This document addresses gene-based tests for the screening, detection and management of prostate cancer. Gene-based tests for the screening, detection and management of prostate cancer include, but are not limited to, gene hypermethylation, molecular tests (gene panels), prostate cancer antigen gene-3 (PCA3 [formerly known as DD3]), single-nucleotide polymorphisms (SNPs), ribonucleic acid (RNA), and TMPRSS fusion genes.
Investigational and Not Medically Necessary:
Gene-based tests for the screening, detection and management of prostate cancer are considered investigational and not medically necessary.
There has been a variety of research surrounding gene-based tests for the screening, detection and management of prostate cancer. Some products of this work have already been translated or are in the process of being translated into commercially available tests. These tests are currently without evidence of clinical utility for diagnosis, prognosis, or risk assessment. Currently, only two tests, the prostate specific antigen (PSA) and digital rectal exam (DRE) are widely recommended for the detection and management of prostate cancer.
Gene hypermethylation for diagnosis and prognosis
The association of a gene hypermethylation marker, GSTP1, with prostate cancer has been investigated. Several studies of GSTP1 hypermethylation using tissue samples reported significant results for identifying prostate cancer with a sensitivity of 92%, a percent specificity of 85%, and an area under curve (AUC) of about 0.9 (Eilers, 2007; Ellinger, 2008). Trock and colleagues (2011) reported on a small (86 subjects) diagnostic exploratory cohort study showing hypermethylation of adenomatous polyposis coli (APC) was associated with a high sensitivity and high specificity for cancer on repeat biopsy. The authors indicated that the potential of APC methylation to reduce unnecessary repeat prostate biopsies needs validation in a larger prospective study. In addition, there was no evidence suggesting how this test should be used to change management. Two other studies did not find significant associations between GSTP1 methylation and prostate cancer recurrence (Henrique, 2007; Woodson, 2006).
The Confirm MDx (MDx Health, Irvine, CA) is a multiplex polymerase chain reaction (PCR) assay measuring DNA methylation of three biomarkers associated with prostate cancer: GSTP1, APC and RASSF1. It is used to predict the results of repeat prostate biopsy after an initial negative biopsy. Van Neste and colleagues (2012) explored the use of an epigenetic, multiplex polymerase approach to GSTP1, APC and RASSF1 testing and compared it to individual, singleplex assays of the biomarkers. The authors found that the multiplex assay approach was similar to the individual singleplex approach, but had the advantage of use with smaller tissue volumes and therefore could be used on older tissues with small quantities and poorer quality DNA.
Molecular testing panels
Because no single gene markers have been found that are both highly sensitive and highly specific for diagnosing and managing prostate cancer, particularly in men already known to have elevated PSA levels, some investigators are combining several markers into a single diagnostic panel. Gene panels commercially available for prostate cancer management include a cell cycle progression (CCP) score or Prolaris test (Myriad Genetics, Salt Lake City, Utah), a 46 gene based panel, and the Oncotype DX Prostate Cancer Assay (Genomic Health, Redwood City, CA), a 17 gene biopsy-based test that produces a Genomic Prostate Score.
In 2012, Cuzick and colleagues investigated the CCP score as a predictor of prostate cancer outcomes. In their series, 776 men had been diagnosed with prostate cancer and needle biopsies were available from 527 of them. Of these, 349 (79%) produced a CCP score. Total ribonucleic acid (RNA) was extracted from specimens and the CCP score was calculated from expression levels of 31 genes. In univariate analysis (n=349), the hazard ratio (HR) for death from prostate cancer was 2.02 (95% confidence interval [CI], 1.62, 2.53; p<10[-9]) for a one-unit increase in CCP score. The CCP score was only weakly correlated with standard prognostic factors and in a multivariate analysis, CCP score dominated (HR for one-unit increase=1.65, 95% CI [1.31,.09], p=3 × 10[-5]), with Gleason score (p=5 × 10[-4]) and prostate-specific antigen (PSA) (p=0.017) providing additional contributions. Study limitations included a lack of availability of specimens for follow-up. The authors stated that the most obvious clinical use of the CCP score is to help identify low-risk men who can be safely managed by surveillance. However, since deaths from prostate cancer are rare in this group, a larger cohort is needed to fully demonstrate the value of the CCP score in identifying those at low-risk.
More recently, additional evaluations of the CCP score have been performed (Bishoff, 2014; Cooperberg, 2013; Crawford, 2014; Freedland, 2013; Shore, 2013). However, none of these studies demonstrated that choices made on the basis of the test lead to improved outcomes compared to choices made using Gleason score and PSA and all authors indicated a need for additional validation.
