
Cancer Antigen 19-9	Gallbladder cancer initial workup (on findings such as jaundice or a mass found on imaging) and surveillance. CA 19-9 is a baseline test and should not be done to confirm diagnosis. Consider baseline CA 19-9 after biliary decompression. Intrahepatic (such as isolated intrahepatic mass) and extrahepatic cholangiocarcinoma workup. CA 19-9 is a baseline test and should not be done to confirm diagnosis	NCCN Hepatobiliary Cancers Version 1.2022 (NCCN, 2022k)
Cancer Antigen 19-9	May be clinically indicated in the workup and management of epithelial ovarian, fallopian tube, primary peritoneal, and less common ovarian cancers	NCCN Ovarian Cancer Version 1.2022 (NCCN, 2022r)
CA-125	May be clinically indicated in the workup and management of epithelial ovarian, fallopian tube, primary peritoneal, and less common ovarian cancers	NCCN Ovarian Cancer Version 1.2022 (NCCN, 2022r).
CA-125	BRCA mutation-positive individuals – for those individuals who have not elected RRSO or TVUS serum CA-125 screening may be considered at the clinician’s discretion starting age 30 – 35 years	NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic Version 2.2022 (NCCN, 2022h)
CA-125	Endometrial carcinoma: Consider CA-125 for suspected extrauterine disease, serous carcinoma, clear cell carcinoma, carcinosarcoma, undifferentiated/dedifferentiated carcinoma; surveillance if initially elevated	NCCN Uterine Neoplasms Version 1.2022 (NCCN, 2021j)
CA-125	Occult Primary – localized adenocarcinoma or carcinoma not otherwise specified workup for individuals assigned female sex at birth	NCCN Occult Primary Version 1.2022 (NCCN, 2021f)
CA-125	Lynch Syndrome: surveillance/prevention strategies. CA-125 is an additional ovarian screening test with caveats similar to transvaginal ultrasound	Genetic/Familial High-Risk Assessment: Colorectal Version 2.2021 (NCCN, 2022i)
CA-125	CA-125 may be considered in the initial evaluation of malignant peritoneal mesothelioma	NCCN Malignant Peritoneal Mesothelioma Version 1.2022 (NCCN, 2021d)
CEA	Colon cancer appropriate for resection (non-metastatic) workup and surveillance every 3 – 6 months for 2 years, then every 6 months for a total of 5 years for stages II-III cancer. Not recommended beyond 5 years Suspected or proven metastatic synchronous adenocarcinoma workup Pedunculated or sessile polyp with invasive cancer but fragmented specimen/unknown margin or unfavorable histology	NCCN Colon Cancer Version 1.2022 (NCCN, 2022f)
CEA	Workup and surveillance for small bowel adenocarcinoma	NCCN Small Bowel Adenocarcinoma Version 1.2022 (NCCN, 2022v)
CEA	Pedunculated or sessile polyp with invasive cancer but fragmented specimen/unknown margin or unfavorable histology Workup, monitoring, and/or surveillance for rectal cancer	Rectal Cancer Version 1.2022 (NCCN, 2022u)
CEA	Intrahepatic (such as isolated intrahepatic mass) and extrahepatic cholangiocarcinoma workup and monitoring. CEA is a baseline test and should not be done to confirm diagnosis	NCCN Hepatobiliary Cancers Version 1.2022 (NCCN, 2022k)
CEA	Gallbladder cancer initial workup (on findings such as jaundice or a mass found on imaging) and surveillance. CEA is a baseline test and should not be done to confirm diagnosis	NCCN Hepatobiliary Cancers Version 1.2022 (NCCN, 2022k)
CEA	Thyroid carcinoma – medullary carcinoma diagnostic procedure, additional workup, and surveillance; surveillance 2 – 3 months postoperatively, then every 6 – 12 mo.	NCCN Thyroid Carcinoma Version 2.2022 (NCCN, 2022aa)
CEA	May be clinically indicated in the workup and management of epithelial ovarian, fallopian tube, primary peritoneal, and less common ovarian cancers	NCCN Ovarian Cancer Version 1.2022 (NCCN, 2022r).
CEA	Initial diagnostic evaluation for Malignant pleural or peritoneal mesothelioma	NCCN Malignant Peritoneal Mesothelioma Version 1.2022 (NCCN, 2021d) and Malignant Pleural Mesothelioma Version 1.2022 (NCCN, 2021e)
CEA	Monitoring of metastatic breast cancer	NCCN Breast Cancer Version 3.2022 (NCCN, 2022c)
CEA	Neuroendocrine and Adrenal Tumors - Multiple Endocrine Neoplasia, Type 2: initial diagnostic evaluation and/or surveillance	NCCN Neuroendocrine and Adrenal Tumors Version 1.2022 (NCCN, 2022q)
CEA	Initial workup for non-small cell lung cancer	NCCN Non-Small Cell Lung Cancer Version 3.2022 {NCCN, 2022 #156}
CEA	Commonly used immunohistochemistry marker for unknown primary cancers	NCCN Occult Primary Version 1.2022 NCCN {NCCN, 2021 #102}
Calcitonin (CALCA)	Thyroid carcinoma - medullary carcinoma basal evaluation, post-surgical evaluation, and surveillance (surveillance every 6 – 12 mo.)	NCCN Thyroid Carcinoma Version 2.2022 (NCCN, 2022aa)
Calcitonin (CALCA)	Cervical cancer - workup	NCCN Cervical Cancer Version 1.2022 (NCCN, 2021b)
Calcitonin (CALCA)	Multiple endocrine neoplasia, type 2 – clinical evaluation	NCCN Neuroendocrine and Adrenal Tumors Version 1.2022 {NCCN, 2022 #133}
Calcitonin (CALCA)	Workup for occult primary adenocarcinoma or anaplastic/undifferentiated tumors of the head and neck, or otherwise unspecified	NCCN Head and Neck Cancers Version 2.2022 (NCCN, 2022j)
Serum Free-light chain (FLC) assay	Plasma cell disorders, such as myelomas, immunoglobulin light chain amyloidosis, B-cell lymphoma, Waldenström's macroglobulinemia/ lymphoplasmacytic lymphoma, and solitary plasmocytoma—included in initial diagnostic workup; surveillance (as needed) for multiple myeloma	NCCN Multiple Myeloma Version 5.2022 (NCCN, 2022m), B-Cell Lymphomas Version 3.2022 (NCCN, 2022b), Systemic Light Chain Amyloidosis (NCCN, 2021i), Waldenström's macroglobulinemia/ lymphoplasmacytic lymphoma Version 3.2022 (NCCN, 2022ab)
Inhibin (INHA)	May be clinically indicated in the workup and management of an undiagnosed pelvic mass, epithelial ovarian, fallopian tube, primary peritoneal, and less common ovarian cancers	NCCN Ovarian Cancer Version 1.2022 (NCCN, 2022r).
Inhibin (INHA)	Occult primary – additional workup	NCCN Occult Primary Version 1.2022 (NCCN, 2021f)
Inhibin (INHA)	Uterine Sarcoma – diagnostic evaluation	NCCN Uterine Neoplasms Version 1.2022 (NCCN, 2021j)
LDH	May be clinically indicated in the workup and management of epithelial ovarian, fallopian tube, primary peritoneal, and less common ovarian cancers	NCCN Ovarian Cancer Version 1.2022 (NCCN, 2022r)
LDH	Acute Lymphoblastic Leukemia (ALL) workup as part of a tumor lysis syndrome panel; useful for workup under certain circumstances; essential for Richter’s transformation	NCCN Acute Lymphocytic Leukemia Version 1.2022 (NCCN, 2022a)
LDH	Pediatric Acute Lymphoblastic Leukemia (ALL) workup as part of a tumor lysis syndrome panel	NCCN Pediatric Acute Lymphoblastic Leukemia Version 1.2022 (NCCN, 2021g)
LDH	Acute myeloid leukemia workup (evaluation)	NCCN Acute Myeloid Leukemia. Version 1.2022 (NCCN, 2022e)
LDH	Chronic lymphocytic leukemia workup for histologic transformation (Richter’s) and progression; workup for tumor lysis syndrome. Listed as “useful under certain circumstances”	NCCN Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Version 2.2022 {NCCN, 2022 #114}
LDH	Hairy cell leukemia workup	NCCN Hairy Cell Leukemia. Version 1.2022 (NCCN, 2021c)
LDH	Prognostic factor, 1.5 times the upper limit of normal amount; included in the initial workup for kidney cancer	NCCN Kidney Cancer. Version 4.2022 (NCCN, 2021c)
LDH	Prognostic factor, metastatic disease. Utilized also for stage IV metastatic workup to predict outcomes.	NCCN Cutaneous Melanoma. Version 3.2022 (NCCN, 2022g)
LDH	Workup and/or surveillance may be indicated for: Follicular lymphoma, Extranodal marginal zone B-cell lymphoma, Gastric and non-gastric MALT, Nodal marginal zone lymphoma, Splenic marginal zone lymphoma, Mantle cell lymphoma, Diffuse large B-cell lymphoma, Burkitt lymphoma, AIDS-related B-cell lymphomas, Post-transplant lymphoproliferative disorders, Castleman’s disease, lymphoblastic lymphoma. Workup for Hodgkin Lymphoma	NCCN B-cell Lymphomas Version 3.2022, Hodgkin Lymphoma Version 2.2022 (NCCN, 2022b)
LDH	Testicular cancer workup (for “suspicious testicular mass”).; LDH, along with other tumor markers are critical in diagnosing GCTs, determining prognosis and assessing treatment outcomes	NCCN Testicular Cancer Version 2.2022 (NCCN, 2022y)
LDH	Osteosarcoma and Ewing Sarcoma workup and/or surveillance. Elevated levels at initial diagnosis and initial recurrence are considered adverse prognostic indicators. ALP measurement may have clinical relevance and should be done before treatment.	NCCN Bone Cancer Version 2.2022 (NCCN, 2021a)
LDH	Multiple Myeloma initial workup, follow-up/surveillance and staging	NCCN Multiple Myeloma Version 5.2022 (NCCN, 2022m)
LDH	Initial Workup for Systemic Light Chain Amyloidosis	NCCN Systemic Light Chain Amyloidosis Version 1.2022 (NCCN, 2021i)
LDH	Waldenström's Macroglobulinemia/ Lymphoplasmacytic Lymphoma essential workup	NCCN Waldenström's Macroglobulinemia/ Lymphoplasmacytic Lymphoma Version 3.2022 (NCCN, 2022ab)
LDH	Initial evaluation for myelodysplastic syndromes or in the workup of suspected myeloproliferative neoplasms; initial evaluation for cytopenia and myelodysplasia	NCCN Myelodysplastic Syndromes Version 3.2022 (NCCN, 2022m) Myeloproliferative Neoplasms Version 2.2022 (NCCN, 2022o)
LDH	Prognostic factor, “one of the most important”	NCCN Small Cell Lung Cancer Version 2.2021 (NCCN, 2021h)
LDH	Workup for primary cutaneous lymphomas	NCCN Primary Cutaneous Lymphoma Version 1.2022(NCCN, 2022t)
LDH	T-cell lymphomas – workup, prognosis (except Breast Implant-Associated ALCL). May be used in staging breast implant-associated ALCL	NCCN T-Cell Lymphomas Version 2.2022 (NCCN, 2022x)
Troponin T	Diagnostic Workup and staging for systemic light chain amyloidosis	Systemic Light Chain Amyloidosis Version 1.2022 (NCCN, 2021i)
Tryptase	Serum total tryptase is a WHO diagnostic criterion for systemic mastocytosis. Serum tryptase may also be useful in risk classification and monitoring response to therapy	NCCN Systemic Mastocytosis Version 1.2022 (NCCN, 2022w)
Tryptase	Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes - Initial evaluation	NCCN Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase fusion genes Version 1.2022 (NCCN, 2022n)

