Coverage Policy Manual
Policy #: 104
Category: Laboratory
Initiated: January 01, 2013
Last Review: December 05, 2023

  Self-Insured group specific policy will supersede this general policy when group supplementary plan document or individual plan decision directs otherwise. This policy does not apply to the Wal-Mart Associates Group Health Plan participants. Wal-Mart Associates Group Health Plan coverage policy can be accessed by Plan participants at My Benefits.
  Genetic Test: Genetic and Protein Biomarkers for the Diagnosis and Cancer Risk Assessment of Prostate Cancer

Description:
Prostate cancer is the second most common cancer in men, with a predicted 161,360 incidence cases and 26,730 deaths expected in the United States in 2017 (Siegal, 2017).
 
Prostate cancer is a complex, heterogeneous disease, ranging from microscopic tumors unlikely to be life-threatening to aggressive tumors that can metastasize, leading to morbidity or death. Early localized disease can usually be treated with surgery and radiotherapy, although active surveillance may be adopted in men whose cancer is unlikely to cause major health problems during their lifespan or for whom the treatment might be dangerous. In patients with inoperable or metastatic disease, treatment consists of hormonal therapy and possibly chemotherapy. The lifetime risk of being diagnosed with prostate cancer for men in the United States is approximately 16%, while the risk of dying of prostate cancer is 3% (Howlader et al, 2017). African American men have the highest prostate cancer risk in the United States; the incidence of prostate cancer is about 60% higher and the mortality rate is more than 2 to 3 times greater than that of white men (Odedina et al, 2009). Autopsy results have suggested that about 30% of men age 55 and 60% of men age 80 who die of other causes have incidental prostate cancer (Bell et al, 2015), indicating that many cases of cancer are unlikely to pose a threat during a man’s life expectancy.
 
Grading
The most widely used grading scheme for prostate cancer is the Gleason system (Gleason, 1966) It is an architectural grading system ranging from 1 (well differentiated) to 5 (poorly differentiated); the score is the sum of the primary and secondary patterns. A Gleason score of 6 or less is low-grade prostate cancer that usually grows slowly; 7 is an intermediate grade; 8 to 10 is high-grade cancer that grows more quickly. A revised prostate cancer grading system has been adopted by the National Cancer Institute and the World Health Organization (NCI, 2018). A cross-reference of the grading systems is shown below.
 
 
Grade 1 Gleason Score:  6 or less Cells: Well differentiated (low grade)
Grade 2 Gleason Score:  7 (3 + 4) Cells: Moderately differentiated (moderate grade)
Grade 3 Gleason Score:  7 (4 + 3) Cells: Poorly differentiated (high grade)
Grade 4 Gleason Score:  8  Cells: Undifferentiated (high grade)
Grade 5 Gleason Score:  9-10  Cells: Undifferentiated (high grade)
 
 
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. This policy will address these types of tests, as well as single nucleotide polymorphisms (SNPs) testing for cancer risk assessment. Testing to determine cancer aggressiveness after a tissue diagnosis of cancer has been made is addressed in Policy No. 970.
 
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.
 
Related Policies:
498 - Genetic Test: Microarray-based Gene Expression Profile Analysis for Prostate Cancer Management
 
 

Policy/
Coverage:
 
The following genetic and protein biomarkers for the diagnosis of prostate cancer are considered investigational:
    • Kallikrein markers (eg, 4Kscore Test)
    • Prostate Health Index (phi)
    • HOXC6 and DLX1 testing (eg, SelectMDx)
    • PCA3, ERG, and SPDEF RNA expression in exosomes (eg, ExoDx Prostate IntelliScore)
    • Autoantibodies ARF 6, NKX3-1, 5’-UTR-BMI1, CEP 164, 3’-UTR-Ropporin, Desmocollin, AURKAIP-1, and CSNK2A2 (eg, Apifiny) effective 12/2018
    • PCA3 testing (eg, Progensa PCA3 Assay)
    • TMPRSS:ERG fusion genes (eg, MyProstate Score; previously Mi-Prostate (MiPS)
    • Gene hypermethylation testing (eg, ConfirmMDx)
    • Mitochondrial DNA variant testing (eg, Prostate Core Mitomics Test)
    • PanGIA Prostate effective 12/2021
    • Candidate gene panels
    • Hepsin testing
    • Metabolomic profiles (eg, Prostarix™)
 
 
Single nucleotide variant testing for cancer risk assessment of prostate cancer is considered investigational.
 
Investigational services are Plan exclusions.
 
 
 
Coding  
    • 81313 PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen]) ratio (eg, prostate cancer)
    • 81539 Oncology (high-grade prostate cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA, and human kallikrein-2 [hK2]), utilizing plasma or serum, prognostic algorithm reported as a probability score
    • 81551 Oncology (prostate), promoter methylation profiling by real-time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy
    • 81542 Oncology (prostate) mRNA microarray gene expression profiling of 22 content genes, utilizing formalin-fixed paraffin embedded tissue, algorithm reported as metastasis risk score eff 01/01/20
    • 0005U Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score. Used for the ExoDx Prostate Intelliscore by Exosome Diagnostics, Inc
    • 0021U Oncology (prostate), detection of 8 autoantibodies (ARF 6, NKX3-1, 5'-UTR-BMI1, CEP 164, 3'-UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score. Used for the Apifiny test by Armune Bioscience, Inc
    • 0047U Oncology (prostate), mRNA, gene expression profiling by real-time RT-PCR of 17 genes (12 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a risk score. Used for Oncotype DX Genomic Prostate Score test from Genomic Health, Inc.
    • 0113U Oncology (prostate), measurement of PCA3 and TMPRSS2-ERG in urine and PSA in serum following prostatic massage, by RNA amplification and fluorescence-based detection, algorithm reported as risk score eff 10/01/19.  Used for MyProstate Score
    • 0228U Oncology (prostate), multianalyte molecular profile by photometric detection of macromolecules adsorbed on nanosponge array slides with machine learning, utilizing first morning voided urine, algorithm reported as likelihood of prostate cancer. Used for PanGIA Prostate
    • 0339U Oncology (prostate), mRNA expression profiling of HOXC6 and DLX1, reversetranscription polymerase chain reaction (RT-PCR), first-void urine following digital rectalexamination, algorithm reported as probability of high-grade cancer. PLA for SelectMDx forProstate Cancer
    • 0343U Oncology (prostate), exosome-based analysis of 442 small noncoding RNAs (sncRNAs) by quantitative reverse transcription polymerase chain reaction (RT-qPCR), urine, reported as molecular evidence of no-, low-, intermediate- or high-risk of prostate cancer
 
If the test includes multiple assays, uses an algorithmic analysis, and is reported as a numeric score or a probability, the unlisted multianalyte assay with algorithmic analysis code 81599 would be reported.
 