The Oncotype DX Prostate Cancer Assay is a real time polymerase chain reaction (RT-PCR) assay designed for analysis of prostate core needle biopsies. The assay measures the expression of multiple cancer-related genes which are algorithmically combined to calculate a Genomic Prostate Score. It has been investigated as a predictor for risk of recurrence, prostate cancer death, and especially adverse pathology at radical prostatectomy (Bostrom, 2015).
Knezevic and colleagues (2013) studied the analytical performance of the Oncotype DX Prostate Cancer Assay. Fixed paraffin-embedded (FPE) needle biopsy samples and FPE prostate cancer samples from radical prostatectomies were obtained and RNA was quantified. The lowest quartile of RNA yields from prostate needle biopsies (six 5 μm sections) was between 19 and 34 ng. Amplification efficiencies, analytical sensitivity, and accuracy of gene assays were measured by diluting RNA samples and analyzing features of the linear regression between RNA expression. Gene assays measured expression over a wide range of inputs (from as low as 0.005 ng to 320 ng). Analytical accuracy had average biases at qPCR inputs representative of samples < 9.7% across all assays while amplification efficiencies were within ± 6% of the median. Assessments of reproducibility and precision were completed by testing 10 prostate cancer RNA samples over multiple instruments, reagent lots, operators, days (precision), and RNA input levels (reproducibility) using parameterized linear mixed models. The standard deviations for analytical precision and reproducibility were 1.86 and 2.11 GPS units (100-unit scale) respectively. The authors concluded that the Oncotype DX Prostate Cancer Assay complements traditional clinical and diagnostic features and assists in the discrimination of indolent prostate cancer from aggressive prostate cancer.
In 2014, Klein and colleagues evaluated the Genomic Prostate Score for its ability to predict high-grade or high-stage prostate cancer at diagnosis. Gene expression was quantified by reverse transcription-polymerase chain reaction for three studies: a prostatectomy study (n=441), a biopsy study (n=167) and a prospective clinical validation study (n=395). A total of 732 candidate genes were analyzed. Of these, 288 (39%) were reported as being able to predict clinical recurrence and 198 (27%) were predictive of aggressive disease, after adjustments were made. Multiple study limitations reported by the authors were:
Cullen and colleagues (2015) evaluated the association of the Genomic Prostate Score with recurrence of prostate cancer after radical prostatectomy and adverse pathology at surgery. A total of 431 biopsies obtained from men treated for NCCN very low-, low-, or intermediate-risk prostate cancer were tested to validate the association. GPS results were obtained in 402 cases (93%). Of these, 62 (15%) men had biochemical recurrence, 5 developed metastasis, and 163 had adverse pathology. Median follow-up was 5.2 years. The authors reported that the Genomic Prostate Score predicted time to biochemical recurrence and predicted time to metastasis, however, the event rate was low (n=5). Additionally, it was found to be associated with adverse pathology. Study limitations included a small number of metastatic events and a limited amount of available biopsy tissue.
PCA3 for disease detection
PCA3, a prostate cancer antigen gene, has been investigated as a possible additional tool in the detection of prostate cancer. The PCA3 gene (formerly known as DD3) is markedly upregulated in cancerous prostate cells and is not expressed, or expressed only at very low levels in normal or hyperplastic prostatic tissue. The identification of the PCA gene relies on detection of the overexpression of the associated messenger ribonucleic acid (mRNA) in blood or urine after a digital rectal examination.
A prospective, multicenter European study (Haese, 2008) evaluated the clinical utility of PCA3 urine assay in men scheduled for repeat prostate biopsies. All of the participants had previously had one or two negative prostate biopsies. Urine samples were collected after a digital rectal exam (DRE) and prior to the biopsy procedure. Simultaneously, blood samples were obtained and utilized to determine total and free PSA levels. Using a PCA3 assay, the urine samples were processed to quantify PCA3 and PSA messenger ribonucleic acid (mRNA) concentrations. Sensitivity and specificity were determined by comparing the PCA3 score to the biopsy results. Out of 470 participants, 467 urine samples had sufficient concentrations of both PCA3 and PSA mRNA to calculate the PCA3 score. Conclusive biopsy results were obtained in 463 men out of the 467. A total of 128 men (28%) had cancer diagnosed by the repeat biopsy. Participants with a positive biopsy had statistically significant higher age, higher total PSA, suspicious DRE and a higher mean PCA3 score compared to the participants with negative biopsy results. While this and other studies found that an optimal PCA3 score of 35 would optimize the balance between sensitivity and specificity, using this cutoff score would still result in missing 21% of cancers even though 67% of unnecessary biopsies would have been avoided. Conversely, using a lower cutoff score of 20 would miss only 9% of cancers while avoiding only 44% of unnecessary biopsies. Thus the authors agree that even though the score had greater diagnostic accuracy than free PSA percentage in this study, further studies are needed to better delineate its role in the diagnosis and management of prostate cancer.
