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MP 2.04.33

Gene-Based Tests for Screening, Detection, and/or Management of Prostate Cancer


Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature Search/4:2014
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Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.



There are a variety of gene-based biomarkers associated with prostate cancer. These tests have the potential to improve the accuracy of risk prediction, diagnosis, staging, or prognosis of prostate cancer.


Prostate cancer is a complex, heterogeneous disease. At the extremes of the spectrum, if left untreated, some prostate cancers behave aggressively, metastasize quickly, and cause mortality, while others are indolent and never progress to cause harm. Current challenges in prostate cancer care are risk assessment; early and accurate detection; monitoring low-risk patients undergoing surveillance only; prediction and detection of recurrence after initial treatment; and assessing efficacy of treatment for advanced disease.

A variety of exploratory research is ongoing in response to the need for better biomarkers for risk assessment, diagnosis, and prognosis. Some products of this work have already been translated or are in the process of being translated into commercially available tests, including:

  • single nucleotide polymorphisms (SNPs) for risk assessment
  • prostate cancer antigen 3 (PCA3) for disease diagnosis and prognosis
  • transmembrane serine protease (TMPRSS) fusion genes for diagnosis and prognosis
  • multiple gene tests (gene panels) for prostate cancer diagnosis
  • gene hypermethylation for diagnosis and prognosis

Although studies using these tests generate much information that may help elucidate the biologic mechanisms of prostate cancer and eventually help design treatments, the above-mentioned tests are in a developmental phase. Examples are:

  • SNP testing as part of genome-scanning tests for prostate cancer risk assessment are offered by a variety of laboratories, such as Navigenics, LabCorp (23andme), and ARUP (deCode), as laboratory-developed tests.
  • The PCA3 test is offered in the U.S. by a number of reference laboratories including ARUP, Mayo Medical Laboratories, and LabCorp. Reagents used in testing are developed by Gen-Probe.
  • The Prostate Gene Expression Profile was widely announced as available from Clarient Inc. in January 2009; as of March 2011, the test no longer appears on the listing at the company website.
  • Two hypermethylation analyses are currently available or in development:
    • LabCorp (Burlington, NC) offers a test for hypermethylated GSTP1 (“Glutathione S-transferase Gene [GSTP1, pi-class] Methylation Assay”), and the required specimen is formalin-fixed, paraffin-embedded tissue. The test is stated to be an adjunct to histopathology.
    • MDxHealth (Irvine, CA) offers ConfirmMDx®, a diagnostic test for hypermethylated GSTP1, adenomatous polyposis coli (APC), and RASSF1 (Ras association [RalGDS/AF-6] domain family member 1]. The test is marketed as “an epigenetic assay to reduce repeat prostate biopsies,”(1) and the required specimen is formalin-fixed, paraffin-embedded tissue.

Regulatory Status

Only 1 PCA3 test has been submitted to the U.S. Food and Drug Administration (FDA) for premarket approval. The Gen-Probe Progensa® PCA3 Assay was approved by FDA on February 15, 2012, through the premarket approval process. According to the company’s press release, this assay is “indicated for use in conjunction with other patient information to aid in the decision for repeat biopsy in men 50 years of age or older who have had 1 or more previous negative prostate biopsies and for whom a repeat biopsy would be recommended by a urologist based on the current standard of care, before consideration of Progensa PCA3 assay results.”

Other tests mentioned in this policy, if available, are offered as laboratory-developed tests under the Clinical Laboratory Improvement Amendments (CLIA) licensed laboratories. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratories offering such tests as a clinical service must meet general regulatory standards of the Clinical Laboratory Improvement Act (CLIA) and must be licensed by CLIA for high-complexity testing.


Genetic tests for the screening, detection, and management of prostate cancer are considered investigational. This includes, but is not limited to the following:

  • single nucleotide polymorphisms (SNPs) for risk assessment;
  • PCA3 for disease diagnosis and prognosis;
  • TMPRSS fusion genes for diagnosis and prognosis;
  • multiple gene tests (gene panels) for prostate cancer diagnosis; or
  • gene hypermethylation for diagnosis and prognosis.