Rationale:
This evidence review has been updated regularly with searches of the PubMed database. The most recent literature update was performed through September 26, 2023.
 
In general, the evidence for genetic tests related to prostate cancer screening, detection, and management addresses either preliminary clinical associations between genetic tests and disease states or, in some cases, the clinical validity of these tests, i.e., the association of the test result with outcomes of interest, expressed in terms of clinical performance characteristics such as sensitivity, specificity, predictive value, and comparisons to current standards using receiver-operating curve (ROC) analysis and/or logistic regression. There is no evidence of clinical utility, i.e., that using a test will change treatment decisions and improve subsequent outcomes that matter to the patient such as mortality, morbidity, or quality of life.
 
Existing screening tools have led to unnecessary prostate biopsies. More than 1 million prostate biopsies are performed annually in the United States, with a resulting cancer diagnosis in 20% to 30% of men. About one-third of men who undergo prostate biopsy experience transient pain, fever, bleeding, and urinary difficulties. Serious biopsy risks (eg, bleeding or infection requiring hospitalization) are rare, with estimated rates ranging from less than 1% to 3% (Rosario et al, 2012; Liss et al, 2016).
 
Biomarker Testing for Selection of Men for Initial Prostate Biopsy
Commercially Available Tests to Determine Candidates for Initial Prostate Biopsy (Listed by test name, Manufacturer and Product Description)
    • 4Kscore. OPKO lab. Blood test that measures 4 prostate-specific kallikreins, which are combined into an algorithm to produce a risk score estimating the probability of finding high-grade prostate cancer (defined as a Gleason score > or = 7) if a prostate biopsy were performed.
    • Prostate Health Index (phi). Beckman Coulter. Blood assay that combines several components of PSA (total PSA, free PSA, [-2]proPSA) in an algorithm that includes patient age.
    • Mi-Prostate (MiPS) renamed MyProstate score 2021. University of Michigan MLabs and LynxDx. Measures TMPRSS2-ERG gene fusion and calculates a probability score that incorporates serum PSA or the PCPT, and urine TMPRSS2-ERG and PCA3 scores
    • SelectMDx. MDxHealth. Clinical model that combines post-DRE urinary panel for HOXC6 and DLX1 gene expression with other risk factors
    • ExoDx Prostate IntelliScore (EPI). Exosome Diagnostics. Urine panel for PCA3, ERG, and SPDEF RNA expression in exosomes
    • Apifiny Armune BioScience (acquired by Exact Sciences in 2017). Algorithm with detection of 8 autoantibodies (ARF 6, NKX3-1, 5' -UTR-BMI1, CEP 164, 3' -UTR-Ropporin, Desmocollin, AURKAIP-1, CSNK2A2) in serum
    • PCA3 score (eg Progensa). Hologic Gen-Probe. Many labs offer PCA3 tests (eg, ARUP Laboratories, Mayo Medical Laboratories, LabCorp). Measures PCA3 mRNA in urine samples after prostate massage. PCA3 mRNA may be normalized using PSA level to account for prostate cells.  
    • PanGIA Prostate. Genetics Institute of America. Analysis of a signature of small molecules, proteins, and cells with a proprietary machine learning algorithm.
 
Kallikreins Biomarkers and 4Kscore Test (OPKO Lab)
Russo et al (2017) Mostly prospective, observational study from 2010-2015.  The study included 23 studies that were mostly prospective and rated as moderate quality.27 There was high heterogeneity across studies, but pooled estimates showed generally low NPV (5% to 63%) and low specificity (25% to 35%) when sensitivity was 90% to 93%
 
Mi et al (2021) performed a systematic review and meta-analysis of studies reporting the diagnostic accuracy of the 4K score to detect high-grade prostate cancer using cutoff values of 7.5% to 10%.
25, Pooled analysis found acceptable diagnostic accuracy. However, significant heterogeneity among the included studies lowered confidence in the results.
 
The performance of the 4Kscore Test was validated in a total of 1012 patients who were enrolled from October 2013 to April 2014 in a blinded, prospective study at 26 urology centers in the United States (Parekh et al, 2014).  Enrollment into the study was open to all men who were scheduled for a prostate biopsy, regardless of age, PSA level, DRE, or prior prostate biopsy. Each patient underwent a transrectal ultrasound (TRUS)‒guided prostate biopsy of at least 10 cores. A blinded blood sample that was collected before biopsy was sent to OPKO Lab for the 4 kallikrein markers. The results of the kallikrein markers, prostate biopsy histopathology, patient age, DRE, and prior biopsy status were unblinded and analyzed. The authors have also conducted multiple studies predicting the use of the test in patient cohorts from the European Randomized Study of Prostate Cancer. Parekh et al (2015) estimated that 307 biopsies could have been avoided and 24cancer diagnoses would have been delayed with a 9% 4Kscore cutoff for biopsy, and 591 biopsies would have been avoided with 48 diagnoses delayed with a 15% cutoff. However, inferences on clinical utility cannot be made due to deficiencies in estimating the clinical validity that is described in the previous section.
 
Punnen et al (2018) reported on a second prospective validation study of the 4Kscore test conducted at 8 US Veterans Affairs hospitals from July 2015 to October 2016. One aim of the study was to evaluate test performance in African American men; of 366 men enrolled and evaluated, 205 (56%) were African American. In a comparative analysis, there was no difference in test performance in African American and non-African American men (P =.32).
 