Wang and colleagues (2009) evaluated the ability of the PCA3 with the PSA to detect prostate cancer. From September 2006 to December 2007, urine samples were collected in a urology outpatient clinic following digital rectal exam from 187 men before ultrasound-guided 12-core prostate biopsy. Urine PCA3/PSA mRNA ratio scores were assessed within 1 month and serum PSA within 6 months of biopsy. Overall, 87/187 (46.5%) biopsies were positive for cancer. Sensitivity and specificity of PCA3 score greater than or equal to 35 for positive biopsy were 52.9% and 80.0%; positive and negative predictive values were 69.7% and 66.1%. Study limitations include that study cohorts consisted only of pre-screened individuals undergoing biopsy for an elevated PSA. The authors concluded:
To date, there is no definitive evidence demonstrating that PCA3 prognosticates for lethal prostate cancer, and in the absence of such evidence, these biomarkers may only contribute to the continued over-diagnosis of prostate cancer.
Roobol and colleagues (2010) investigated the performance characteristics of PCA3 and compared this to the PSA. A total of 721 men between the ages of 63-75 were screened for prostate cancer from September 2007 to February 2009. Both PCA3 scores and serum PSA levels were measured. Men with a PSA greater than or equal to 3.0 ng/ml or a PCA3 score greater than or equal to 10 underwent a DRE, transrectal ultrasounds, and biopsy. It was noted that the correlation between PSA and PCA3 was poor. The authors concluded that the value of PCA3 for improving detection in the low PSA ranges and after previous negative biopsies was hampered by small numbers, is unclear and needs to be further explored.
A meta-analysis by Ruiz-Aragon and Marquez-Pelaez (2010) reviewed 14 studies of PCA3 for use in predicting prostate biopsy results. Sensitivity of testing ranged from 46.9% to 82.3% and specificity from 56.3% to 89%. Global results provided a sensitivity of 85% (confidence interval [CI], 84 to 87) and a specificity of 96% (CI, 96 to 97).
Tosian and colleagues (2010) reported on a short-term prospective cohort study evaluating PCA3 in relation to outcomes in an active surveillance program involving 294 subjects. PCA3 did not appear to distinguish subjects with stable disease from those developing more aggressive features.
In an industry sponsored study, Aubin and colleagues (2010) evaluated the PCA3 alone and with covariates as an indicator of concurrent and future prostate biopsy results in men with increased serum prostate specific antigen and previous negative prostate biopsy results. In a sub-study of the placebo arm of the REDUCE trial, a prostate cancer risk reduction study, urine PCA3 scores were obtained before year 2 and year 4 biopsies from subjects in the placebo arm of the trial. The men had moderately increased serum prostate specific antigen results and negative biopsy at baseline. PCA3 scores were measurable from 1072 of 1140 subjects (94% informative rate). PCA3 scores were associated with positive biopsy rate (p<0.0001) and correlated with biopsy Gleason score (p=0.0017). PCA3 at year 2 was a predictor of year 4 biopsy results (AUC 0.634, p=0.0002). Additionally, serum prostate specific antigen and free prostate specific antigen were not found to be predictive (p=0.3281 and 0.6782, respectively). The authors concluded that their results confirm that PCA3 can be used in combination with other clinical information to help guide prostate biopsy decisions.
Van Poppel and colleagues (2012) evaluated the relationship between PCA3 and prostate cancer significance in two European multi-centre open-label prospective studies with a total enrollment of 1009 men. The authors reported that the association between the PCA3 score and prostate cancer aggressiveness needs further evaluation.
A prospective, community based clinical trial (Crawford, 2012) evaluated the PCA3 score before any biopsy. Samples were obtained from 1962 men with increased serum prostate specific antigen (greater than 2.5 ng/ml) with or without abnormal digital rectal examination before transrectal prostate needle biopsy from 50 urology practices in the United States. Study samples consisting of urinary PCA3 and biopsies were analyzed by a single laboratory. A total of 1913 urine samples (97.5%) were adequate for PCA3 testing. Of 802 cases diagnosed with prostate cancer, 222 had high grade prostatic intraepithelial neoplasia or atypical small acinar proliferation and were suspicious for cancer, and 889 cases were benign. The traditional PCA3 cutoff of 35 reduced the number of false-positives from 1089 to 249, a 77.1% reduction. However, false-negatives increased from 17 to 413. Lowering the PCA3 cutoff to 10 reduced the number of false-positives 35.4% and false-negatives only increased 5.6%. Clinical utility of the PCA3 has yet to be defined and further study is needed.
