Coverage Policy Manual
Policy #: 2013045
Category: Medicine
Initiated: November 2013
Last Review: June 2018
  Genetic Test: Microarray-based Gene Expression Profile Analysis for Prostate Cancer Management

Description:
Microarray-based gene expression profile analysis has been proposed as a means to risk-stratify patients with low-risk prostate cancer, diagnosed by needle biopsy, to guide treatment decisions.
 
Prostate cancer is the second most common cancer diagnosed among men in the U.S.  According to the National Cancer Institute (NCI), nearly 240,000 new cases are expected to be diagnosed in the U.S. in 2013, and associated with around 30,000 deaths.  Autopsy studies in the pre-prostate-specific antigen (PSA) screening era have identified incidental cancerous foci in 30% of men 50 years of age, with incidence reaching 75% at age 80 years (Dall'Era, 2008).  However, NCI Surveillance Epidemiology and End Results data show age-adjusted cancer-specific mortality rates for men with prostate cancer have declined from 40 per 100,000 in 1992 to 22 per 100,000 in 2010.  This decline has been attributed to a combination of earlier detection via PSA screening and improved therapies.   
 
Localized prostate cancers may appear very similar clinically at diagnosis (Bangma, 2007). However, they often exhibit diverse risk of progression that may not be captured by accepted clinical risk categories (e.g., D’Amico criteria) or prognostic tools that are based on clinical findings, including PSA titers, Gleason grade, or tumor stage (Johansson, 2004; Ploussard, 2011; Hamden, 2008; Brimo, 2013; Eylert, 2012). In studies of conservative management, the risk of localized disease progression based on prostate cancer-specific survival rates at 10 years may range from 15% (8, 9) to 20% (Thompson, 2013) to perhaps 27% at 20-year follow-up (Albertsen, 2005). Among elderly men (70 years or more) with this type of low-risk disease, comorbidities typically supervene as a cause of death; these men will die with prostate cancer present, rather than from the cancer.  Other very similar-appearing low-risk tumors may progress unexpectedly rapidly, quickly disseminating and becoming incurable.   
 
The divergent behavior of localized prostate cancers creates uncertainty whether or not to treat immediately (Borley, 2009; Freedland, 2011). A patient may choose definitive treatment upfront (Ip, 2011). Surgery (radical prostatectomy), external-beam radiation therapy (EBRT), brachytherapy, high-intensity-focused ultrasound, systemic chemotherapy, hormonal therapy, cryosurgery, or combinations are used to treat patients with prostate cancer (Freedland, 2011; Thompson, 2007). Complications associated with those treatments most commonly reported (radical prostatectomy, EBRT) and with the greatest variability were incontinence (0-73%) and other genitourinary toxicities (irritative and obstructive symptoms); hematuria (typically 5% or less); gastrointestinal and bowel toxicity, including nausea and loose stools (25-50%); proctopathy, including rectal pain and bleeding (10-39%); and erectile dysfunction, including impotence (50-90%) (Thompson, 2007).    
 
American Urological Association  (AUA) Guidelines suggest patients with low- and intermediate-risk disease have the option of “active surveillance”, taking into account patient age, patient preferences, and health conditions related to urinary, sexual, and bowel function (Thompson, 2007). With this approach the patient will forgo immediate therapy and continue regular monitoring until signs or symptoms of disease progression are evident, at which point curative treatment is instituted (Whitson, 2010; Albertsen, 2010).   
 
Given the unpredictable behavior of early prostate cancer, additional prognostic methods to biologically stratify this disease are under investigation. These include gene expression profiling, which refers to analysis of mRNA expression levels of many genes simultaneously in a tumor specimen, and protein biomarkers (Wu, 2013; Spans, 2013; Schoenborn, 2013;Haung, 2013; Yu. 2012; Agell, 2012).  Two gene expression profiling tests and one protein biomarker test are now offered, intended to biologically stratify prostate cancers diagnosed on prostate needle biopsy: Prolaris® (Myriad Genetics, Salt Lake City, UT) and Oncotype Dx® Prostate Cancer Assay (Genomic Health, Redwood City, CA) are gene expression profiling tests which use archived tumor specimens as the mRNA source, reverse transcriptase polymerase chain reaction (RT-PCR) amplification, and the TaqMan low-density array platform (Applied Biosystems, Foster City, CA). Prolaris® is used to quantify expression levels of 31 cell cycle progression (CCP) genes and 15 housekeeper genes to generate a CCP score. Oncotype Dx® Prostate is used to quantify expression levels of 12 cancer-related and 5 reference genes to generate a Genomic Prostate Score (GPS). In the final analysis, the CCP score or GPS is combined in proprietary algorithms with clinical risk criteria (PSA, Gleason grade, tumor stage) to generate new risk categories (ie,  eclassification) intended to reflect biological indolence or aggressiveness of individual lesions, and thus inform management decisions. A protein biomarker test, Promark™ (Metamark Genetics, Cambridge, MA), is an automated quantitative imaging method to measure protein biomarkers by immunofluorescent staining in defined areas in intact formalin-fixed paraffin-embedded biopsy tissue, in order to provide independent prognostic information to aid in the stratification of patients with prostate cancer to active surveillance or therapy.
 
After radical prostatectomy (RP), accurate risk stratification can identify those patients at high risk of prostate cancer specific mortality who would most likely benefit from additional therapy versus those patients who may be cured by surgery alone and could be spared the potential impact of additional treatment (Klein, 2015).
 
The optimal timing of radiation therapy (RT) after RP is a debate. Adjuvant RT may maximize cancer control outcomes; however, salvage RT can minimize overtreatment and still lead to acceptable oncologic outcomes (Den, 2015). Several analyses have shown conflicting conclusions as to whether adjuvant RT is favored over salvage RT (with salvage RT typically being initiated at a post RP PSA level of 0.3 to 0.6 ng/mL).
 
Decipher® (GenomeDx Biosciences, Vancouver, BC, Canada) is a tissue-based tumor 22-biomarker gene expression profile test that is intended to guide the use of radiation after radical prostatectomy. The
 
Decipher test classifies patients as low risk, who can delay or defer radiation after prostatectomy, or high risk, as those who would potentially benefit from early radiation. The gene expression classifier is a continuous risk score between 0 and 1, with higher risk scores indicating a greater probability of metastasis.
 
MetaMark offers ProMark®, an 8-biomarker proteomic assay to provide prognostic information in patients with prostate cancer. The test gives an individualized ProMark Score between 0 and 100 with a personalized risk of aggressive disease based on the ProMark score. ProMark utilizes automated imaging technology to measure the following eight protein biomarkers: DERL1, CUL2, SMAD4, PDSS2, HSPA9, FUS, pS6, and YBOX1.
 