The NCCN guidelines on ovarian cancer (version 2.2020) also stated that certain biomarker panels such as OVA1, ROMA (Risk of Ovarian Malignancy Algorithm) and OVERA have been approved by the FDA for “estimating risk of ovarian cancer in women with an adnexal mass for which surgery is planned, and have not yet been referred to an oncologist”. However, “currently, the NCCN Panel does not recommend the use of these biomarkers for determining the status of an undiagnosed adnexal/pelvic mass.” The NCCN further notes that CA-125, HE4, mesothelin, B7-H4, decoy receptor 3 (DcR3), and spondin-2 “do not increase early enough to be useful in detecting early-stage ovarian cancer” (NCCN, 2022r) .

Monitoring of disease relapse with any tumor markers is not recommended for breast cancer. Ki-67 is not recommended for any assessment of breast cancer. Testing for immunohistochemical markers such as ER/PR and HER2 is recommended for assessment of breast cancer (NCCN, 2022c).

Cardiac biomarkers such as troponin I or T and BNP (or NT-proBNP) may be considered important predictors of outcome of systemic light chain amyloidosis (NCCN, 2021i).

The 2020 NCCN Guidelines on Hepatocellular Carcinoma states, “serum biomarkers such as AFP may incrementally improve the performance of imaging-based screening and surveillance, but their cost effectiveness has not been established; their use as supplementary surveillance tests is optional.” (NCCN, 2022k)

For Merkel Cell Carcinoma, the NCCN stated a neuroendocrine marker such as chromogranin, CD56, neurofilament protein, neuron-specific enolase, or synaptophysin may be used (NCCN, 2022l). Small cell lung cancers (SCLCs) also stain positive for biomarkers of neuroendocrine differentiation but cannot be used to differentiate SCLCs from NSCLCs (NCCN, 2022l).

NCCN recommends against using OVA1 or OvaSure as screening for ovarian cancer (NCCN, 2022p, 2022r).

International Mesothelioma Interest Group (Husain et al., 2018)
The Interest Group considers the following biomarkers to be “very useful”: Calretinin Cytokeratin 5/6, WT1, Podoplanin (D2-40) (for epitheloid mesothelioma), Claudin 4, MOC31, B72.3, CEA, BER-EP4, BG8 (LewisY), TTF-1, and Napsin A (for lung adenocarcinoma) (Husain et al., 2018).

North American Neuroendocrine Tumor Society (Halfdanarson et al., 2020; NANETS, 2017)
NANETS notes that although most of its expert panel’s members measure CgA and/or pancreastatin, a majority of them believed that “these tumor markers assist in patient management only occasionally or rarely”. No consensus was reached on whether these tumor markers should be routinely measured (NANETS, 2017).

In 2020, NANETS published a guideline focusing on the “Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors”. In it, they remark that “Use of nonspecific tumor markers such as CgA, pancreastatin (PcSt), and others is not recommended for routine use in patients with pNETs”, stating that these marker analyses “rarely, if ever” influence treatment (Halfdanarson et al., 2020)

American Thyroid Association (ATA) (Haugen et al., 2016; Wells et al., 2015).
The ATA cannot recommend for or against routine measurement of serum calcitonin in patients with thyroid nodules. Furthermore, the ATA cautions that unusual levels of calcitonin may occur with a variety of other conditions apart from MTC, and notes that calcitonin levels are often elevated in young children and males compared to females (Haugen et al., 2016; Wells et al., 2015).

American Association for the Study of Liver Diseases (AASLD, 2018)
The AASLD states that ultrasound surveillance for hepatocellular carcinoma may be done with or without AFP, every 6 months. However, other biomarkers apart from AFP need more research and validation (AASLD, 2018).

European Association for the Study of the Liver (EASL, 2018)
EASL stated “Tumour biomarkers for accurate early detection are still lacking. The data available show that the biomarkers tested (i.e. AFP, AFP-L3 and DCP) are suboptimal in terms of cost-effectiveness for routine surveillance of early HCC (evidence low) (EASL, 2018).”

American College of Radiology (ACR, 2017)
The ACR recommends against screening with AFP alone due to “inadequate sensitivity” and state that adding AFP to the ultrasound does not show a significant improvement in HCC detection. The ACR acknowledges a review that showed AFP ≥20 ng/mL to have a sensitivity of 0.41-0.65 and specificity of 0.80 to 0.94 (ACR, 2017).