In 2013, Goode and colleagues evaluated the value of the PCA3 urine assay in predicting prostate cancer. Both PSA and PCA3 levels were taken from 456 men with no known personal history of prostate cancer prior to prostate biopsy. A total of 289 men underwent an initial prostate biopsy and 167 had a repeat prostate biopsy. PSA and PCA3 levels were compared to the prostate biopsy results. Analyzed data demonstrated that PCA3 scores were independent of prostate volume and PSA level. PCA3 scores were higher in men with prostate cancer confirmed by biopsy compared to those with negative biopsy results. In logistic regression, PCA3 showed a higher area under the curve (AUC) than PSA with this difference persisting at examination of the initial biopsy subgroup. However, PCA3 was not as helpful in the repeat biopsy subgroup. The authors stated:
Further studies are needed to determine the appropriate use of PCA-3 in counseling patients at higher risk of prostate cancer. The use of PCA3 in men with previous negative biopsies is another area of interest. More studies are also needed to determine the influence of pre-neoplastic conditions on PCA-3 score and the correlation between PCA-3 score and cancer aggressiveness and prognosis.
Gittleman and colleagues (2013) evaluated the usefulness of the PROGENSA PCA3 Assay for predicting repeat prostate biopsy outcomes. A total of 466 men scheduled for repeat prostate biopsy who had at least one previous negative biopsy were evaluated at 14 centers in the United States. Prior to transrectal biopsy being performed, blood samples and post-digital rectal exam urine samples were obtained. Urinary PCA3 scores and biopsy outcomes were assessed by logistic regression analysis. Prostate cancer was identified in 21.9% of the men. A PCA3 score cutoff of 25 yielded 77.5% sensitivity, 57.1% specificity, and negative and positive predictive values of 90% and 33.6%, respectively. Multivariable logistic regression indicated that men with a PCA3 score below 25 were 4.58 times less likely to have a positive repeat biopsy than men with a score of 25 or more. The authors concluded that the PCA3 assay supplements serum PSA and other clinical information for more accurately predicting repeat biopsy outcome.
A 2013 Agency for Healthcare Research and Quality (AHRQ) comparative effectiveness review by Bradley and colleagues on PCA3 testing reported:
There was low strength of evidence that PCA3 had better diagnostic accuracy for positive biopsy results than tPSA elevations, but insufficient evidence that this led to improved intermediate or long-term health outcomes. For all other settings, comparators, and outcomes, there was insufficient evidence.
A single center retrospective review (Chevli, 2014) evaluated the predictive value of the PCA3 test. A PCA3 had been obtained from 3073 men prior to initial prostate biopsy sampling of 12 to 14 areas. Data revealed the mean PCA3 was 27.2 and 52.5 respectively for men without and with cancer. Prostate cancer was identified in 1341 (43.6%) men. Upon analysis, PCA3 was found to be significantly associated with prostate cancer and high grade prostate cancer after adjustments were made for prostate specific antigen, free prostate specific antigen, age, family history, abnormal digital rectal examination, prostate volume and body mass index. Using ROC analysis PCA3 outperformed prostate specific antigen in the prediction of prostate cancer but not for high grade prostate cancer. The authors reported that their results suggest that further exploration of the value of PCA3 is warranted.
A validation study of the PCA3 urinary assay (Wei, 2014) enrolled a total of 859 men from 11 centers who were scheduled for a diagnostic prostate biopsy between December 2009 and June 2011. Primary outcomes included a positive predictive value (PPV) of 80% (95% CI, 72% to 86%) in the initial biopsy group, and a negative predictive value (NPV) of 88% (95% CI, 81% to 93%) in the repeat biopsy group. Limitations of the study included that the findings did not extend to men who had not been prescreened. The authors reported that the addition of PCA3 may decrease morbidity; however, it could also result in some high grade prostate cancers not being detected.