Policy Guidelines

Effective January 1, 2015, there is a specific CPT code for PCA3 testing:

81313 PCA3/KLK3 (prostate specific antigen 3 [non-protein coding]/ kallikrein-related peptidase 3 [prostate specific antigen]) ratio (eg, prostate cancer)

Prior to 2015 for PCA3 testing and currently for the other types of testing mentioned above, there are no specific CPT codes. The unlisted molecular pathology code 81479 would be used.

Prior to 2013, a series of molecular diagnostic codes (83890-83912) would likely have been used.

Effective April 1, 2012, there is a specific HCPCS “S” code for the PCA3 test

S3721 Prostate Cancer Antigen 3 (PCA3) testing.

Benefit Application
BlueCard/National Account Issues



This policy was created in 2004 and updated periodically with literature search. The most recent period of literature review covers the period through March 16, 2014. In 2009, this policy was extensively updated and broadened in scope, primarily based on a 2008 TEC Special Report, entitled “Recent Developments in Prostate Cancer Genetics and Genetic Testing.”(2) The following text is a summary of current evidence.

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. In some cases, the clinical validity of these tests, ie, the association of the test result with outcomes of interest, is expressed in terms of sensitivity, specificity, predictive value, and/or comparisons to current standards using receiver operating curve (ROC) analysis. There is no direct evidence of clinical utility, ie, 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.

Single Nucleotide Polymorphisms for Risk Assessment and Prognosis

Several large population studies have identified single nucleotide polymorphisms (SNPs) that are predictors of prostate cancer risk, although the genes and biologic mechanisms behind these associations are as yet unknown. In a 2010 review by Ioannidis et al,(3) 27 gene variants across a large range of chromosomal locations were identified that increased risk for prostate cancer, although in all cases, the observed incremental risk was modest (odds ratio [OR], ≤1.36). More recently Lindstrom et al (2011), in a study of 10,501 cases of prostate cancer and 10,831 controls, identified 36 SNPs showing association with prostate cancer risk including 2 (rs2735893 and rs266849) that showed differential association with Gleason grade.(4) Per allele ORs ranged from 1.07 to 1.44.

Because SNPs individually provide relatively modest incremental information on both the occurrence of cancer and its behavior, investigators have begun to explore use of algorithms incorporating information from multiple SNPs to increase the clinical value of testing. Gudmundsson et al (2008), using 22 prostate cancer risk variants, estimated that carriers in the top 1.3% of the risk distribution have a 2.5 times increase in risk of developing disease compared with the general population.(5) Zheng et al (2008) identified 5 chromosomal regions in a Swedish population (2893 patients with prostate cancer, 1781 controls) and developed an algorithm that incorporated family history and appeared to predict 46% of prostate cancer cases.(6) Salinas et al (2009) also evaluated use of 5 SNPs plus family history to predict risk of prostate cancer.(7) Although the authors identified a significant association with risk, they were unable to demonstrate improved models for predicting who is at risk of having or dying from prostate cancer, once known risk or prognostic factors were taken into account. Helfand et al (2010) developed an expanded algorithm using 9 genomic regions that identified patients with a 6-fold increased risk for prostate cancer.(8) Two of the regions studied (2p15 and 11q13) were more likely to be associated with tumors with aggressive features.

Kader et al (2012) evaluated a panel of 33 prostate cancer-associated SNPs that were identified from genome-wide association studies in 1654 men.(9) Genetic score was a significant (p<0.001) independent predictor of prostate cancer, with an OR of 1.72 (95% confidence interval [CI], 1.44 to 2.09) after adjustment for clinical variables and family history. Addition of genetic markers to the classification of prostate cancer risk resulted in 33% of men reclassified into a different risk quartile. Approximately half of these (n=267) were downgraded to a lower risk quartile, and the other half (n=265) were upgraded into a higher risk quartile. The net reclassification benefit was 10% (p=0.002). The authors concluded that with the additional information of genetic score, the same number of cancers could be detected by using 15% fewer biopsies.

