Tumor Markers for Diagnosis and Management of Cancer
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Tumor Markers for Diagnosis and Management of Cancer

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Tumor Markers for Diagnosis and Management of Cancer Tumor Markers for Diagnosis and Management of Cancer Document Transcript

  • CIGNA HEALTHCARE COVERAGE POSITION Revised Date ........................... 10/15/2007 Subject Tumor Markers for Diagnosis Original Effective Date ............. 9/15/2004 Coverage Position Number ............. 0172 and Management of Cancer Table of Contents Hyperlink to Related Coverage Positions Coverage Position............................................... 1 Assays of Genetic Expression in Tumor General Background ........................................... 4 Tissue as a Prognosis in Patients with Coding/Billing Information ................................. 19 Breast Cancer References ........................................................ 20 Circulating Tumor Cells Testing Colorectal Cancer Screening and Surveillance Gene-Based Testing for Prostate Cancer Screening, Detection and Disease Monitoring Prostate-Specific Antigen (PSA) Screening for Prostate Cancer Proteomic Pattern Analysis of Blood for the Early Detection of Ovarian Cancer (e.g., OvaCheck™) Tumor In Vitro Chemosensitivity and Chemoresistance Assays INSTRUCTIONS FOR USE Coverage Positions are intended to supplement certain standard CIGNA HealthCare benefit plans. Please note, the terms of a participant’s particular benefit plan document [Group Service Agreement (GSA), Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Positions are based. For example, a participant’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Position. In the event of a conflict, a participant’s benefit plan document always supercedes the information in the Coverage Positions. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable group benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Positions and; 4) the specific facts of the particular situation. Coverage Positions relate exclusively to the administration of health benefit plans. Coverage Positions are not recommendations for treatment and should never be used as treatment guidelines. ©2007 CIGNA Health Corporation Coverage Position CIGNA HealthCare covers the following serum tumor markers as medically necessary for the screening, diagnosis, monitoring and follow-up of the specific cancer indications noted: • alpha-fetoprotein (AFP) for the diagnosis and monitoring of hepatocellular cancer for the screening of hepatocellular cancer (i.e., prior to transplant) • alpha-fetoprotein and b-HCG (in combination) for the diagnosis and monitoring of testicular or ovarian cancer • beta2-microglobulin (B2M) to assess the tumor burden within patients diagnosed with multiple myeloma • calcitonin for the diagnosis of early medullary carcinoma of the thyroid • cancer antigen (CA 19-9) Page 1 of 29 Coverage Position Number: 0172
  • for treatment monitoring in patients with known gastric and pancreatic cancer for follow-up in patients with gastric or pancreatic cancer • cancer antigen (CA-125) for follow-up in patients with known ovarian cancer to assess the need for second-look surgery to rule out ovarian cancer in patients with adenocarcinoma of unknown primary origin for the diagnosis and staging of endometrial cancer • cancer antigen (CA 15-3), CA27-29 or Truquant RIA to monitor the treatment of patients with advanced breast cancer for the follow-up of breast cancer in a symptomatic patient • carcinoembryonic antigen (CEA) for preoperative staging and surgical planning in patients with known colorectal cancer to monitor treatment response for metastatic disease of the colon for follow-up of colorectal cancer after surgical and/or medical intervention for the diagnosis of hepatocellular cancer • chromogranin A (CgA) for the diagnosis of neuroendocrine tumors (e.g., carcinoid tumors, neuroblastoma, and small cell lung cancer) • estrogen and progesterone receptors for primary breast cancer or metastatic lesions for treatment planning to determine the appropriate use of endocrine forms of adjuvant therapy to determine an appropriate course of therapy for recurrent or metastatic breast cancer • HER-2-Neu for primary breast cancer or metastatic lesions for treatment planning • human chorionic gonadotropin (HCG) to monitor treatment in patients with known trophoblastic tumors (invasive hydatiform moles and choriocarcinomas) of the ovaries and testes as follow-up of trophoblastic tumors after treatment to screen high-risk women for choriocarcinomas • neuron-specific enolase (NSE) to predict the prognosis and follow-up of patients with small cell cancer of lung for recurrence • prostatic acid phosphatase (PAP) to monitor response to treatment for prostate cancer • prostate-specific antigen (PSA) to monitor response to treatment for prostate cancer as follow-up of prostate cancer after treatment • thyroglobulin as follow-up for patients with follicular or papillary carcinoma of the thyroid CIGNA HealthCare does not cover ANY of the following cancer tests for the stated indications because such testing is considered experimental, investigational or unproven (this list may not be all-inclusive): • CEA used for ANY of the following: as a screening test for colorectal cancer as a sole determinant to treat a colorectal cancer patient with adjuvant therapy, or systemic therapy for presumed metastatic disease for the screening, diagnosis, staging, or routine follow-up for patients with lung or breast cancer after primary therapy • CA 19-9 for screening, diagnosis, staging, follow-up, or monitoring treatment of colorectal, liver or breast cancer • CA 125 as a routine screening test for colorectal cancer, or ovarian cancer (other than as indicated above), or for differential diagnosis of patients with symptoms of ovarian, colonic disease, gastric, liver, or pancreatic cancer Page 2 of 29 Coverage Position Number: 0172
  • CIGNA HealthCare covers the following bladder-tumor tests as medically necessary for the monitoring and surveillance of treatment response in patients with documented bladder cancer: • Bladder-tumor (BTA) Stat test • Nuclear-matrix protein (NMP22) test • Aura-Tek (FDP) test- fibrin/fibrinogen degradation products • UroVysion fluorescent in situ hybridization (FISH) CIGNA HealthCare does not cover the following bladder-tumor tests for the screening of bladder cancer because these tests are considered experimental, investigational or unproven for that indication (this list may not be all-inclusive): • Bladder-tumor (BTA) Stat test • Nuclear-matrix protein (NMP22) test • Aura-Tek (FDP) test- fibrin/fibrinogen degradation products • UroVysion fluorescent in situ hybridization (FISH) CIGNA HealthCare does not cover ANY of the following serum tumor markers for screening, diagnosis, staging, routine surveillance or monitoring of cancer because these tests are considered experimental, investigational or unproven (this list may not be all-inclusive): • A2-PAG (pregnancy-associated alpha2 glycoprotein) • BCM (breast cancer mucin) • CA50 (cancer antigen 50) • CA72-4 (cancer antigen 72-4) • CA 195 (cancer antigen 195) • CA 242 (cancer antigen 242) • CA 549 (cancer antigen 549) • CA-SCC (squamous cell carcinoma) • CAM 17-1 (monoclonal antimucin antibody 17-1) • CAM 26 (monoclonal antimucin antibody 26) • CAM 29 (monoclonal antimucin antibody 29) • CAR 3 (antigenic determinant recognized by monoclonal antibody AR3) • Cathepsin-D (Ab-1 monoclonal antibody) • CYFRA21-1 (cytokeratin fragment 19) • DU-PAN-2 (sialylated carbohydrate antigen DU-PAN-2) • GCC (Guanylyl cyclase C) • 5-Hydrocyindoleascetic Acid (5-HIAA) • LASA (lipid-associated sialic acid) • LPA (lysophosphatidic acid) • M26 (monoclonal antimucin antibody) • M29 (monoclonal antimucin antibody) • MAM-6 (monoclonal antibody mouse antigen) • MSA (mammary serum antigen) • MCA (mucin-like cancer antigen) • P53 (monoclonal antibody) • P-LAP (placental alkaline phosphatase) • PNA-ELLA (peanut lectin-bonding assay) • PSMA (prostate-specific membrane antigen) • Ras (Ras Proto-oncogenes) • SCC-Ag (squamous cell carcinoma antigen) • S-100 • SLEX sialylated Lewis x-antigen) • SLX (sialylated SSEA-1 antigen) • SPAN-1 (sialylated carbonated antigen SPAN-1) Page 3 of 29 Coverage Position Number: 0172
  • • ST-439 (sialylated carbonated antigen ST-439) • TA-90 • TAG12 (tumor-associated glycoprotein 12) • TAG72 (tumor-associated glycoprotein 72) • TAG72.3 (tumor-associated glycoprotein 72.3) • TAG72.5 (tumor-associated glycoprotein 72.5) • TATI (tumor-associated trypsin inhibitor) • TNF-a (tumor necrosis factor alpha) • TPA (tissue polypeptide antigen) General Background Tumor markers are substances produced by tumor cells or by other cells within the body in response to cancer or certain benign conditions. These markers may be detected within exfoliated or distributed cells, or as circulating agents within the peripheral blood or plasma. Other surrogate biological specimens, typically bodily fluids (e.g., urine, saliva, sputum, cerebrospinal fluid, or effusions) may also carry tumor markers (NCI [a;b], 2006). Although an abnormal level of these markers may suggest cancer, their presence does not confirm a diagnosis of cancer. Measurements of these markers are combined with other diagnostic tests (e.g., biopsy, radiological imaging) to confirm a diagnosis of cancer (National Cancer Institute [NCI-a;b], 2006; Nordenson, 2002). Although numerous tumor markers have been identified, a review of the literature states that measurements of most tumor marker levels alone are often insufficient to diagnose cancer for the following reasons: 1) tumor marker levels can be elevated in people with benign conditions; 2) tumor marker levels are not elevated in every person with cancer, especially in the early stages of the disease; 3) many tumor markers are not specific to a particular type of cancer; and 4) the level of a tumor marker can be elevated by more than one type of cancer (NCI [b], 2006). As a result of these findings, guidelines and recommendations for the use of tumor markers in a range of cancers have been developed. These guidelines have been published by the American Society of Clinical Oncology (ASCO), the American Cancer Society (ACS), the