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Prostate-Specific Antigen Screening for Prostate Cancer and Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer

» Summary» Procedure Codes
» Description» Selected References
» Prior Approval» Policy History
» Policy
 

Medical Policy: 02.04.25 
Original Effective Date: October 2009 
Reviewed: December 2015 
Revised: December 2015 


Benefit Application
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.


Description: 

Prostate cancer is the most commonly diagnosed non-skin cancer in men in the United States, with a lifetime risk for diagnosis currently estimated at 15.9%. Most cases of prostate cancer have a good prognosis even without treatment, but some cases are aggressive; the lifetime risk for dying of prostate cancer is 2.8%. Prostate cancer is rare before age 50 years, and very few men die of prostate cancer before age 60 years. Seventy percent of deaths due to prostate cancer occur after age 75 years. 
 
Prostate Cancer Screening

The primary goal of prostate cancer screening is to reduce deaths due to prostate cancer, therefore, increasing length of life. An additional important outcome would be a reduction in the development of symptomatic metastatic disease. Screening asymptomatic men for prostate cancer has become a widespread practice in the United States. Test procedures used for prostate cancer screening include digital rectal examination (DRE) and prostate specific antigen (PSA).
   
Although PSA was originally introduced as a tumor marker to detect cancer recurrence or disease progression following treatment, it became widely adopted for cancer screening. PSA is a glycoprotein produced by the prostate epithelial cells. PSA levels may be elevated in men with prostate cancer because PSA production is increased and because tissue barriers between the prostate gland lumen and the capillary are disrupted, releasing more PSA into the serum. Elevations of serum PSA may also be associated with other prostatic diseases including benign prostatic hypertrophy (BPH) which is a major clinical problem with PSA screening. It is recommended that the interpretation of PSA values should always take into account age, the presence of urinary tract infection or prostate disease, recent diagnostic procedures and prostate directed treatments. 

 

Prostate cancer screening has been a controversial issue. There is evidence that PSA based screening leads to substantial overdiagnosis of prostate tumors and there is a high incidence for physicians and patients to elect to treat most cases of screen detected cancer, given the current inability to distinguish tumors that will remain indolent from those destined to be lethal. Thus, many men are being subjected to the harms of treatment of prostate cancer that will never become symptomatic. Even for men whose screen-detected cancer would otherwise have been later identified without screening, most experience the same outcome and are, therefore, subjected to the harms of treatment for much longer period. There is convincing evidence that PSA based screening for prostate cancer results in considerable overtreatment and its associated harms.

 

Even though some guidelines (i.e. USPSTF) discourage the use of screening tests for which the benefits do not outweigh the harms in the target population, they do recognize the common use of PSA screening in practice today and that some physicians will continue to offer it. The decision to initiate or continue PSA screening should reflect an understanding of the possible benefits and harms and respect the patient’s preferences. Physicians should not offer or order PSA screening unless they are prepared to engage in shared decision making that enables an informed choice by the patient. Similarly, patients requesting PSA screening should be provided with the opportunity to make informed choices to be screened that reflect their values about specific benefits and harms.  

 

Summary
At this time, evidence that prostate specific antigen (PSA) testing for prostate cancer screening reduces long-term mortality is lacking. It is recommended that healthcare professionals discuss the possible benefits, side effects, and questions about prostate specific antigen (PSA) testing for prostate cancer screening so that men can make informed decisions taking into account their own situation and risk. There is promising evidence from large-scale observational studies to conclude that PSA in conjunction with DRE can detect potentially curable prostate cancer.   

 

Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer
There are a variety of genetic and protein biomarkers associated with prostate cancer. These tests have the potential to improve the accuracy of differentiating which men should undergo prostate biopsy or rebiopsy after a prior negative biopsy.

 

Conventional decision-making tools for identifying men who should undergo prostate biopsy include serum prostate-specific antigen (PSA), digital rectal exam (DRE) and patient risk factors such as age, race and family history of prostate cancer. However, these screening tools lead to unnecessary prostate biopsies because of their lack of specificity and inability to discriminate low from high risk prostate cancer.

 

Prostate cancer is a complex, heterogeneous disease, in which numerous genetic alterations have been described, with the potential for use of these molecular markers to improve decision making as to whom should undergo prostate biopsy or rebiopsy after an initial negative biopsy.

 

For assessing future prostate cancer risk, numerous studies have demonstrated the association of many different SNPs with prostate cancer, and these studies generally show a modest degree of association with future risk for prostate cancer.