Bhattu et al (2021) conducted a retrospective exploratory analysis using data from the 2 previously published validation studies, to determine test performance with a cut-off of 7.5% as the indication to proceed with biopsy.
 
Longer-term data on the incidence of prostate cancer in men who do not have a biopsy following testing with the marketed version of 4Kscore are not available. However, a case-control study by Stattin et al (2015), which was a nested cohort study of more than 17,000 Swedish men, estimated that, for men age 60 with PSA levels of 3 or higher and a kallikrein-related peptidase3 risk score less than 10%, the risk of metastasis at 20 years was 1.95% (95% confidence interval [CI], 0.64% to 4.66%).
 
Verbeek et al (2019) conducted a retrospective comparison of the discriminatory ability of the 4K score compared to the Rotterdam Prostate Cancer Risk Calculator. The cohort included 2,872 men with PSA > 3.0 from the European Randomized Study of Screening for Prostate Cancer Rotterdam. The 4K panel was measured in frozen serum samples. The AUCs were similar, with an AUC of 0.88 for the 4K score and 0.87 for the Rotterdam Prostate Cancer Risk Calculator (p=0.41). Addition of the 4K score to the Rotterdam Prostate Cancer Risk Calculator had a modest, though statistically significant improvement in discriminatory ability with an AUC of 0.89. A limitation of this study is that men were included who
had PSA outside of the levels of interest, which would be between 3 and 10 ng/ml.
 
Konety et al (2015) reported on the results of a survey of 35 U.S. urologists identified through the 4Kscore database at OPKOLab as belonging to practices that were large users of the test.
All 611 patients of participating urologists to whom men werereferred for an abnormal PSA level or DRE and had a 4Kscore test were included. Urologists, who received the 4Kscore as acontinuous risk percentage, were retrospectively asked about their plans for biopsy before and after receiving the test results andwhether the 4Kscore test results influenced their decisions. The physicians reported that the 4Kscore results influenceddecisions in 89% of men and led to a 64.6% reduction in prostate biopsies. The 4Kscore risk categories (low-risk: <7.5%,intermediate risk: 7.5% to 19.9%, high-risk: 20%) correlated highly (p<.001) with biopsy outcomes in 171 men with biopsyresults.
 
proPSA and Prostate Health Index
Several systematic reviews and meta-analyses have evaluated the clinical validity of p2PSA (proPSA) and PHI tests. All primary studies were observational andmost were retrospective. Reviews included studies of men with a positive, negative, or inconclusive DRE; Pecoraro et al(2016)
restricted eligibility to studies including PSA levels between 2 ng/mL and 10 ng/mL, while Russo et al (2017) restricted eligibility to studies including PSA levels between 2 ng/mL and 20 ng/mL. Anyango (2021) included studies in men of any agewith any range of PSA levels and reported results according to different cutoffs.
Pecoraro et al (2016) rated most of the 17 primary studies as low quality due to the design (most were retrospective), lack ofblinding of outcome assessors to reference standard results, lack of clear cutoffs for diagnosis, and lack of explicit diagnosticquestion. Russo et al (2017) included 23 studies that were mostly prospective and rated as moderate quality.There washigh heterogeneity across studies but pooled estimates showed generally low NPV (5% to 63%) and low specificity (25% to35%) when sensitivity was 90% to 93%.
 
Loeb et al (2017) conducted a modeling study to compare established risk calculators with and without phi. The population for this retrospective analysis included 728 men from the prospective multicenter clinical trial of phi (Catalona et al,2011). The probability of aggressive prostate cancer was evaluated at each value of phi from 1 to 100. The addition of phi to the PCPT 2.0 risk calculator increased the AUC for the discrimination of aggressive prostate cancer from 0.575 to 0.696 (p<0.001), while the addition of phi to the ERSPC 4 plus DRE risk calculator increased the AUC from 0.650 to 0.711 (p=0.014).
 
Tosoian et al (2017) found a 9% reduction in the rate of biopsy of 345 men who underwent phi testing compared with 1318 men who did not. There was an associated 8% reduction in the incidence of negative biopsies in men who had phi testing, but interpretation of results is limited because the use of the phi test was based solely on provider discretion. A prospective multicenter study by White et al (2018) evaluated physician recommendations for biopsy before and after receiving the phi test result.33 The phi score affected the physician’s management plan in 73% of cases, with biopsy deferrals when the phi score was low and the decision to perform biopsies when the phi score was 36 or more.
 
TMPRSS Fusion Genes and MyProstate Score
Sanda et al (2017) calculated that by restricting biopsy to participants with positive findings on TMPRSS2- ERG score, PCA3 score, or PSA level at thresholds of 8, 20, and 10, respectively, would have avoided 42% of unnecessary biopsies (true negative) and 12% of low-grade cancers.34 It was estimated that 7% of cancers would be missed using the combined threshold, compared with 21% using a PCA3 threshold of 7.
 
In the study by Tomlins et al (2016), 80% of the 1244 patients were undergoing initial biopsy due to elevated PSA levels. Thresholds were not defined and the AUCs for predicting any cancer using PSA alone, PCPT risk calculator alone, or the Mi-Prostate Score (MiPS). The AUC for MiPS was significantly improved compared with the PCPT risk calculator (p<.001). However, a study by Ankerst et al (2019) found that adding TMPRSS2-ERGto a PCPT risk calculatorplusPCA3did not improve the AUC. The online PCPT risk calculator now includes both the PCA3and TMPRSS2-ERGscores, which will be used for further validation.
 
Tosoian et al (2021) reported on a study to establish and validate a threshold for the MyProstateScore test (previously named MiPS) to rule out Gleason Group > 2 prostate cancer. A threshold of < 10 was identified in a training cohort and validated using a combined dataset that included 977 biopsy naive men from the validation study previously reported in Tomlins et al (2016) and 548 biopsy naive men prospectively enrolled as part of an Early Detection Research Network study that did not evaluate the
MyProstateScore. In the overall cohort, sensitivity was 97.0%, specificity was 32.6%, NPV was 97.5%, and PPV was 29.1%. Results were similar in the subgroup of men with PSA between 3 and 10 or with PSA <3 with suspicious DRE. The study authors are co-founders and have equity in LynDx, which has licensed the urine biomarkers evaluated in the study.
 