NCI, and the National Comprehensive Cancer Network (NCCN). Currently, the primary use of tumor markers is to assess a cancer's response to treatment and to check for cancer recurrence. In some types of cancer, tumor marker levels may reflect the extent or stage of the disease and can be useful in predicting how well the disease will respond to treatment. A decrease or return to normal in the level of a tumor marker may indicate that the cancer has responded favorably to therapy. If the tumor marker levels continue to rise, it may indicate that the cancer has advanced or that it is resistant to the current treatment. Additionally, measurements of tumor marker levels may be used after treatment has ended as a part of follow-up care to check for recurrence (ACS, 2006; NCI [b], 2006). The National Cancer Institute (NCI) is currently conducting the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) screening trial to determine if certain screening tests may reduce patient mortality from these cancers. Along with other screening tools, PLCO researchers are studying the use of prostate- specific antigen (PSA) to screen for prostate cancer and cancer antigen (CA) 125 to screen for ovarian cancer. The final results of this trial will not be available for several years (NCI [b], 2006). Specific Tumor Markers Tumor markers can assist in determining if a cancer is present; they can assist in determining the source of widespread cancer when the origin of the cancer is unknown. By using the information that these markers can provide, patient-specific treatment protocols can be developed, implemented, and monitored for improved patient outcomes (ACS, 2006). According to numerous societies and oncology textbooks, some of the most commonly-used tumor markers include the following (this list may not be all-inclusive): Alpha-fetaprotein (AFP): AFP is normally produced by a developing fetus. AFP levels begin to decrease soon after birth, and are usually undetectable in the blood of healthy adults, except during pregnancy. AFP is determined by the enzyme-linked immunosorbent assay, which uses monoclonal antibodies in Page 4 of 29 Coverage Position Number: 0172
  • combination with other monoclonal or polyclonal antibodies. The normal adult serum concentration is usually less than 15 nanograms/milliliter (ng/mL). Approximately 10–20% of clinical stage I non-seminomatous germ cell tumors (NSGCT), 20–40% of low- volume clinical stage II, and 40–60% of advanced tumors will have increased AFP levels. Increased AFP levels are usually not seen in pure seminoma (Adkins, 2006; ACS, 2006; Bosl, 2005). An elevated level of AFP strongly suggests the presence of either primary liver cancer (hepatocellular carcinoma), or germ cell cancer of the ovary or testicle, according to accepted guidelines by ASCO, the ACS (2006), the National Academy of Clinical Biochemistry (NACB, 2006), and the NCCN (2006). As AFP is an established test for the diagnosis and monitoring of hepatoma, it is used as a screening tool to rule out the presence of a liver neoplasm before considering liver transplantation. This is especially pertinent in cases where there is an increased risk of developing a primary liver tumor (e.g., cirrhosis). AFP can also be elevated in nonmalignant liver disease. To increase the sensitivity and specificity for hepatocellular carcinoma (HCC) screening, AFP may also be measured along with des-gamma-carboxy prothrombin (DCP) and lectin reactive AFP (AFP-L3) (Sterling, 2007). Beta2 –microglobulin (β 2M): This marker has become a standard measure of multiple myeloma (MM) tumor burden (NCCN [m], 2007). β2M levels may be present in other conditions, including chronic lymphocytic leukemia (CLL), some lymphomas, Crohn’s disease and hepatitis. Levels of β 2M may also be used to determine possible causes of renal failure (American Association for Clinical Chemistry [AACC], 2006). Normal levels are usually below 2.5 micrograms per milliliter (ug/ml). β 2M is useful in helping to determine prognosis in some cancers (ACS, 2006). Beta2 –microglobulin in combination with C-reactive protein as a surrogate marker for interleukin-6 and lactic hydrogenase (LDH) can serve as a measure of tumor burden in lymphoma-like or plasmablastic myeloma (Adkins, 2006). Cytogenetics with or without fluorescence in situ hybridization (FISH) tests may detect chromosomal abnormalities that may suggest a worse prognosis for patients with MM. FISH provides valuable information for risk stratification in addition to standard prognostic factors and should be considered as part of the patient workup (NCCN [m], 2007). Bladder Tumor Antigens (BTA) and NMP22: These urine-based bladder antigens have been shown to have clinical utility in detecting recurrent low-grade bladder tumors. For patients with a history of bladder cancer, these markers may assist in determining the need for additional cystoscopic assessment. Urine cytology with confirmatory cystoscopy remains the standard test for the identification and diagnosis of bladder tumors, according to guidelines by the ACS (2006). However, the subjectivity and low sensitivity of cytology led to the development of several urine-based tests that identify urinary molecular cancer markers (AACC, 2006; Shipley, 2005). Urine-based tests that have been approved for use in the monitoring of molecular markers include the BARD Stat™ Test ([BTA], Bard Diagnostic, Redmond, WA); the NMP22® BladderChek™ Kit (Matritech, Newton, MA); the AuraTek FDP ([AccuDX™], PerImmune, Rockville, MD); and the UroVysion™ Bladder Cancer Kit (UroVysion Kit, Vysis, Inc. [a wholly-owned subsidiary of Abbott Laboratories] Downers Grove, IL) (Food and Drug Administration [FDA] 1995; 2002; 2005). According to the ACS (2006), these urine-based tests are recommended for use in the follow-up of treatment for bladder cancer; monitoring for eradication of the cancer; and recurrence after eradication. So far, no single bladder tumor marker has emerged as the generally accepted test of choice, and none has been established as a screening tool for bladder malignancy. The United States Preventive Services Task Force (USPSTF) has also addressed the role of screening for bladder cancer. They noted that screening tests have a low positive predictive value and yield many false-positive results, leading to unnecessary invasive procedures. As a result, the USPSTF concluded that the potential harms of screening for bladder cancer outweigh any potential benefits (USPSTF, 2004). Outcomes from prospective randomized trials are needed before the clinical utility of these tests can be incorporated into the routine diagnosis and management of superficial bladder cancer. Page 5 of 29 Coverage Position Number: 0172
  • Cancer Antigen (CA-125): CA-125 is an antigen produced by a variety of cells, but particularly by ovarian cancer cells, and is used primarily in the management of treatment for ovarian cancer (ACS, 2006; Eaton, 2007). There is insufficient evidence available in the literature to support the measurement of CA-125 as an effective screening marker in the general population. The test is not likely to decrease ovarian cancer mortality because of the lack of specificity of the test and high case fatality rate of ovarian cancer (Eaton, 2007; NCI, 2006; Kumar, 2005; Carlson, 1994). CA-125 levels may also be elevated by cancers of the uterus, cervix, pancreas, liver, colon, breast, lung, and digestive tract. Noncancerous conditions that can cause elevated CA-125 levels include: endometriosis, pelvic inflammatory disease, peritonitis, pancreatitis, liver disease, and any condition that inflames the pleura. Menstruation and pregnancy can also cause an increase in CA-125. However, according to the available literature, changes in CA-125 levels can be effectively used in the management of treatment for ovarian cancer. In women with ovarian cancer being treated with chemotherapy, the literature suggests a falling CA-125 level generally indicates that the cancer is responding to treatment and increased survival is expected. Increasing CA-125 levels during or after treatment, on the other hand, may suggest that the cancer is not responding to therapy or that residual cancer remains. Under accepted guidelines and standards of practice, CA-125 levels can also be used to monitor patients for recurrence of ovarian cancer. Although an elevated CA-125 level is highly correlated with the presence of ovarian cancer, the literature suggests a normal value does not exclude residual or recurrent disease (NCCN [n], 2007; Sokoll, 2004). Cancer Antigen (CA 15-3) (also referred to as CA 27-29 or Truquant RIA): CA 15-3 is a serum cancer antigen that is used in the management of patients with breast cancer. According to the available literature, its low detection rate in early-stage disease indicates that CA 15-3 cannot be used to screen or diagnose patients with breast cancer (ACS, 2006; ASCO, 2000). It has been widely used to monitor the effectiveness of treatment for metastatic cancer. Cancers of the ovary, lung, and prostate may also raise CA 15-3 levels. The literature indicates elevated levels of CA 15-3 may be associated with noncancerous conditions, such as benign breast or ovarian disease, endometriosis, pelvic inflammatory disease, and hepatitis. Similar to the CA 15-3 antigen, CA 27-29 is found in the blood of most breast cancer patients. The literature indicates CA 27-29 levels may be used in conjunction with other procedures (e.g., mammograms, and measurements of other tumor marker levels) to check for recurrence in women previously treated for stage II and stage III breast cancer (Sokoll, 2004). CA 27-29 levels can also be elevated by cancers of the colon, stomach, kidney, lung, ovary, pancreas, uterus, and liver. Non- cancerous conditions that can also elevate CA 27-29 levels include: first trimester pregnancy, endometriosis, ovarian cysts, benign breast disease, kidney disease, and liver disease (AACC, 2006; Dickson, 2005; Sokoll, 2004). Cancer Antigen (CA 19-9): CA-19 can be produced by adenocarcinomas of the pancreas, stomach, gall- bladder, colon, ovary and lung. Levels of CA 19-9 have also been identified in patients with hepatocellular and bile duct cancer. In individuals who have pancreatic cancer, the literature indicates that higher levels of CA 19-9 tend to be associated with more advanced disease (ACS, 2006). Although levels of CA 19-9 may be relatively high in patients with advanced pancreatic cancer, its levels may also be elevated in patients with benign pancreatic or liver disease. CA 19-9 is commonly expressed and shed in pancreatic and hepatobiliary disease as well as in many malignancies; thus, it is not tumor- specific (NCCN [o], 2007) Noncancerous conditions that may elevate CA 19-9 levels include gallstones, pancreatitis, cirrhosis of the liver, and cholecystitis. Neither CA19-9 nor CEA have proven sensitivity or specificity levels to warrant their use in the routine screening for pancreatic cancer (ACS, 2006; Clark, 2006). Although numerous studies have addressed the potential utility of CA 19-9 in adenocarcinoma of the colon and rectum, the sensitivity of CA 19-9 was always less than that of the carcinoembryonic antigen (CEA) test for all stages of disease (ACS, 2006). Its use for screening asymptomatic populations has been hampered by a false-positive rate of 15–30%, in patients with non-neoplastic diseases of the pancreas, liver, and biliary tract. Only a few studies have addressed the use of CA 19-9 in monitoring Page 6 of 29 Coverage Position Number: 0172