Kim et al (2006) published a meta-analysis evaluating 30 SNPs associated with prostate cancer in Caucasians.(10) ORs observed with 13 SNPs exhibited significant heterogeneity and ranged from 1.1 to 1.8. The proportion of total genetic variance attributed by each SNP ranged from 0.2% to 0.9%, and the 30 SNPs in sum explained about 13.5% of the total genetic variance in the at-risk population. Whether this level of performance has any impact on practice or outcomes remains an unanswered question.

Ishaak and Giri (2011) reviewed 11 replication studies involving 30 SNPs (19 in men of African descent and 10 in men with familial prostate cancer).(11) ORs were positively associated with prostate cancer, although the magnitude of association was generally small (range, 1.11-2.63).

In 2013, 2 groups from Asia published studies of prostate cancer-associated SNP panels. Ren et al reported areas under the curve (AUCs) of 0.62 with a panel of 29 SNPs and 0.62 with a subset of 13 SNPs.(12) Tsuchiya et al identified 14 SNPs in 6 genes (XRCC4, PMS1, GATA3, IL13, CASP8, IGF1) that were statistically associated with cancer-specific survival.(13) Using a subset of 6 SNPs, 3 subgroups of men with prostate cancer were defined by the number of SNPs present (0-1, 2-3, or 4-6). Median cancer-specific survival in these subgroups was 13.3, 7.0, and 3.8 years, respectively (log-rank test, p<0.001).

To date, there has been no report of clinical validity for testing using standard terms for diagnostic use (eg, sensitivity, specificity, positive or negative predictive values) and no evidence that testing has any impact on health outcomes.

Section Summary

Numerous studies have demonstrated the association of many different SNPs with prostate cancer. These studies generally show a modest degree of association with future risk for prostate cancer and/or with prognosis in patients with prostate cancer. The clinical utility of these tests is uncertain; there is no evidence that information obtained from SNP testing can be used to change management in ways that will improve outcomes.

PCA3 for Prostate Cancer Diagnosis

PCA3 is overexpressed in prostate cancer, and PCA3 mRNA can be detected in urine samples collected after prostate massage. When normalized using prostate-specific antigen (PSA) to account for prostate cells released into the urine (PCA3 score), the test has significantly improved specificity compared with serum PSA and may better discriminate patients with benign findings on (first or second) biopsy from those with malignant biopsy results. In particular, the test may be especially helpful for identifying patients with elevated PSA levels but negative first biopsy results, who need a follow-up biopsy. Based on several studies,(14-19) average PCA3 score sensitivity and specificity for a positive prostate biopsy result is about 61% and 74%, respectively.

Ankerst et al (2008) reported that incorporating PCA3 score into the Prostate Cancer Prevention Trial risk calculator improved diagnostic accuracy of the calculator (from area under the ROC curve [AUC] of 0.653 to 0.696).(20) Chun et al (2009), using a multivariate nomogram, demonstrated a 5% gain in predictive accuracy when PCA3 was incorporated with other predictive variables such as age, digital rectal examination (DRE) results, PSA levels, prostate volume, and past biopsy history.(21) In a 2011 study of 218 patients with PSA values of 10 ng/mL or less, Perdona et al performed a head-to-head comparison of these 2 risk assessment tools and suggested both might have value in clinical decision making.(22)

Several studies have focused on evaluating PCA3 score as a tool for distinguishing between patients with indolent cancers who may need only active surveillance and patients with aggressive cancers who warrant aggressive therapy. Three studies from 2008—Haese et al,(18) Nakanishi et al,(23) and Whitman et al(24)—demonstrated an association between PCA3 scores and evidence of tumor aggressiveness. However, these findings were not confirmed in a 2005 study by Bostwick et al(25) or a 2008 study by vans Gils et al.(26) Auprich et al (2010) reported that PCA3 scores appeared to enhance identification of indolent disease but not pathologically advanced or aggressive cancer.(27)

A 2010 meta-analysis by Ruiz-Aragon and Marquez-Pelaez reviewed 14 studies of PCA3 for use in predicting prostate biopsy results.(28) Sensitivity of testing ranged from 47% to 82% and specificity from 56% to 89%. Global results yielded sensitivity of 85% (CI, 84 to 87) and specificity of 96% (CI, 96 to 97). No publications on how this information affected decision making or either short- or long-term outcomes has been published.