Table of Terminology

Term	Definition
A2-PAG	Pregnancy associated alpha 2 glycoprotein
AACC	American Association for Clinical Chemistry
AASLD	American Association for the Study of Liver Diseases
ACCP	American College of Chest Physicians
ACR	American College of Radiology
AFP	Alpha fetoprotein
AGCT	Adult-type granulosa cell tumor
AIDS	Acquired immune deficiency syndrome
ALL	Acute lymphoblastic leukemia
ALP	Alkaline phosphatase
AMH	Anti-müllerian hormone
AML	Acute myeloid leukemia
ASCO	American Society of Clinical Oncology
ATA	American Thyroid Association
AUC	Area under curve
B7-H4	V-set domain-containing T-cell activation inhibitor 1
B2M	Beta-2 microglobulin
BCM	Breast cancer mucin
beta-HCG	Beta human chorionic gonadotropin
BNP	Brain natriuretic peptide
BRCA	Breast cancer gene
BRCA1	BReast CAncer gene 1
BRCA2	BReast CAncer gene 2
CA	Cancer antigen
CALCA	Calcitonin
CAM 17-1	Antimucin monoclonal antibody
CAM-26	Carcinoma associated mucin antigen
CAM-29	Carcinoma associated mucin antigen
CAR-3	Antigenic determinant recognized by monoclonal antibody AR-3
CA-SCC	Squamous cell carcinoma antigen
CEA	Carcinoembryonic antigen
CEACAM6	Carcinoembryonic antigen cell adhesion molecule 6
CEACAM-7	Carcinoembryonic antigen cellular adhesion molecule-7
CEP17	Chromosome 17 centromere
CFL1	Cofilin
CgA	Chromogranin A
CLIA ’88	Clinical Laboratory Improvement Amendments of 1988
CMS	Centers for Medicare & Medicaid Services
CRC	Colorectal cancer
CSS	Cancer specific survival
CTC	Circulating tumor cell
CUP	Cancers of unknown primary
CYP2D6	Cytochrome P450 2D6
DCIS	Ductal carcinoma in situ
DCP	Des-γ-carboxy prothrombin
DcR3	Decoy receptor 3
DFS	Disease-free survival
DMSA	Pentavalent technetium-99mm dimercaptosuccinic
Du-PAN-2	Sialylated carbohydrate antigen
EASL	European Association for the Study of the Liver
ECM	Extracellular matrix protein
EGFR	Epidermal growth factor receptor
ELISA	Enzyme-linked immunosorbent assay
EPCAM	Epithelial cell adhesion molecule
ER	Estrogen receptor
FDA	Food and Drug Administration
FLC	Free-light chain
FOXP3	Forkhead box P3
GC	Gastric cancer
GCTs	Germ cell tumors
GRP78	78-kDa glucose-regulated protein
HCC	Hepatocellular carcinoma
HE4	Human epididymis protein 4
HEC1	Highly expressed in cancer protein
HER2	Human epidermal growth factor receptor 2
HR	Hazard ratio
HYAL1	Hyaluronoglucosaminidase
IGF	Insulin-like growth factors
IgA	Immunoglobulin A
IgG	Immunoglobulin G
IgM	Immunoglobulin M
IHC	Immunohistochemistry
INHA	Inhibin
Ki-67	Antigen KI-67
KRAS	Kirsten rat sarcoma viral oncogene homolog
LCA	Lens culinaris agglutinin
LCOC	Less common ovarian cancers
LCOH	Less common ovarian histopathologies
LDH	Lactate dehydrogenase
LDT	Laboratory-developed test
LINE-1	Long interspersed nuclear elements 1
MALDI	Matrix-assisted laser desorption/ionization
MAP	Microtubule-associated protein
MCA	Mucinous carcinoma associated antigen
MGUS	Monoclonal gammopathy of undetermined significance
MHC	Major histocompatibility complex
MINDACT	Microarray in node-negative disease may avoid chemotherapy
MMP-1	Matrix metalloproteinase-1
mRNA	Messenger ribonucleic acid
MSA	Mammary serum antigen
MTC	Medullary thyroid carcinoma
NACB	National Academy of Clinical Biochemistry
NANETS	North American Neuroendocrine Tumor Society
NCCN	National Comprehensive Cancer Network
NET	Neuroendocrine tumor cells
NICE	National Institute for Health and Clinical Excellence
NMP22	Nuclear matrix protein 22
non-HCC	Non-hepatocellular carcinoma
NSE	Neuron specific enolase
NSGCT	Nonseminomatous germ cell tumor
NT-proBNP	N-terminal-pro hormone brain natriuretic peptide
OS	Overall survival
P53	Tumor protein P53
PAGE	Polyacrylamide gel electrophoresis
PAI-1	Plasminogen activator inhibitor type 1
PAM50-ROR	Prediction analysis of microarray 50-risk of recurrence
PcSt	Pancreastatin
PD-L1	Programmed Death-ligand 1
PED-ALL	Pediatric acute lymphoblastic leukemia
PgR	Plant growth regulator
PIVKA-II	Protein induced by vitamin K absence/antagonist-II
P-LAP	Placental alkaline phosphatase
PNA-ELLA	Peanut lectin bonding assay
PR	Progesterone receptor
PSA	Prostate specific antigen
PTEN	Phosphatase and tensin homolog
RCC	Renal cell carcinoma
RMI I	Risk of Malignancy Index I
ROC	Receiver operating characteristic
ROMA	Risk of ovarian malignancy algorithm
ROR	Risk of recurrence
RRSO	Risk-reducing salpingo-oopherectomy
SCC	Squamous cell carcinoma
SCLCs	Small cell lung cancers
SLEX	Sialylated lewis-x antigen
SLX	Sialylated SSEA-1 antigen
SPAN-1	Sialylated carbonated antigen span-1
ST-439	Sialylated carbohydrate antigen st-439
STMs	Serum tumor markers
TAG	Tumor associated glycoprotein
TATI	Tumor associated trypsin inhibitor
TILs	Tumor-infiltrating lymphocytes
TIMP-1	Tissue Inhibitor Of Metalloproteinase-1
TKI	Tyrosine kinase inhibitor
TN	Triple-negative
TNF-a	Tumor necrosis factor alpha
TOP2A	Deoxyribonucleic acid topoisomerase II alpha
TPA	Tissue polypeptide antigen
TPS	Tissue polypeptide specific antigen
TTF-1	Thyroid transcription factor-1
TVUS	Transvaginal ultrasound
uPA	Urokinase plasminogen activator
uPAR	Urokinase plasminogen activator receptor
WT1	Wilms' tumor protein

References:

AASLD. (2018). Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. https://www.aasld.org/sites/default/files/2019-06/AASLD_2018_HCC_Guidance_on_Diagnosis%2C_Staging_and_Management_hep_29913%20%281%29.pdf
Abdel-Aziz, M. M., Elshal, M. F., Abass, A. T., El-Kafrawy, S., Ezzat, S., & Abdel-Wahab, M. (2016). Comparison of AFP-L3 and p53 Antigen Concentration with Alpha-Fetoprotein as Serum Markers for Hepatocellular Carcinoma. Clin Lab, 62(6), 1121-1129. https://www.ncbi.nlm.nih.gov/pubmed/27468575
ACR. (2017). American College of Radiology ACR Appropriateness Criteria® Chronic Liver Disease https://acsearch.acr.org/docs/3098416/Narrative/
ACS. (2018a). What Is Multiple Myeloma? https://www.cancer.org/cancer/multiple-myeloma/about/what-is-multiple-myeloma.html
ACS. (2018b). What Is Waldenstrom Macroglobulinemia? https://www.cancer.org/cancer/waldenstrom-macroglobulinemia/about/what-is-wm.html
Akar, H., Seldin, D. C., Magnani, B., O'Hara, C., Berk, J. L., Schoonmaker, C., Cabral, H., Dember, L. M., Sanchorawala, V., Connors, L. H., Falk, R. H., & Skinner, M. (2005). Quantitative serum free light chain assay in the diagnostic evaluation of AL amyloidosis. Amyloid, 12(4), 210-215. https://doi.org/10.1080/13506120500352339
Allison, K. H., Hammond, M. E. H., Dowsett, M., McKernin, S. E., Carey, L. A., Fitzgibbons, P. L., Hayes, D. F., Lakhani, S. R., Chavez-MacGregor, M., Perlmutter, J., Perou, C. M., Regan, M. M., Rimm, D. L., Symmans, W. F., Torlakovic, E. E., Varella, L., Viale, G., Weisberg, T. F., McShane, L. M., & Wolff, A. C. (2020). Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. Journal of Clinical Oncology, JCO.19.02309. https://doi.org/10.1200/JCO.19.02309
Beppu, T., Sugimoto, K., Shiraki, K., Tameda, M., Kusagawa, S., Nojiri, K., Tanaka, J., Yamamoto, N., Takei, Y., Takaki, H., Uraki, J., Nakatsuka, A., Yamakado, K., & Takeda, K. (2010). Clinical significance of tumor markers in detection of recurrent hepatocellular carcinoma after radiofrequency ablation. Int J Mol Med, 26(3), 425-433. http://dx.doi.org/
Berrebi, A., Shvidel, L., Arditti, F. D., Bassous, L., Haran, M., & Shtalrid, M. (2009). The Significance of Elevated Beta 2-Microglobulin (b2-m) in B-CLL: Evidence of in Vitro b2-m Secretion Following Activation of B-CLL Cells. Blood, 114(22), 4380. http://www.bloodjournal.org/content/114/22/4380.abstract
Bhole, M. V., Sadler, R., & Ramasamy, K. (2014). Serum-free light-chain assay: clinical utility and limitations. Ann Clin Biochem, 51(Pt 5), 528-542. https://doi.org/10.1177/0004563213518758
Bind, M. K., Mishra, R. R., Kumar, V., Misra, V., & Singh, P. A. (2021). Serum CA 19-9 and CA 125 as a diagnostic marker in carcinoma of gallbladder. Indian J Pathol Microbiol, 64(1), 65-68. https://doi.org/10.4103/ijpm.Ijpm_494_19
Cautha, S., Gupta, S., Hanif, A., Moirangthem, V., & Jain, K. (2022). Lymphoplasmacytic Lymphoma with Only Lambda Light Chain Monoclonal Paraprotein Expression. Eur J Case Rep Intern Med, 9(2), 003106. https://doi.org/10.12890/2022_003106
Caviglia, G. P., Abate, M. L., Petrini, E., Gaia, S., Rizzetto, M., & Smedile, A. (2016). Highly sensitive alpha-fetoprotein, Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein and des-gamma-carboxyprothrombin for hepatocellular carcinoma detection. Hepatol Res, 46(3), E130-135. https://doi.org/10.1111/hepr.12544
Chappuis, P. O., Dieterich, B., Sciretta, V., Lohse, C., Bonnefoi, H., Remadi, S., & Sappino, A. P. (2001). Functional evaluation of plasmin formation in primary breast cancer. J Clin Oncol, 19(10), 2731-2738. https://doi.org/10.1200/jco.2001.19.10.2731
Chen, F., Shen, J., Wang, J., Cai, P., & Huang, Y. (2018). Clinical analysis of four serum tumor markers in 458 patients with ovarian tumors: diagnostic value of the combined use of HE4, CA125, CA19-9, and CEA in ovarian tumors. Cancer Manag Res, 10, 1313-1318. https://doi.org/10.2147/cmar.S155693
Chen, Y., Xie, Y., Xu, L., Zhan, S., Xiao, Y., Gao, Y., Wu, B., & Ge, W. (2017). Protein content and functional characteristics of serum-purified exosomes from patients with colorectal cancer revealed by quantitative proteomics. Int J Cancer, 140(4), 900-913. https://doi.org/10.1002/ijc.30496
Cheng, J., Wang, W., Zhang, Y., Liu, X., Li, M., Wu, Z., Liu, Z., Lv, Y., & Wang, B. (2014). Prognostic role of pre-treatment serum AFP-L3% in hepatocellular carcinoma: systematic review and meta-analysis. PLoS One, 9(1), e87011. https://doi.org/10.1371/journal.pone.0087011
Detterbeck, F. C., Mazzone, P. J., Naidich, D. P., & Bach, P. B. (2013). Screening for lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest, 143(5 Suppl), e78S-e92S. https://doi.org/10.1378/chest.12-2350
Dispenzieri, A. (2022). Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis. https://www.uptodate.com/contents/clinical-presentation-laboratory-manifestations-and-diagnosis-of-immunoglobulin-light-chain-al-amyloidosis?search=systemic%20light%20chain%20amyloidosis&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Dorigo, O., & Berek, J. S. (2011). Personalizing CA125 levels for ovarian cancer screening. Cancer Prev Res (Phila), 4(9), 1356-1359. https://doi.org/10.1158/1940-6207.Capr-11-0378
Duffy, M. J. (2001). Carcinoembryonic Antigen as a Marker for Colorectal Cancer: Is It Clinically Useful? Clinical Chemistry, 47(4), 624. http://clinchem.aaccjnls.org/content/47/4/624.abstract
EASL. (2018). EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. https://easl.eu/wp-content/uploads/2018/10/EASL-CPG-Management-of-hepatocellular-carcinoma-.pdf
Farkkila, A., Koskela, S., Bryk, S., Alfthan, H., Butzow, R., Leminen, A., Puistola, U., Tapanainen, J. S., Heikinheimo, M., Anttonen, M., & Unkila-Kallio, L. (2015). The clinical utility of serum anti-Mullerian hormone in the follow-up of ovarian adult-type granulosa cell tumors--A comparative study with inhibin B. Int J Cancer, 137(7), 1661-1671. https://doi.org/10.1002/ijc.29532
Febbo, P. G., Ladanyi, M., Aldape, K. D., De Marzo, A. M., Hammond, M. E., Hayes, D. F., Iafrate, A. J., Kelley, R. K., Marcucci, G., Ogino, S., Pao, W., Sgroi, D. C., & Birkeland, M. L. (2011). NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology. J Natl Compr Canc Netw, 9 Suppl 5, S1-32; quiz S33. http://www.jnccn.org/content/9/Suppl_5/S-1.full.pdf
Feng, F., Tian, Y., Xu, G., Liu, Z., Liu, S., Zheng, G., Guo, M., Lian, X., Fan, D., & Zhang, H. (2017). Diagnostic and prognostic value of CEA, CA19-9, AFP and CA125 for early gastric cancer. BMC Cancer, 17(1), 737. https://doi.org/10.1186/s12885-017-3738-y
Feng, L. X., Wang, J., Yu, Z., Song, S. A., Zhai, W. X., Dong, S. H., Yu, H. S., & Zhang, Y. (2019). Clinical significance of serum EGFR gene mutation and serum tumor markers in predicting tyrosine kinase inhibitor efficacy in lung adenocarcinoma. Clin Transl Oncol, 21(8), 1005-1013. https://doi.org/10.1007/s12094-018-02014-6
Foekens, J. A., Peters, H. A., Look, M. P., Portengen, H., Schmitt, M., Kramer, M. D., Brunner, N., Janicke, F., Meijer-van Gelder, M. E., Henzen-Logmans, S. C., van Putten, W. L., & Klijn, J. G. (2000). The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res, 60(3), 636-643. http://dx.doi.org/
Gershenson, D. (2017). Sex cord-stromal tumors of the ovary: Granulosa-stromal cell tumors. https://www.uptodate.com/contents/sex-cord-stromal-tumors-of-the-ovary-granulosa-stromal-cell-tumors?search=inhibin%20cancer%20marker&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Gershenson, D. (2020). Sex cord-stromal tumors of the ovary: Epidemiology, clinical features, and diagnosis in adults. Retrieved 1/13/21 from https://www.uptodate.com/contents/sex-cord-stromal-tumors-of-the-ovary-granulosa-stromal-cell-tumors?search=inhibin%20cancer%20marker&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Gilligan, T. D., Seidenfeld, J., Basch, E. M., Einhorn, L. H., Fancher, T., Smith, D. C., Stephenson, A. J., Vaughn, D. J., Cosby, R., & Hayes, D. F. (2010). American Society of Clinical Oncology Clinical Practice Guideline on uses of serum tumor markers in adult males with germ cell tumors. J Clin Oncol, 28(20), 3388-3404. https://doi.org/10.1200/jco.2009.26.4481
Goff, B. (2016). Human chorionic gonadotropin: Testing in pregnancy and gestational trophoblastic disease and causes of low persistent levels. https://www.uptodate.com/contents/human-chorionic-gonadotropin-testing-in-pregnancy-and-gestational-trophoblastic-disease-and-causes-of-low-persistent-levels?search=beta%20human%20chorionic%20gonadotropin&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2