  • patients' post-primary therapy. Significant post-surgical decreases are observed for CA 19-9, but these decreases have not been correlated with survival or disease-free interval. In monitoring response to treatment, decreases in CEA have been found to more accurately reflect response to therapy than did decreases of CA 19-9. Progressive increases of the marker may signal disease progression in 25% of the patients who express the CA 19-9 marker, but this monitoring may provide an average lead time of one to possibly a year in some patients (NACB [d], 2006) In monitoring patients with colorectal cancer (CRC), CA 19-9 has not been shown to improve patient outcomes. According to texts, CA 19-9 is not recommended for screening, diagnosis, surveillance, or staging of CRC. The serum CA 19-9 level does not add significant information to that provided by CEA, which is currently regarded as the marker of choice for this neoplasm (ASCO, 2006; Libutti, 2005). Calcitonin: This is a hormone produced by certain cells (i.e., parafollicular C cells) in the thyroid gland. It helps to regulate blood calcium levels. In cancers of the parafollicular C cells, called medullary carcinoma of the thyroid, levels of this hormone are elevated. This is one of the rare tumor markers that can be used to help diagnose early cancer (ACS, 2006). Because medullary carcinoma of the thyroid is often inherited, blood calcitonin can be measured to detect the cancer in its earliest stages in family members who are at risk. Other cancers, particularly lung cancers, can produce calcitonin, but measurement of its level in the blood is not usually used to follow these cancers (ACS, 2006; Sokoll, 2004). Carcinoembryonic Antigen (CEA): CEA is a normal cell product that is overexpressed by adenocarcinomas, primarily of the colon, rectum, breast, pancreas, and lung (ACS, 2006). It is normally found in small amounts in the blood of most healthy people, but may become elevated in people who have cancer or some benign conditions (e.g., liver dysfunction, hydronephrosis, peptic ulcer disease, pancreatitis, biliary obstruction, bowel obstruction, inflammatory bowel disease, and post-5-fluroouracil (5- FU)/-levamisole chemotherapy). In patients with primary gastric cancer, elevated levels of CEA have also been found. Although CEA as a marker for gastric cancer has a low sensitivity, when levels of this antigen are elevated, it may correlate with the stage of the cancer involved. The sensitivity of this marker can be improved in the detection of gastric cancer by combining CEA results with outcomes of other markers such as sialylated Lewis antigens CA19-9 or CA50 (Pisters, 2005). According to the available literature, the primary use of CEA is in monitoring colorectal cancer (CRC), especially when the disease has metastasized (ACS, 2006). CEA has a low sensitivity and specificity; therefore, it should not be used as a screening tool. Elevated levels of CEA correlate with the various stages of CRC and may be measured after treatment to check for recurrent CRC (Clark, 2006; Libutti, 2005). The National Comprehensive Cancer Network (NCCN [f], 2007) clinical practice guidelines for colon cancer include the determination of CEA levels in patients who present with invasive colon cancer as part of their comprehensive staging workup. After surgical resection has occurred, should CEA levels become elevated, the panel recommends the use of diagnostic studies. If local recurrence or isolated lesions of metastasis within the liver or lung are identified, then surgical resection may be an option (NCCN, 2007; ASCO, 2005). In 2005, the American Society of Clinical Oncology (ASCO) updated their practice guidelines on the use of CEA in patients with colorectal cancer. Postoperative CEA levels in patients with stage II or III disease may become falsely elevated during active treatment, it is advised that these levels be obtained after adjuvant treatment is completed (Desch, 2005). According to ASCO (2006): “Screening: CEA is not recommended to be used as a screening test for colorectal cancer. It may be ordered preoperatively in patients with colorectal carcinoma if it would assist in staging and surgical treatment planning. Although elevated preoperative CEA (> 5 nanograms/milliliter [ng/mL]) may correlate with poorer prognosis, data is insufficient to support the use of CEA to determine whether to treat a patient with adjuvant therapy. Postoperative: serum CEA testing should be preformed every three months in patients with stage II or III disease for at least three years after diagnosis, if the patient is a candidate for surgery or Page 7 of 29 Coverage Position Number: 0172
  • systemic therapy. An elevated CEA, if confirmed by retesting, warrants further evaluation for metastatic disease, but by itself does not justify systemic therapy for presumed metastatic disease. Because chemotherapy may falsely elevate CEA levels, waiting until chemotherapy is finished to initiate surveillance is advised. Monitoring Response to Therapy: CEA is regarded as the marker of choice for monitoring metastatic colorectal cancer during systemic therapy. CEA should be measured at the start of treatment for metastatic disease and every one to three months during active treatment. Persistently rising values above baseline should prompt restaging but suggest progressive disease even in the absence of corroborating radiographs. Caution should be used when interpreting a rising CEA level during the first four to six weeks of a new therapy, since spurious early rises may occur especially after oxaliplatin” (Locker 2006). CEA has not been recommended for the screening, diagnosis, staging, or follow-up in patients with lung or breast cancer after primary therapy (Sokoll, 2004; Bigbee, 2003). Chromogranin A (CgA): CgA is produced by neuroendocrine tumors, which include carcinoid tumors, neuroblastoma, and small cell lung cancer. The blood level of CgA is often elevated in people with carcinoid tumors or other neuroendocrine tumors. It is probably the most sensitive tumor marker for carcinoid tumors, being abnormal in one out of three people with localized disease and two out of three with metastatic cancer. It may be ordered in conjunction with other tumor markers to differentiate tumor cell types. Levels can also be elevated in some advanced forms of prostate cancer that have neuroendocrine features. The range of normal blood level varies between testing centers, but is generally less than 76 ng/ml in men and less than 51 ng/ml in women (Borglum, 2007; ACS, 2006; NACB [i], 2006). Estrogen Receptors (ERs) and Progesterone Receptors (PRs): These are intracellular receptors that are measured directly in tumor tissue. Most oncologists use the estrogen receptor and the progesterone receptor not only to predict the probability of response to hormonal therapy at the time of diagnosis, but also to predict the likelihood of recurrence. Patients with invasive breast cancer whose tumors lack ERs and PRs may not respond to or derive benefit from hormonal therapy (ACS, 2006). Estrogen and progesterone receptors are usually not used for monitoring or follow-up, as their measurements are determined directly from tissue samples (Pister, 2005). Two large databases that encompassed more than 15,000 women were reviewed to determine the efficacy of measuring ERs and PRs prior to initiating tamoxifen therapy. Patients with negative tumor receptors did not receive endocrine treatment, while those with positive receptors did receive treatment. The researchers concluded that these measurements accurately correlated with the response that was seen during the treatment in these patients (Pister, 2005). HER-2/neu (c-erbB-2) Markers: The human epidermal growth factor receptor 2 gene ERBB2 (commonly referred to as HER-2) is amplified in approximately 18–20% of breast cancers. HER-2 overexpression is associated with clinical outcomes in patients with breast cancer, and is also predictive of several systemic therapies. The clinical utility of these markers assist in the personal stratification of patients to anti-HER-2- based therapies. The measurement of HER-2 in primary breast tumors at the time of diagnosis or at the time of recurrence has been recommended by ASCO. These markers are measured directly by immuno- histological staining of the tumor tissue (Wolff, 2007; NCCN [c], 2007; ACS, 2006; Abeloff, 2004; Bigbee, 2003). At this time, these genetic markers are not used for the continuous monitoring or follow-up, as additional research is underway to better understand the complexity of their response to chemotherapeutic and antihormonal agents (Wolff, 2007; ACS, 2006; Pister, 2005). In 2007, the NCCN [c] published guidance on the use of tumor markers during post-therapy surveillance and follow-up of patients treated for breast cancer. Their guidance is based on a lack of evidence within the published literature to support the use of tumor markers during this time, in the asymptomatic patient, as their clinical utility provides no advantage in survival or ability to palliate recurrent disease. Page 8 of 29 Coverage Position Number: 0172