The prospective multi-institutional Canary Prostate Surveillance Study (PASS) was reported by Newcomb et al (2019). The study included 782 men under active surveillance (2,069 urine samples) to examine the association of urinary PCA3 and TMPRSS2:ERG with biopsy-based reclassification. Under the PASS protocol, PSA is measured every 3 months and ultrasound-guided biopsies are performed 12 and 24 months after diagnosis, then every 2 years. Post-DRE urine samples were collected every 6 months. Modeling showed minimal benefit of adding PCA3 to a model with clinical variables, improving the AUC from 0.743 to 0.753.
 
In a prospective, multicenter study, Leyten et al. (2014) investigated the predictive value of PCA3 and TMPRSS2 as individual biomarkers and as part of a panel in a prospective, multicenter study of 443 men.  TMPRSS2 was found to be highly specific (93%) for predicting clinically significant prostate cancer on biopsy. Because of this high specificity, the authors suggested that rebiopsy or MRI be performed in TMPRSS2:ERG-positive patients who do not have prostate cancer detected on initial biopsy. The authors stated that if PCA3 in combination with TMPRSS2 data had been used to select men for prostate biopsy, 35% of biopsies could have been avoided.
 
SelectMDx for Prostate Cancer
Van Neste et al (2016) evaluated a risk calculator that added HOXC6 and DLX1 expression to a clinical risk model. A training set in 519 men and an independent validation set in 386 men were assessed. When evaluating the risk model in men who were in the “gray zone” of PSA level between 3 ng/mL and 10 ng/mL, the AUC was significantly higher than a clinical risk model alone, Prostate Cancer Prevention Trial Risk Calculator (PCPTRC) for detection of any cancer or for detection of high-grade cancer (see Table 16). A limitation of this study is the inclusion of men with an abnormal DRE (see Tables 17 and 18), which was the strongest predictor of prostate cancer in the training set (OR=5.53; 95% CI, 2.89 to 10.56). The OR for HOXC6 and DLX1 expression in this model was 1.68 (95% CI, 1.38 to 2.05; p<0.003).
 
Development and validation studies on a revised risk model that included HOXC6 and DLX1 expression along with patient age, DRE, and PSA density in men undergoing initial biopsy was reported by Haese et al (2019). The new analysis included data from the Dutch patients in the report by Van Neste et al (2016) along with additional cohorts from France and Germany. In the validation cohort of men with all PSA levels, the AUC was 0.82 with 89% sensitivity and 53% specificity. The PCPTRC AUC was 0.76. Since some clinicians will proceed to biopsy when there is a positive DRE, results were also calculated for patients who had PSA <10 ng/ml and a negative DRE. For this cohort (n=591), the AUC was 0.80 with sensitivity of 84% and specificity of 57%. Comparison with the PCPTRC in this subgroup was not reported.
 
Hendriks et al evaluated the SelectMDx test to detect high-grade prostate cancer in biopsy-naive men (Hendriks, 2021). In total, 599 men in the Netherlands with PSA level of 3 ng/mL or greater scheduled for their initial biopsy were included in the study. All subjects underwent a multi-parametric magnetic resonance imaging (MRI) test and biopsy after urine sample and DRE were complete. The primary outcome was the detection rates of low- and high-grade prostate cancer and the number of biopsies avoided in 4 distinct diagnostic strategies: (1) SelectMDx test only, (2) MRI only, (3) SelectMDx test followed by MRI when SelectMDx test was positive (conditional strategy), and (4) SelectMDx and MRI in all (joint strategy). Decision curve analysis was performed to assess clinical utility. Overall, prevalence of high-grade prostate cancer was 31% (183/599). Thirty-eight percent of patients had negative SelectMDx tests in whom biopsy could be avoided. Decision curve analysis showed the highest net benefit for the MRI only strategy, followed by the conditional strategy at risk thresholds over 10%. Investigators also found that SelectMDx test led to a 35% reduction of over detection of low-grade prostate cancer and could save 38% of MRIs, at the cost of missing 10% of high-grade prostate cancers compared to biopsy for all patients. However, the use of MRI alone in all patients to select for prostate biopsy had the highest net benefit as a prebiopsy stratification tool.
 
ExoDx Prostate (IntelliScore)
McKiernan et al (2016) conducted a multicenter validation study of urine exosome PCA3, ERG, and SPDEF RNA expression to predict high-grade (Gleason score 7) prostate cancer (see Table 19). 37 The threshold for a positive test was derived from a training set separate from the validation set. The assay improved on the standard of care alone, with an AUC of 0.73 compared with 0.63 for standard of care and 0.62 for the PCPTRC.
 
Tutrone et al (2020) reported a trial that evaluated the effect of ExoDx Prostate on the decision to biopsy. The multicenter, prospective, blinded RCT was conducted in partnership with CareFirst BlueCross/BlueShield of Maryland and included 1094 men with PSA 2 to 10 ng/ml who were considered for prostate biopsy based on clinical criteria. All patients had the test, but only patients randomized to the ExoDx Prostate arm received the test results. The primary outcome of the study was to determine if ExoDX Prostate could reduce initial biopsies. The secondary endpoint was the successful diagnosis of high-grade prostate cancer. A total of 942 patients (86.1%) had complete data and usable samples. In the ExoDx Prostate arm, 93 patients received low risk test results and 106 patients (23%) received recommendations to defer biopsy. High risk ExoDx Prostate scores led to a recommendation for biopsy in 87% of the 365 ExoDx Prostate positive patients. Compliance with a recommendation for biopsy was 72% in the ExoDx Prostate arm compared to about 40% of the control arm, leading to increased biopsy rates in the ExoDx Prostate arm (58%) compared to controls (39%). In African American patients, who represented 23% of the patient population, 91% had high risk scores. The study did not meet its primary
endpoint. The main effect of the test was to increase biopsies with an increase in the number of at least GG2 cancers, but there was also an increase in the number of men biopsied who had no cancer or low-grade cancer compared to the control arm. Additional limitations of the study are the inclusion of men with very low PSA (2 ng/ml) and the lack of information on what screening had preceded the referral for biopsy. It is unclear if the standard of care of repeat PSA and %fPSA were assessed prior to the decision to biopsy, if controls received this standard of care, or if the test was intended as a replacement for repeat PSA and %fPSA.
 