Halfdanarson, T. R., Strosberg, J. R., Tang, L., Bellizzi, A. M., Bergsland, E. K., OʼDorisio, T. M., Halperin, D. M., Fishbein, L., Eads, J., Hope, T. A., Singh, S., Salem, R., Metz, D. C., Naraev, B. G., Reidy-Lagunes, D. L., Howe, J. R., Pommier, R. F., Menda, Y., & Chan, J. A. (2020). The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors. Pancreas, 49(7), 863-881. https://doi.org/10.1097/mpa.0000000000001597
Harris, L., Fritsche, H., Mennel, R., Norton, L., Ravdin, P., Taube, S., Somerfield, M. R., Hayes, D. F., & Bast, R. C., Jr. (2007). American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol, 25(33), 5287-5312. https://doi.org/10.1200/jco.2007.14.2364
Harris, L. N., Ismaila, N., McShane, L. M., Andre, F., Collyar, D. E., Gonzalez-Angulo, A. M., Hammond, E. H., Kuderer, N. M., Liu, M. C., Mennel, R. G., Van Poznak, C., Bast, R. C., & Hayes, D. F. (2016). Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology, 34(10), 1134-1150. https://doi.org/10.1200/JCO.2015.65.2289
Harris, L. N., Ismaila, N., McShane, L. M., Andre, F., Collyar, D. E., Gonzalez-Angulo, A. M., Hammond, E. H., Kuderer, N. M., Liu, M. C., Mennel, R. G., Van Poznak, C., Bast, R. C., & Hayes, D. F. (2016). Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol, 34(10), 1134-1150. https://doi.org/10.1200/jco.2015.65.2289
Harvey, R. A. (2019). Human chorionic gonadotropin: Biochemistry and measurement in pregnancy and disease. Retrieved 1/13/21 from https://www.uptodate.com/contents/human-chorionic-gonadotropin-testing-in-pregnancy-and-gestational-trophoblastic-disease-and-causes-of-low-persistent-levels?search=beta%20human%20chorionic%20gonadotropin&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2
Haugen, B. R., Alexander, E. K., Bible, K. C., Doherty, G. M., Mandel, S. J., Nikiforov, Y. E., Pacini, F., Randolph, G. W., Sawka, A. M., Schlumberger, M., Schuff, K. G., Sherman, S. I., Sosa, J. A., Steward, D. L., Tuttle, R. M., & Wartofsky, L. (2016). 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid, 26(1), 1-133. https://doi.org/10.1089/thy.2015.0020
Hotakainen, K., Ljungberg, B., Paju, A., Rasmuson, T., Alfthan, H., & Stenman, U. H. (2002). The free beta-subunit of human chorionic gonadotropin as a prognostic factor in renal cell carcinoma. Br J Cancer, 86(2), 185-189. https://doi.org/10.1038/sj.bjc.6600050
Hottinger, A., & Hormigo, A. (2011). Serum Biomarkers. In Encyclopedia of Cancer (pp. 3390-3394). Springer Berlin Heidelberg. https://doi.org/10.1007/978-3-642-16483-5_5269
Husain, A. N., Colby, T. V., Ordonez, N. G., Allen, T. C., Attanoos, R. L., Beasley, M. B., Butnor, K. J., Chirieac, L. R., Churg, A. M., Dacic, S., Galateau-Salle, F., Gibbs, A., Gown, A. M., Krausz, T., Litzky, L. A., Marchevsky, A., Nicholson, A. G., Roggli, V. L., Sharma, A. K., . . . Wick, M. R. (2018). Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group. Arch Pathol Lab Med, 142(1), 89-108. https://doi.org/10.5858/arpa.2017-0124-RA
Isaksson, S., Jönsson, P., Monsef, N., Brunnström, H., Bendahl, P. O., Jönsson, M., Staaf, J., & Planck, M. (2017). CA 19-9 and CA 125 as potential predictors of disease recurrence in resectable lung adenocarcinoma. PLoS One, 12(10), e0186284. https://doi.org/10.1371/journal.pone.0186284
Katou, H., Kanno, T., Hoshino, M., Hagihara, Y., Tanaka, H., Kawai, T., Hasegawa, K., Naiki, H., & Goto, Y. (2002). The role of disulfide bond in the amyloidogenic state of beta(2)-microglobulin studied by heteronuclear NMR. Protein Sci, 11(9), 2218-2229. https://doi.org/10.1110/ps.0213202
Katzmann, J. A., Clark, R. J., Abraham, R. S., Bryant, S., Lymp, J. F., Bradwell, A. R., & Kyle, R. A. (2002). Serum reference intervals and diagnostic ranges for free kappa and free lambda immunoglobulin light chains: relative sensitivity for detection of monoclonal light chains. Clin Chem, 48(9), 1437-1444. https://www.ncbi.nlm.nih.gov/pubmed/12194920
Kim, N. H., Lee, M. Y., Park, J. H., Park, D. I., Sohn, C. I., Choi, K., & Jung, Y. S. (2017). Serum CEA and CA 19-9 Levels are Associated with the Presence and Severity of Colorectal Neoplasia. Yonsei Med J, 58(5), 918-924. https://doi.org/10.3349/ymj.2017.58.5.918
Kindler, H. L., Ismaila, N., Armato, S. G., Bueno, R., Hesdorffer, M., Jahan, T., Jones, C. M., Miettinen, M., Pass, H., Rimner, A., Rusch, V., Sterman, D., Thomas, A., & Hassan, R. (2018). Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology, 36(13), 1343-1373. https://doi.org/10.1200/JCO.2017.76.6394
Kobayashi, M., Kuroiwa, T., Suda, T., Tamura, Y., Kawai, H., Igarashi, M., Fukuhara, Y., & Aoyagi, Y. (2007). Fucosylated fraction of alpha-fetoprotein, L3, as a useful prognostic factor in patients with hepatocellular carcinoma with special reference to low concentrations of serum alpha-fetoprotein. Hepatol Res, 37(11), 914-922. https://doi.org/10.1111/j.1872-034X.2007.00147.x
Krop, I., Ismaila, N., Andre, F., Bast, R. C., Barlow, W., Collyar, D. E., Hammond, M. E., Kuderer, N. M., Liu, M. C., Mennel, R. G., Van Poznak, C., Wolff, A. C., & Stearns, V. (2017). Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. J Clin Oncol, Jco2017740472. https://doi.org/10.1200/jco.2017.74.0472
Kumar, S., Dispenzieri, A., Katzmann, J. A., Larson, D. R., Colby, C. L., Lacy, M. Q., Hayman, S. R., Buadi, F. K., Leung, N., Zeldenrust, S. R., Ramirez-Alvarado, M., Clark, R. J., Kyle, R. A., Rajkumar, S. V., & Gertz, M. A. (2010). Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood, 116(24), 5126-5129. https://doi.org/10.1182/blood-2010-06-290668
Kyrtsonis MC, K. E., Bartzis V, Pessah I, Nikolaou E, Karalis V, Maltezas D, Panayiotidis P, Harding S. (2012). Monoclonal Immunoglobulin. In Multiple Myeloma - A Quick Reflection on the Fast Progress. https://doi.org/10.5772/55855
Li, J., Yin, M., Song, W., Cui, F., Wang, W., Wang, S., & Zhu, H. (2018). B Subunit of Human Chorionic Gonadotropin Promotes Tumor Invasion and Predicts Poor Prognosis of Early-Stage Colorectal Cancer. Cell Physiol Biochem, 45(1), 237-249. https://doi.org/10.1159/000486770
Li, X., Dai, D., Chen, B., Tang, H., Xie, X., & Wei, W. (2018). Clinicopathological and Prognostic Significance of Cancer Antigen 15-3 and Carcinoembryonic Antigen in Breast Cancer: A Meta-Analysis including 12,993 Patients. Dis Markers, 2018, 9863092. https://doi.org/10.1155/2018/9863092
Liu, R., Cao, J., Gao, X., Zhang, J., Wang, L., Wang, B., Guo, L., Hu, X., & Wang, Z. (2016). Overall survival of cancer patients with serum lactate dehydrogenase greater than 1000 IU/L. Tumour Biol, 37(10), 14083-14088. https://doi.org/10.1007/s13277-016-5228-2
Lucarelli, G., Ditonno, P., Bettocchi, C., Vavallo, A., Rutigliano, M., Galleggiante, V., Larocca, A. M., Castellano, G., Gesualdo, L., Grandaliano, G., Selvaggi, F. P., & Battaglia, M. (2014). Diagnostic and prognostic role of preoperative circulating CA 15-3, CA 125, and beta-2 microglobulin in renal cell carcinoma. Dis Markers, 2014, 689795. https://doi.org/10.1155/2014/689795
Magnani, J. L. (2004). The discovery, biology, and drug development of sialyl Lea and sialyl Lex. Archives of Biochemistry and Biophysics, 426(2), 122-131. https://doi.org/https://doi.org/10.1016/j.abb.2004.04.008
Malmstrom, P., Bendahl, P. O., Boiesen, P., Brunner, N., Idvall, I., & Ferno, M. (2001). S-phase fraction and urokinase plasminogen activator are better markers for distant recurrences than Nottingham Prognostic Index and histologic grade in a prospective study of premenopausal lymph node-negative breast cancer. J Clin Oncol, 19(7), 2010-2019. https://doi.org/10.1200/jco.2001.19.7.2010
Marcillac, I., Troalen, F., Bidart, J.-M., Ghillani, P., Ribrag, V., Escudier, B., Malassagne, B., Droz, J.-P., Lhommé, C., Rougier, P., Duvillard, P., Prade, M., Lugagne, P.-M., Richard, F., Poynard, T., Bohuon, C., Wands, J., & Bellet, D. (1992). Free Human Chorionic Gonadotropin β Subunit in Gonadal and Nongonadal Neoplasms. Cancer Research, 52(14), 3901. http://cancerres.aacrjournals.org/content/52/14/3901.abstract
Marcinko, T. M., Dong, J., LeBlanc, R., Daborowski, K. V., & Vachet, R. W. (2017). Small molecule-mediated inhibition of β-2-microglobulin-based amyloid fibril formation. J Biol Chem, 292(25), 10630-10638. https://doi.org/10.1074/jbc.M116.774083
Matuszczak, M., Schalken, J. A., & Salagierski, M. (2021). Prostate Cancer Liquid Biopsy Biomarkers' Clinical Utility in Diagnosis and Prognosis. Cancers (Basel), 13(13). https://doi.org/10.3390/cancers13133373
Merlini, G., Wechalekar, A. D., & Palladini, G. (2013). Systemic light chain amyloidosis: an update for treating physicians. Blood, 121(26), 5124-5130. https://doi.org/10.1182/blood-2013-01-453001