  • Human Chorionic Gonadotropin (HCG): HCG (also known as beta-HCG [β-HCG]) is a glycoprotein that can be elevated in patients with some types of testicular and ovarian cancer (e.g., germ cell tumors) and in gestational trophoblastic disease (i.e., choriocarcinoma). This marker may also be elevated due to mediastinal cancer that originates from testicular cancer cells (mediastinal germ cell neoplasms), bladder, prostate, ureteral, and renal cancers. Levels of these markers can be used to assist in diagnosing these conditions and can be used to monitor the effectiveness of treatment. The reappearance of these markers following treatment may be an indication of cancer recurrence (Sokoll, 2004; Bigbee, 2003; Nordenson, 2002). In the evaluation of patients suspected of having testicular germ cell tumors, levels of HCG, AFP and LDH are obtained. These presurgical levels can be used diagnostically for staging of the tumor, as prognostic information, as well as for measuring disease progression and response to therapy (Small, 2004). Accepted guidelines provide that HCG levels can be used to screen for choriocarcinoma (a rare cancer of the uterus) in women who are at high risk for the disease and to monitor the treatment of trophoblastic disease (a rare cancer that develops from an abnormally fertilized egg). The literature states that elevated HCG levels may also indicate the presence of cancers of the testis, ovary, liver, stomach, pancreas, and lung. Also reported have been false elevations of HCG secondary to either cross-reactivity of the antibody with luteinizing hormone (LH); treatment-induced hypogonadism, which may resolve with testosterone replacement; or pituitary production of HCG (Muggia, 2005). Neuron-Specific Enolase (NSE): NSE has been detected in patients with neuroblastoma, small cell lung cancer, Wilms' tumor, melanoma, and cancers of the thyroid, kidney, testicle, and pancreas. However, studies of NSE as a tumor marker have concentrated primarily on patients with neuroblastoma, and small cell lung cancer. According to the available literature, measurement of NSE level in patients with lung cancer can provide information about the extent of the disease, the patient's prognosis, and the patient's response to treatment. This marker is not used as a screening test for cancer (ACS, 2006; NACB [g], 2006; ASCO, 2003; Nordenson, 2002). Prostate-Specific Antigen (PSA): PSA is present in low concentrations in the blood of all adult males. It is produced by both normal and abnormal prostate cells. Elevated levels of PSA may be found in the blood of men with benign prostate conditions, such as prostatitis and BPH, or with a malignant growth in the prostate (NCI [c,d], 2006; ACS, 2006). While PSA does not allow distinction between benign prostate conditions and cancer, an elevated PSA level may indicate that other tests are necessary to determine whether cancer is present. PSA levels are useful for determining the success of initial surgical or radiation treatment of prostate cancer. After radical prostatectomy, PSA concentrations should decrease to undetectable levels if the tumor was organ-confined and all prostatic tissue was removed. After allowing for sufficient clearance of pretreatment PSA (total PSA half-life of two to three days), finding detectable post-treatment PSA suggests remaining prostate tissue or the presence of metastases (Sokoll, 2004). It has also been determined that there is no PSA level below which a man can be assured that he has no risk of prostate cancer (NCI [d], 2007). Within the NCCN guidelines for prostate cancer, the incorporation of a risk stratification scheme has been applied that uses prostate tumor stage, grade and PSA levels to assign individuals to risk groups that predict the probability of biochemical failure (i.e., probability of a rising PSA, which is also termed biochemical recurrence or PSA failure). Predicting prognosis is essential for patient decision-making, treatment selection, and adjuvant therapy with surveillance (NCCN [o], 2007). The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) has completed its accrual, and is now studying the effect of early prostate screening using serum PSA levels, and digital rectal exams are being measured. Outcomes from this study will not be available until 2015 (NCI [o], 2007). Prostatic Acid Phosphatase (PAP): While useful for monitoring prostate malignancy, this is less useful than the PSA test. The PAP test was used before the PSA test was developed. It is rarely used now, because the PSA test is much more sensitive (ACS, 2006; Sokoll, 2004). Page 9 of 29 Coverage Position Number: 0172
  • Thyroglobulin: Produced by the thyroid gland, thyroglobulin is elevated in many thyroid diseases. However, when thyroid cancer is surgically removed, the whole thyroid gland is usually also removed. Any elevation of the thyroglobulin level above 10 ng/ml suggests the cancer has returned. According to the ACS, thyroglobulin levels can be followed to evaluate the results of treatment for metastatic thyroid cancer (Sokoll, 2004). Some individuals’ immune system make antibodies against thyroglobulin, which may affect the test results; because of this, levels of anti-thyroglobulin antibodies may also be measured (ACS, 2006; NACB [o], 2006). Summary of Currently Accepted Tumor Markers: Based on a review of the peer-reviewed literature; numerous medical and oncology textbooks and guides from the American Cancer Society (ACS); the American Society of Clinical Oncology (ASCO); the National Academy of Clinical Biochemistry (NACB); the National Cancer Institute (NCI); and the National Comprehensive Cancer Network (NCCN), there is sufficient evidence for the use of specific serum tumor markers for the diagnosis of cancer, staging, monitoring of treatment response and follow-up in specific patient populations. Common Cancers and Associated Tumor Markers Bladder Cancer: At the present time, there are no tumor markers that can be used for the screening of bladder cancer. The management of bladder cancer is based on the pathologic findings of biopsy specimen (histology type, tumor grade, depth of invasion). These factors (i.e., bladder tumor antigen [BTA] and NMP22) are used to estimate the probability of recurrence and progression to a more advanced stage in conjunction with cytoscopy and urinary cytology (ACS, 2006; NACB [a], 2005; NCCN [b], 2007). Researchers have proposed the use of newer tests that assist in the early detection of bladder changes that may be precursors of recurrent bladder cancer. These tests have been approved for use in the detection of bladder tumors and include the BARD Stat™ Test ([BTA], Bard Diagnostic, Redmond, WA); approved in 1995 by the FDA as a class II device for the detection of bladder tumor antigens in the urine of patients with a history of bladder cancer. The presence of these antigens could signify the recurrence of bladder cancer. The use of this test aids in the management of bladder cancer in conjunction with cystoscopic examination and was approved for use in the laboratory or in the home setting. In 2002, the FDA approved the use of the NMP22® BladderChek™ Kit (Matritech, Newton, MA) as a class II device to aid in the qualitative detection of the nuclear matrix protein NMP22 in the urine of patients with a history of bladder cancer. This approval was based on the predicate approval of the BTA Stat™ Test. This test could be used in the physician’s office or by prescription for home use, in conjunction with other standard diagnostic procedures. Clinical trials of the NMP22 test versus standard cystoscopy produced sensitivity levels of 45.9% and specificity levels of 86.3%, versus sensitivity levels of 56.3 and specificity of 89.0%, respectively. The AuraTek FDP ([AccuDX™], PerImmune, Rockville, MD) test is a rapid urine dipstick immunoassay laboratory test for the detection of fibrin/fibrinogen degradation products. These positive results may be indicative of the recurrence of bladder cancer, and its use should be in conjunction with other diagnostic procedures. This lab test is categorized by the FDA as part of their clinical laboratory improvement amendments (CLIA). In 2005, the FDA granted premarket approval for the use of the UroVysion™ Bladder Cancer Kit (UroVysion Kit, Vysis, Inc. [a wholly-owned subsidiary of Abbott Laboratories], Downers Grove, IL) in conjunction with and not in lieu of current standard diagnostic procedures, as an aid for initial diagnosis of bladder carcinoma in patients with hematuria and subsequent monitoring for tumor recurrence in patients with a history of bladder cancer. This is a Class II quantitative device with reported sensitivity and clinical specificity levels of 68.6% and 77.7% compared to urine cytology with sensitivity and relative specificity levels of 39.2% and 91.5%. Summary—Bladder Cancer: Because the clinical benefit of ploidy, vascularity, p53 status, and other markers (e.g., NMP-22, BTA, M344) remains unknown, these markers are not recognized as diagnostic indicators, but may be used during the monitoring of treatment or surveillance of patients with a history of bladder cancer (ACS, 2006; NCCN [b], 2007). Page 10 of 29 Coverage Position Number: 0172