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Prolaris®, Oncotype DX® Prostate, and Decipher® gene expression profiling, and the ProMark™ protein biomarker test are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
 
In November 2015, the FDA’s Office of Public Health Strategy and Analysis published a document on public health evidence for FDA oversight of laboratory developed tests (FDA, 2015). The document argued that many tests need more FDA oversight than the regulatory requirements of CLIA. CLIA standards relate to laboratory operations, but do not address inaccuracies or unreliability of specific tests. Prolaris is among the 20 case studies in the document cited as needing FDA oversight. The document asserted that patients are potentially receiving inappropriate prostate cancer care because there is no evidence that results from the test meaningfully improved clinical outcomes.
  
Coding
 
Effective October 1, 2017, there is a specific CPT multianalyte assay with algorithmic analysis (MAAA) code for the NeoLAb Prostate- Liquid Biopsy:
 
0011M 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.
 
There is no specific CPT code for this testing. If the test utilizes an algorithm for analysis of the results of testing for multiple genes and the results are reported as a type of score, the unlisted multianalyte assay with algorithmic analysis (MAAA) unlisted code 81599 should be reported. If no algorithm is performed and the results are not reported as a score, the unlisted molecular pathology code 81479 maybe reported. Medicare instructs that Prolaris for example be reported with the 84999 unlisted chemistry code.
 
  

Policy/
Coverage:
Microarray-based gene expression analysis to guide management of prostate cancer does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, microarray-based gene expression analysis to guide management of prostate cancer is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 

Rationale:
This policy is based on a literature review through June 2013. Full-length publications were sought that described the analytic validity, clinical validity, and clinical utility of either Prolaris® or Oncotype Dx® Prostate gene expression profiling.  We reviewed evidence on the use of either test to predict the aggressiveness (or indolence) of newly diagnosed (by needle biopsy), localized prostate cancer.   
 
Analytic Validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)   
 
Published data on the analytic validity of Prolaris® or OncotypeDx® Prostate was not identified.  Information is available on the performance of the TaqMan microarray platform (Applied Biosystems, Foster City, CA) used in Prolaris® and Oncotype Dx® Prostate through the MicroArray Quality Control (MAQC) project (Shi, 2006). In the MAQC project, initiated and led by FDA scientists, expression data on 4 titration pools from 2 distinct reference RNA samples were generated at multiple test sites on 7 microarray-based and 3 alternative technology platforms, including TaqMan  According to the investigators, the results provide a framework to assess the potential of microarray technologies as a tool to provide reliable gene expression data for clinical and regulatory purposes. The results showed very similar performance across platforms, with a median coefficient of variation of 5% to 15% for the quantitative signal and 80% to 95% concordance for the qualitative detection call between sample replicates.   
 
Clinical Validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)
 
Prolaris®
One full-length, peer-reviewed article reports results of a validation study of Prolaris® to determine its prognostic value for prostate cancer death in a conservatively managed needle biopsy cohort (Cuzick, 2012). Cuzick et al. did not state whether this study adheres to the PRoBE (prospective-specimen-collection, retrospective-blinded evaluation) criteria suggested by Pepe and colleagues for an adequate biomarker validation study (Pepe, 2008). They note that the cell cycle expression data were read blind to all other data, which conforms to the criteria; however, patients were identified retrospectively from tumor registries, and there were no case-control subjects, which does not conform.
 
Patients were identified from 6 cancer registries in Great Britain and were included if they had clinically localized prostate cancer that was diagnosed by needle biopsy between 1990 through 1996; were younger than 76 years at diagnosis; had a baseline prostate-specific antigen (PSA) measurement; and were conservatively managed.  Potentially eligible patients who underwent radical prostatectomy, died, or showed evidence of metastatic disease within 6 months of diagnosis were excluded.  Those who received hormone therapy prior to diagnostic biopsy also were excluded.  The original biopsy specimens were retrieved and centrally reviewed by a panel of expert urological pathologists to confirm the diagnosis and, where necessary, to reassign Gleason scores by use of a contemporary and consistent interpretation of the Gleason scoring system (Montironi, 2005).    
 
Tumor cells were microdissected from needle biopsy blocks, the amount determined by the length of the cancer available in the core and to enable preservation of any remaining cancer tissue for tissue microarray studies.  A cell cycle progression (CCP) score, consisting of expression levels of 31 predefined cell cycle progression genes and 15 housekeeper genes, was generated using TaqMan low-density arrays.  The values of each of the 31 CCP genes were normalized by subtraction of the average of up to 15 nonfailed housekeeper genes for that replicate.   
 
Of 776 patients diagnosed by needle biopsy and for which a section was available to review histology, needle biopsies were retrieved for 527 (68%), 442 (84%) of which had adequate material to assay.  Among the 442, a proportion, 349 (79%), produced a CCP score and had complete baseline and follow-up information.  The median potential follow-up time was 11.8 years, during which a total 90 deaths from prostate cancer occurred within 2,799 person-years of actual follow-up.  The main assessment of the study was a univariate analysis of the association between death from prostate cancer and the CCP score (Cuzick, 2012).  A further predefined assessment of the added prognostic information after adjustment for the baseline variables was also undertaken.  The primary end point was time to death from prostate cancer.  A number of covariates were evaluated: centrally reviewed Gleason primary grade and score; baseline PSA value; clinical stage; extent of disease (percent of positive cores); age at diagnosis; Ki-67 immunohistochemistry; and initial treatment.
 
Oncotype Dx® Prostate  
No full-length publications on the clinical validity of Oncotype Dx® Prostate were identified.  The Genomic Health website presents information on gene panel development studies and a clinical validation study
 
that was performed to evaluate this test in specimens obtained by needle biopsy in a cohort of men in the U.S.  The latter study was presented at the 2013 annual meeting of the American Urological Association, but slides are not available (abstract 2131 at http://www.aua2013.org/abstracts/archive/abstracts_POD35.cfm).  According to the website, the developer of the test and their collaborators from the University of California San Francisco (UCSF) evaluated the Oncotype Dx® prostate test on needle biopsy tissue from patients who could have been candidates for active surveillance but underwent radical prostatectomy, then correlated the biopsy results to their radical prostatectomy specimens.  This information is insufficient to assess the clinical validity of this test.   
 
Clinical Utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
 
No published data on the clinical utility of Prolaris® or Oncotype Dx® Prostate were identified.  At present, no conclusions can be reached on this topic.  
 