Tutrone et al (2023) reported on a retrospective outcome analysis follow-up study of 2.5 year of the initial 2020 study reported above. Of the original 1094 cohort, 833 patients had complete follow-up data at 2.5 years. In this analysis, patients returned to routine standard of care after enrollment in the clinical utility trial, and a retrospective outcome analysis was conducted. The average time from ExoDX Prostate testing to the first biopsy was significantly longer in the low-risk ExoDX Prostate arm (216days) compared to high-risk ExoDX Prostate arm (68.7 days; p <.001) and when compared to low-risk ExoDX Prostate patients in the standard of care arm (79.4 days; p <.001). In the ExoDx Prostate arm, low-risk patients had significantly fewer biopsies than high-risk patients (44.6% vs 79.0%, p<.001); in the standard of care arm the decision to defer was independent of ExoDxProstate score and, as a result, did not differ between low-risk and high-risk scores. Patients in both arms with low-risk ExoDxProstate scores had lower rates of high-grade prostate cancer at 2.5 years than high-risk ExoDx Prostate score patients(7.9%vs. 26.8%; p<.001), and the ExoDx Prostate arm discovered 21.8% (106 vs 87) more high-grade prostate cancer than the standard of care arm. Limitations of this interim analysis mimic limitations that were described in the above study; the study was also retrospective in nature.
 
Apifiny
Schipper et al (2015) identified 8 autoantibodies associated with prostate cancer in a case-control study of men 40 to 70 years old with prostate cancer and PSA levels between 2.5 ng/mL and 20 ng/mL, compared to healthy men 25 to 40 years of age with PSA levels less than 1.0 ng/mL.38 When the algorithm was applied to an independent validation set, the AUC was 0.69 (95% CI, 0.62 to 0.75).
 
PanGIA Prostate
No studies were identified on PanGia Prostate
 
Comparative Studies
 
4Kscore and SelectMDx
Wysock et al (2020) compared the performance of 4Kscore and SelectMDx to inform decisions of whether to perform a prostate biopsy.44, New referrals (n=128) with elevated PSA were advised to undergo both 4K score and SelectMDX; 114 men underwent both tests. There was poor concordance between the two tests, with discordant guidance in 45.6% of the population. Since biomarker results were used to determine which patients should undergo biopsy (ie the reference test was not obtained for all patients), it cannot be determined which of the tests was more accurate.
 
PCA3 Score (eg, Progensa PCA3 Assay)
Several systematic reviews and meta-analyses have described the clinical validity of the Progensa PCA3 Assay. The studies assessed both initial and repeat biopsy and had a quality rating of moderate to high.
 
Rodriguez et al (2020) conducted a systematic review of PCA3 in men who had not yet undergone biopsy. Nine studies in men without prior biopsy were identified, and 5 studies that used a cutoff of 35 were included in the meta-analysis. The study found pooled sensitivity of 69% and specificity of 65% in the 5 studies that used a cutoff of 35 in men without prior biopsy.
 
In the meta-analysis by Cui et al (2016), the most common PCA3assay cutoff for categorizing low- and high-risk was 35 (25 of 46 studies).The estimates of AUC were lower for studies that included men having repeated (0.68) versus initial (0.80) biopsies.
 
The assessment by Nicholson et al (2015) for the National Institute for Health and Care Excellence included 11 cohorts of men for whom initial prostate biopsy results were negative or equivocal. Nicholson et al (2015) included 13 reports describing 11 cohorts, including 1 from the placebo arm of an RCT. Referral criteria for repeat biopsy, were varied, often unclear, and differed based on whether normal or abnormal DREs were included. The mean or median PSA, when reported, ranged from 4.9 to 11.0 ng/mL and the prevalence of cancer on repeat biopsy varied from 11.4%to 68.3%. Meta-analyses were not performed due to heterogeneity. The addition of PCA3 to clinical assessment, as a continuous or categorical variable, generally led to an improvement in AUC, but studies that fixed sensitivity and derived specificity and those that reported decision-curve analysis had mixed results.
 
Prospective Studies
A 2014, the National Cancer Institute conducted a prospective trial to validate the diagnostic use of PCA3 to complement PSA-based detection of prostate cancer (Wei et al, 2014).  The target population included men who had been screened for prostate cancer, primarily with a PSA test, some of whom had undergone a previous prostate biopsy. The study included 859 men from 11 centers in the United States. The primary study end point was the diagnosis of prostate cancer on biopsy and the secondary study end point was diagnosis of high-grade prostate cancer, defined as a Gleason score greater than 6. The primary analyses, including PCA3 thresholds, were determined a priori, and statistical power was based on independent analyses of pre-validation data from similar cohorts. Of the men in the study, 562 were presenting for their initial prostate biopsy. Positive predictive value was 80% (95% CI, 72% to 86%), and using a PCA3 score of more than 60, diagnostic sensitivity and specificity of PCA3 was 0.42 (95% CI, 0.36 to 0.48) and 0.91 (95% CI, 0.87 to 0.94), respectively. For patients who underwent a repeat biopsy, the negative predictive value was 88% (95% CI, 81% to 93%), and by using a PCA3 score of less than 20, sensitivity and specificity were 0.76 (95% CI, 0.64 to 0.86) and 0.52 (95% CI, 0.45 to 0.58), respectively. For the detection of high-grade cancer, PCA3 performance in combination with Prostate Cancer Prevention Trial’s (PCPT) risk calculator was improved by the addition of PCA3 to the PCPT risk calculator factors with an AUC improvement of 0.74 to 0.78 for initial biopsy and 0.74 to 0.79 on repeat biopsy (p0.003).
 