 

Commercially available tests include:

  • 4Kscore Test (OPKO Lab), a blood test that measures 4 prostate specific kallikreins, which are combined into an algorithm to decide whether a patient should proceed to prostate biopsy.
  • Prostarix (Metabolon/Bostwick Laboratories) is a post DRE urine test based on several metabolites and an algorithm to decide whether a patient should proceed to prostate biopsy or undergo repeat biopsy after an initial negative biopsy.
  • The PCA3 test focuses on the detection of PCA3 in urine samples following a digital rectal exam. The test is offered by a number of reference laboratories including ARUP, Mayo Medical Laboratories, and LabCorp. Reagents used in testing are developed by Gen-Probe.
  • Prostate Core Mitomics Test (Mitomics (formerly Genesis Genomics), which measures mitochondrial DNA mutations in a negative prostate biopsy to determine whether a patient should undergo repeat biopsy.
  • ConfirmDX (MDxHealth) measures hypermethylation of 3 genes in a negative prostate biopsy to determine whether a patient should undergo repeat biopsy.
  • SNP testing as part of genome-scanning tests for prostate cancer risk assessment are offered by a variety of laboratories, such as Navigenics (now Life Technologies), LabCorp (23andme), and ARUP (deCode), as laboratory developed tests.
     

Diagnosis: Whether to Perform a Prostate Biopsy or Rebiopsy

 

4Kscore Test (OPKO Lab)
The 4Kscore Test is a blood test that generates a risk score for the probability of finding high-grade prostate cancer (defined as a Gleason Score > 7) if a prostate biopsy were performed. The intended use of the test is to aid in the decision of whether or not to proceed with a prostate biopsy. The test algorithm combines the measurement of 4 prostate-specific kallikreins (total prostate specific antigen (tPSA), free PSA (fPSA), intact PSA (iPSA), and human kallikrein 2 (hK2), which are combined in an algorithm with patient age, digital rectal exam (DRE) (nodules or no nodules), and whether the patient has had a prior negative prostate biopsy. A kallikrein is a subgroup of enzymes that cleave peptide bonds in proteins.

 

The test is not intended to be used in patients with a previous diagnosis of prostate cancer, a patient who has had a DRE in the previous 4 days, a patient who has received 5-alpha reductase inhibitor therapy in the previous 6 months, or a patient who has undergone any procedure or therapy to treat symptomatic benign prostatic hypertrophy in the previous 6 months.

 

Prostarix (Metabolon/Bostwick Laboratories)
Prostarix is a post-DRE urine test that is based on a panel of biomarkers and is used in the early detection of prostate cancer. The results are intended to aid in clinical decision making as to whether to biopsy or repeat biopsy the prostate, particularly in patient who have a suspicious DRE and modestly elevated PSA (2.5-10 ng/mL). The test addresses metabolic abnormalities that have been associated with prostate cancer. Prostarix measures the concentration of several metabolites: sarcosine, alanine, glycine, and glutamate, and these quantitative measurements are combined in a logistic regression algorithm to generate a Prostarix Risk Score. If PSA level and TRUS-determined prostate volume are available, they can be used along with the metabolite measurements to generate the Prostarix-PLUS Risk Score. The test claims to have increased sensitivity and specificity over standard assessment tools to predict the likelihood of a positive prostate biopsy.

 

PCA3 (Prostate Cancer Gene 3)    
PCA3 (prostate cancer gene 3), a prostate-specific gene that is highly overexpressed in prostate cancer tissue.  PCA3 testing in clinical practice focuses on the detection of the PCA3 in urine samples following a digital rectal exam (DRE). The test may be especially helpful for identifying patients with elevated PSA levels but negative first biopsy results, who need a follow up biopsy.

 
Diagnosis: Whether to Perform a Prostate Rebiopsy

Prostate Core Mitomics Test (Mitomics (Formerly Genesis Genomics))
The Prostate Core Mitomics Test (PCMT) is a proprietary test that is intended to determine whether a patient has prostate cancer, despite a negative prostate biopsy, by analyzing deletions in the mitochondrial DNA by polymerase chain reaction (PCR) to detect “tumor field effect.” The test is performed on the initial negative prostate biopsy tissue. A negative PCMT result confirms the results of the negative biopsy (i.e. the patient does not have prostate cancer) and the patient can avoid a second biopsy, but that a positive PCMT means the patient is at high risk of undiagnosed prostate cancer.

 

ConfirmMDx (MDxHealth)
ConfirmMDx is intended to distinguish true from false negative prostate biopsies to avoid the need for repeat biopsy in cases of true negative and to identify men who may need a repeat biopsy. The test measures methylation of the genes GSTP1, APC and RASSF-1.