Conclusions:
The analytic validity of microarray-based gene expression analysis for prostate cancer management is indirectly suggested by results from the MicroArray Quality Control project, but remains to be specifically established.   
 
Peer-reviewed evidence on the clinical validity of Prolaris® comprises a retrospective cohort (n=349) culled from 6 cancer registries in Great Britain.  In the primary univariate analysis, a 1-unit increase in CCP score was associated with a 2.02-fold (95% confidence interval [CI]: 1.62 to 2.53, p=8.6 ´ 10-10) increase in the hazard of death from prostate cancer at 10-year follow-up.  Multivariate analyses showed only the CCP score (hazard ratio [HR] for a 1-unit increase in CCP score = 1.65, 95% CI: 1.31 to 2.09, p=2.6 ´ 10-5), Gleason score <7 (HR=0.61, 95% CI: 0.32 to 1.16, p=5.0 ´ 10-4) and prostate-specific antigen (PSA) titer (HR=1.37, 95% CI: 1.05 to 1.79, p=0.017) were statistically associated with prostate cancer-specific mortality at 10 years.   The investigators assert the CCP score alone was more prognostic than either PSA titer or Gleason score for tumor-specific mortality at 10-year follow-up.  Although the patients may be similar to those of a modern U.S. cohort, comparability is unclear from the single publication that is available.  Furthermore, the study is limited by the use of archived biopsy specimens, with attendant issues of reproducibility and test reliability.   
 
No peer-reviewed, published evidence on the clinical validity of Oncotype Dx® Prostate was identified.   
 
No evidence is available on the clinical utility of either test for any clinical end point.
 
Ongoing Clinical Trials
 
No active clinical trials were identified in a search of the Clinicatrials.gov website as of October 14, 2013.
 
Summary    
 
Two microarray-based gene expression analysis tests—Prolaris® and Oncotype Dx® Prostate—are commercially available.  The test results are intended to be used in combination with accepted clinical criteria (Gleason score, prostate-specific antigen [PSA], clinical stage) to stratify biopsy-diagnosed localized prostate cancer according to biological aggressiveness, and direct initial patient management.  Direct evidence is insufficient to establish the analytic validity, clinical validity, or clinical utility of either test.     
 
2014 Update
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Oncotype Dx® Prostate
Knezevic et al reported on the analytic validity of Oncotype Dx® Prostate.26 Estimates of analytic precision and reproducibility were derived from analysis of RNA prepared from 10 microdissected prostate tumor samples obtained by needle biopsy. Individual Gleason scores were assigned using the 2005 International Society of Urological Pathology Consensus guidelines (Epstein. 2005). The results showed that the assay could accurately measure expression of the 12 cancer-related and 5 reference genes over a range of absolute RNA inputs (0.005-320 ng); the limit of detection in a sample was 0.5 ng/uL. The analytic accuracy showed average variation of less than 9.7% across all samples at RNA inputs typical of needle biopsy specimens. The amplification efficiency for the 17 genes in the test ranged from 88% to 100%, with a median of 93% (SD=6%) for all 17 genes in the assay. Analytic precision was assessed by examining variability between replicate results obtained using the same mRNA input. Reproducibility was measured by calculating both within and between mRNA input variation. A low input level of 5 ng mRNA was used to reflect the lowest 2.5 percentile of a tumor sample of 0.023 cm3. When converted to GPS units (unit measure for reporting test results), the standard deviation for analytic precision was 1.86 GPS units (95% confidence interval [CI], 1.60 to 2.20) on the 100-unit scale. The standard deviation for reproducibility was 2.11 GPS units (95% CI, 1.83 to 2.50) on the 100-point scale.
 
Section Summary
The analytic validity of gene expression analysis for prostate cancer management using Prolaris® is indirectly suggested by results from the MAQC project, but remains to be specifically established. The study by Knezevic et al provides sufficient evidence to establish the analytic validity of Oncotype Dx®
Prostate (Knezevic, 2013).
 
Oncotype Dx® Prostate
 
One publication compiled results of 3 cohorts of contemporary (1997-2011) patients in a prostatectomy study (N=441; Cleveland Clinic database, 1987-2004), a biopsy study (N=167; Cleveland Clinic database, 1998-2007), and an independent clinical validation study cohort (N=395; mean age, 58 years; University of California, San Francisco Urologic Oncology Data Base, 1998-2011). Results from the clinical validation study and prostatectomy study provide information on the potential clinical validity of this test. The cohorts had a mix of low to low-intermediate clinical risk characteristics using National Comprehensive Cancer Network (NCCN) or American Urological Association (AUA) criteria. Patients included in the validation and prostatectomy studies would be considered (a) eligible for active surveillance based on clinical and pathologic findings and (b) representative of patients in contemporary clinical practice. However, all patients elected radical prostatectomy within 6 months of their initial diagnostic biopsies.
 
The clinical validation study was designed to evaluate the ability of Oncotype Dx® Prostate to predict tumor pathology in needle biopsy specimens. It was prospectively designed, used masked review of prostatectomy pathology results, and as such met the REMARK (Reporting Recommendations for Tumor Marker Prognostic Studies) guidelines for biomarker validation.  In the prostatectomy study, all patients with clinical recurrence (local recurrence or distant metastasis) were selected, together with a random sample of those who did not recur, using a stratified cohort sampling method to construct a 1:3 ratio of recurrent to nonrecurrent patients. The prespecified primary end point of the validation study was the ability of the Genomic Prostate Score (GPS) to predict the likelihood of favorable pathology in the needle biopsy specimen. Favorable pathology was defined as freedom from high-grade or non-organ-confined disease. In the prostatectomy study, the ability of the GPS to further stratify patients within AUA groupings was related to clinical recurrence-free interval in regression-to-the-mean estimated survival curves.
 
The validation study results show that the GPS could refine stratification of patients within specific NCCN criteria grouping. These findings suggest that a lower GPS would reclassify the likelihood of favorable pathology (ie, less biologically aggressive disease) upward (ie, a potentially lower risk of progression), and vice versa within each clinical stratum. For example, among patients in the cohort classified by NCCN criteria as low risk, the mean likelihood of favorable pathology in a tumor biopsy was about 76%, with 24% then having unfavorable pathology. With the GPS, the estimated likelihood of favorable tumor pathology was broadened, ranging from 55% to 86%, conversely reflecting a 45% to 14% likelihood of adverse pathology, respectively (Klein, 2014). In effect, the risk of adverse tumor pathology indicated by the GPS could be nearly halved (24%-14%) at 1 extreme, or nearly doubled (24%-45%) at the other, but the actual number of patients correctly or incorrectly reclassified between all 3 categories cannot be ascertained from the data provided. The results suggest that the combination of GPS plus clinical criteria can reclassify patients on an individual basis within established clinical risk categories. However, whether these findings support a conclusion that the GPS could predict the biological aggressiveness of a tumor—hence its propensity to progress— based solely on the level of pathology in a biopsy specimen is unclear. Moreover, extrapolation of this evidence to a true active surveillance population, for which the majority in the study would be otherwise eligible, is difficult because all patients had elective radical prostatectomy within 6 months of diagnostic biopsy.
 