Xue and colleagues (2014) performed a meta-analysis of 13 prospective studies (3245 participants) to evaluate the clinical value of the PCA3 biomarker urine level for the diagnosis of prostate cancer. The pooled sensitivity, specificity, positive likelihood ratio (+LR), negative likelihood ratio (-LR), diagnosis odds ratio (DOR) and area under the curve (AUC) were 0.62 (95% CI, 0.59-0.65), 0.75 (95% CI, 0.73-0.76), 6.16 (95% CI, 3.39-11.21), 0.50 (95% CI, 0.43-0.59), 5.49 (95% CI, 3.76-8.019) and 0.75 (95% CI, 0.71-0.78), respectively. The authors reported that "pooled data indicated that urine PCA3 test has acceptable sensitivity and specificity in diagnosis of prostate cancer." However, they further noted that the small number of trials and significant heterogeneity across studies made their conclusion conservative.
Cremers and colleagues (2015) evaluated the value of adding the PCA3 urine test to serum PSA in prostate cancer screening for breast cancer early-onset gene (BRCA) mutation carriers. Individuals were enrolled in the IMPACT study, a large international trial on the effectiveness of PSA screening among BRCA mutation carriers. Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 non-carriers. A total of 23 cases of prostate cancer were diagnosed, 20 cases involved men who had an elevated PSA level in the initial screening round. The authors indicated that there was a lack of evidence demonstrating that PCA3 was a useful additional indicator of prostate biopsies in BRCA mutation carriers because many participants had an elevated PCA3 in the absence of prostate cancer. However, they also indicated that this must be interpreted with caution.
Merola and colleagues (2015) evaluated the clinical utility of the PCA3 test in 407 Italian men with two or more risk factors for prostate cancer and at least a previous negative biopsy. Of the 407 subjects enrolled, 195 were positive for prostate cancer and 114 of them received an accurate staging with evaluation of the Gleason score. In this study, the PCA3 score was correlated to biopsy outcome and the diagnostic and prognostic utility were evaluated. From the 407 biopsies performed after the PCA3 test, 195 (48%) were positive for prostate cancer. The authors reported that their data suggested that the PCA3 test could predict a prostate cancer. However, it was also noted that the choice to enroll only men with a certain risk for prostate cancer or a number of previous biopsies, could drive data towards an easier or less easy association between the result of the PCA3 test and the tumor aggressiveness.
Vlaeminck-Guillem and colleagues (2015) performed a prospective study of all persons referred to a single French urology department between December 2007 and May 2014 for prostate biopsy. A total of 1029 men had a urinary PCA3 test prior to having a prostate biopsy for suspicion of prostate cancer. The median PCA3 score was higher in those with positive biopsies. At a cutoff of 35, sensitivity was 68%, specificity 71%, positive and negative predictive values 67% and 71%, and 69% accuracy. At a cutoff of 20, approximately half of the ultimately unnecessary biopsies may have been avoided. Of note, the PCA3 score correlated with tumor volume but did not correlate with Gleason score. The authors indicated that a high PCA3 score is not necessarily synonymous with cancer (false positives) and that low or even very low scores are not necessarily synonymous with the absence of cancer (false negatives).
NCCN guidelines (V2.2016) for early detection of prostate cancer report that the PCA3 may be considered for men who have had at least one prior negative biopsy and are thought to be at higher risk. Additionally, the panel indicates that the PCA3 is inappropriate to use in the initial biopsy setting.
The 2013 American Urologic Association guidelines for early detection of prostate cancer include the following information concerning PCA3:
Novel urinary markers (PCA3), and prostate imaging should be considered secondary tests (not primary screening tests) with potential utility for determining the need for a prostate biopsy, but with unproven benefit as primary screening tests. The Panel recognizes that these tests can be used as adjuncts for informing decisions about the need for a prostate biopsy –or repeat biopsy- after PSA screening, but emphasizes the lack of evidence that these tests will increase the ratio of benefit to harm.
The 2015 European Association of Urology prostate cancer guidelines state that "currently the main indication for the Progensa test is to determine whether repeat biopsy is needed after an initially negative biopsy."
SNPs for risk assessment
Studies have identified SNPs that are highly significant predictors of prostate cancer risk, although the genes and biologic mechanisms behind these associations are as yet unknown. Several SNPs combined explain a significant proportion of prostate cancer, but not all. A few different groups are commercializing specific SNP panels (Gudmundsson, 2008; Zheng, 2008), combined in one case with family history, as risk assessment tools. Additional research has been reported by other groups, e.g., in the United Kingdom, where results of a trial in progress may lead to a commercial test (Eeles, 2008); by the National Cancer Institute (Thomas, 2008; Yeager, 2007); and by the University of Washington (Salinas, 2009). The work cited in these example publications is supported by a large number of studies that searched for and validated common, inherited gene variations present in individuals with prostate cancer, but not in controls.