  • Breast Cancer • BRCA1, BRCA2, HER-2/neu: No specific tumor marker has been found that can be used for screening of the general population for the diagnosis of early stage breast cancer. Individuals with a familial history of breast cancer may be tested for the presence of the BRCA1and/or BRCA2 markers within their serum. The presence of these markers can identify individuals who are at an increased risk for the development of breast cancer due to inherited risk. Histological samples of breast tumor tissue may be used to evaluate the presence or absence of estrogen or progesterone receptors, BRCA1 or BRCA2 proteins, as well as the HER-2/neu antigen. This information, along with histological grading and tumor staging may provide information for patient-specific treatment regimens to be determined and response to therapeutic interventions can be followed. These markers are not recommended to be used during the on- going surveillance of patients with early-stage disease but may be helpful in the surveillance of patients with advanced breast cancer (ACS, 2006; NACB [b], 2006; Khatcheressian, 2006; NCCN [c], 2007; Sukumvanich, 2007; Wolff, 2007). • CA 15-3, CA27-29 or Truquant RIA: Other markers (i.e., CA 15-3, CA27-29 or Truquant RIA) may also be used to monitor patient response to treatment. These markers are not as specific as serum levels of estrogen or progesterone receptors and are therefore used as adjunct markers of treatment response (ACS, 2006; NACB, 2006). These markers are recommended as part of the surveillance protocol for high-risk patients with advanced cancer and/or for symptomatic patients following treatment of their primary breast cancer (Khatcheressian, 2006, HAYES [d], 2007; Keating, 2007; Hayes D, 2007; NCCN [c], 2007). • Mammaglobulin, Mucin 1: While numerous secreted and cell surface proteins (e.g., mammoglobulin, mucin I) have been identified and potentially linked to the development of breast cancer, only a few have been studied and demonstrate specificity for clinical utility. Many of these proteins have been found as surrogate markers for various types of cancer, including ovarian cancer (Ferguson, 2005). Zehentner et al. (2004) conducted a study to measure the potential clinical utility of a mammaglobulin multigene reverse transcription-PCR assay and a mammaglobulin sandwich enzyme-linked immunosorbent assay (ELISA) as diagnostic tools in breast cancer. During this study, 147 untreated women with biopsy-confirmed breast cancer were evaluated along with 94 serum samples from healthy individuals (control group). The researchers noted that most of the women in this study had advanced disease and large tumors, with only 33% of tumors being 5 centimeters or less in size, whereas 43% were ten centimeters or greater. Nodal involvement was found in 92% of the patients, and 80% of the cancers were stage III and higher. Circulating mammaglobulin was detected in the serum of 142 women with confirmed breast cancer and was detected in 70% of the serum samples. A concentration of 1.71µg/l was established as a positive level, giving a breast cancer specific mammaglobulin protein concentration that was positive in 38% of the 142 cancer serum samples but only 3% of the 91 control samples. Mammaglobulin serum protein was marginally associated with increasing tumor size (P=0.09), but not with lymph node involvement (P=0.5). This serum protein was marginally associated with increasing clinical stage of disease (P=0.10), with only 29% of women with stage I or II cancer compared to 31% of those with stage IIIA, 34% of those with stage IIIB, and 48% of those with stage IV. When the assay was read using the ELISA, 84% of the women had increased mammaglobulin or detectable multigene transcripts. The researchers concluded that circulating mammaglobulin may be a good marker to monitor treatment and detect disease recurrence. It may also have a clinical utility when used in combination with other markers, but additional studies are needed within healthy populations to identify the conditions that could influence the serum mammaglobulin protein concentration levels. This study was small in size and consisted of a study population of known breast cancer patients with advanced disease. It has yet to be determined what patient population should be tested and what specific level of mammaglobulin would be clinically useful to determine disease presence or treatment response. The possible use of mammaglobulin A (SCGB2A2) and lipophilin B (SCGB1D2) in the diagnosis and treatment monitoring of patients with breast cancer led Zafrakas and colleagues (2006) to conduct a systematic analysis on a panel of 309 solid tumors, corresponding normal tissue samples and in 11 Page 11 of 29 Coverage Position Number: 0172
  • cell lines, to evaluate their tissue specific expression and co-expression pattern(s). The researchers found that mammoglobulin A expression was abundant in malignant and normal samples from the breast, uterus, ovaries and uterine cervix. It was absent in the majority of other tumor types including prostate, kidney, colon, rectum, small intestine, stomach, pancreas, lung and thyroid. In a small number of samples, it was present in both malignant and normal tissue. Lipophilin B was abundant in malignant and normal samples from the breast, uterus, ovaries, and uterine cervix. It was also found abundantly in matched samples from the kidney and the prostate. Co-expression of mammaglobulin A and lipophilin B was highly significant in breast, uterine and ovarian tissues (each P< 0.01) but failed to reach significance in cervical tissues due to small sample size (n=2). Among the normal tissue tested, mammaglobulin expression was highest in normal tissue from the uterine cervix, followed in descending order by normal breast tissue, thyroid, uterus, testis, trachea, and stomach. Lipophilin B expression was highest in normal tissue of the cervix, then the uterus, breast, kidney, colon, pancreas, heart, placenta, and testis. These results were obtained using non-radioisotopic riboneucleic acid (RNA) in situ hybridization and immunohistochemical analysis. The researchers concluded that: 1) mammaglobulin A is expressed by various normal and malignant tissues other than the breast and therefore is not an ideal breast-specific marker, 2) based on these findings, mammaglobulin A could also be used in diagnostic assays for the detection of gynecologic malignancies, and 3) the co-expression of lipophilin B and mammaglobulin A are not restricted to breast tumors but are also found in normal and malignant tissue of the uterus, ovaries, and uterine cervix. The potential use of these expressions may lead to less specific results in the diagnosis of breast cancer. • TP53: A surrogate marker, TP53 is also being studied to determine its clinical utility in determining patient prognosis as well as possible chemolytic drug resistance in the treatment of breast cancer. Studies that have been conducted have produced ambiguous results concerning the direct use of this marker (Abeloff, 2004). Combination Study of Breast Tumor Antigens during Surveillance: In 2007, Keating et al. conducted a population-based cohort study of early-stage breast cancer survivors at low risk of recurrence for cancer to measure the use of radiographic imaging (i.e, bone scans, MRIs, chest films), and tumor antigen levels and provider trends in testing during a three-year surveillance period. Surveillance periods were defined as: months seven to 18; 19–30, and 31–42 after diagnosis. Of the 44,511 early-stage breast cancer survivors, 37,967 were observed through surveillance year one; 30,406 were observed through surveillance year two; and 23,016 were observed through surveillance year three. Throughout surveillance year one of 37,967 patients observed, 13.3% had at least one bone scan; 29.2% had a tumor antigen tests; 10.9% had chest/abdominal imaging; and 58.8% had a chest x-ray. Of 23,016 patients observed through the end of surveillance year three, 2.1% had yearly bones scans; 16.0% had yearly tumor antigen testing; 1.0% had yearly chest/abdominal imaging; and 29.2% had yearly chest x-rays. Women who were being seen by medical oncologists had high rates of annual testing (e.g., 37% received a tumor antigen tests annually versus 6.7% of the women with no visits to a medical oncologist; (P<.001). The researchers note that their data does not allow for a clear review of why the tests were ordered—for surveillance or for the evaluation of symptoms. Another unknown is whether the additional testing led to an increase in the early detection of recurrent disease. The high rates or annual testing within this low-risk population suggests that these tests are being ordered on a routine basis. This study was based on data gleaned from the American Medical Association database, and information from the Surveillance, Epidemiology, and End Results registries. This could have led to minimal information being used for this analysis, and the researchers noted that certain conclusions could not be reached due to incomplete data sets. Summary— Breast Cancer: While there is no tumor marker that can be used for screening an individual for the present of breast cancer, through the use of serum samples and histological staining, adjuvant levels of BRCA1, BRCA2, and HER-2 neu can assist in confirming a diagnosis of breast cancer or the possible existence of metastasis. Estrogen and progesterone receptors, as well as antigen (CA15-3 or CA27-29) levels can be used for the development of a patient-specific treatment protocol and, during treatment, a patient’s response to therapy. Once the patient has completed therapy and they are not considered a high-risk individual, the ongoing measurement of these antigens is no longer recommended. If a patient is symptomatic or signs of possible recurrence are present, then the use of these markers can be advantageous. Page 12 of 29 Coverage Position Number: 0172