Clinical utility studies using assay results for decision making for initial biopsy, repeat biopsy, or treatment have not been reported. One group reported potential reductions in unnecessary biopsies of 48% to 52% with attendant increases in missed prostate cancers of 6% to 15% using either a PCA3-based nomogram (Ruffion, 2013) or PCA3 level corrected for prostate volume (PCA3 density) (Ruffion, 2014).  Although both studies were prospective, neither assessed utility of the test for clinical decision making because all patients underwent biopsy. Also, recurrence or survival outcomes were not evaluated.
 
Merdan et al (2015) used decision analysis to simulate long-term outcomes associated with the use of the PCA3 score to trigger repeat biopsy compared with the PCPT risk calculator in men with at least 1previous negative biopsy and elevated PSA levels.
 
 
Biomarker Testing for Selection of Men for Repeat Prostate Biopsy
 
Commercially Available Tests to Determine Candidates for Repeat Prostate Biopsy
    • PCA3 Score (eg,Progensa PCA3 Assay)
    • ConfirmMDx
    • Prostate Core MitomicsTest (PCMT)
    • Gene panel testing
    • MyProstate Score 2.0
 
PCA3 is a noncoding long-chain RNA that is highly overexpressed in prostate cancer compared with noncancerous prostate tissue and is detectable in urine. The Progensa PCA3 Assay is approved by the FDA to facilitate decision making among men with prior negative prostate biopsies.
 
Epigenetic changes, chromatin protein modifications that do not involve changes to the underlying DNA sequence, but which can result in changes in gene expression, have been identified in specific genes. There is an extensive literature reporting significant associations of epigenetic DNA modifications with prostate cancer.  Studies are primarily small, retrospective pilot evaluations of hypermethylation status of various candidate genes for discriminating prostate cancer from benign conditions (diagnosis) or for predicting disease recurrence and association with clinicopathologic predictors of aggressive disease (prognosis). A review of recently published studies reveals an area of clinical research that has not yet identified the best markers for diagnosis and prognosis or the best way to measure them and in which sample type. No standardized assays and interpretation criteria have been agreed on yet to enable consistency and comparison of results across studies.
 
The Prostate Core Mitomics Test (PCMT; Mitomics; formerly Genesis Genomics) is a proprietary test intended to determine whether a patient has prostate cancer, despite a negative prostate biopsy, by assessing a 3.4-kilobases deletion in mitochondrial DNA by polymerase chain reaction to detect “tumor field effect.” The test is performed on the initial negative prostate biopsy tissue and is being evaluated in men who have had an initial negative biopsy. A negative PCMT result is intended to confirm theresult of the negative biopsy so that the patient can avoid a second biopsy, while a positive PCMT is intended to indicate that the patient is at high-risk of undiagnosed prostate cancer.
 
Single nucleotide variants (SNVs) occur when a single nucleotide is replaced with another and are the most common type of genetic variation in humans. They occur normally throughout the genome and can act as biologic markers for disease association. Genome-wide association studies have identified correlations between prostate cancer risk and specific SNVs. However, it is widely accepted that, individually, SNV-associated disease risk is low and of no value in screening, although multiple SNVs in combination may account for a higher proportion of prostate cancer. Investigators have begun to explore the use of algorithms incorporating information from multiple SNVs to increase the clinical value of testing.
 
Watherhouse et al (2018) performed a retrospective study on ConfirmMDx performed on first biopsy    The study population was archived, cancer-negative prostate biopsy core tissue samples from 211 African American men from 7 U.S. urology centers.
 
Two blinded multicenter validation studies of the ConfirmMDx test have been performed (Partin et al, 2014; Stewart et al, 2013). One evaluated archived, cancer-negative prostate biopsy core tissue samples from 350 men from a total of 5 U.S. urological centers. All of the patients underwent repeat biopsy within 24 months. The ConfirmMDx test, performed on the first biopsy, resulted in a negative predictive value of 88% (95% CI, 85 to 91). Multivariate analysis of potential predictors of cancer on repeat biopsy, corrected for age, PSA, DRE, first biopsy histopathology characteristics and race, showed that the ConfirmMDx test was the most significant independent predictor of patient outcome (odds ratio [OR], 2.69; 95% CI, 1.60 to 4.51).
 
Stewart and colleagues (2013) investigated a quantitative methylation assay (including GSTP1, APC, and RASSF1) as a predictive test for occult prostate cancer.  The study retrospectively assayed 498 prostate biopsy tissue samples from patients who had negative histopathologic findings on first biopsy, but who received a follow-up biopsy within 30 months. The authors reported a sensitivity of 68% (95% CI: 57-77) a specificity of 64% (95% CI: 59-69) for the assay score in predicting occult cancer. The negative predictive value of the test was 90% (95% CI: 87-93), which offered a significant improvement compared with histologic diagnosis alone (70% NPV). On multivariate analysis, the assay score was a significant predictor or prostate cancer on second biopsy, with an odds ratio of 3.17 (95% CI 1.81–5.53, p<0.0001).
 
Van Neste et al (2016) and Partin et al (2016) reported on results of combined data from the DOCUMENT and MATLOC studies for patients with high-grade (Gleason score, 7) prostate cancer.
DNA methylation was the most significant and important predictor of high-grade cancer, with an NPV of 96% (precision not reported) and an OR of 9.80 (95% CI, 2.12 to 45.23).
 
Prostate Core Mitomics Test
In 2010, Robinson et al. assessed the clinical value of the 3.4-kb deletion described in the Maki study in predicting re-biopsy outcomes.  Levels of the deletion were measured by quantitative PCR in prostate biopsies negative for cancer from 101 patients who underwent repeat biopsy within 1 year and had known outcomes. Of the 101 first biopsies, the diagnosis was normal in 8, atypical and/or had prostatic intraepithelial neoplasia in 50, and hyperplasia or inflammation in 43. Using an empirically established cycle threshold cutoff, the lowest cycle threshold as diagnostic of prostate cancer, and the histopathologic diagnosis on second biopsy, the clinical performance of the deletion was calculated. The final data were based on 94 patients, who on second biopsy had 20 malignant and 74 benign diagnoses. The cycle cutoff
gave a sensitivity and specificity of 84% and 54%, respectively, with the area under a ROC curve of 0.75. Negative predictive value was 91%.
 