The prostatectomy study provides estimates of clinical recurrence rates stratified by AUA criteria (Epstein et al), compared with rates after further stratification according to the GPS from the validation study. The survival curves for clinical recurrence reached a duration of nearly 18 years based on the dates individuals in the cohort were entered into the database (1987-2004). The GPS groups are defined by tertiles defined in the overall study.
 
In the NCCN intermediate group, for example, the 10-year recurrence rate among radical prostatectomy patients was 9.6%. When the GPS was used in the analysis, the 10-year recurrence rate fell to as low as 2.0% (71% reduction) among patients in the low GPS group and 5.1% (47% reduction) in the intermediate GPS group, but rose to 14.3% (49% increase) in the high GPS group. These data suggest the GPS can reclassify a patient’s risk of recurrence based on a specimen obtained at biopsy. However, the findings do not necessarily reflect a clinical scenario of predicting disease progression in untreated patients under active surveillance.
 
Peer-reviewed evidence on the clinical validity of Prolaris® comprises a retrospective cohort (n=349) culled from 6 cancer registries in Great Britain. The investigators assert the CCP score alone was more prognostic than either PSA titer or Gleason score for tumor-specific mortality at 10-year follow-up. Although the patients may be similar to those of a modern U.S. cohort, comparability is unclear from the single publication that is available. Furthermore, the study is limited by the use of archived biopsy specimens, with attendant issues of reproducibility and test reliability.
 
The evidence from the Klein paper on clinical validity for Oncotype Dx® Prostate suggests the GPS can reclassify a patient’s risk of recurrence based on a specimen obtained at biopsy.33 However, whether these findings support a conclusion that the GPS could predict the biological aggressiveness of a tumor— hence its propensity to progress—based solely on the level of pathology in a biopsy specimen is unclear. Moreover, extrapolation of this evidence to a true active surveillance population, for which most in the study would be otherwise eligible, is difficult because all patients had elective radical prostatectomy within 6 months of diagnostic biopsy. Thus the findings do not reflect a clinical scenario of predicting disease progression in untreated patients under active surveillance.
 
Prolaris®
No studies were identified to directly support the clinical utility of Prolaris®. However, we identified 2 retrospective survey studies that assessed the potential impact of Prolaris® on physicians’ treatment Decisions (Crawford, 2014; Shore, 2014). The authors of each study have suggested their findings support the “clinical utility” of the test, based on whether the results would lead to a change in treatment. Although this information may be useful in assessing the potential test uptake by urologists, it does not demonstrate clinical utility in clinical settings.
 
Oncotype Dx® Prostate
Klein et al also reported a decision-curve analysis (Vickers, 2006) that they have proposed reflects the clinical utility of Oncotype Dx® Prostate (Klein, 2014). In this analysis, they investigated the predictive impact of the GPS in combination with the Cancer of the Prostate Risk Assessment (CAPRA) validated tool37 versus the CAPRA score alone on the net benefit for the outcomes of patients with high-grade disease (Gleason >4+3), high-stage disease, and combined high-grade and high-stage disease. They reported that, over a range of threshold probabilities for implementing treatment, “incorporation of the GPS would be expected to lead to fewer treatments of patients who have favorable pathology at prostatectomy without increasing the number of patients with adverse pathology left untreated.” Thus, an individual patient could use the findings to assess his balance of benefits and harms (net benefit) when weighing the choice to proceed immediately to curative radical prostatectomy with its attendant adverse sequelae, or deciding to enter an active surveillance program. The latter would have an immediate benefit realized by forgoing radical prostatectomy, but perhaps would be associated with greater downstream risks of disease progression and subsequent therapies.
 
No active clinical trials were identified in a search of the ClinicalTrials.gov website as of September 30, 2014.
 
Two reverse transcriptase-polymerase chain reaction (RTPCR)-based gene expression tests—Prolaris® and Oncotype Dx® Prostate—are commercially available in the United States. They are used in combination with current clinical criteria (Gleason score, prostate specific antigen [PSA] serum levels, clinical stage) to further stratify biopsy-diagnosed, localized prostate cancer according to expression levels of discrete sets of genes that, when overexpressed, are considered to reflect increased biological aggressiveness of a lesion. Such information would be used to assist in initial clinical disease management, specifically to decide whether a patient should proceed to definitive therapy (ie, surgery), or could safely proceed to active surveillance. Published evidence is sparse and insufficient to draw conclusions on the analytic validity, clinical validity, or clinical utility of Prolaris®, and is insufficient to determine the clinical validity or utility of Oncotype Dx® Prostate in patients contemplating entry into an active surveillance program.
 
2015 Update
A literature search conducted through October 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Analytic validity is the technical accuracy of a test in detecting a mutation that is present or in excluding a mutation that is absent.
 
Clinical validity reflects the diagnostic performance of a test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease.
 
Clinical utility reflects how the results of a diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
 
Promark™
Analytic validity
Shipitsin and colleagues reported on the analytic validity of the automated quantitative multiplex immunofluorescence in situ imaging approach assessing: the ability of the test to quantitate markers in a defined region of interest (tumor versus surrounding benign), tissue quality control, assay staining format and reproducibility (Shipitsin, 2014). To evaluate tissue sample quality, they assessed the staining intensities of several protein markers in benign tissue and using these, categorized prostate cancer tissue blocks into four quality groups, of which the best two groups were used to generate tumor microarray blocks; 508 prostatectomy specimens were used and of these, 418 passed quality testing and were used for the tumor microarray blocks. For intra-experiment reproducibility, two consecutive sections from a prostate tumor test microarray block were stained in the same experiment and scatter plots compared the mean values of the staining intensities; signals from consecutive sections showed R2 correlation values above 0.9 and differences in absolute values typically less than 10%.
 