 

Gene Hypermethylation for Diagnosis      
One of the epigenetic mechanisms that is considered to be involved in the development of prostate cancer is DNA methylation. Hypermethylation within promotor region of tumor suppressor genes is an important mechanism of gene inactivation and has been described for many different tumor types. These types of alterations are also potentially reversible, unlike genetic alterations such as mutations, which may lead them being considered as possible targets for gene therapy. Currently, aberrant promoter hypermethylation has been investigated in specific genes from the following groups: tumor-suppressor genes, proto-oncogenes, genes involved in cell adhesion, and genes involved in cell-cycle regulation. Glutathione S-transferase P1 (GSTP1) has been shown to be a biomarkers for prostate cancer. Other genes, e.g. CD44, PTGS2, E-cadherin, CHD13 and cyclin D2 have been found to be prognostic markers for prostate cancer. The published studies are primarily small, retrospective pilot evaluations of hypermethylation status of various candidate genes for discriminating prostate cancer from benign conditions or for predicting disease recurrence and association with clinicopathologic predictors of aggressive disease (prognosis).   


TMPRSS Fusion Genes for Diagnosis and Prognosis
TMPRSS2 is an androgen-regulated transmembrane serine protease that is preferentially expressed in normal prostate tissue. In prostate cancer, it may be fused to an ETS (E26 transformation-specific) family transcription factor (ERG, ETV1, ETV4, or ETV5), which modulates transcription of target genes involved in cell growth, transformation and apoptosis. The result of gene fusion with an ETS transcription gene is that the androgen-responsive promoter of TMPRSS2 upregulates expression of the ETS gene, suggesting a mechanism for neoplastic transformation. Fusion genes may be detected in tissue, serum and urine. Attention has been directed at using post-DRE urine samples to look for fusion genes as markers of prostate cancer.

 

Candidate Gene Panels for Prostate Cancer Diagnosis
Since no single gene markers have been found that are both highly sensitive and highly specific for diagnosing prostate cancer, particularly in men that have an elevated PSA level, some investigators are combining several promising markers into a single diagnostic panel. This may appear promising in concept, however, there is very limited evidence available for these applications.

 

There is insufficient evidence found in the scientific literature regarding the use of candidate gene panels in prostate cancer diagnosis.  

 

Summary
The evidence on clinical validity of genetic and protein biomarkers related to prostate cancer diagnosis is variable and incomplete, leaving considerable uncertainty regarding the clinical performance characteristics such as sensitivity, specificity and predictive value. Some tests show evidence of predictive ability in the diagnosis of prostate cancer; however, incremental accuracy in comparison with currently available tests has not been consistently demonstrated. In addition, these data do not demonstrate clinical utility, i.e., that using a test will change treatment decisions and improve subsequent outcomes. Therefore, the use of genetic and protein biomarkers for the diagnosis of prostate cancer is considered investigational.


Single Nucleotide Polymorphisms Testing for Cancer Risk Assessment
Single nucleotide polymorphisms (SNPs) occur when a single nucleotide is replaced with another, and they are the most common type of genetic variation in humans. They occur normally throughout the genome and can act as biological markers for disease association. Genome-wide association studies have identified associations between prostate cancer risk and specific SNPs. However, it is generally accepted that individually, SNP-associated disease risk is low and of no value in screening for disease, although multiple SNPs in combination may account for a higher proportion of prostate cancer. Investigators have begun to explore the use of algorithms incorporating information from multiple SNPs to increase the clinical value of testing.


Studies have demonstrated the association of many different SNPs with prostate
cancer. A 2012 Agency for Healthcare Research and Quality report on multigene panels in prostate cancer risk assessment reviewed the literature on SNP panel tests for assessing risk of prostate cancer. All of the studies included in the review had poor discriminative ability for predicting risk of prostate cancer, had moderate risk of bias, and none of the panels had been evaluated in routine clinical settings. The conclusions of the review were that the evidence on currently available SNP panels does not permit meaningful assessment of analytic validity, the limited evidence on clinical validity is insufficient to conclude that SNP panels would perform adequately as a screening test and that there is no evidence available on the clinical utility of current panels. 

 

Summary
Numerous studies have demonstrated the association of many different SNPs with prostate cancer, and these studies generally show a modest degree of association with future risk for prostate cancer. However, the clinical utility of these tests is uncertain; there is no evidence that information obtained from SNPs testing can be used to change management in ways that improve outcomes. Therefore, SNPs testing for cancer risk assessment of prostate cancer is considered investigational.