Legisi et al (2016) queried a pathology services database to identify (1) men who had a negative initial prostate biopsy and a negative PCMT (n=644), and (2) men who had a negative initial prostate biopsy and a repeat biopsy (n=823).54 Of the 644 patients with a negative PCMT, 35 had a repeat biopsy and 5 (14.2%) were false negatives who were found to have cancer on re-biopsy. The number of false negatives of the patients who did not have a repeat biopsy cannot be determined from this study. Of the second group of 823 men who had a repeat biopsy, 132 had a PCMT. Changes in physician decision-making led to earlier detection of prostate cancer by 2.5 months and an increase in cancer detection rates, but this was only observed when men with atypical small acinar proliferation on index biopsy were not included. Interpretation of these results is limited because testing was not random or consecutive.
 
Candidate Gene Panels
A 3-gene panel (HOXC6,TDRD1,DLX1) developed by Leyten et al (2015) is now commercially available as SelectMDx. Xiao et al (2016) reported the development of an 8-gene panel (PMP22,HPN,LMTK2,FN1,
EZH2,GOLM1,PCA3,GSTP1) that distinguished high-grade prostate cancer from indolent prostate cancer with a sensitivity of 93% and NPV of 61%.
 
MyProstate Score
Tosoian et al (2023) evaluated the MyProstate Score test in men with persistent risk of Grade Group 2 cancer after a negativebiopsy who are being considered for repeat biopsy. A total of 422 men underwent repeat biopsy in the primary study cohort;the validation cohort consisted of 268 men. Thresholds of 15 and 40 met pre-defined performance criteria in the primary cohort(median PSA 6.4; IQR, 4.3 to 9.1); upon biopsy, 58 men (14%) were found to have Grade Group 2 cancer, and 25 men (5.9%)had Grade Group 3 cancer. In the validation cohort, repeat biopsy was negative in 205 men (76%), and revealed Grade Group1 cancer in 38 men (14%); it also demonstrated Grade Group 2 cancer in 25 men (9.3%).The rule-out threshold of 15 provided100% NPV and 100% sensitivity for Grade Group 2 cancer. Using the upper threshold of 40 to rule-in biopsies for only men athighest risk would have avoided 179 biopsies (67%) maintained a 95% NPV value.
 
SUMMARY OF EVIDENCE
For individuals who are being considered for an initial prostate biopsy biopsy who receive testing for genetic and protein biomarkers of prostate cancer (eg, kallikreins biomarkers and 4Kscore Test, proPSA and Prostate Health Index, TMPRSS fusion genes and MyProstate Score, SelectMDx for Prostate Cancer, ExoDx Prostate, Apifiny, PCA3 score), the evidence includes systematic reviews, meta-analyses, and primarily observational studies. Relevant outcomes are overall survival, disease-specific survival, test validity, resource utilization, and quality of life. The evidence supporting clinical utility varies by test but has not been directly shown for any biomarker test. Absent direct evidence of clinical utility, a chain of evidence might be constructed. However, the performance of biomarker testing for directing biopsy referrals is uncertain. While some studies have shown a reduction or delay in biopsy based on testing, a chain of evidence for clinical utility cannot be constructed due to limitations in clinical validity. Test validation populations have included men with a positive digital rectal exam, a PSA level outside of the gray zone (between 3 or 4 ng/mL and 10 ng/mL), or older men for whom the information from test results are less likely to be informative. Many biomarker tests do not have standardized cutoffs to recommend a biopsy. In addition, comparative studies of the many biomarkers are lacking. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who are being considered for repeat biopsy who receive testing for genetic and protein biomarkers of prostate cancer (eg, Gene Hypermethylation and ConfirmMDx test, Prostate Core Mitomics Test), the evidence includes systematic reviews and meta-analyses and primarily observational studies. Relevant outcomes are overall survival, disease-specific survival, test validity, resource utilization, and quality of life. The performance of biomarker testing for guiding rebiopsy decisions is lacking. The tests are associated with a diagnosis of prostate cancer and aggressive prostate cancer, but studies on clinical validity are limited and did not compare performance characteristics with standard risk prediction models. Direct evidence supporting clinical utility has not been shown. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov registry identified several currently unpublished trials that might influence this policy.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
American Urological Association
In 2023, the American Urological Association (AUA) and the Society of Urologic Oncology (SUO) published updated guidelineson the early detection of prostate cancer. Specific guidance related to diagnosis, risk assessment, and utilization of biomarker (Wei et al, 2023a and 2023b).
 
Relevant AUA/SUO Guideline Statements on Prostate Cancer Screening and Biopsy
 
    • Guideline Statement: When screening for prostate cancer, clinicians should use PSA as the first screening test. Evidence Grade and Strength: Strong Recommendation; Evidence Level: Grade A
    • Guideline Statement: For people with a newly elevated PSA, clinicians should repeat the PSA prior to a secondary biomarker, imaging, or biopsy. Evidence Grade and Strength: Expert Opinion
    • Guideline Statement: Clinicians may use digital rectal exam (DRE) alongside PSA to establish risk of clinically significant prostate cancer. Evidence Grade and Strength: Conditional Recommendation; Evidence Level: Grade C
    • Guideline Statement: For people undergoing prostate cancer screening, clinicians should not use PSA velocity as the sole indication for a secondary biomarker, imaging, or biopsy. Evidence Grade and Strength: Strong Recommendation; Evidence Level: Grade B
    • Guideline Statement: Clinicians may use adjunctive urine or serum markers when further risk stratification would influence the decision regarding whether to proceed with biopsy. Evidence Grade and Strength: Conditional Recommendation; Evidence Level: Grade C
    • Guideline Statement: After a negative biopsy, clinicians should not solely use a PSA threshold to decide whether to repeat the biopsy. Evidence Grade and Strength: Strong Recommendation; Evidence Level: Grade B
    • Guideline Statement: After a negative biopsy, clinicians may use blood-, urine-, or tissue-based biomarkers selectively for further risk stratification if results are likely to influence the decision regarding repeat biopsy or otherwise substantively change the patient’s management
    • Evidence Grade and Strength: Conditional Recommendation; Evidence Level: Grade C
    • Guideline Statement: In patients with multifocal HGPIN [high-grade prostatic intraepithelial neoplasia], clinicians may proceed with additional risk evaluation, guided by PSA/DRE and mpMRI findings
    • Evidence Grade and Strength: Expert Opinion
 