Tosoian et al (2010) reported on a short-term prospective cohort study evaluating PCA3 in relation to outcomes in an active surveillance program involving 294 patients.(29) PCA3 did not distinguish patients who had stable disease from those who developed more aggressive features. Durand et al (2012) found that PCA3 score offered some predictive prognostic accuracy in a cohort of 160 men.(30) PCA3 scores were significantly associated with increased tumor volume and positive surgical margins. However, in multivariate analysis, PCA3 score and Gleason score (≥7) did not emerge as independent predictors of pathologic stage.

In 2013, the Agency for Healthcare Quality and Research (AHRQ) published a comparative effectiveness review entitled, “PCA3 Testing for the Diagnosis and Management of Prostate Cancer.”(31) Literature was searched and updated through May 15, 2012. Forty-three studies were included; all were rated poor quality. In their conclusion, the authors stated, “For diagnostic accuracy, there was a low strength of evidence that PCA3 had better diagnostic accuracy for positive biopsy results than [serum] total PSA elevations, but insufficient evidence that this led to improved intermediate or long-term health outcomes.” This finding appeared to apply to both initial and repeat biopsies. Evidence was insufficient to assess the use of PCA3 in treatment decision making for men with positive biopsy.

Several studies published in 2013 and 2014 reported positive associations between PCA3 levels and prostate cancer diagnosis.(32-37) Predictive value was increased when PCA3 testing was combined with PSA level and other clinical information.(38,39) Other groups reported moderate diagnostic accuracy of PCA3 testing. Among men with PSA level greater than 3 ng/mL, AUC of PCA3 was 0.74.(40) Conversely, in men with PCA3 scores of 100 or greater, positive predictive value was 39%.(41) In a Japanese study of 647 men, sensitivity and specificity were 67% and 72%, respectively; AUC was 0.742.(42) Two studies compared PCA3 with multiparametric magnetic resonance imaging (MRI); MRI was more accurate than PCA3,(43) but the combination was better than either alone.(44)

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(45) or PCA3 level corrected for prostate volume (PCA3 density).(46). 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.

Section Summary

Studies of PCA3 as a diagnostic test for prostate cancer reported sensitivities and specificities in the moderate range. In general, these studies are preliminary and report on clinical performance characteristics in different populations and with various assay cutoff values, reflecting the lack of standardization in performance and interpretation of PCA3 results. One study reported a modest incremental improvement in diagnostic accuracy when PCA3 was tested in combination with PSA. The clinical utility of this test is uncertain, as there is no evidence that the use of PCA3 can be used to change management in ways that improve outcomes.

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, or urine.

TMPRSS2:ERG gene rearrangements have been reported in 50% or more of primary prostate cancer samples.(47) Although ERG appears to be the most common ETS family transcription factor involved in the development of fusion genes, not all are associated with TMPRSS2. About 6% of observed rearrangements are seen with SLC45A3, and about 5% appear to involve other types or rearrangement.(28)

TMPRSS2 fusion-gene detection has been studied for prognostic value, eg, to identify aggressive disease or to predict disease recurrence. There is conflicting evidence regarding the association of TMPRSS2 fusion-gene detection and biochemical recurrence or survival outcomes in prostate cancer.(48-53) Fusion-gene subtypes may have more significant associations with biochemical recurrence.(51,54,55). TMPRSS2 fusion genes are strongly associated with higher disease stage,(48,49,55) but associations with Gleason scores are conflicting (eg, (49,50,52,55,56)).