Moreau AS, L. X., Manning R, Coiteux V, Darre S, Hatjiharisi E, Hunter Z, Jia X, Ngo H, O'Sullivan G, Santos D, Treon S, Facon T, Anderson K, Ghobrial I. (2006). Serum Free Light Chain in Waldenstrom Macroglobulinemia. https://doi.org/https://doi.org/10.1182/blood.V108.11.2420.2420
NANETS. (2017). The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Midgut Neuroendocrine Tumors. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642985/
NCCN. (2021a). Bone Cancer Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/bone.pdf
NCCN. (2021b). Cervical Cancer. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf
NCCN. (2021c). Hairy Cell Leukemia Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf
NCCN. (2021d). Malignant Peritoneal Mesothelioma. https://www.nccn.org/professionals/physician_gls/pdf/mpem.pdf#Page=4
NCCN. (2021e). Malignant Pleural Mesothelioma. https://www.nccn.org/professionals/physician_gls/pdf/mpm.pdf
NCCN. (2021f). Occult Primary, V.1.2022. https://www.nccn.org/professionals/physician_gls/pdf/occult.pdf
NCCN. (2021g). Pediatric Acute Lymphoblastic Leukemia Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf
NCCN. (2021h). Small Cell Lung Cancer Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf
NCCN. (2021i). Systemic light chain amyloidosis, V.1.2022. https://www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf
NCCN. (2021j). Uterine Neoplasms, V.1.2022. https://www.nccn.org/professionals/physician_gls/pdf/uterine.pdf
NCCN. (2022a). Acute Lymphoblastic Leukemia Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf
NCCN. (2022b). B-Cell Lymphomas V3.2022. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
NCCN. (2022c). Breast Cancer. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
NCCN. (2022d). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
NCCN. (2022e). Chronic Myeloid Leukemia, V.3.2022. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf
NCCN. (2022f). Colon Cancer. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf
NCCN. (2022g). Cutaneous Melanoma Version 3.2022. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf
NCCN. (2022h). Genetic/Familial High-Risk Assessment: Breast and Ovarian. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf#Page=39
NCCN. (2022i). Genetic/Familial High-Risk Assessment: Colorectal. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf#Page=32
NCCN. (2022j). Head and Neck Cancers. https://www.nccn.org/professionals/physician_gls/pdf/head-and-neck.pdf#Page=71
NCCN. (2022k). Hepatobiliary Cancers. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf
NCCN. (2022l). Merkel Cell Carcinoma. https://www.nccn.org/professionals/physician_gls/pdf/mcc.pdf
NCCN. (2022m). Multiple Myeloma, Version 5.2022. https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf
NCCN. (2022n). Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes. https://www.nccn.org/professionals/physician_gls/pdf/mlne.pdf#Page=7
NCCN. (2022o). Myeloproliferative Neoplasms Version 2.2022. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
NCCN. (2022p). NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/default.aspx
NCCN. (2022q). Neuroendocrine and Adrenal Tumors. https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine.pdf
NCCN. (2022r). Ovarian Cancer, V.1.2022. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf
NCCN. (2022s). Pancreatic Adenocarcinoma, V.1.2022. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
NCCN. (2022t). Primary Cutaneous Lymphomas Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/primary_cutaneous.pdf
NCCN. (2022u). Rectal Cancer. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf
NCCN. (2022v). Small Bowel Adenocarcinoma. https://www.nccn.org/professionals/physician_gls/pdf/small_bowel.pdf
NCCN. (2022w). Systemic Mastocytosis Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf
NCCN. (2022x). T-Cell Lymphomas. https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf
NCCN. (2022y). Testicular Cancer, V.2.2022. https://www.nccn.org/professionals/physician_gls/pdf/testicular.pdf
NCCN. (2022z). Thymomas and Thymic Carcinomas, V.1.2021. https://www.nccn.org/professionals/physician_gls/pdf/thymic.pdf
NCCN. (2022aa). Thyroid Carcinoma, V.2.2022. https://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf
NCCN. (2022ab). Waldenström's Macroglobulinemia / Lymphoplasmacytic Lymphoma V.3.2022. https://www.nccn.org/professionals/physician_gls/pdf/waldenstroms.pdf
NICE. (2011). Ovarian cancer: recognition and initial management. https://www.nice.org.uk/guidance/cg122/chapter/1-Guidance
NICE. (2018). Myeloma: diagnosis and management. https://www.nice.org.uk/guidance/ng35/chapter/Recommendations
O'Neill, R. S., & Stoita, A. (2021). Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket? World J Gastroenterol, 27(26), 4045-4087. https://doi.org/10.3748/wjg.v27.i26.4045
Oyaert, M., Boone, E., De Ceuninck, L., Moreau, E., Van Dorpe, J., Vanpoucke, H., & Deeren, D. (2014). Clonal multicentric Castleman's disease with increased free Kappa light chains in a patient with systemic lupus erythematosus. Ann Hematol, 93(7), 1255-1257. https://doi.org/10.1007/s00277-013-1962-3
Park, S. J., Jang, J. Y., Jeong, S. W., Cho, Y. K., Lee, S. H., Kim, S. G., Cha, S. W., Kim, Y. S., Cho, Y. D., Kim, H. S., Kim, B. S., Park, S., & Bang, H. I. (2017). Usefulness of AFP, AFP-L3, and PIVKA-II, and their combinations in diagnosing hepatocellular carcinoma. Medicine (Baltimore), 96(11), e5811. https://doi.org/10.1097/md.0000000000005811
Pinzani, P., D'Argenio, V., Del Re, M., Pellegrini, C., Cucchiara, F., Salvianti, F., & Galbiati, S. (2021). Updates on liquid biopsy: current trends and future perspectives for clinical application in solid tumors. Clin Chem Lab Med, 59(7), 1181-1200. https://doi.org/10.1515/cclm-2020-1685
Pucino, V., Bombardieri, M., Pitzalis, C., & Mauro, C. (2017). Lactate at the crossroads of metabolism, inflammation, and autoimmunity. European Journal of Immunology, 47(1), 14-21. https://doi.org/10.1002/eji.201646477
Qin, J., Yang, Q., Ye, H., Wang, K., Zhang, M., Zhu, J., Wang, X., Dai, L., Wang, P., & Zhang, J. (2020). Using Serological Proteome Analysis to Identify and Evaluate Anti-GRP78 Autoantibody as Biomarker in the Detection of Gastric Cancer. J Oncol, 2020, 9430737. https://doi.org/10.1155/2020/9430737
Raby, B. (2020). Personalized medicine. Retrieved 12/24/20 from https://www.uptodate.com/contents/personalized-medicine?search=proteomics&source=search_result&selectedTitle=1~61&usage_type=default&display_rank=1
Raby, B. (2021). Personalized medicine. Retrieved 1/13/21 from https://www.uptodate.com/contents/personalized-medicine?search=proteomics&source=search_result&selectedTitle=1~61&usage_type=default&display_rank=1
Ryu, T., Takami, Y., Wada, Y., Tateishi, M., Matsushima, H., Mikagi, K., & Saitsu, H. (2017). Double- and Triple-Positive Tumor Markers Predict Early Recurrence and Poor Survival in Patients with Hepatocellular Carcinoma within the Milan Criteria and Child-Pugh Class A. J Gastrointest Surg, 21(6), 957-966. https://doi.org/10.1007/s11605-017-3394-1
Saito, Y., Shimada, M., Utsunomiya, T., Morine, Y., Imura, S., Ikemoto, T., Mori, H., Hanaoka, J., Yamada, S., & Asanoma, M. (2012). Prediction of recurrence of hepatocellular carcinoma after curative hepatectomy using preoperative Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein. Hepatol Res, 42(9), 887-894. https://doi.org/10.1111/j.1872-034X.2012.01004.x
Santos Schraiber, L. d., de Mattos, A. A., Zanotelli, M. L., Cantisani, G. P., Brandao, A. B., Marroni, C. A., Kiss, G., Ernani, L., & Santos Marcon, P. d. (2016). Alpha-fetoprotein Level Predicts Recurrence After Transplantation in Hepatocellular Carcinoma. Medicine (Baltimore), 95(3), e2478. https://doi.org/10.1097/md.0000000000002478
Schefer, H., Mattmann, S., & Joss, R. A. (1998). Hereditary persistence of α-fetoproteinCase report and review of the literature. Annals of Oncology, 9(6), 667-672. https://doi.org/10.1023/A:1008243311122
Seo, S., Hong, J. Y., Yoon, S., Yoo, C., Park, J. H., Lee, J. B., Park, C. S., Huh, J., Lee, Y., Kim, K. W., Ryu, J. S., Kim, S. J., Kim, W. S., Yoon, D. H., & Suh, C. (2016). Prognostic significance of serum beta-2 microglobulin in patients with diffuse large B-cell lymphoma in the rituximab era. Oncotarget, 7(47), 76934-76943. https://doi.org/10.18632/oncotarget.12734