National Comprehensive Cancer Network
The NCCN guidelines (v.2.2023) recommend that any man with a PSA level greater than 3 ng/mL undergo workup for benign disease, repeat PSA, and digital rectal examination. The guidelines also recommend consideration of biomarkers that improve the specificity of screening that includes percent free PSA, with consideration of phi, SelectMDx, ExoDx Prostate (IntelliScore) (EPI), or 4Kscore in
patients with a PSA level greater than 3 ng/mL who have not yet had a biopsy. Percent free PSA, phi, 4Kscore, PCA3, ExoDx Prostate (IntelliScore) (EPI), and ConfirmMDx might be considered in men who had a negative biopsy but are thought to be at higher risk (category 2A evidence). The NCCN noted that these tests may be especially useful in men with PSA levels between 3 ng/mL and 10 ng/mL. The NCCN considers the Mi-Prostate Score (MiPS) to be investigational at the time of the update. The status of SelectMDx was changed from investigational in 2019 to potentially informative in the 2020 update.
 
National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence (2019) did not recommend the Progensa PCA3 Assay or the phi test for use in men with suspicion of prostate cancer who had a negative or inconclusive prostate biopsy.
 
U.S. Preventive Services Task Force Recommendations
The U.S. Preventive Services Task Force (2018) updated recommendations for prostate cancer screening. Genetic and protein biomarkers addressed in this evidence review, including PCA3, were not mentioned.
 
The U.S. Preventive Services Task Force advises individualized decision making about screening for prostate cancer after discussion with a clinician for men ages 55 to 69 (C recommendation) and recommends against PSA-based screening in men 70and older (D recommendation).
 
REGULATORY STATUS
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed under the Clinical Laboratory Improvement Amendments for high-complexity testing. The following laboratories are certified under the Clinical Laboratory Improvement Amendments: BioReference Laboratories and GenPath Diagnostics (subsidiaries of OPKO Health; 4Kscore®), ARUP Laboratories, Mayo Medical Laboratories, LabCorp, BioVantra, others (PCA3 assay), Clinical Research Laboratory (Prostate Core Mitomic Test™), MDx Health (SelectMDx, ConfirMDx), Innovative Diagnostics (phiTM), and ExoDx® Prostate (Exosome Diagnostics). To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
 
In February 2012, the Progensa® PCA3 Assay (Gen-Probe; now Hologic) was approved by the FDA through the premarket approval process. The Progensa PCA3 Assay (Hologic Gen-Probe) has been approved by the FDA to aid in the decision for repeat biopsy in men 50 years or older who have had one or more negative prostate biopsies and for whom a repeat biopsy would be recommended based on current standard of care. The Progensa PCA3 Assay should not be used for men with atypical small acinar proliferation on their most recent biopsy. FDA product code: OYM.
 
In June 2012, proPSA, a blood test used to calculate the Prostate Health Index (phi; Beckman Coulter) was approved by the FDA through the premarket approval process. The phi test is indicated as an aid to distinguish prostate cancer from a benign prostatic condition in men ages 50 and older with prostate specific antigen levels of 4 to 10 ng/mL and with digital rectal exam findings that are not suspicious. According to the manufacturer, the test reduces the number of prostate biopsies. FDA product code: OYA.

CPT/HCPCS:
0005UOncology (prostate) gene expression profile by real time RT PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score
0021UOncology (prostate), detection of 8 autoantibodies (ARF 6, NKX3 1, 5' UTR BMI1, CEP 164, 3' UTR Ropporin, Desmocollin, AURKAIP 1, CSNK2A2), multiplexed immunoassay and flow cytometry serum, algorithm reported as risk score
0047UOncology (prostate), mRNA, gene expression profiling by real time RT PCR of 17 genes (12 content and 5 housekeeping), utilizing formalin fixed paraffin embedded tissue, algorithm reported as a risk score
0113UOncology (prostate), measurement of PCA3 and TMPRSS2 ERG in urine and PSA in serum following prostatic massage, by RNA amplification and fluorescence based detection, algorithm reported as risk score
0228UOncology (prostate), multianalyte molecular profile by photometric detection of macromolecules adsorbed on nanosponge array slides with machine learning, utilizing first morning voided urine, algorithm reported as likelihood of prostate cancer
0339UOncology (prostate), mRNA expression profiling of HOXC6 and DLX1, reverse transcription polymerase chain reaction (RT-PCR), first-void urine following digital rectal examination, algorithm reported as probability of high-grade cancer
0343UOncology (prostate), exosome-based analysis of 442 small noncoding RNAs (sncRNAs) by quantitative reverse transcription polymerase chain reaction (RT-qPCR), urine, reported as molecular evidence of no-, low-, intermediate- or high-risk of prostate cancer
0403UOncology (prostate), mRNA, gene expression profiling of 18 genes, first-catch post-digital rectal examination urine (or processed first-catch urine), algorithm reported as percentage of likelihood of detecting clinically significant prostate cancer
81313PCA3/KLK3 (prostate cancer antigen 3 [non protein coding]/kallikrein related peptidase 3 [prostate specific antigen]) ratio (eg, prostate cancer)
81479Unlisted molecular pathology procedure
81539Oncology (high grade prostate cancer), biochemical assay of four proteins (Total PSA, Free PSA, Intact PSA, and human kallikrein 2 [hK2]), utilizing plasma or serum, prognostic algorithm reported as a probability score
81542Oncology (prostate), mRNA, microarray gene expression profiling of 22 content genes, utilizing formalin fixed paraffin embedded tissue, algorithm reported as metastasis risk score
81551Oncology (prostate), promoter methylation profiling by real time PCR of 3 genes (GSTP1, APC, RASSF1), utilizing formalin fixed paraffin embedded tissue, algorithm reported as a likelihood of prostate cancer detection on repeat biopsy
81599Unlisted multianalyte assay with algorithmic analysis

ICD9:

ICD10:

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