Recently, increased attention has been directed at using post-DRE urine samples to look for fusion genes as markers of prostate cancer. Laxman et al (2006) developed an assay to measure ERG and TMPRSS2:ERG transcripts in urine samples after prostatic massage in 19 patients with prostate cancer.(57) The authors observed a strong concordance between the presence of these transcripts and prostate cancer. In a subsequent study of 234 patients presenting for biopsy or radical prostatectomy (138 with cancer; 86 with benign disease), Laxman et al (2008) confirmed the association between cancer and TMPRSS2:ERG but did not demonstrate a significant association between cancer and ERG transcripts.(58) An algorithm was created using 7 candidate biomarkers including SPINK1, PCA3, GOLPH2, and TMPRSS2:ERG. The AUC for this multiplex model was 0.785; sensitivity was 66%, and specificity was 76%. Because the study was performed on a population enriched for cancer, external validation would be critical in properly defining and understanding test performance.

Rice et al (2010) developed an assay directed at evaluation of ERG RNA in urine normalized for PSA RNA.(59) In a study of 237 men scheduled for prostate biopsy, this assay was found to identify cancer with an AUC of 0.592, sensitivity of 31%, and specificity of 84%. Higher urine ERG values were significantly associated with positive biopsy, although these did not correlate with clinical stage or biopsy Gleason scores. Performance of the test was noted to be particularly good in Caucasian males with a PSA value of 4 ng/mL or less. Adding ERG to PSA results and other clinical parameters in a multivariate logistic regression model did not significantly improve performance in predicting biopsy results. The authors concluded that “further studies examining the long-term prognostic significance of these markers will show their full potential in augmenting the appropriate diagnosis and treatment of prostate cancer.”

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.(60) 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.

In 2013, Yao et al published a systematic review with meta-analysis of TMPRSS2:ERG for the detection of prostate cancer.(61) Literature was searched through July 30, 2013, and 32 articles were included. Pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 47% (95% CI, 46 to 49), 93% (95% CI, 92 to 94), 8.9 (95% CI, 5.7 to 14.1), and 0.49 (95% CI, 0.43 to 0.55), respectively. Statistical heterogeneity was high (I2>85%). It was unclear whether studies in screening populations were pooled with enriched patient samples, eg, elevated PSA and/or biopsy-negative. There also was variability in the type of tissue samples analyzed (urine, prostatic secretions, biopsy, surgical specimens); the type of TMPRSS2:ERG assays used (fluorescence in situ hybridization [FISH], immunohistochemistry, real-time reverse transcriptase polymerase chain reaction, transcription-mediated amplification); and in TMPRSS2:ERG threshold cutoff values.

Several studies published in 2013 and 2014 reported positive associations between TMPRSS2 fusion gene levels and prostate cancer diagnosis.(36,37,62,63) One study reported lack of association between TMPRSS2-ERG status and biochemical relapse-free rate in 244 men treated with image-guided radiotherapy (IGRT) for prostate cancer.(64) The authors observed that “TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.”

Whelan et al (2014) compared 2 multivariate models to assess upstaging in 216 patients meeting National Comprehensive Cancer Network (NCCN) criteria for active surveillance.(65) One model included TMPRSS2:ERG plus serum PSA; the other model included serum PSA, total RNA in expressed prostatic secretion (EPS; collected by milking the urethra after prostatic massage), and total EPS volume. AUCs were similar (0.80 [95% CI, 0.75 to 0.85] and 0.79 [95% CI, 0.73 to 0.84], respectively). However, the second model was more accurate for detecting patients who were upstaged, or upstaged and upgraded, by NCCN criteria. Specifically, the second model decreased the risk of upstaging in patients with a negative test approximately 8-fold (from 7% to 1%); decreased the risk of upstaging plus upgrading approximately 5-fold (from 5% to 1%); and doubled the prevalence of upstaging in the positive test group. In comparison, the TMPRSS2:ERG model decreased upstaging 2.4-fold (from 7% to 3%) and decreased upstaging and upgrading approximately 3-fold (from 5% to 2%).