  • Colon Cancer: There is no tumor marker that can be used to screen for the presence of colon cancer. • CEA: Levels of CEA are used during the staging and treatment planning for colon cancer. Levels are taken preoperatively and may be used to determine whether to treat the patient with adjuvant therapy. Post-therapy levels are used for surveillance of recurrent cancer or possible metastases (NCCN [f], 2007; Locker, 2006). • Dihydropyrimidine Dehydrogenase (DPD), Thymidine Synthase (TS) and Thymidine Phophorylase (TP): While these tissue markers have been used to predict a patient’s response to treatment of established carcinomas, they are not recommended for use in screening for colon cancer. None of these markers are recommended for use in determining prognosis or in predicting response to therapy. Their role in monitoring therapeutic response has also not been determined (Locker, 2006). Based on literature reviews, ASCO has determined that there is insufficient evidence to support the use of CA 19-9, p53 expression, or ras oncogene for screening, diagnosis, staging, surveillance, or monitoring treatment of patients with colon cancer. Levels of CA 19-9 may be obtained in the presence of localized disease and then used as a reference along with other diagnostic tests as an indicator of progressive disease (Locker, 2006). There is also insufficient evidence for the use of assaying the loss of heterozygosity (LOH) on chromosome 18 (18q), determining DCC protein or microsatellite instability (MSI) measures to determine prognosis or to predict response to therapy (Locker, 2006). Summary—Colon Cancer: At the present time, CEA is the standard tumor marker that is used to assist in staging, determining patient-specific treatment protocols. Levels of this marker may also be utilized in the post-therapy phase for the surveillance of cancer recurrence or metastases. Endometrial Cancer: Endometrial cancer is a surgically treated and staged tumor. During the pretreatment evaluation, the detection of unresectable disease and a determination of operative risk are foremost. A serum CA-125 assay may be predictive of occult extrauterine disease and may be useful as a tumor marker. Data suggesting a prognostic role for DNA ploidy, S-phase fraction, oncogenes, tumor suppressor genes, AgNOR, and nuclear morphometric features should be considered preliminary, as some tumors are aneuploid or overexpress p53 (Burke, 2005). • CA -125: CA-125 may be a useful marker in diagnosing endometrial cancer. Although this marker may have elevated levels in the presence of other cancers, it can also be used to monitor a patient’s response to therapy or in the detection of co-existing cancers (Locker, 2006). • G Protein Coupled Estrogen Receptor (GPR30) and Epidermal Growth Factor Receptor (EGFR): These are two markers that are currently being studied for possible use in the management of endometrial cancer. Smith and colleagues (2007) conducted a study of 47 consecutive women who were diagnosed with endometrial cancer between 1997 and 2001 (tissue acquisition and surveillance are ongoing). At the time of surgery, serum samples were obtained along with tissue samples. The purpose of this investigation was to evaluate expression of G protein coupled estrogen receptor (GPR30) and to correlate these findings with the expression of classic steroid receptors (ER, PR), epidermal growth factor receptor (EGFR), and mouse monoclonal antibody (Ki-67), a proliferative marker predictive of survival in endometrial cancer. The majority of patients (63.8%) had stage I disease, and both EGFR and GPR30 were overexpressed more frequently in advanced disease and in tumors with deep myometrial invasion (P=.035 versus P=.059, respectively). The researchers did not find these outcomes to be statistically significant in relation to levels observed for Ki-67, ER or PR. This study links GPR30, a newly discovered estrogen receptor, with many clinical and pathological features for patients with type II endometrial tumors, as well as a direct correlation with poor survival. Additional studies are needed to verify this data in larger populations, with even distribution of endometrial disease before its clinical utility can be determined. Additional populations would also require study for its clinical use in other solid tumors that are linked to estrogen and progesterone receptors. Page 13 of 29 Coverage Position Number: 0172
  • Summary— Endometrial Cancer: CA-125 is the most useful marker at this time for use in patients diagnosed with endometrial cancer. There are several additional makers that are currently under study for possible use in the diagnosing and management of endometrial cancer. Hepatocellular Carcinoma (HCC): The majority of patients with HCC have underlying liver dysfunction from cirrhosis; routine liver function tests are poor screening tests for the presence of HCC. One relatively sensitive test for the presence of HCC is alpha-fetaprotein (AFP) (NCCN [i]; Weber, 2004). • Alpha-fetaprotein (AFP): Although AFP is not sensitive or specific, an AFP level above 200ng/dl is highly suspicious for HCC (del Pozo, 2007). Patients with cirrhosis are often incidentally discovered to have HCC because of an elevated AFP level or a liver mass found at the time of routine examination (Weber, 2004). Serum AFP is relatively sensitive for screening when HCC is suspected. An AFP level of greater than 20 ng/ml in a patient with a liver mass is highly sensitive but not specific enough for the diagnosis of HCC. AFP levels of greater than 500 are diagnostic of HCC, and an AFP level greater than 2000 is a poor prognostic indicator. Although AFP is the most widely-used screening and diagnostic test for HCC, it may be measured along with des-y-carboxy prothrombin (DCP) and Lens culinaris agglutin-reactive fraction (AFP-L3), as the co-existence of these measures may be indicative of disease burden. Risk factors for recurrence of HCC, once treated, include tumor size, vascular invasion, and high preoperative levels of AFP. Measuring levels of AFP as part of post-treatment surveillance is an accepted protocol for patients with HCC (Weber, 2004). Lung Cancer—Chromagranin A: Levels of Chromagranin A are normally found in endocrine cells and neurons and is a promising tumor marker because most neuroendocrine tumors, including silent tumors without secretion of known hormones, express and release CgA. Ovarian Cancer—AFP and b-HCG: The use of AFP and b-HCG in combination has been shown to have clinical utility in diagnosing ovarian cancer. CA-125 may be used to assist in monitoring patient treatment response and in the early detection of cancer recurrence. A tumor marker does not exist for the screening of ovarian cancer (Thigpen, 2004; ACS, 2006; NCCN [n], 2007). Pancreatic Cancer—CA 19-9: There is insufficient evidence to support the use of CA 19-9 as a screening marker of pancreatic cancer. Levels that are determined prior to surgical intervention may be useful for the surveillance of disease recurrence. CA 19-9 levels have also been used as a measure of therapeutic response to chemotherapeutics and are used to assist in personalizing therapeutic regimens for patients with locally advanced or metastatic disease (Locker, 2006). Prostate Cancer • PSA, PAP: As part of the PLCO trial, the use of PSA in the screening of individuals for prostate cancer is currently being studied in conjunction with rectal examinations. Serum PSA levels have become an integral part of the diagnosis, treatment monitoring and surveillance regimens that are currently practiced in patients with prostate cancer (NCCN [o], 2007). Researchers are also studying the clinical utility of PSA levels over time, instead of a single test result (ACS, 2006; NCI, 2007). An older marker that could be used, although its sensitivity is less than that of PSA, is the prostate acid phosphatase (PAP) (Sokoll, 2004). • Early Prostate Cancer Antigen (EPCA-2.22): There are newer markers and assays also being studied for use in the early detection of prostate cancer that may be more specific than PSA. One such study was conducted to measure the effectiveness of the EPCA-2.22 (an early prostate cancer antigen) in delineating individuals with organ-confined from individuals with nonorgan-confined prostatic cancer. The researchers did find that the assay had a high specificity and shows promise as a serum-based biomarker for prostate cancer. Additional validation studies are needed that would the clinical utility of this assay and permit a more accurate blood-based assay to be developed for use in the general population (Leman, 2007). • Thymidylate Synthase (TS): Another case series was conducted to determine if thymidylate synthase (TS) a key enzyme in DNA synthesis, may be overexpressed at higher levels in prostate Page 14 of 29 Coverage Position Number: 0172
  • cancer specimens than in normal prostatic tissue (Li [b], et al., 2007). Fifty-two specimens were analyzed with TS and DPD levels determined. TS was detected in 5 (9%) of the 52 normal specimens and in 35 (67%) of the prostate cancer specimens. The patients were divided into two groups, those with positive TS expression versus those with negative TS expression, in order to determine the post- operative clinical course. At five years of follow-up, patients with negative TS expression had a greater recurrence-free rate than compared to those with positive TS expression (P=0.0183). Statistical significance was not found when TS expression was compared to Gleason score 7 or greater, nor was statistical significance found between TS expression and PSA levels. The researchers concluded that TS could be a prognostic indicator, with negative TS expression a good prognostic sign, although the role of TS expression in prostate cancer has not been previously studied. Additional prospective studies are warranted to define the role of TS in selecting patients for adjuvant therapy for prostate cancer. This study is small; the patient population did not include individuals who had received hormonal therapy prior to surgery; therefore, this may have influenced the outcomes that were found during this study. Renal Cell Cancer (RCC): At this time, there are no reliable tumor markers that can be used in the diagnosis, treatment management or surveillance of patients with RCC (Cookson, 2007). • Multiple Markers for clear cell Renal Cell Carcinoma (ccRCC): Phuoc et al. (2007) conducted a case study of 119 patients who underwent radical nephrectomy for clear cell renal cell carcinoma (ccRCC) from 1987 to 2003. The goal of this study was to analyze seven biologic markers (Ki-67; p53 [an inducer of apoptosis]; bcl-2 [an inhibitor of apoptosis]; cyclin-D1; vascular endothelial growth factor (VEGF); Caveolin-1; and HER-2) to identify strong prognostic markers for disease-specific survival (DSS) for patients with ccRCC. Normal kidney tissue adjacent to the tumor served as an internal control. Immunostaining was conducted by three individuals blinded to the clinicopathologic variables. Follow-up period ranged from 3.6 to 215.2 months; during this time, 33 patients died of RCC (grade III) and 11 died of other causes. The researchers found high-level staining for Ki-67 (P<0.0001), p53 (P=0.0029), VEGF (P=0.0062), and caveolin-I (P= 0.0396) was associated with decreased survival. High-level staining for bcl-2 (P<0.0001) and cyclin-D1 (P=0.0002) was associated with increased survival. Only HER-2 expression was not related to survival (P=0.1131). The presence of metastasis (P=0.0001) and high-level staining for p53 (P=0.0059) or bcl-2 (P=0.0413) were independent prognostic factors for DSS. The researchers concluded: 1) only bcl-2 and p53 attained independent prognostic significance in all cases and in cases of grade I–II ccRCC; 