Clinical validity
Blume-Jensen and colleagues reported on a study of 381 biopsies matched to prostatectomy specimens which were used to develop an 8-biomarker proteomic assay to predict prostate final pathology on prostatectomy specimen using risk scores (Blume-Jensen, 2015).  Biomarker risk scores were defined as favorable if less than or equal to 0.33 and non-favorable if greater than 0.80 with a possible range between 0 and 1 based on false-negative and false-positive rates of 10% and 5%, respectively. The risk score generated for each patient was compared with two current risk stratification systems, National Comprehensive Cancer Network (NCCN) guideline categories and the D’Amico system. Results from the study showed that, at a risk score of less than or equal to 0.33, the predictive value of the assay for favorable pathology in very low- and low-risk NCCN and low-risk D’Amico groups were 95%, 81.5%, and 87.2%, respectively, while the NCCN and D’Amico risk classification groups alone had predictive values of 80.3%, 63.8% and 70.6%, respectively. The positive predictive value for identifying favorable disease with a risk score of less than or equal to 0.33 was 83.6% (specificity 90%). At a risk score of greater than 0.80, 77% had non-favorable disease. Overall, 39% of the patients in the study had risk scores less than or equal to 0.33 or greater than 0.8, 81% or which were correctly identified with the 8-biomarker assay. Of the patients with intermediate risk scores (>0.33 to ≤0.8), 58.3% had favorable disease.
 
The performance of the assay was evaluated on a second blinded study of 276 cases to validate the assay’s ability to distinguish “favorable” pathology (defined as Gleason score on prostatectomy less than or equal to 3+4 and organ-confined disease) versus “non-favorable” pathology (defined as Gleason score on prostatectomy greater than or equal to 4+3 or non-organ-defined disease). The second validation study separated favorable from non-favorable pathology (AUC=0.68, p<0.001; odds ratio, 20.9).
 
Clinical utility
No published studies on the clinical utility of the Promark™ test were identified.
 
Promark summary
 
Data are insufficient to establish the analytic and clinical validity and clinical utility of the Promark™ test
 
Prostate Cancer Risk Stratification Post Radical Prostatectomy
Decipher®
Analytic validity
Published data on the analytic validity of the Decipher test consists of one study, which was performed on surgical resection specimens from patients with prostate cancer identified to be in a post-surgery high-risk population. The Decipher test platform was performed in formalin-fixed, paraffin-embedded (FFPE) tissue to assess the differential expression in the discovery, validation and clinical application (Den, 2014). Matched FFPE and unfixed fresh-frozen specimens from paired tumor and normal samples from kidney, lung and colon were compared and the microarray signals derived from the degraded RNA extracted from FFPE specimens was found to be highly analogous to the signals from the RNA in the fresh frozen specimens. According to the company’s website, additional analytic performance studies were conducted, and the test was subjected to reagent and analytical verification studies in the laboratory according to CLIA guidelines, reproducibility was demonstrated by evaluation of day-to-day and operator-operator precision and the assay showed concordant results between the clinical laboratory, R & D laboratories and pathology.
 
Clinical validity
The clinical validity of the Decipher test has been reported in seven studies to predict the possibility of metastasis after radical prostatectomy (RP) in patients with post-operative high-risk features like pathologic stage T2 with positive margins, pathologic stage T3 disease or a rising PSA (Klein, 2015; Den, 215; Den, 2014; Cooperberg, 2015; Ross, 2014; Karnes, 2013; Erho, 2013; Presnsner, 2014).Over 2000 patients from multiple academic institutions have been retrospectively studied using the genomic classifier score generated blinded to clinical data or outcomes. The results have been compared to the use of standard practice parameters (including preoperative PSA and Gleason score) in the determination of the need for postoperative radiation (RT).
 
Den and colleagues reported on the use of the Decipher genomic classifier (GC) to provide prognostic and predictive information into the development of metastases in men receiving post-RP RT (either 3-D conformal or IMRT) (Den, 2015). Genomic classifier scores were calculated from 188 men who were identified within the GenomeDx prostate cancer database with pathologic stage T3 or margin-positive prostate cancer and had received post-RP RT at one of two academic centers between 1990 and 2009. The primary endpoint was metastatic disease (regional or distant) documented on CT or bone scan. Adjuvant versus salvage RT was defined by PSA levels ≤0.2 and >0.2 ng/mL before initiation of RT. The clinical characteristics of eligible patients included 72% of men with extraprostatic extension, 35% with seminal vesicle invasion, and 78% with positive surgical margins. Twenty-one percent of patients had a Gleason score of ≥8.. Fifty one percent of patients received adjuvant RT (89% within 12 months of RP) and overall, patients received RT at a median of 5 months after RP (range 1-160 months). Thirty percent of patients received hormonal therapy with RT. Median follow-up after RP and RT was 10 and 8 years, respectively. Cumulative incidence of metastatic disease at 5 years after RT for low, average and high GC scores was 0%, 9% and 29% (p=.002). In a multivariate analysis, GC and pre-RP PSA were independent predictors of metastasis (both p<.01). In the low GC score group (score <0.4) there was no difference in cumulative incidence of metastasis compared to patients who received adjuvant or salvage RT (p=0.79), however, for patients with higher GC scores (≥04), the cumulative incidence of metastasis at 5 years was 6% for patients treated with adjuvant RT compared to 23% treated with salvage RT (p<.01). The authors concluded that patients with low GC scores are best treated with salvage RT and those with high GC scores with adjuvant RT.
 
Klein and colleagues reported on the use of Decipher, in addition to standard risk-stratification tools, to predict rapid metastasis (within 5 years of surgery) in a cohort of 169 men who did not receive adjuvant RT (Klein, 2015). The study population consisted of patients who underwent RP at the Cleveland Clinic between 1987 and 2008 and met the following criteria: 1) preoperative PSA of >20, pathologic stage T3 or margin Positive disease, or Gleason score ≥8, 2) pathologic lymph node negative, 3) undetectable post-RP PSA and, 4) had not receive neoadjuvant or adjuvant RT. Follow-up was a minimum of 5 years. Fifteen patients developed rapid metastasis, at a median of 2.3 years. In a multivariate analysis, the Decipher score was a significant predictor of rapid metastasis (odds ratio: 1.48; p=0.018) after adjusting for clinical risk factors. Patients with a low-risk Decipher score had 95% metastasis-free survival at 5 years.
 
Cooperberg and colleagues assessed the use of the Decipher test independently and in combination with Cancer of the Prostate Risk Assessment Postsurgical (CAPRA-S) to predict prostate cancer death after radical prostatectomy (Shipitsin, 2015). Between the years 2000 and 2006, a cohort of 1010 patients at high risk of recurrence of prostate cancer after RP was treated at the Mayo Clinic. High-risk was defined by 0reoperative PSA of >20 ng/mL, Gleason score ≥8, or pathologic stage T3b. A random sample of this cohort identified 225 patients, among whom CAPRA-S and GC could be determined for 185 patients. Among the 185 patients, 28 experienced cancer specific mortality. For Decipher high-risk patients, the multivariate hazard ratio was 11.26 (p<0.001) relative to Decipher low-risk patients, and the cumulative incidence of prostate cancer specific mortality for Decipher high-risk patients was 45% at 5 years, versus Decipher low risk patients who had 99% prostate cancer specific mortality free survival, including after adjusting for use of adjuvant therapy.
 