Section Summary

Limited evidence reports that measurement of TMPRSS:ERG may improve the ability to predict prostate cancer and/or the ability to estimate prognosis. However, results are inconsistent and available studies differ as to the accuracy of TMPRSS:ERG for this purpose. Additionally, clinical utility of this test is uncertain, ie, no studies report that the test leads to changes in management that result in improved health outcomes.

TMPRSS2:ERG in Combination With PCA3

Tomlins et al (2011) have recently developed a transcription-mediated amplification assay to measure TMPRSS2:ERG fusion transcripts in parallel with PCA3.(66) Combining results from these 2 tests and incorporating them into the multivariate Prostate Cancer Prevention Trial risk calculator appeared to improve identification of patients with clinically significant cancer by Epstein criteria and high-grade cancer on biopsy. Although the study was large (1312 men at multiple centers), it was confounded by assay modifications during the course of the study and by the use of cross-validation rather than independent validation, using independent training and testing sets. Further studies are warranted.

In 2014, this same group evaluated 45 men using a multivariable algorithm that included serum PSA plus urine TMPSS2:ERG and PCA3 from a post-DRE sample.(67) Samples were collected before prostate biopsy at 2 centers. For cancer prediction, sensitivity and specificity were 80% and 90%, respectively. AUC was 0.88.

Robert et al (2013) retrospectively examined tissue levels of TMPRSS2:ERG and PCA3 in 48 men with benign prostatic hypertrophy, 32 men with normal prostate tissue sampled next to prostate cancer, and 48 men with prostate cancer.(68) Sensitivity, specificity, and positive and negative predictive values for the tests in combination were 94%, 98%, 96%, and 96%, respectively.

Section Summary

Concomitant detection of TMPRSS2:ERG and PCA3 may more accurately identify men with prostate cancer. However, current evidence is insufficient evidence to support its use. Estimated accuracy varies across available studies, and comparative studies, demonstrating improvements in health outcomes with the test compared with no testing, are lacking.

Candidate Gene Panels for Prostate Cancer Diagnosis and Prognosis

Because no single gene marker that is both highly sensitive and highly specific for diagnosing prostate cancer has been found, particularly in men already known to have elevated PSA levels, some investigators are combining several markers into a single diagnostic panel. Although promising in concept, only single studies of various panels have been published, and none apparently is offered as a clinical service.

Clarient, Inc. launched a “patent protected combination of four genes that have been shown to accurately identify the presence of Grade 3 or higher” prostate cancer in prostate tissue in 2009. This test is reportedly based on a study that has been submitted for publication but has not yet been accepted for publication or available for evaluation. It appears that Clarient Inc. is not currently offering this assay.

Ma et al (2014) examined various algorithms for cancer diagnosis and prognosis using urine and plasma levels of multiple genes, including PCA3, PSA, TMPRSS2, and ERG.(69) One algorithm distinguished prostate cancer from benign prostatic hypertrophy with AUC 0.78. Another algorithm distinguished men with Gleason score 7 or higher from men with Gleason score less than 7 (AUC=0.88). Combination of these 2 algorithms into a scoring system predicted the presence of Gleason score 7 or higher in 75% of men. Qu et al (2013) reported preliminary results of a 3-gene panel (androgen receptor [AR], PTEN, and TMPRSS2:ERG) analyzed by FISH.(70) Thirty-one percent of 110 archived primary tumor samples and 97 metastatic tumor samples from a separate cohort of patients were analyzable. Chromosomal abnormalities were detected in 53% of primary prostate cancers and 87% of metastatic tumors (p<0.001).

Section Summary

Gene panels for prostate cancer diagnosis and prognosis are in an investigational phase of development.

Gene Hypermethylation for Diagnosis and Prognosis

Epigenetic changes—chromatin protein modifications that do not involve changes to the underlying DNA sequence but can result in changes in gene expression—have been identified in specific genes. An extensive literature reports significant associations between epigenetic DNA modifications and prostate cancer. Studies are primarily small, retrospective pilot evaluations of the 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 2008 TEC Special Report noted that the best markers for diagnosis and prognosis had not yet been identified. Research gaps included nonstandardized assays, interpretation criteria, and sample types for measuring potential biomarkers. Consistency and comparison of results across studies is therefore lacking.