2) this information may be useful in selecting markers to predict for survival and plan therapy for patients with ccRCC; and 3) that an analysis of prognostic markers should be considered a work in progress as new markers independent of clinical variables to be identified. This study was small and included numerous biologic markers that may have influenced the strength of outcomes that were noted. Thyroid Cancer—Calcitonin: Calcitonin assay levels have been determined to have specificity high enough that they can be used in the early diagnosis of medullary thyroid cancer (MTC). From 2003 to 2006, Boi and colleagues (2007) conducted the first study to evaluate the usefulness of calcitonin (CT) assay in fine-needle aspiration biopsy fluid (FNABF) or combined with cytology in the detection of primary medullary thyroid cancer and its neck lymph node metastases or recurrences. Eighteen thyroid nodules (14 patients) were studied. Ten nodules were clearly positive on FNABF, with seven being positive for MTC based on cytology. Serum calcitonin levels were increased in all cases. Histological evaluations confirmed MTC in all cases. Eight nodules were determined to be negative by FNAB and cytology; serum CT levels were considered borderline in these individuals. These patients did not undergo thryroidectomy, and no evidence of MTC was found during the follow-up of 1.5–2.5 years. Of the 12 cervical lymph nodes that were studied, six nodes that were clearly positive on FNAB were surgically removed and final histology confirmed MTC metastasis. Cytology was positive for two and nondiagnostic on four. The FNAB was able to detect all 21 histologically proven primary or recurrent/metastatic MTCs, while cytology correctly identified only 13 cases (61.9%). None of the 15 lesions with negative FNAB was MTC. Calcitonin levels from the FNAB specimens reached a sensitivity of 100%, and the researchers concluded that their outcomes demonstrate the high reliability of FNAB in the identification of primary and recurrent/metastatic MTC. Additional longitudinal studies are needed that encompass a larger population base; the researchers also determined their own cut-off level of positive calcitonin at three times the maximal concentration found in this group. This may have influenced the outcomes of this study. Page 15 of 29 Coverage Position Number: 0172
  • Emerging Markers Numerous proteins, receptors and antigens are currently being studied to determine their accuracy in cancer detection, measurement of tumor treatment response and determination of recurrence. The role of these markers in the management of cancer has not yet been established. Additional research through well-designed, randomized controlled trials needs to occur before the diagnostic utility of these additional tumor markers can be determined and added to the standards of care for patient cancer screening, diagnosis, monitoring and follow-up. According to the literature, markers that are currently under investigation include (this list may not be all- inclusive): Breast Cancer Mucin (BCM): BCM is an enzyme immunoassay that utilizes two monoclonal antibodies for the identification of a mucin-like glycoprotein in serum of breast cancer patients. Studies have failed to show the effectiveness of this enzyme in the diagnosis, prognosis or surveillance of patients with breast cancer (NCCN [c], 2007). CAM 17-7 (monoclonal mucin-based antibody): The diagnostic sensitivity of CAM has not proven to be as effective as CA 19-9 in studies that have been conducted to date. This antibody appears to be influenced by the presence of the Lewis antigen and has provided conflicting results in its possible use with pancreatic cancer (NACB [k], 2006). Cancer Antigen 50 (CA-50): This antigen has yet to be proven effective in the diagnosis, prognosis, management or surveillance of pancreatic cancer (NACB [k], 2006). Cancer Antigen 72-4 (CA 72-4): CA 72-4 is currently being studied for possible prognostic use and post- operative surveillance of patients who have been diagnosed with gastric cancer. Studies have also provided conflicting results when this antigen was studied in the presence of pancreatic cancer (NACB [k], 2006; Nordenson, 2002). Cancer Antigen 195 (CA-195): In studies conducted to date, this antigen has yet to be proven effective in the diagnosis, prognosis, management or surveillance of pancreatic cancer (NACB [k], 2006). Cancer Antigen 242 or 549 (CA-242 or CA-549): These antigens can also detect mucin-like molecules, although they are less sensitive than CEA in the surveillance of patients with CRC. The initial studies have indicated that these antigens may be promising as prognostic markers for CRC; however, their use remains under study at this time. CA-242 is also being studied for possible use in the diagnosis, prognosis, management and surveillance of pancreatic cancer (NACB [d], 2006). Cathespin D: This is an Ab-1 monoclonal antibody that is currently being studied as a possible marker that could be used in determining breast cancer prognosis. The results obtained from the studies thus far have been conflicting. Researchers are attempting to measure its ability to provide prognostic value in node-negative breast cancer patients (ASCO [b], 2006; NACB [b], 2006). C-reactive protein: While C-reactive protein may have other clinical applications, according to the National Comprehensive Cancer Network (NCCN [g], 2007) guides for esophageal cancer, this biological marker needs additional research in order to determine its efficacy to impact possible cancer treatment protocols. Cytokeratin-19 fragments (CYFRA 21-1): This tumor marker has been found in the presence of urological, gastrointestinal, and gynecological cancers. It has also been found in various benign diseases. Although some study results are promising for the use of this marker in detecting squamous cell tumors, additional research is needed to determine if its specificity can be useful in the diagnosis and treatment of patients with lung cancer (Lokeshwar, 2005; NACB [g], 2006). Deoxyribonucleic Acid Ploidy (DNA ploidy): DNA can be found in all cells and contains a genetic code that controls cell growth and function. A DNA ploidy test can measure DNA in tumor cells. Researchers have proposed its use in detecting breast cancer; however, studies to date have failed to show its Page 16 of 29 Coverage Position Number: 0172
  • effectiveness in the diagnosis or surveillance of breast cancer. ASCO does not recommend the use of this tumor marker as a prognostic indicator or as a monitor of treatment response in women with breast cancer (ACSO, 2006). DU-PAN-2 (sialylated carbohydrate antigen DU-PAN-2): This antigen has yet to be proven effective in the diagnosis, prognosis, management or surveillance of pancreatic cancer (NACB [k], 2006). Guanyl Cyclase C (GCC): GCC is a heat-stable enterotoxin receptor that may be useful as a marker to identify patients with colorectal cancer or early pre-malignant changes in the upper gastrointestinal tract. GCC is normally expressed in the intestinal tract on the luminal side of the intestinal epithelial cells, and it persists after neoplastic changes occur. The use of this potential marker is currently being studied, according to ASCO (2003). 5-Hydroxyindoleascetic Acid (5-HIAA): 5-HIAA is a byproduct of the degradation of free-serotonin metabolized by monoamine oxidase in the liver and lung. This byproduct is then eliminated via urine from the body. Research has shown that urinary 5-HIAA is the most important marker for mid-gut tumors. 5-HIAA can also be measured within plasma, but its levels may fluctuate; therefore, its use as a long-term follow-up marker has not been proven (NACB [f,i,], 2006). Human Mammoglobulin (hMAM or MG): hMAM is part of the uterogobin family. Its expression has been linked to the mammary gland and breast tumor cells. There is minimal information in the literature that demonstrates the clinical utility of hMAM expression or patient net health outcomes from its clinical application. The use of this genetic expression is being studied (Nunez-Villar, 2003; ASCO, 2001). Lipid Associated Sialic Acid in Plasma (LASA-P): LASA-P has been studied as a possible marker for ovarian cancer as well as several other cancers. This marker has not been proven to be valuable in the detection of cancer. As it is being studied, this marker has been replaced by the use of more specific markers. LASA-P is not specific for any particular cancer or even for cancer in general, as it can also be elevated in some noncancerous conditions. It may be occasionally used along with other markers to follow response to treatment (ACS, 2006). Studies to date have not shown the efficacy of using these markers for the diagnosis, monitoring or follow-up of colon cancer in patients. These studies have shown elevated LASA levels in patients with colon polyps as well as patients with colorectal cancer. According to ASCO, there is currently insufficient evidence to recommend a role for LASA in patients with colorectal cancer (ASCO, 2003). Lysophosphatidic acid (LPA): LPA has been found to stimulate cancer cell proliferation, intracellular calcium release, and tyrosine phosphorylation, including mitogen-activated protein kinase activation. LPA is a multifunctional signaling molecule in fibroblasts and other cells. Its presence has been found in patients with ascitic fluid due to ovarian cancer cell proliferation. Additional studies are needed to determine how this protein marker may be used in the treatment of cancer (ASCO, 2006; Hussain, 2005). Melanoma Cell Adhesion Molecule (MCAM): This molecule is an integral membrane glycoprotein with independent cell adhesive properties, which can result in dynamic actin-cytoskeleton rearrangements. This activity can lead to cell detachment and migration which are key functions in metastases and invasion of cancers. The presence of this glycoprotein has been noted in the presence of several cancers, but promising findings have been noted in its relation to melanoma. Its use is currently under investigation to determine its ability to be utilized as a tumor marker for this specific cancer (NACB [h], 2006; NCCN [m], 2006). Monoclonal Antibody (P53): P53, according to the literature, is consistently altered in a majority of gastric cancers. Although researchers have used immunohistochemical assays in an attempt to determine if the detection of P53 could be used as a marker for gastric cancer, their findings have been inconclusive. Additional studies are needed to determine what role this antibody, along with several others, will have in gastric tumorigenesis. High-throughput assays (i.e., microarrays) are being researched for possible gene expression of DNA pattern recognition (ASCO, 2006; Pisters, 2005). Page 17 of 29 Coverage Position Number: 0172