Den and colleagues reported that in within a Decipher low-risk group that was treated post-RP with RT, there was no difference in oncologic outcomes (either biochemical failure or metastasis) whether they received adjuvant or salvage RT (Den, 2014).  For the men classified as high-risk by Decipher, a median four year PSA-free survival advantage was observed in the patients that received adjuvant versus salvage RT. Of these men classified as high-risk by GC, those who received adjuvant radiation had a 3% cumulative incidence of metastases as compared to 23% incidence of metastasis by 8 years in those who delayed treatment and received salvage radiation.
 
Clinical utility
The clinical utility of the Decipher test has been published in studies which reported the influence of the Decipher test on physicians’ post-RP treatment decisions (Badani, 2013; Badani, 2015; Michalopoulous, 2014).
 
 Michalopoulos and colleagues assessed the effect of the GC test on urologists’ decisions regarding treatment of men with high-risk disease post-RP (Michalopoulos, 2014). Participating urologists were from 15 community practices who had ordered the GC test for 146 prostate cancer patients with either pathologic stage T3 or positive surgical margins post-RP. The urologists were asked to provide their treatment recommendations before and after receiving the GC test report. Prior to availability of the GC test result treatment recommendations were based on Gleason score and CAPRA-S risk: 40 (27.4%) were recommended to undergo adjuvant therapy, 102 (69.9%) close observation and 4 (2.7%) “other”. Using the GC risk score, 61.6% and 38.4% of patients were identified as low- and high-risk of metastasis, respectively. More than 60% of high-risk patients were reclassified as low risk after the GC test results. Overall, adjuvant treatment recommendations were modified for 30.8% (95%CI; 23-39%) of patients. With the GC test results, 42.5% of patients who were initially recommended for adjuvant therapy were subsequently recommended observation. The GC test score also influenced the intensity of the treatment recommendation; with ~40% of patients classified as high-risk by GC score recommended more intense therapy versus 1.1% of those deemed low-risk by GC score. Limitations to the study included that treatment recommendations were submitted electronically and did not track the actual treatment administered, it was not possible to assess patient influence on the decision-making process, the association between GC test results and treatment recommendations was determined using “early adopters” of the test, and all participants were community-based physicians whose treatment recommendations may differ from those of academic centers.
 
Badani and colleagues assessed the impact of the GC test on clinical practice decision-making about adjuvant therapy for patients with high-risk prostate cancer after RP (Badani, 2014). One hundred and ten case histories were available for review from medical records of patients with pathologic T3 disease or those with positive surgical margins. Urologists who reviewed the records were asked to make treatment recommendations for 10 cases randomly drawn from the pool of patient case histories; these urologists were recruited to the study through key opinion leaders from the AUA membership directory and high volume surgeons referred by the coauthors of the study. A total of 51 urologists consented to participate in the study and provided 530 adjuvant treatment recommendations with and without GC test results. The GC test classified 72% of patients as being low risk for metastasis. Without the GC test results, observation was recommended for 57% of patients, adjuvant RT for 36% and other treatment for 7%. Overall, 31% (95% CI; 27-35%) of treatment recommendations changed with the knowledge of the GC test result. Of the initial adjuvant RT recommendations, with the GC test result 40% were changed to observation (95% CI; 33-47%). Patients with low-risk disease according to the GC test were recommended for observation 81% of the time and those with high-risk disease by the GC test were recommended for treatment 65% of the time.
 
Decipher summary
 
The analytic validity of the Decipher test has been reported in one published study.
 
The clinical validity of the Decipher test has been studied in several retrospective, blinded evaluations and appears to accurately predict metastasis following radical prostatectomy.
 
No studies to directly support the clinical utility of Decipher™ were identified. Two retrospective survey studies that assessed the potential impact of Decipher™ on physicians’ treatment decisions have been published. Although this information may be useful in assessing the potential changes in treatment decisions by urologists, it does not demonstrate clinical utility in clinical settings.
 
Data on the analytic and clinical validity and clinical utility of the Promark test are lacking.
 
The analytic validity of the Decipher test has been reported in one published study. The clinical validity of the Decipher test has been studied in several retrospective, blinded evaluations and appears to accurately predict metastasis following radical prostatectomy. No studies to directly support the clinical utility of Decipher™ were identified.
 
Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer (v1.2015) state that, for Prolaris and Oncotype, “their clinical utility awaits evaluation by prospective, randomized controlled trials, which are unlikely to be done. The marketplace and comparative effective research may be the only means for these tests and others like them to gain their proper place for better risk stratification for men with clinically localized prostate cancer”.
 
NCCN guidelines do not address the use of the Promark or Decipher tests.
  
2016 Update
A literature search conducted through October 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In the Prostate Testing for Cancer and Treatment (ProtecT) trial, active surveillance, RP, and EBRT for the treatment of clinically localized prostate cancer were compared in 1643 men who were identified through PSA testing (Hamdy, 2016). At a median of 10-year follow-up, prostate cancer–specific mortality was low and similar in the 3 treatment groups: 1.5 (95% confidence interval [CI], 0.7 to 3.0) deaths per 1000 person-years in active surveillance, 0.9 (95% CI, 0.4 to 2.2) per 1000 person-years in the surgery group, and 0.7 (95% CI, 0.3 to 2.0) per 1000 person years in the radiotherapy (RT) group. Surgery and RT were associated with lower incidences of disease progression and metastases compared to active surveillance.
 
The level of evidence (LOE) will be evaluated according to the Simon and colleagues framework for study classification and levels of evidence for prognostic studies using archived specimens (Simon, 2009). Category A studies are prospective, randomized trials designed to evaluate prognostic markers; 1 such study would establish LOE 1. Category B studies are prospective trials designed for another purpose but with prospectively described use of archived samples (“prospective – retrospective” studies); 2 or more such studies are required for LOE 1. Category C studies are prospective observational registry studies with treatment and follow-up not dictated. As noted by Simon and colleagues, studies considered category C are LOE III but "may be validated to LOE II if 2 or more subsequent studies provide similar results. However, it is unlikely that category C studies would ever be sufficient to change practice, except under particularly compelling circumstances.” Category D studies are retrospective in design and represent LOE IV and V.
 