 

Evidence on the clinical validity of genetic tests related to prostate cancer screening, detection, and management is variable and incomplete, leaving considerable uncertainty regarding clinical performance characteristics such as sensitivity, specificity and predictive value. Some tests show evidence for predictive ability in the diagnosis or prognosis of prostate cancer; however, incremental accuracy in comparison with currently available tests has not been consistently demonstrated. In addition, the data does not demonstrate clinical utility, i.e. that using a test will change treatment decisions and improve patient outcomes. Therefore, the use of gene based testing for risk assessment, diagnosis, prognosis and management of prostate cancer is considered investigational.   

 

Practice Guidelines and Position Statements 

 

U.S. Preventative Services Task Force (USPSTF)
In 2012, The USPSTF published recommendations for prostate cancer screening that recommends against prostate specific antigen (PSA) based screening for prostate cancer. The USPSTF assigned a Grade D recommendation to this statement since there is moderate or high certainty that the service has no net benefit or that harms outweigh the benefits.

 

Clinical Considerations
Although the USPSTF discourages the use of screening tests for which the benefits do not outweigh the harms in the target population, it recognizes the common use of PSA screening in practice today and understands that some men will continue to request screening and some physicians will continue to offer it. The decision to initiate or continue PSA screening should reflect an explicit understanding of the possible benefits and harms and respect the patients’ preferences. Physicians should not offer or order PSA screening unless they are prepared to engage in shared decision making that enables an informed choice by the patients. Similarly, patients requesting PSA screening should be provided with the opportunity to make informed choices to be screened that reflect their values about specific benefits and harms.   
 
American Urological Association (AUA)

In 2013, the American Urological Association (AUA) published guidelines for the early detection of prostate cancer:

 

Guideline Statements

  • The Panel recommends against PSA screening men under age 40 years. (Recommendation; Evidence Strength Grade C). In this age group there is a low prevalence of clinically detectable prostate cancer, no evidence demonstrating benefit of screening and likely the same harms of screening as in other age groups.

  • The Panel does not recommend routine screening in me between ages 40 to 54 years at average risk. (Recommendation; Evidence Strength Grade C). For men younger than age 55 years at higher risk (e.g. positive family history or African American race), decisions regarding prostate cancer screening should be individualized.

  • For men ages 55 to 69 years the Panel recognizes that the decision to undergo PSA screening involves weighing the benefits of prostate cancer mortality in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment. For this reason, the Panel strongly recommends shared decision making for men age 55 to 69 years that are considering PSA screening, and proceeding based on a man’s values and preferences. (Standard; Evidence Strength Grade B). The greatest benefit of screening appears to be in men ages 55 to 69 years.

  • To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in those men who have participated in shared decision making and decided on screening. As compared to annual screening, it is expected that screening intervals of two years preserve the majority of the benefits and reduce overdiagnosis and false positives. (Option; Evidence Strength Grade C). Additionally, intervals for rescreening can be individualized by a baseline PSA level.

  • The Panel does not recommend routine PSA screening in men age 70+ years or any man with less than a 10 to 15 year life expectancy. (Recommendation; Evidence Strength Grade C). Some men age 70+ years who are in excellent health may benefit from prostate cancer screening.

The panel concluded that PSA based screening should not be performed in the absence of shared decision making. Thus, they recommend against organized screening in settings where shared decision making is not part of routine practice (e.g., including but not limited to health fairs, health system promotions, community organizations).

 

Testing Frequency: There is evidence to suggest that annual screening is not likely to produce significant incremental benefits when compared with an inter-screening interval of two years. The PCLO trial compared annual screening with opportunistic screening in the US population, which corresponded to screening on average every two years. Prostate cancer mortality rates were similar in the two groups through 13 years of follow up.  

 

Modeling studies have projected that screening intervals of two years will preserve most of the benefits of screening and reduce the harms (i.e. false positive tests and overdiagnosis) when compared with screening every year.

 

The Panel believes that annual PSA screening as a routine should be discouraged for those who choose to be screened, that two year PSA intervals are reasonable approach and will be unlikely to miss a curable prostate cancer in most men, and that for men over 60 with PSA levels below 1.0ng/ml, longer PSA screening intervals (e.g. of four years) could be considered.    