The men sampled in these studies were primarily of European Caucasian ancestry, which limited the generalizability of assays developed from these studies to other populations. However, these tests do not predict certainty of disease nor do they clearly predict aggressive versus indolent disease. While the monitoring of high-risk men identified by these assays may improve outcomes, it is also possible that these could be offset by the harms of identifying and treating additional cases of indolent disease.
Ishaak and Giri (2011) performed a review of 11 replication studies involving 30 SNPs (19 in men of African descent and 10 in men with familial prostate cancer). Odds ratios were positively associated with prostate cancer, although the magnitude of association was generally small (ranging from 1.11 to 2.63).
Guidelines suggest that asymptomatic men with prostate specific antigen (PSA) results of 3.0 ng/mL or less who will be regularly monitored by PSA testing should be given information on prostate cancer prevention with 5-alpha reductase inhibitors (Kramer, 2009). It is possible that future risk assessment assays with evidence supporting generalizability to a variety of populations will help identify those who would most benefit from preventive therapy. However, one study found that adding 5 SNP risk factors to standard clinical predictors (age, serum PSA, and family history) did not improve prediction models for determining who is at high risk for getting prostate cancer (Salinas, 2009). Discovery of genetic variants that can predict likelihood of aggressive versus indolent prostate cancer would be much more effective at defining a population in need of preventive therapy and regular surveillance.
A 2012 Agency for Healthcare Research and Quality (AHRQ) assessment reported the following conclusions regarding SNP panels:
The evidence on currently available SNP panels does not permit meaningful assessment of analytic validity. The limited evidence on clinical validity is insufficient to conclude that the panels assessed would perform adequately as screening or risk stratification tests. No evidence is available on the clinical utility of current panels.
TMPRSS fusion genes for diagnosis and prognosis
TMPRSS2 fusion gene detection has been investigated as a means 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 of prostate cancer (Demichelis, 2007; Fitzgerald, 2008; Mehra, 2007; Nam, 2007a; Nam, 2007b; Wang, 2006; Winnes, 2007). Fusion gene structure is complex and variable, making it a difficult assay target (Clark, 2007; Wang, 2006). As a result, assays have not yet been standardized; once they are, larger studies will be needed to determine clinical utility.
One small study (n=74) describes the ability of TMPRSS2-ERG fusion genes to predict prostate cancer screening biopsy outcome, and association with high versus low Gleason scores (Clark, 2008). Fusion gene detection improved on PSA plus DRE for predicting the biopsy result (from AUC 0.645 to 0.823) and for predicting Gleason score greater than 7 (from AUC 0.688 to AUC 0.844). These results need further validation in larger studies.
Tomlins and colleagues (2011) have recently developed a transcription mediated amplification assay to measure TMPRSS2: ERG fusion transcript in parallel with PCA3. Combining results from these two tests and incorporating them into the multivariate Prostate Cancer Prevention Trial risk calculator appeared to improve identification of men with clinically significant cancer by Epstein criteria and high-grade cancer on biopsy. While the study was large (1312 men at multiple centers), it was confounded by the fact that the assay was modified during the course of the study and also by the fact that some evaluations were performed using cross-validation rather than independent validation using independent training and testing sets.
Exosome Gene Expression Assay
A prospective study by McKiernan and colleagues (2016) evaluated a noninvasive, urinary three-gene expression assay (ExosomeDx® Prostate [IntelliScore]). The assay measures "exosomal RNA Ct values of ERG, PCA3 and SAM pointed domain-containing Ets transcription factor (SPDEF)" to derive a urine exosome gene expression assay score. The exosome gene expression assay plus standard of care (SOC) (PSA level, age, race, and family history) was compared to SOC alone for differentiating between Gleason score (GS)7 and GS6 and benign disease on initial biopsy. Using reverse-transcriptase PCR, urine exosome gene expression assays were compared to biopsy outcomes in 499 subjects with PSA levels of 2 to 20 ng/mL. The derived prognostic score was then validated in 1064 subjects. Eligible participants included men free of prostate cancer, 50 years or older, scheduled for an initial or repeated prostate needle biopsy due to suspicious digital rectal examination (DRE) findings and/or PSA levels (limit range, 2.0-20.0 ng/mL). In 255 men (median age 62 years and median PSA level 5.0 ng/mL, and initial biopsy), the urine exosome gene expression assay plus SOC was found to be associated with improved discrimination between GS7 or greater and GS6 and benign disease. Independent validation in 519 subjects' urine exosome gene expression assay plus SOC was reported as superior to SOC. The authors concluded the exosome gene expression assay has the potential to reduce the total number of biopsies performed in men with a suspicion of prostate cancer. Study limitations included a lack of central pathology review and the inability to include the DRE and free PSA as part of the SOC variables.