Sepulveda, A. R., Hamilton, S. R., Allegra, C. J., Grody, W., Cushman-Vokoun, A. M., Funkhouser, W. K., Kopetz, S. E., Lieu, C., Lindor, N. M., Minsky, B. D., Monzon, F. A., Sargent, D. J., Singh, V. M., Willis, J., Clark, J., Colasacco, C., Rumble, R. B., Temple-Smolkin, R., Ventura, C. B., & Nowak, J. A. (2017). Molecular Biomarkers for the Evaluation of Colorectal Cancer: Guideline From the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. Journal of Clinical Oncology, 35(13), 1453-1486. https://doi.org/10.1200/JCO.2016.71.9807
Song, B. C., Suh, D. J., Yang, S. H., Lee, H. C., Chung, Y. H., Sung, K. B., & Lee, Y. S. (2002). Lens culinaris agglutinin-reactive alpha-fetoprotein as a prognostic marker in patients with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization. J Clin Gastroenterol, 35(5), 398-402. http://dx.doi.org/
Stankowski-Drengler, T., Gertz, M. A., Katzmann, J. A., Lacy, M. Q., Kumar, S., Leung, N., Hayman, S. R., Buadi, F., Kyle, R. A., Rajkumar, S. V., & Dispenzieri, A. (2010). Serum immunoglobulin free light chain measurements and heavy chain isotype usage provide insight into disease biology in patients with POEMS syndrome. Am J Hematol, 85(6), 431-434. https://doi.org/10.1002/ajh.21707
Stephens, R. W., Brunner, N., Janicke, F., & Schmitt, M. (1998). The urokinase plasminogen activator system as a target for prognostic studies in breast cancer. Breast Cancer Res Treat, 52(1-3), 99-111. http://dx.doi.org/
Stoffel, E. M., McKernin, S. E., Brand, R., Canto, M., Goggins, M., Moravek, C., Nagarajan, A., Petersen, G. M., Simeone, D. M., Yurgelun, M., & Khorana, A. A. (2018). Evaluating Susceptibility to Pancreatic Cancer: ASCO Provisional Clinical Opinion. Journal of Clinical Oncology, 37(2), 153-164. https://doi.org/10.1200/JCO.18.01489
Strosberg, J. (2017). https://www.uptodate.com/contents/diagnosis-of-the-carcinoid-syndrome-and-tumor-localization?search=chromogranin%20A&source=search_result&selectedTitle=1~40&usage_type=default&display_rank=1
Strosberg, J. (2019). Diagnosis of carcinoid syndrome and tumor localization. Retrieved 1/13/21 from https://www.uptodate.com/contents/diagnosis-of-the-carcinoid-syndrome-and-tumor-localization?search=chromogranin%20A&source=search_result&selectedTitle=1~40&usage_type=default&display_rank=1
Sturgeon, C. M., Duffy, M. J., Hofmann, B. R., Lamerz, R., Fritsche, H. A., Gaarenstroom, K., Bonfrer, J., Ecke, T. H., Grossman, H. B., Hayes, P., Hoffmann, R. T., Lerner, S. P., Lohe, F., Louhimo, J., Sawczuk, I., Taketa, K., & Diamandis, E. P. (2010). National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines for use of tumor markers in liver, bladder, cervical, and gastric cancers. Clin Chem, 56(6), e1-48. https://doi.org/10.1373/clinchem.2009.133124
Sturgeon, C. M., Duffy, M. J., Stenman, U. H., Lilja, H., Brunner, N., Chan, D. W., Babaian, R., Bast, R. C., Jr., Dowell, B., Esteva, F. J., Haglund, C., Harbeck, N., Hayes, D. F., Holten-Andersen, M., Klee, G. G., Lamerz, R., Looijenga, L. H., Molina, R., Nielsen, H. J., . . . Diamandis, E. P. (2008). National Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers. Clin Chem, 54(12), e11-79. https://doi.org/10.1373/clinchem.2008.105601
Sturgeon, C. M., Hoffman, B. R., Chan, D. W., Ch, ng, S.-L., Hammond, E., Hayes, D. F., Liotta, L. A., Petricoin, E. F., Schmitt, M., Semmes, O. J., Söletormos, G., van der Merwe, E., & 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. https://doi.org/10.1373/clinchem.2007.094144
Theodoros, F., & Bergh, J. (2019). Prognostic and predictive factors in early, nonmetastatic breast cancer - UpToDate. In D. Hayes (Ed.), UpToDate. https://www.uptodate.com/contents/prognostic-and-predictive-factors-in-early-non-metastatic-breast-cancer
Tian, T., Gao, J., Li, N., Li, Y., Lu, M., Li, Z., Lu, Z., Li, J., & Shen, L. (2016). Circulating Chromogranin A as A Marker for Monitoring Clinical Response in Advanced Gastroenteropancreatic Neuroendocrine Tumors. PLoS One, 11(5), e0154679. https://doi.org/10.1371/journal.pone.0154679
Tormey, W. P., Byrne, B., Hill, A. D., Sherlock, M., & Thompson, C. J. (2017). Should serum calcitonin be routinely measured in patients presenting with thyroid nodule? Minerva Endocrinol, 42(4), 306-310. https://doi.org/10.23736/s0391-1977.17.02566-4
Tosi, P., Tomassetti, S., Merli, A., & Polli, V. (2013). Serum free light-chain assay for the detection and monitoring of multiple myeloma and related conditions. Ther Adv Hematol, 4(1), 37-41. https://doi.org/10.1177/2040620712466863
Tuttle, M. (2018). Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging. https://www.uptodate.com/contents/medullary-thyroid-cancer-clinical-manifestations-diagnosis-and-staging?search=calcitonin%20medullary%20thyroid%20carcinoma&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Tuttle, R. M. (2020). Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging. Retrieved 1/13/21 from https://www.uptodate.com/contents/medullary-thyroid-cancer-clinical-manifestations-diagnosis-and-staging?search=calcitonin%20medullary%20thyroid%20carcinoma&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
Ueland, F. (2017). Serum biomarkers for evaluation of an adnexal mass for epithelial carcinoma of the ovary, fallopian tube, or peritoneum. https://www.uptodate.com/contents/serum-biomarkers-for-evaluation-of-an-adnexal-mass-for-epithelial-carcinoma-of-the-ovary-fallopian-tube-or-peritoneum?search=Carcinoembryonic%20antigen&source=search_result&selectedTitle=1~101&usage_type=default&display_rank=1
Ueland, F. R., Li, Andrew John. (2020). Serum biomarkers for evaluation of an adnexal mass for epithelial carcinoma of the ovary, fallopian tube, or peritoneum. Retrieved 1/13/21 from https://www.uptodate.com/contents/serum-biomarkers-for-evaluation-of-an-adnexal-mass-for-epithelial-carcinoma-of-the-ovary-fallopian-tube-or-peritoneum?search=Carcinoembryonic%20antigen&source=search_result&selectedTitle=1~101&usage_type=default&display_rank=1
Van Poznak, C., Somerfield, M. R., Bast, R. C., Cristofanilli, M., Goetz, M. P., Gonzalez-Angulo, A. M., Hicks, D. G., Hill, E. G., Liu, M. C., Lucas, W., Mayer, I. A., Mennel, R. G., Symmans, W. F., Hayes, D. F., & Harris, L. N. (2015). Use of Biomarkers to Guide Decisions on Systemic Therapy for Women With Metastatic Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol, 33(24), 2695-2704. https://doi.org/10.1200/jco.2015.61.1459
Walentowicz, P., Krintus, M., Sadlecki, P., Grabiec, M., Mankowska-Cyl, A., Sokup, A., & Walentowicz-Sadlecka, M. (2014). Serum inhibin A and inhibin B levels in epithelial ovarian cancer patients. PLoS One, 9(3), e90575. https://doi.org/10.1371/journal.pone.0090575
Wells, S. A., Jr., Asa, S. L., Dralle, H., Elisei, R., Evans, D. B., Gagel, R. F., Lee, N., Machens, A., Moley, J. F., Pacini, F., Raue, F., Frank-Raue, K., Robinson, B., Rosenthal, M. S., Santoro, M., Schlumberger, M., Shah, M., & Waguespack, S. G. (2015). Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 25(6), 567-610. https://doi.org/10.1089/thy.2014.0335
Wu, D., Lim, M. S., & Jaffe, E. S. (2018). Pathology of Castleman Disease. Hematol Oncol Clin North Am, 32(1), 37-52. https://doi.org/10.1016/j.hoc.2017.09.004
Wu, M., Liu, H., Liu, Z., Liu, C., Zhang, A., & Li, N. (2018). Analysis of serum alpha-fetoprotein (AFP) and AFP-L3 levels by protein microarray. J Int Med Res, 46(10), 4297-4305. https://doi.org/10.1177/0300060518789304
Yamao, T., Yamashita, Y. I., Imai, K., Umezaki, N., Tsukamoto, M., Kitano, Y., Arima, K., Miyata, T., Nakagawa, S., Okabe, H., Hayashi, H., Chikamoto, A., Ishiko, T., & Baba, H. (2019). Clinical Significance of Preoperative Hepatocellular Carcinoma With High Lens culinaris Agglutinin-reactive Fraction of Alpha-Fetoprotein, But Low Alpha-Fetoprotein. Anticancer Res, 39(2), 883-889. https://doi.org/10.21873/anticanres.13189
Yang, X., Yang, Y., Li, Z., Cheng, C., Yang, T., Wang, C., Liu, L., & Liu, S. (2015). Diagnostic value of circulating chromogranin a for neuroendocrine tumors: a systematic review and meta-analysis. PLoS One, 10(4), e0124884. https://doi.org/10.1371/journal.pone.0124884
Yi, X., Yu, S., & Bao, Y. (2013). Alpha-fetoprotein-L3 in hepatocellular carcinoma: a meta-analysis. Clin Chim Acta, 425, 212-220. https://doi.org/10.1016/j.cca.2013.08.005
Zhang, X. F., Lai, E. C., Kang, X. Y., Qian, H. H., Zhou, Y. M., Shi, L. H., Shen, F., Yang, Y. F., Zhang, Y., Lau, W. Y., Wu, M. C., & Yin, Z. F. (2011). Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein as a marker of prognosis and a monitor of recurrence of hepatocellular carcinoma after curative liver resection. Ann Surg Oncol, 18(8), 2218-2223. https://doi.org/10.1245/s10434-011-1613-7