 

Novel Urinary Biomarkers
Much effort has been invested in the discovery of methods of improving the ability of PSA to predict the presence of prostate cancer. At this point, the use of  DRE, PSA derivatives (PSA density and age specific reference ranges) and PSA kinetics (velocity and doubling time), PSA molecular forms (percent free PSA and proPSA),  novel urinary markers and biomarkers (PCA3) and prostate imaging should be considered secondary tests (not primary screening tests) with potential utility for determining the need for prostate biopsy, but with unproven benefit as primary screening tests. The Panel recognizes that these tests can be used as adjuncts for informing decisions about the need for a prostate biopsy or repeat biopsy after PSA screening, but emphasizes the lack of evidence that these tests will increase the ratio of benefit to harm. 

 

Evaluation of Genomic Applications in Practice and Prevention (EGAPP)
In 2013, the Evaluation of Genomic Applications in Practice and Prevention Working Group published the following recommendations for PCA3 testing in prostate cancer, based on the Agency for Healthcare Quality and Research comparative effectiveness review:

  • Evidence was insufficient to recommend PCA3 testing to inform decisions for when to rebiopsy previously biopsy negative patients for prostate cancer, or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (e.g. previous elevated PSA or suspicious digital rectal examination (DRE))
  • Evidence was insufficient to recommend PCA3 testing in men with cancer positive biopsies to determine if the disease is indolent or aggressive in order to develop an optimal treatment plan.
  • The overall certainty of clinical validity to predict the diagnosis of prostate cancer using PCA3 is deemed “low.” Clinical use for diagnosis is discouraged unless further evidence supports improved clinical validity.
  • The overall certainty of net health benefit is deemed “low.” Clinical use is discouraged unless further evidence supports improved clinical outcomes.   

National Comprehensive Cancer Network (NCCN), Prostate Cancer Early Detection Version 2.2015   
Age at Which to Initiate Testing

Most Panel members favor informed testing beginning at age 45 years. Repeat testing at 1 to 2 year intervals is recommended for men who have a PSA value > 1.0 ng/mL and at 2 to 4 year intervals for men with PSA <1 ng/mL.

 

Age at Which to Discontinue Testing
The Panel supports screening in men until age 75, and then continuing screening only in very select patients (category 2B). The panel notes that although some men in this older age group present with high-risk disease, very few men older than age 75 years benefit from PSA screening.

 

Screening in High Risk Populations
African-American men and men with a first degree relative with prostate cancer (especially cancer found at a younger age) have a higher risk of developing prostate cancer. In fact, having a first degree relative with prostate cancer diagnosed before theage of 60 increases the likelihood of prostate cancer diagnosis by 2.1 to 2.5 fold.

 

The Panel believes that current data are insufficient to inform the best strategy for prostate cancer screening in these populations and also note that baseline PSA value is a stronger predictive factor that a positive family history or race. Therefore, although these individuals may require a higher level of vigilance and potentially different considerations when analyzing the results of screening tests, the panel does not give separate screening recommendations for these men at this time.

 

Biomarker Testing
The Panel recommends consideration of percent free PSA (%f PSA), 4Kscore, and Prostate Health Index (phi) in patienst with PSA levels >3 ng/mL who have not yet had a biopsy. Percent free PSA, 4Kscore, phi and PCA3 may also be considered for men who have had at least one prior negative biopsy and are thought to be a higher risk.  Results of any of these tests, when performed, should be included in discussions between clinician and patient to assist in decisions regarding whether to proceed with the biopsy.


ConfirmMDx
ConfirmMDx is a tissue based, multiplex epigenetic assay that aims to improve the stratification of men being considered for repeat prostate biopsy. Hypermethylation of the promotor regions of GSTP1, APC, and RASSF1 are assessed in core biopsy tissue samples. The European MATLOC study blindly tested this assay in archived tissue from 498 men with negative biopsies who had repeat biopsies within 30 months. The NPV was 90%. Despite the good NPV of this test, the Panel noted that the NPV of first negative biopsy alone is already in the range of 75% to 80% and questioned the true value added by the test results. Therefore, until prospective data for this test or data comparing this test to other tests are available, the Panel does not recommend its use.     


The American Cancer Society (ACS)
The American Cancer Society recommends that men make an informed decision with their health care provider about whether to be tested for prostate cancer. Research has not yet proven that the potential benefits of testing outweigh the harms of testing and treatment. We believe that men should not be tested without first learning about what we know and don’t know about the risks and possible benefits of testing and treatment.

  

Starting at age 50, men should talk to a health care provider about the pros and cons of testing so they can decide if testing is the right choice for them.

 

If African American or have a father or brother who had prostate cancer before age 65, these individuals should have this talk with a health care provider starting at age 45.

 

Men who decide to be tested, should get a PSA blood test with or without a rectal exam. The frequency of testing will depend on the PSA level.