Koch and colleagues evaluated whether the CCP score could discriminate between systemic disease and local recurrence in patients with biochemical recurrence after RP (Koch, 2016).  All patients treated with RP as primary therapy at an academic medical center between 1995 and 2010 for whom RP samples were available and who had a BCR and either developed metastatic disease or received external beam salvage RT with at least 2 years of follow-up were eligible for retrospective analysis (n=60). Data from 5 patients were excluded for failing to meeting clinical eligibility requirements (no clarification provided) or because data were incomplete, sample blocks from 3 patients contained insufficient tumor for assay and data from 6 patients were excluded due to lack of "passing" CCP scores. Forty-seven patients were included in analysis. The outcome was categorized into 3 categories: (1) metastatic disease (n=22), (2) nonresponse to salvage external-beam radiotherapy (EBRT; n=14), and (3) durable response to salvage EBRT (n=11). Analyses were performed with a binary outcome (categories 1 and 2 combined). For each 1-unit change in the CCP score, the univariate odds ratio (OR) for metastatic disease or nonresponse was 3.72 (95% CI, 1.29 to 10.7). The CCP score was correlated with each of the clinical characteristics. Multivariate analysis was performed; however, due to the very small number of participants in the durable response group, confidence intervals were very wide and estimates are likely unstable.
 
After EBRT
Freedland and colleagues described the prognostic ability of the CCP score for predicting BCR in men who received primary EBRT (Freedland, 2013). The retrospective data included 141 men diagnosed with prostate cancer who had available biopsy samples and follow-up of at least 3 years who were treated with EBRT from 1991 to 2006. Nineteen (13%) of men experienced a BCR by 5 years. The univariate hazard ratio for BCR for each 1-unit increase in CCP was 2.55 (95% CI, 1.43 to 4.55). The multivariable hazard ratio for BCR associated with 1-unit increase in CCP including adjustment for pretreatment PSA, Gleason, percent positive cores, and concurrent androgen deprivation therapy was 2.11 (95% CI, 1.05 to 4.25).
 
In 2016, results of a systematic review and meta-analyses supported by the manufacturer were reported (Sommariva, 2016). Published and unpublished studies of prognostic validity or clinical utility of CCP testing were eligible for inclusion. Seven published studies were identified; 5 of these studies were clinical validity studies and have all been reviewed in the previous paragraphs (needle biopsy conservative management cohorts and postprostatectomy cohorts). The remaining 2 studies are discussed in the following section. Including 4 validity studies (Cuzick, 2011; Cooperberg, 2013; Bishoff, 2014; Freedland, 2013), (that reported the outcome of biochemical recurrence, the pooled estimate of the hazard ratio, calculated with random-effects meta-analytic methods, for BCR for a 1-unit increase in CCP was 1.9 (95% CI, 1.6 to 2.3). Two studies reported on the outcome of disease specific mortality (Cuzick, 2015; Cuzick, 2011).The pooled hazard ratio estimate of disease specific mortality for a 1-unit increase in CCP was 2.4 (95% CI, 1.7 to 3.5). However, there was evidence of heterogeneity in both models; reviewers did not report any variables associated with heterogeneity.
 
The FDA’s Office of Public Health Strategy and Analysis published a document on the need for public health evidence for FDA oversight of laboratory developed tests (FDA,2015). The document argued that many tests need more FDA oversight than the regulatory requirements of CLIA. Prolaris is among the 20 case studies in the document cited as needing FDA oversight. The document asserted that the test is being used to make management changes (citing Crawford et al, 2014) without evidence those changes lead to meaningfully improved clinical outcomes.
 
In 2016, Brand and colleagues combined the Klein et al (2014) and Cullen et al (2015) studies using a patient specific meta-analysis (Brand, 2016). The GPS score was compared to CAPRA score, NCCN risk group, and AUA/EAU risk group. The authors tested whether GPS added predictive value for the likelihood of favorable pathology above the clinical risk assessment tools. The model including GPS and CAPRA provided the best risk discrimination; the AUC improved from 0.68 to 0.73 by adding GPS to CAPRA. The AUC improved from 0.64 to 0.70 by adding GPS to NCCN risk group. The improvements were reported to be significant but the confidence intervals for AUC were not provided.
 
Whalen and colleagues prospectively evaluated the correlation of GPS with final pathology at RP in a clinical practice setting. Eligible men were 50 years of age and older with greater than 10-year life expectancy, PSA levels of 20 ng/mL or less, stage cT1c-cT2c newly diagnosed, untreated prostate cancer and met NCCN classification as very low risk, low risk, or low-intermediate risk (Whalen, 2016). Men were enrolled from May 2013 to August 2014 at an academic medical center. After initial review at the institution, Genomic Health further reviewed biopsy samples to assign Gleason score and tumor length. Samples with Gleason grade discrepancy between initial and central review were excluded from analyses. Clinicians were blinded to GPS when counseling patients regarding management with active surveillance versus definitive treatment. Genomic Health reclassified patients’ cancers as “less favorable,” “consistent with” or “more favorable” than what would be predicted by their NCCN risk group. The primary outcome was adverse pathology at RP defined as any pT3 stage and primary Gleason grade of 4 or any pattern 5. Fifty patients had RP pathology and the reclassification results for these participants are discussed here; 21 (42%) met the definition of adverse pathology. The NCCN risk classification categorized 2 (4%) patients as very low risk, 34 (68%) as low risk and 14 (28%) as low-intermediate risk. Twenty-three (46%) of patients were reclassified using GPS and the percentage with adverse pathology for the reclassification. Confidence intervals were not provided.
 
Three analyses of overlapping retrospectively assembled cohorts of men undergoing either adjuvant or salvage RT. One study examined the prognostic ability of the GC for BCR, while the other 2 examined its prognostic ability for metastases. The median follow-up in Den et al (2014) and Den et al (2015) exceeded 10 years; the median follow-up in Freedland et al (2016) was 7.4 years. Just over three-quarters of the men in the studies had positive surgical margins or a larger proportion than in the other validation studies. Den et al (2014) found that the GC’s AUC for biochemical recurrence was 0.75 compared with 0.70 for the Stephenson nomogram.61 In Den et al (2015), the AUC for metastases was 0.83 versus 0.66 for CAPRA-S; 7 (21.2%) of men with high GC scores (>0.6) developed metastases compared with 12 (15.2%) men with CAPRA-S scores exceeding 5.28 However, overall only 19 men (10.1%) had developed metastases. Among the 160 men not developing metastases, the GC reclassified 27 of 67 men with high CAPRA-S scores into a low-risk group, but given the small number of men developing metastases, the reclassifications were somewhat uncertain. Finally, the authors explored whether the classifier might identify men likely to benefit from adjuvant RT over salvage, suggesting that adjuvant therapy might be preferred in men with a GC score greater than 0.4. However, that result was based on only 14 men with GC scores of 0.4 and 3 men with values that were lower. In Freedland and colleagues, the C-index for metastases was 0.85 for GC compared to 0.63 for CAPRA-S and 0.65 for Briganti (Freedland, 2016).Twenty men developed metastases. In a reclassification analysis, 31 (39%) patients in the upper 2 tertiles of risk by Briganti were classified as low risk by GC and 1 of these developed metastases during follow-up. Seventy-three (49%) patients who were categorized as intermediate or high risk with CAPRA-S were classified as GC low-risk; 3 developed metastases during follow-up.
 