The American Society of Clinical Oncology (ASCO) endorsement panel (Chen, 2016) reviewed and endorsed Cancer Care Ontario's guideline on Active Surveillance for the Management of Localized Prostate Cancer. Cancer Care Ontario is a Canadian agency responsible for improving cancer care. ASCO's endorsement of the guideline includes the following recommendations:
At this time, the evidence for genetic tests related to prostate cancer screening, detection, and management does not demonstrate clinical utility. Use of these tests has not been shown to change treatment decisions and improve subsequent outcomes that matter to the individual such as mortality, morbidity, or quality of life.
According to the American Cancer Society (ACS) (2016), prostate cancer is the most common form of cancer, other than skin cancer, among men in the United States. It is second only to lung cancer as a cause of cancer-related death among men. In 2016, it is estimated that there will be about 180,890 new cases of prostate cancer diagnosed in the United States and approximately 26,120 deaths from the disease. The current available testing for the screening of prostate cancer involves a DRE and a blood test for a substance in the blood, PSA. Elevated levels of PSA in the blood are known to be associated with the presence of prostate cancer and this test is commonly used in the diagnosis and management of prostate cancer.
The published literature surrounding gene-based tests for the screening, detection and management of prostate cancer initially focused on the technical feasibility of identifying a novel prostate cancer-specific gene, PCA3 gene and its possible function. The PCA3 gene appears to be a non-coding gene, (that is, there is no protein product that can be easily identified with an immunoassay), and thus its identification relies on the detection of the overall expression of the associated mRNA. mRNA is a molecule that results when a cell "reads" a DNA strand. PCA3 testing in clinical practice focuses on the detection of the PCA3-associated mRNA in blood and urine samples following a DRE. PCA3 is therefore a genetic test.
Only PCA3 has been submitted to the U.S. Food and Drug Administration (FDA) for premarket approval. The PROGENSA® PCA3 Assay (Gen-Probe Inc., San Diego, CA) was approved by the FDA on February 15, 2012 through the premarket approval process. According to the FDA, 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 one 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.
The FDA summary of safety and effectiveness for the PROGENSA PCA3 warns of the following potential adverse effects of the device on health:
The risk associated with the PROGENSA PCA3 Assay is a false assay result (i.e., a false positive or false negative result). A false negative result from the PROGENSA PCA3 Assay may defer necessary follow-up procedures (e.g., delay a follow-up prostate biopsy). The associated risk of delaying clinical action is that the cancer may continue to spread leading to an irreversible adverse condition. Although the test is indicated for use in men for whom a repeat biopsy would be recommended by a urologist based on current standard of care, a false positive result from the PROGENSA PCA3 Assay may lead to more aggressive follow-up procedures (e.g., increased number of cores taken at a subsequent biopsy), which may expose the patient to increased risk. The PROGENSA PCA3 Assay is intended to be used in conjunction with other clinical information; it is not meant to be used as the sole determinant for follow-up procedures. Therefore, the decision in determining appropriate patient management (e.g., the decision for repeat biopsy) must be based on an assessment of multiple risk indicators and not solely on the PROGENSA PCA3 Assay result.
Other tests included in this document are offered as laboratory-developed tests under the Clinical Laboratory Improvement Amendments (CLIA) licensed laboratories. In addition to the PCA3, this group of gene-based tests has now evolved to include, but is not limited to, gene hypermethylation, multiple gene tests (gene panels), SNPs, and TMPRSS fusion genes.
Exosomes: Small, double-lipid membrane vesicles that are secreted from cells and encapsulate a portion of the parent cell cytoplasm . Exosomes shed into biofluids, including blood and urine.
Fusion gene: A hybrid gene created by joining portions of two different genes.
Genetic testing: A type of test that is used to determine the presence or absence of a specific gene or genetic alteration that may indicate an increased risk for developing a specific disease or disorder.
Messenger ribonucleic acid (mRNA): A molecule that results when a cell "reads" a DNA strand.
Methylation: The attachment of methyl groups to DNA at cytosine bases; correlated with reduced transcription of the gene and thought to be the principal mechanism in X-chromosome inactivation and imprinting.