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Prior Approval: 

 

Not applicable


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Policy: 

Prostate Cancer Screening

 

Prostate cancer screening using prostate specific antigen (PSA) may be considered medically necessary for any of the following indications after informed decision with a health care provider:

  • Asymptomatic men 40-49 years of age who are at high risk of prostate cancer due to any of the following factors:
    • African-American race
    • More than one first degree relative (father, brother, or son) diagnosed with prostate cancer at an early age (younger than age 65).
  • Asymptomatic men age 50 and over with a life expectancy of at least 10 years.

After the initial PSA is determined, the time interval for repeat testing is dependent upon the PSA value. For those men with a PSA of:

  • < 2.5 ng/ml retesting may be performed every 2 years
  • > 2.5 ng/ml retesting may be performed yearly

Prostate cancer risk using prostate specific antigen (PSA) in men > 40 years of age being considered for testosterone therapy may be considered medically necessary prior to initiation of therapy. If baseline PSA is greater than 0.6 ng/ml, additional PSA testing after 3 and 6 months of testosterone therapy may be considered medically necessary.

 

All other screening indications are considered not medically necessary.

 

The percent free PSA test (fPSA) when used in conjunction with the total PSA test to aid in distinguishing between malignant and benign prostate conditions, may be considered medically necessary if all of the following criteria are met:

  • Have a total PSA level between 4 and 10 ng/mL
  • Digital rectal exam is not suspicious for malignancy

Genetic and Protein Biomarkers

Genetic and protein biomarkers for the diagnosis of prostate cancer are considered investigational. This includes, but is not limited to the following:

  • PCA3 testing
  • Kallikrein markers (e.g. 4KscoreTM Test)
  • TMPRSS fusion genes
  • Gene hypermethylation
  • Metabolomic profiles (e.g. ProstarixTM)
  • Mitochondrial DNA mutation testing (e.g. Prostate Core Mitomics TestTM)
  • Candidate gene panels

The evidence on clinical validityof genetic and protein biomarkers related to prostate cancer diagnosis is variable and complete, leaving considerable uncertainty regarding the clinical performance characteristics such as sensitivity, specificity and predictive value. Some tests show evidence of predictive ability in the diagnosis of prostate cancer; however, incremental accuracy in comparison withcurrently available tests has not been consistentlydemonstrated. In addition, these data do not demonstrate clinical utility, i.e., that using a test will change treatment decisions and improve subsequent outcomes. Therefore, the use of genetic and protein biomarkers for the diagnosis of prostate cancer is considered investigational.   

 

Single nucleotide polymorphisms (SNPs) testing for cancer risk assessment of prostate cancer is considered investigational

 

Numerous studies have demonstrated the association of many different SNPs with prostate cancer, and these studies generally show a modest degree of association with future risk for prostate cancer. However, the clinical utility of these tests is uncertain; there is no evidence that information obtained from SNPs testing can be used to change management in ways that improve outcomes. Therefore, SNPs testing for cancer risk assessment of prostate cancer is considered investigational. 





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Procedure Codes and Billing Guidelines: 

  • To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 0010M Oncology (High-Grade Prostate Cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA and human kallikrein 2 (hK2) plus patient age, digital rectal examination status, and no history of positive prostate biopsy, utilizing plasma, prognostic algorithm reported as a probability score (4Kscore Test)
  • 81229 Interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities
  • 81313 PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen] ratio (eg, prostate cancer)
  • 81479  unlisted molecular pathology procedure
  • 84152 Prostate-specific antigen (PSA); complexed (direct measurement)
  • 84153 Prostate specific antigen (PSA); total
  • 84154 Prostate-specific antigen (PSA); free

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Selected References: 