GSTP1 is the most widely studied methylation marker for prostate cancer, usually as a diagnostic application. Two recent studies of GSTP1 hypermethylation using tissue samples reported significant results for identifying cancer with sensitivity of 92%, specificity of 85%, and AUC of about 0.9.(71,72) However, 2 other studies did not find significant associations with disease.(73,74) In spite of these contradictory results, several investigators have evaluated detection of hypermethylation products in biological fluids for early detection of prostate cancer. Suh et al studied the ejaculates of patients with prostate cancer and observed methylated GSTP1 in 4 of 9 patients.(75) Goessl et al(76) confirmed the presence of the methylated biomarker in ejaculates (50%) and demonstrated an association with cancer using serum (82% of cancer patients), urine (36%), and urine after prostatic massage (73%).

Subsequently, Ellinger et al studied hypermethylation of GSTP1 with additional genes (T1G1, Reprimo, PTGS2) in 226 patients (168 with prostate cancer) in an effort to provide a more consistent yield of positive results.(77) Detection of aberrant methylation in serum DNA had high specificity (92%) but variable and more modest sensitivity (42 to 47%) for cancer. Sunami et al(78) assayed blood from 40 healthy individuals and 83 men with prostate cancer using a 3-gene cohort (GSTP1, RASSF1, RARβ2) and demonstrated sensitivity of 28% for cancer patients.

In a (2011) meta-analysis of 30 peer reviewed studies evaluating hypermethylation of GSTP1 and other genes in prostate tissue, Van Neste et al suggested that a valuable first step in diagnostic use might be to test for methylated genes to select patients undergoing prostate biopsy who might not require repeat biopsy.(79)

Trock et al (2011) conducted a small (86-patient) diagnostic exploratory cohort study and showed that hypermethylation of adenomatous polyposis coli (APC) was associated with high sensitivity and high specificity for cancer on repeat biopsy.(80) There was no evidence suggesting how this test should be used to change management.

Stewart et al (2013) investigated a quantitative methylation assay (including GSTP1, APC, RASSF1) as a predictive test for occult prostate cancer.(81) The study retrospectively assayed 498 prostate biopsy tissue samples from patients who had negative histopathologic findings on first biopsy but received follow-up biopsy within 30 months. The authors reported sensitivity of 68% (95% CI, 57 to 77) and specificity of 64% (95% CI, 59 to 69) for the assay to predict occult cancer. Negative predictive value was 90% (95% CI, 87 to 93), which offered a significant improvement compared with histologic diagnosis alone (negative predictive value, 70%). On multivariate analysis, assay score was a significant predictor of prostate cancer on second biopsy, with odds ratio of 3.17 (95% CI, 1.81 to 5.5; p<0.001).

In 2013, several studies reported associations between DNA hypermethylation at various gene loci (RASSF1A, APC, GSTP1, PTGS2, RAR-beta, TIG1, AOX1, C1orf114, GAS6, HAPLN3, KLF8, MOB3B) and prostate cancer.(82-84) In contrast, Kachakova et al (2013) found that HIST1H4K hypermethylation was more likely due to aging than to prostate carcinogenesis.(85)

Section Summary

Results from studies reporting diagnostic accuracy and predictive ability of gene hypermethylation are inconsistent. It is therefore difficult to determine whether hypermethylation is a useful parameter for diagnosis and/or prognosis of prostate cancer. Further research is needed to elucidate the clinical validity of this test and to determine whether use of this test improves outcomes.

Ongoing Clinical Trials

A randomized controlled trial (NCT01632930) aims to observe whether availability of the PCA3 test reduces the number of unnecessary prostate biopsies in multiple French centers. The trial aims to enroll 650 participants with a completion date of June 2019.

A clinical study (NCT00977457) cosponsored by the City of Hope Medical Center (Duarte, California) and the National Cancer Institute aims to evaluate the ability of urinary biomarkers collected after prostatic massage to predict the likelihood of biochemical recurrence after surgery. Estimated enrollment is 1200 men, and estimated completion date is February 2016.