Screening: The testing of persons, in either the general population or those at high risk, for specific diseases or conditions.
Single-nucleotide polymorphisms (SNPs): DNA sequence variations that occur when a single nucleotide in the genome sequence is altered.
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services are Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen]) ratio (eg, prostate cancer)
Unlisted molecular pathology procedure [when specified as gene-based prostate cancer testing such as gene hypermethylation, gene panels, SNP, and TMPRSS fusion gene tests]
Oncology (prostate), mRNA gene expression profiling by real-time RT-PCR of 46 genes (31 content and 15 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a disease-specific mortality risk score
Prolaris, Myriad Genetic Laboratories, Inc.
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
ConfirmMDx for Prostate Cancer, MDxHealth, Inc.
Unlisted multianalyte assay with algorithmic analysis [when specified as a prostate cancer risk assessment test such as Oncotype DX Prostate]
Oncology, prostate cancer, mRNA expression assay of 12 genes (10 content and 2 housekeeping), RT-PCR test utilizing blood plasma and/or urine, algorithms to predict high-grade prostate cancer risk
Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
ConfirmMDx for Prostate Cancer
Exosome Gene Expression Assay
Glutathione S-transferase Gene (GSTP1, pi-class) Methylation Assay
Oncotype DX® Genomic Prostate Score (GPS)
Oncotype DX Prostate Cancer Assay
Prostate Cancer, Gene-Based Tests for
Prostate Gene Expression Profile
Proveri Prostate Cancer Assay (PPCA™ )
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|02/21/2018||Updated Coding section; added CPT code 0011M.|
|12/27/2017||The document header wording updated from “Current Effective Date” to “Publish Date.” Coding section updated with 01/01/2018 CPT changes; added codes 81541 and 81551.|
|Reviewed||05/04/2017||Medical Policy & Technology Assessment Committee (MPTAC) review.|
|Reviewed||05/03/2017||Hematology/Oncology Subcommittee review. Description, Rationale, Definitions, Index and References sections updated. Updated Coding section with 05/01/2017 CPT changes.|
|Reviewed||11/02/2016||Hematology/Oncology Subcommittee review. Rationale, Background and Reference sections updated.|
|Reviewed||11/04/2015||Hematology/Oncology Subcommittee review. Rationale and Reference sections updated. Updated Coding section with 01/01/2016 HCPCS changes; removed S3721 deleted 12/31/2015; also removed ICD-9 codes.|
|Reviewed||05/06/2015||Hematology/Oncology Subcommittee review. Rationale, Background, Reference and Index sections updated.|
|01/01/2015||Updated Coding section with 01/01/2015 CPT changes.|
|Reviewed||05/14/2014||Hematology/Oncology Subcommittee review. Rationale, Reference and Index sections updated|
|Reviewed||05/08/2013||Hematology/Oncology Subcommittee review. Rationale, Background, Reference and Index sections updated.|
|01/01/2013||Updated Coding section with 01/01/2013 CPT changes.|
|Reviewed||05/09/2012||Hematology/Oncology Subcommittee review. Rationale, Background, Reference, and Index sections updated.|
|04/01/2012||Updated Coding section with 04/01/2012 HCPCS changes.|
|Reviewed||05/18/2011||Hematology/Oncology Subcommittee review. Rationale, Background, Definition, Reference, and Index sections updated.|
|Reviewed||5/12/2010||Hematology/Oncology Subcommittee review. Rationale, background and references updated.|
|Reviewed||05/20/2009||Hematology/Oncology Subcommittee review. Rationale, references and websites updated.|
|Reviewed||05/14/2008||Hematology/Oncology Subcommittee review. Rationale and background updated. References and websites updated.|
|02/21/2008||The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.|
|Reviewed||05/16/2007||Hematology/Oncology Subcommittee review. References updated.|
|Reviewed||03/08/2007||MPTAC review. Classification changed from LAB to GENE.|
|Reviewed||06/08/2006||MPTAC review. Rationale and references updated.|
|Reviewed||06/07/2006||Hematology/Oncology Subcommittee review.|
|11/21/2005||Added reference for Centers for Medicare and Medicaid Services (CMS) – National Coverage Determination (NCD).|
|Revised||07/14/2005||MPTAC review. Revision based on Pre-merger Anthem and Pre-merger WellPoint Harmonization.|
Last Review Date
|LAB.00010||Gene-Based Tests for Screening, Detection, or Management of Prostate Cancer|
|WellPoint Health Networks, Inc.||
|2.11.20||Gene-Based Tests for Screening, Detection and/or Management of Prostate Cancer|