  • Barry MJ. Clinical Practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med. 2001 May 3; 344(18):1373-7.
  • Wilson WG et al. Abelhoff’s Clinical Oncology, 4th ed. Churchill Livingstone Elsevier, Philadelphia, PA, 2008, Chap. 88, “Prostate Cancer”.
  • Andriole GL, Crawford ED, Grubb 3rd RL et al. Mortality Results from a Randomized Prostate-Cancer Screening Trial. N Engl J Med 2009; 360(13): 1310-19.
  • Brawley OW, Ankerst DP, Thompson IM. Screening for Prostate Cancer. CA Cancer J Clin 2009[Epub prior to print June 29, 2009].
  • Schroder FH, Hugosson J, Roobol MJ et al. Screening and Prostate Cancer Mortality in a Randomized European Study. N Engl J Med 2009; 360(13): 1320-28.
  • Miller MC, O’Dowd GJ, Partin AW et al. Contemporary use of complexed PSA and calculated percent free PSA for early detection of prostate cancer: Impact of changing disease demographics. Urology. 2001 Jun;57(6):1105-11.
  • Catalona WJ, Partin AW, Slawin KM et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: A prospective multicenter clinical trial. JAMA. 1998 May 20; 279(19):1542-7.
  • Lin K, Lipsitz R, Miller T et al. Benefits and Harms of Prostate-specific Antigen Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149(3):192-99.
  • Lim LS, Sherin K, and the American College of Preventive Medicine (ACPM) Prevention Practice Committee. Screening for Prostate Cancer in U.S. Men: ACPM Position Statement on Preventive Practice. Am J Prev Med 2008;34(2):164-70.
  • Wolf AM, Wender RC, Etzioni RB et al. American Cancer Society Prostate Cancer Advisory Committee. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin 2010 Mar-Apr;60(2):70-98
  • Sandblom G, Varenhorst E, Rosell J et al. Randomised prostate cancer screening trial: 20 year follow up. BMJ 2011;342:d1539. doi:10.1136/bmj.d1539.
  • Shao Y-H, Albertsen PC, Roberts CB et al. Risk profiles and treatment patterns among men diagnosed as having prostate cancer and a prostate-specific antigen level below 4.0 ng/mL. Arch Intern Med. 2010;170(14):1256-61.
  • Screening for Prostate Cancer, Topic Page. August 2008. U.S. Preventive Services Task Force.
  • Djulbegovic M, Beyth RJ, Neuberger MM et al. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ 2010;341:c4543. doi:10.1136/bmj.c4543.
  • Crawford ED, Grubb III R, Black A et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol Feb 1,2011;29(4):355-61.
  • Loeb S, Vonesh EF, Metter J et al. What is the true number needed to screen and treat to save a life with prostate-specific antigen testing? J Clin Oncol Feb1, 2011;29(4):464-67.
  • Hugosson J, Carlsson S, Aus G et al. Morality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 11:725-32, 2010.
  • Chou R, Croswell JM, Dana T et al. Screening for prostate cancer: a review of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2011; 155(11):762-71.
  • Cooperberg MR, Broering JM, Carroll PR. Time trends and local variations in primary treatment of localized prostate cancer. J Clin Oncol. 2010; 28(7):1117-1123.
  • US Preventive Services Task Force Screening for Prostate Cancer; US Preventive Services Task Force recommendation statement: draft summary of recommendation and evidence. Accessed April 2012.
  • American  Cancer Society, Recommended Guidelines for Prostate Cancer Screening, Issued 2/27/12
  • National Comprehensive Cancer Network (NCCN) Guidelines, Prostate Cancer Early Detection, Version 2.2012.
  • American Urological Assocation (AUA) 2013 Guidelines, Early Detection of Prostate Cancer.
  • American Society of Clinical Oncology. Screening for Prostate Cancer with Prostate Specific Antigen Testing: American Society of Clinical Oncology Provisional Clinical Opinion. Journal of Clinical Oncology. DOI:10.1200/JCO.2012.43.3441.
  • UpToDate. Screening for Prostate Cancer. Richard M. Hoffman, M.D.,MPH. Topic Last Updated July 24, 2015.
  • ECRI. Emerging Technology Evidence Report. PCA3 Assay (Progensa) for Aiding Repeat Biopsy Decision Making for Suspected Prostate Cancer. April 2013.
  • Sam W. Chan, et al, Early Detection of Clinically Significant Prostate Cancer at Diagnosis: A Prospective Study using Novel Panel of TMPRSS2:ETS Fusion Gene Markers. Cancer Medicine. February 2013. doi: 10.1002/cam4.49
  • Hui-Yi Lin, et al. SNP-SNP Interaction Network in Angiogenesis Genes Associated with Prostate Cancer Agressiveness. PLOS One April 2013, doi: 10.1371/journal.pone.0059688.
  • PubMed. Phe V, et al, Methylated Genes a Potential Biomarkers in Prostate Cancer. BJU Int.2010 May; 105(10):1364-70, doi: 10.1111/j.1464-410X.2009.09167.x.Epub 2010 Jan 8
  • PubMed. Chen Y, et al, APC Gene Hypermethylation and Prostate Cancer: A Systematic Review and Meta Analysis. Eur J Hum Genet. 2013 Sept 21 (9):929-35. Doi: 10.1038/ejhg.2012.281 