Lobo and colleagues (Lobo, 2015) reported an individualized decision analysis comparing GC to “usual care” using data from the cohorts in Karnes et al (2013) and Den et al (2014). The usual care probabilities of receiving each treatment were derived from the published literature. A 6% threshold for GC score was used for GC-based treatment. Using the cohort from Karnes et al (2013), the estimated 10-year probability of metastasis or death was 0.32 (95% CI, 0.32 to 0.33) for usual care compared to 0.31 (95% CI, 0.30 to 0.32) for GC-based treatment. In the cohort from Den et al (2014), the estimated 10-year probability of metastasis or death was 0.28 (95% CI, 0.27 to 0.29) for usual care compared to 0.26 (95% CI, 0.25 to 0.27) for GC-based treatment.
 
Several studies have compared physician’s treatment recommendations before and after receiving GC results (Badani, 2015; Badani, 2013; Guyen, 2015). Because the studies do not include information on outcomes and clinical validity has not been established, it is not known whether these treatment decisions represent clinically appropriate management. Only one representative example will be reviewed here.
 
Ross and colleagues reported results of a retrospective, comparative study of postoperative RT after RP for 422 men with pT3 disease or positive margins (Ross, 2016). The men were from 4 cohorts previously described (Karnes 2013; Den 2014; Ross 2016; Freedland 2016). The 4 treatment groups were adjuvant RT (n=111), minimal residual disease salvage RT (n=70), salvage RT (n=83), and no RT (n=157). The primary end point was metastasis. Thirty-seven men developed metastasis and the median follow-up was 8 years. Both CAPRA-S (HR=1.39; 95% CI, 1.18 to 1.62) and Decipher (HR=1.28; 95% CI, 1.08 to 1.52) were independently associated with metastasis in multivariable analysis. There was no evidence that treatment effect was dependent on genomic risk (interaction p=0.16 for CAPRA-S, p=0.39 for Decipher), Men with low CAPRA-S or low Decipher scores have a low risk of metastatic events regardless of treatment selection and men with high CAPRA-S or Decipher scores benefitted from ART compared to the other treatments.
 
For individuals who have clinically localized prostate cancer who receive Prolaris, the evidence includes 1 study of analytic validity and retrospective cohort studies using archived samples examining clinical validity and decision curve analysis providing indirect evidence for clinical utility. Relevant outcomes include overall survival, disease-specific survival, test accuracy and validity, quality of life, and treatment-related morbidity. Evidence of improved clinical validity or prognostic accuracy for prostate cancer death using Prolaris Cell Cycle Progression score in patients managed conservatively after needle biopsy shows some improvement in areas under the receiver operator characteristic curve over clinicopathologic risk stratification tools. All validation studies are Simon category C or D. There is limited indirect evidence for potential clinical utility. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have clinically localized prostate cancer who receive Oncotype DX Prostate, the includes 2 studies of analytic validity, case-cohort and retrospective cohort studies using archived samples examining clinical validity, and a decision curve analysis from 1 study examining indirect evidence for clinical utility. Relevant outcomes include overall survival, disease-specific survival, test accuracy and validity, quality of life, and treatment-related morbidity. Evidence for clinical validity and potential clinical utility of Oncotype DX Prostate in patients with clinically localized prostate cancer derives from a study predicting adverse pathology following radical prostatectomy. Although a relevant intermediate outcome, it is necessary to establish generalizability to an active surveillance population. All validation studies are Simon category C or D. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have clinically localized prostate cancer who receive the ProMark protein biomarker test, the evidence includes 1 study of analytic validity, 1 retrospective cohort study using archived samples examining clinical validity, and no studies of clinical utility. Relevant outcomes include overall survival, disease-specific survival, test accuracy and validity, quality of life, and treatment-related morbidity. There is insufficient evidence to support improved outcomes with ProMark given that only a single clinical validity study was available. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have intermediate- or low-risk prostate cancer after radical prostatectomy who receive Prolaris, the evidence includes 1 study of analytic validity and retrospective cohort studies using archived samples examining clinical validity. Relevant outcomes include overall survival, disease-specific survival, test accuracy and validity, quality of life, and treatment-related morbidity. Evidence of improved clinical validity or prognostic accuracy for prostate cancer death using Prolaris Cell Cycle Progression score in patients postprostatectomy shows some improvement in areas under the receiver operator characteristic curve over clinicopathologic risk stratification tools. All validation studies are Simon category C or D. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have high-risk prostate cancer after radical prostatectomy who receive the Decipher prostate cancer classifier, the evidence includes 1 study of analytic validity, prospective and retrospective studies with overlapping patients using archived samples examining clinical validity, and  decision curve analyses examining indirect evidence for clinical utility, and prospective decision impact studies without pathology or clinical outcomes. Relevant outcomes include overall survival, disease-specific survival, test accuracy, test validity, quality of life, and treatment-related morbidity. The clinical validity of the Decipher genomic classifier has been evaluated in samples of patients with high-risk prostate cancer undergoing different interventions following radical prostatectomy. Studies reported some incremental improvement in discrimination. However, it is unclear whether there is consistent improved reclassification—particularly to higher risk categories—or whether the test could be used to predict which men will benefit from radiotherapy. All validation studies are Simon category C/D. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
American Urological Association
In 2007, the American Urological Association (AUA) published guidelines on the management of clinically localized prostate cancer.17 AUA reviewed and confirmed the validity of the guidelines in 2011. The guidelines do not address gene expression profile analysis.
 
National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence (NICE) published an updated guideline on the diagnosis and management of prostate cancer in January 2014.87 NICE guidelines do not address gene expression profile analysis.  
 
2017 Update
A literature search conducted through October 2017 did not reveal any new information that would prompt a change in the coverage statement.  
  
 
 
 
 

CPT/HCPCS:
0011MOncology, 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
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
81541Oncology (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
81599Unlisted multianalyte assay with algorithmic analysis

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