  • Osteopontin (OPN): OPN is a secreted adhesive glycoprotein, originally isolated from bone extracellular matrix. In a pilot study, Reiniger and colleagues (2007) studied 28 plasma samples from 27 patients with uveal melanoma to analyze and quantify OPN levels. Within the 28 samples, eight patients showed signs of liver metastasis. The researchers wanted to evaluate the use of OPN as a potential serologic marker for metastatic screening in patients with uveal melanoma. During their analysis, plasma levels of OPN were determined to be 170.72 ng/ml (range, 87.37 to 375.54 ng/ml) in patients without metastatic disease, whereas the median level in patients without metastatic disease was 46.78 ng/ml (range, 14.5 to 118.67 ng/ml). They noted a statistical significance between the levels that were found in these groups. A control sample of eight healthy patients was compared to that of the eight patients with uveal melanoma, and their levels were found to be 54.6 ng/ml. These results were not found to be statistically significant. The researchers concluded that this pilot study demonstrates the use of OPN levels may be a potential marker for metastasis in patients with uveal melanoma. Placental Alkaline Phosphatase (PLAP): PLAP is a tumor-associated isoenzyme that was first described in a patient with lung cancer and then was later detected in the serum of patients with other cancers. Two genes actually encode the activity of this isoenzyme (i.e., placental [PLAP] and germ cell alkaline phosphatase [GCAP]). At the present time, these two proteins cannot be distinguished using routine enzyme or immunohistochemical methods. Serum concentrations of PLAP can also be elevated up to ten times in smokers; it is of little clinical value in this group. As a result of current assay limitations, the clinical application of this isoenzyme is not routinely used in the diagnosis or monitoring of testicular cancer. Additional studies of its usefulness need to be conducted (NACB [n], 2006). Prostate-Specific Membrane Antigen (PSMA): PSMA is valuable in the follow-up of patients with prostate cancer, as an adjunct to nuclear scanning for the detection of metastasis. PSMA may be useful for monitoring the patient’s response to treatment and for follow-up. The use of this marker in relation to immunotherapy treatments is currently being studied (ACS, 2006). Ras Proto-Oncogenes (ras): Although these are normal cellular components, the role they play in cellular proliferation and replication has become an area of concern. Studies conducted have been retrospective in relation to the role that these cellular components have in the proliferation and replication of cancer cells. These studies have failed to prove the predictive value that these components would add to determining patient morbidity and mortality (DeVita, 2005). This oncogene could play a part in the growth of cancer. It can be altered in polyps or cancers of the colon. There is a lack of evidence within the literature to support its use as a tumor marker for colorectal cancer (ASCO, 2006). Squamous Cell Carcinoma Antigen (SCC-Ag): SCC-Ag has been proposed as a possible serum tumor marker to be used for the detection of various types of squamous cell tumors, including non-small cell lung cancer (NSCLC), cervical cancer, and head and neck cancer (HNC). SCC-Ag is measurable in the bloodstream and can be found in higher levels in patients with squamous cell tumors. This marker may also be referred to as tumor-associated antigen (TA-4) because SCC-Ag is thought to be a part of this larger molecule. Studies conducted to date on this antigen have not proven its efficacy on patient morbidity and mortality. Sensitivity and specificity levels have not been analyzed to show the patient population, for which this antigen would be most beneficial in determining prognosis, planning treatment or providing follow-up after treatment (NACB [g], 2006). S-100: S-100 is a protein that can be found in most melanoma cells. Tissue samples may be tested for this marker to help in diagnosing melanoma metastasis. Additional research of this protein is needed to determine its accuracy in being used as a tumor marker (ACS, 2006). TA-90: TA-90 is protein that is found on the outer surface of melanoma cells. Like S-100, it may be used to detect the metastasis of melanoma cells. Its value in following melanoma is still being investigated, and it is not widely used at this time. TA-90 is also being studied for use in the detection of other cancers such as colon and breast cancer (ACS, 2006). Tumor-Associated Trypsin Inhibitor (TATI): This inhibitor was first identified in the urine of patients with ovarian cancer, and its properties are identical to those of the pancreatic secretory trypsin inhibitor. Levels within the urine and serum may be elevated in postoperative patients, in severe inflammatory Page 18 of 29 Coverage Position Number: 0172
  • disease states, and in various types of cancers. Studies conducted to date on this inhibitor have failed to demonstrate its usefulness in the monitoring or surveillance of cancer within patients (NACB [j], 2006). Tissue Polypeptide Antigen (TPA): This protein marker may be present at elevated levels in the presence of absence of cancer. It has been used in combination with other markers to assist in following patients who are currently being treated for lung, bladder, and many other cancers. This protein is not specific to one particular cancer as its presence becomes elevated when there is rapid division of cells (ACS, 2006; NACB [a,g], 2006). Summary There is sufficient evidence in peer-reviewed studies, medical and oncology textbooks and specialty society recommendations to support the use of specific tumor markers in the screening, diagnosis, patient- specific treatment planning and ongoing surveillance of specific cancers. There is also insufficient evidence in the literature, medical and oncology textbooks, and the lack of specialty society recommendations to support the use of numerous other tumor markers in the screening of asymptomatic patients for cancer, or for diagnosis, staging, or the monitoring of response to cancer treatment and follow-up. The National Cancer Institute (NCI [e]) and the European Organization for Research and Treatment of Cancer (NCI-EORTC) have developed guidance on transparent and complete reporting of all relevant information from studies that are conducted concerning the use of tumor markers. Coding/Billing Information Note: This list of codes may not be all-inclusive. Covered when medically necessary: CPT®* Description Codes 82105 Alpha-fetoprotein; serum 82107 Alpha-fetoprotein (AFP); AFP-L3 fraction isoform and total AFP (including ratio) 82232 Beta-2 microglobulin 82308 Calcitonin 82378 Carcinoembryonic antigen (CEA) 83950 Oncoprotein, HER-2/neu 84066 Phosphatase, acid; prostatic 84153 Prostate specific antigen (PSA); total 84154 Prostate specific antigen (PSA); free 84233 Receptor assay; estrogen. Specimen collection is by separately reportable surgical removal. Methods may include biochemical measurement in cytosol fractions of tumor homogenate, dextranestradiol conjugate, immunoperoxidase using tissue sections, enzyme immunoassay (EIA), and in situ hybridization. This test may be ordered to assist in identifying a breast cancer patient’s ability to respond to chemotherapy and endocrine therapy. 84234 Receptor assay; progesterone. Specimen collection is by separately reportable surgical removal. Methods may include sucrose density gradient, steroid binding assay, and enzyme immunoassay. This test assists in identifying a patient’s ability to respond to treatment in breast and other cancers. 84432 Thyroglobulin 84702 Gonadotropin, chorionic (hCG); quantitative 84703 Gonadotropin, chorionic (hCG); qualitative 85362 Fibrin(ogen) degradation (split) products (FDP)(FSP); agglutination slide, semiquantitative 86294 Immunoassay for tumor antigen, qualitative or semiquantitative (eg, bladder tumor antigen) Page 19 of 29 Coverage Position Number: 0172
  • 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 86316† Immunoassay for tumor antigen, other antigen, quantitative (eg, CA 50, 72-4, 549), each 88360 Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, each antibody; manual 88361 Morphometric analysis, tumor immunohistochemistry (eg, Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, each antibody; using computer-assisted technology 88368 Morphometric analysis, in situ hybridization, (quantitative or semi-quantitative) each probe; manual HCPCS Description Codes S3625 Maternal serum triple marker screen including alpha-fetoprotein (APF), estriol, and human chorionic gonadotropin (hCG) ICD-9-CM Description Diagnosis Codes Multiple/ varied † Note: Covered when medically necessary when used to identify the Chromogranin A (CgA) and Neuron-specific enolase(NSE) tests. Experimental/Investigational/Unproven/Not Covered: CPT* Codes Description Multiple/Varied HCPCS Description Codes No specific codes ICD-9-CM Description Diagnosis Codes Multiple/Varied *Current Procedural Terminology (CPT®) ©2006 American Medical Association: Chicago, IL. References 1. Abeloff MD, Wolff AC, Wood WC, McCormick B, Weber BL (authors). Chapter 94: Cancer of the Breast. In: Abeloff: Clinical Oncology, 3rd ed. ©2004 Churchill Livingstone. 2. Adkins ES, Brown R, Windle ML, Billmire DF, Othersen HB, Coppes MJ. Teratomas and other germ cell tumors. Updated May 2006. Accessed Aug 2007. Available at URL address: http://www.emedicine.com/ped/topic3023.htm 3. Agarwal R, Whang DH, Alvero AB, Vistinin I, Lai Y, Segal EA, et al. Marcrophage migration inhibitory factor expression in ovarian cancer. Am J Obstet Gynecol. 2007 Apr;196(4):348.e1-5. Page 20 of 29 Coverage Position Number: 0172
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