  • National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection Version 1.2014. Also available at www.nccn.org
  • ECRI. Product Brief. Progensa PCA3 Urine Test (Gen Probe, Inc) for Determining the Need for Repeat Biopsy of the Prostate. June 2014. Also available at www.ecri.org
  • Agency for Healthcare Research and Quality (AHRQ), Comparative Effectiveness Review Number 98, PCA3 Testing for the Diagnosis and Management of Prostate Cancer, April 2013. Also available at www.ahrq.gov
  • National Institute for Health and Clinical Excellence (NICE), NICE Issues Draft Diagnostics Guidance on Prostate Cancer Tests, Press Release, December 17, 2014. Also available at www.nice.org.uk
  • American Cancer Society Guidelines for Early Detection of Cancer, Prostate Cancer. Last medical review 3/11/2015. Revised 10/20/2015. Also available at www.cancer.org
  • ECRI. Product Brief. 4Kscore Test (OPKO Lab) for Predicting Risk of High Grade Prostate Cancer, June 2014. Also available at www.ecri.org
  • Agency for Healthcare Research and Quality (AHRQ), Evidence Report/Technology Assessment Number 209, Multigene Panels in Prostate Cancer Risk Assessment. 2012. Also available at www.ahrq.gov
  • EGAPP (Evaluation of Genomic Applications in Practice in Prevention) Working Group Recommendation, Does PCA3 Testing for the Diagnosis and Management of Prostate Cancer Improve Patient Health Outcomes. Also available at www.egappreviews.org
  • National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection Version 2.2015. Also available at www.nccn.org
  • MedScape. 4Kscore Predicts High Grade Prostate Cancer Prebiopsy, Nick Mulcahy, May 23, 2014. Also available at www.medscape.com
  • PubMed. Parekh DJ, Punnen S, et. al. A Multi-Institutional Prospective Trial in the USA Confirms that the 4Kscore Accurately Identifies Men with High-Grade Prostate Cancer. Eur Urol 2015 Sep;68(3):464-70
  • PubMed. Porpiglia F, Russo F, et. al. The Roles of Multparametric Magenetic Resonance Imaging, PCA3 and Prostate Health Index Which is the Best Predictor of Prostate Cancer after a Negative Biopsy? J Urol 2014 Jul;192(1):60-6
  • PubMed Ma W, Diep K, et. al. Diagnostic and Prognostic Scoring System for Prostate Cancer Using Urine and Plasma Biomarkers. Genet Test Mol Biomarkers 2014 Mar;18(3):156-63
  • PubMed. Wojno KJ, Costa FJ, et. al. Reduced Rate of Repeated Prostate Biopsies Observed in ConfirmMDx Clinical Utility Field Study. Am Health Drug Benefits 2014 May;7(3):129-34
  • OPKO Lab. 4Kscore Test. Also available at http://clinical.opko.com
  • Punnen S, Pavan N, Parekh D. Finding the Wolf in Sheep’s Clothing: The 4Kscore is a Novel Blood Test that can Accurately Identify the Risk of Aggressive Prostate Cancer. Reviews in Urology Vol. 17 No. 1 2015
  • Hagglof C, Hammarsten P, et. al. TMPRSS-ERG Expression Predicts Prostrate Cancer Survival and Associates with Stromal Biomarkers. PLoS One 9(2):e86824
  • Lin Daniel, Newcomb Lisa, et. al. Urinary TMPRSS2-ERG and PCA3 in an Active Surveillance Cohort: Results from a Baseline Analysis in the Canary Prostae Active Surveillance Study. Clinical Cancer Research 2013 19(9); 2442-50   
  • Hoffman Richard, Screening for Prostate Cancer. New England Journal of Medicine, November 24, 2011; 365:2013-9
  • Khan AP, Rajendiran TM, et. al. The Role of Sacrosine Metabolism in Prostate Cancer Progresssion. Neoplasia May 2013;15(5):491-501
  • Sartori D and Chan Daniel. Biomarkers in Prostate Cancer: Whats New? Curr Opin Oncol 2014 May; 26(3): 259-264

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Policy History: 

 

Date                                        Reason                               Action

May 2011                              Annual review                     Policy renewed

April 2012                             Annual review                     Policy renewed

February 2013                       Interim review                     Policy revised

April 2013                             Annual review                     Policy revised

March 2014                          Annual review                     Policy revised

February 2015                      Annual review                     Policy revised

December 2015                    Annual review                     Policy revised

 


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Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.

 
Contact Information
New information or technology that would be relevant for Wellmark to consider when this policy is next reviewed may be submitted to:
  Wellmark Blue Cross and Blue Shield
  Medical Policy Analyst
  P.O. Box 9232
  Des Moines, IA 50306-9232
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