A clinical study in Denmark (NCT01739062) will assess whether SNP results impact PSA testing in low risk men. Estimated enrollment is 1298 men, and estimated completion date is June 2016.


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, these data do not demonstrate clinical utility, ie, that using a test will change treatment decisions and improve subsequent outcomes. Therefore, use of gene-based testing for risk assessment, diagnosis, prognosis, and management of prostate cancer is considered investigational.

Practice Guidelines and Position Statements

American Urological Association

In 2013, AUA published guidelines for the early detection of prostate cancer.(86) Based on systematic review of the literature to 2013, the guideline panel recognized that novel urinary markers, such as PCA3 and TMPRSS2:ERG, may be “used as adjuncts for informing decisions about the need for a prostate biopsy—or repeat biopsy—after PSA screening,” but emphasized the lack of evidence “that these tests will increase the ratio of benefit to harm.”

Evaluation of Genomic Applications in Practice and Prevention

In 2013, the EGAPP Working Group published the following recommendations for PCA3 testing in prostate cancer, based on the AHRQ comparative effectiveness review(31) summarized earlier(87):

  • Evidence was insufficient to recommend PCA3 testing to inform decisions for when to re-biopsy previously biopsy-negative patients for prostate cancer, or to inform decisions to conduct initial biopsies for prostate cancer in at-risk men (eg, previous elevated PSA or suspicious digital rectal examination).
  • 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

Current NCCN guidelines recommend PCA3 testing in men with a suspicious digital rectal exam, PSA greater than 3.0 ng/mL, or excess risk based on multiple factors (eg, accelerated PSA velocity or elevated risk using a risk calculator tool) who have not undergone a transrectal ultrasound-guided biopsy.(88) PCA3 is recommended as one of several tests to consider for following patients who have had a negative biopsy. Guideline authors note:

“Biomarkers that improve the specificity of detection are not recommended as first-line screening tests, but are reserved mostly for selecting for repeat biopsy, those who have undergone at least one negative biopsy…PCA3 score greater than 35 is strongly suspicious for prostate cancer.”


  1. MDx Health. Epigenetic diagnostics for oncology, 2013. Available online at: Last accessed March 2014.
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No specific code.  See Policy Guidelines



Special screening, prostate cancer 

HCPCS S3721 Prostate cancer antigen 3 (PCA3) testing
ICD-10-CM (effective 10/1/15)    Investigational for all relevant diagnoses
   C61 Malignant neoplasm of prostate
   Z12.5 Encounter for screening for malignant neoplasm of prostate
ICD-10-PCS (effective 10/1/15)    Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.



Gene-based Tests, Prostate Cancer
PCA3, Prostate Cancer
Prostate Cancer, PCA Test
Prostate Cancer, Diagnostic Tests
Prostate Cancer, Screening Tests

Policy History

Date Action Reason
04/16/04 Add policy to Medicine section, Pathology/ Laboratory subsection New policy
08/17/05 Replace policy Policy updated with literature search; no change in policy statement; references 7 and 8 added
02/15/07 Replace policy Policy updated with literature search; no change in policy statement. Reference number 9 added
04/24/09 Replace policy  Policy extensively updated and scope broadened, based on 2008 TEC Special Report. Policy statement updated with 5 types of testing; all testing is considered investigational.
4/14/11 Replace policy Policy updated with literature search; references 2, 3, 7, 16, 17, 20-24, 33-35, 37, 40, 43, 44 added. Minor change to policy statements (“prognosis” added to the policy statement on PCA3)
03/08/12 Replace policy Policy updated with literature search, no change in policy statement. References 8,9,24,25,37,45,46 added
03/14/13 Replace policy Policy updated with literature search through January 2013, references 9, 28, 41, and 51 added. No change in policy statement.
4/10/14 Replace policy Policy updated with literature review through March 16, 2014; references 1, 12-13, 31-46, 60-65, 67-70, and 82-88 added. No change to policy statement.


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