Coding Section

Code	Number	Code Description
CPT	81479	Unlisted molecular pathology procedure
	81500	Oncology (ovarian), biochemical assays of two proteins (CA-125 and HE4), utilizing serum, with menopausal status, algorithm reported as a risk score Proprietary test: Risk of Ovarian Malignancy Algorithm (ROMA)™ Lab/manufacturer: Fujirebio Diagnostics
	81503	Oncology (ovarian), biochemical assays of five proteins (CA-125, apolipoprotein A1, beta-2 microglobulin, transferrin, and pre-albumin), utilizing serum, algorithm reported as a risk score Proprietary test: OVA1™ Lab/manufacturer: Vermillion, Inc
	81538	Oncology (lung), mass spectrometric 8-protein signature, including amyloid A, utilizing serum, prognostic and predictive algorithm reported as good versus poor overall survival Proprietary test: VeriStrat^® Lab/manufacturer: Biodesix, Inc
	81599	Unlisted multianalyte assay with algorithmic analysis
	82105	Alpha-fetoprotein (AFP); serum
	82107	Alpha-fetoprotein (AFP); AFP-L3 fraction isoform and total AFP (including ratio)
	82232	Beta-2 microglobulin
	82308	Calcitonin
	82378	Carcinoembryonic antigen (CEA)
	83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified
	83521	Immunoglobulin light chains (i.e., kappa, lambda), free, each
	83615	Lactate dehydrogenase (LD), (LDH);
	83789	Mass spectrometry and tandem mass spectrometry (e.g., MS, MS/MS, MALDI, MS-TOF, QTOF), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen
	83880	Natriuretic peptide
	83950	Oncoprotein; HER-2/neu
	83951	Oncoprotein; des-gamma-carboxy-prothrombin (DCP)
	84075	Phosphatase, alkaline
	84078	Phosphatase, alkaline; heat stable (total not included)
	84080	Phosphatase, alkaline; isoenzymes
	84484	Troponin, quantitative
	84702	Gonadotropin, chorionic (hCG); quantitative
	84703	Gonadotropin, chorionic (hCG); qualitative
	84704	Gonadotropin, chorionic (hCG); free beta chain
	84999	Unlisted chemistry procedure
	85415	Fibrinolytic factors and inhibitors; plasminogen activator
	86300	Immunoassay for tumor antigen, quantitative; CA 15-3 (27.29)
	86301	Immunoassay for tumor antigen, quantitative; CA 19-9
	86304	Immunoassay for tumor antigen, quantitative; CA 125
	86305	Human epididymis protein 4 (HE4)
	86316	Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each
	86336	Inhibin A
	G0327	Colorectal cancer screening; blood-based biomarker
	0003U	Oncology (ovarian) biochemical assays of five proteins (apolipoprotein A-1, CA 125 II, follicle stimulating hormone, human epididymis protein 4, transferrin), utilizing serum, algorithm reported as a likelihood score Proprietary test: Overa™ (OVA1 Next Generation) Lab/manufacturer: Aspira Labs, Inc, Vermillion, Inc
	0092U	Oncology (lung), three protein biomarkers, immunoassay using magnetic nanosensor technology, CPTsma, algorithm reported as risk score for likelihood of malignancy Proprietary test: REVEAL Lung Nodule Characterization Lab/Manufacturer: MagArray, Inc
	0163U	Oncology (colorectal) screening, biochemical enzyme-linked immunosorbent assay (ELISA) of 3 plasma or serum proteins (teratocarcinoma derived growth factor-1 [TDGF-1, Cripto-1], carcinoembryonic antigen [CEA], extracellular matrix protein [ECM]), with demographic data (age, gender, CRC-screening compliance) using a proprietary algorithm and reported as likelihood of CRC or advanced adenomas Proprietary test: BeScreened™-CRC Lab/Manufacturer: Beacon Biomedical Inc

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

History From 2013 Forward

08/09/2022	Annual review, medical policy updated, adding new coverage criteria related to B-Type natriuretic peptide and free light chain. Ovasure and Coloprint are being removed from the policy. Coverage criteria otherwise reformatted for clarity. Updating description, rationale, and references and coding.
04/06/2022	Updating Annual Review date. No other changes made
07/09/2021	Inerim review updating coding. No other changes made. Added code G0327 effective 7/1/2021
04/19/2021	Annual review, updating poilicy to address epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer workup. Also updating description, rationale and references.
04/27/2020	Annual review, adding numerous additional indications for various tests.
07/18/2019	Interim review updating policy criteria regarding: Castleman's Disease, uPA testing,AFP-L3 testing and REVEAL Lung Nodule Testing. Also updating coding.
04/04/2019	Annual review, major rewrite of policy for clarity and specificity of testing and requirements. Also updating description, rationale, regulatory status, coding and references.
04/17/2018	Interim review, no change to policy intent. Changing review month.
12/7/2017	Interim review, updating complete policy
04/26/2017	Updated category to Laboratory. No other changes.
11/07/2016	Interim review, removing MUC1 gene from Breast Cancer policy section. Adding Myriad MyPlan lung cancer testing as investigational.
04/24/2016	Interim review, removing CPT 82107 from this policy as it relates to LIVER cancer as it is specifically addressed in CAM 20446.
02/17/2016	Interim update, removing Afirma from policy. It is addressed in CAM 20478.
02/01/2016	Annual review, no change to policy intent.
08/13/2015	Removed 83993 (fecal calprotectin) as investigational. No other changes made.
03/02/2015	Annual review, no change to policy intent. Adding appendix detailing tests, adding coding.
02/19/2014	Annual review, changing title, extensively updating the list of investigational testing, updating rationale and references.

Policy List

Edit Policy

{{ navigationConstituentPage.title || 'Medical Policies' }}

Serum Tumor Markers for Malignancies - CAM 277