BlueAdvantage Administrators of Arkansas
Coverage Policy#: 970
Category: Laboratory
Initiated: November 2013
Last Review: December 05, 2023
Last Revision: December 05, 2023
BlueAdvantage National Accounts
Coverage Policy for Participants and Beneficiaries enrolled in Walmart Associates' Health and Welfare Medical Plan
(Developed by BlueAdvantage Administrators and Adopted by the Walmart Plan as Plan Coverage Criteria)

Genetic Test: Gene Expression Profiling and Protein Biomarkers for Prostate Cancer Management


Description:
Gene expression profile analysis and protein biomarkers have been proposed as a means to risk-stratify patients with prostate cancer to guide treatment decisions. These tests are intended to be used either on prostate needle biopsy tissue to guide management decisions for active surveillance or therapeutic intervention, to guide radiotherapy use after radical prostatectomy (RP), or to guide medication selection after progression in metastatic castration-resistant prostate cancer.
 
PROSTATE CANCER
Prostate cancer is the second most common noncutaneous cancer diagnosed among men in the United States. Autopsy studies in the era before the availability of prostate-specific antigen (PSA) screening have identified incidental cancerous foci in 30% of men 50 years of age, with incidence reaching 75% at age 80 years (Dal’Era et al, 2008).
   
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.   
 
Risk Stratification in Newly Diagnosed Disease
In the United States, most prostate cancers are clinically localized at diagnosis due in part to the widespread use of PSA testing. Clinicopathologic characteristics are used to stratify patients by risk based on the extent of the primary tumor (T category), nearby lymph node involvement (N category), metastasis (M category), PSA level and Gleason score. The National Comprehensive Cancer Network (2017) and American Urological Association (2017) risk categories for clinically localized prostate cancer are similar, derived from the D’Amico criteria and broadly include low-, intermediate-, or high-risk as follows as well as subcategories within these groups:
    • Low: T1-T2a and Gleason score < 6 grade group 1 and PSA level <10 ng/mL;
    • Intermediate: T2b-T2c or Gleason score 3+4=7/Gleason grade group 2 or Gleason score 4=3=7/Gleason grade group 3 or PSA level 10-20 ng/mL;
    • High: T3a or Gleason score 8/Gleason grade group 4 or Gleason score 9-10/Gleason grade group 5 or PSA level >20 ng/mL.
 
Risk stratification is combined with patient age, life expectancy, and treatment preferences to make initial therapy decisions.
 
Monitoring After Prostatectomy
All normal prostate tissue and tumor tissue is theoretically removed during radical prostatectomy (RP), so the serum level of PSA should be undetectable following RP. Detectable PSA post-RP indicates residual prostate tissue and presumably persistent or recurrent disease. PSA is serially measured following RP to detect early disease recurrence. The National Comprehensive Cancer Network (2017) recommends monitoring serum PSA every 6 to 12 months for the first 5 years and annually thereafter. Many recurrences following RP can be successfully treated. The American Urological Association has recommended a biochemical recurrence be defined as a serum PSA of 0.2 ng/mL or higher, which is confirmed by a second determination with a PSA level of 0.2 ng/mL or higher (Thompson et al, 2013).
 
Castration-Resistant Prostate Cancer
Androgen deprivation therapy (ADT) is generally the initial treatment for patients with advanced prostate cancer. ADT can produce tumor response and improve quality of life but most patients will eventually progress on ADT. Disease that progresses while the patient is on ADT is referred to as castration-resistant prostate cancer. After progression, continued ADT is generally used in conjunction with other treatments. Androgen pathways are important in the progression of castration-resistant prostate cancer. Several drugs have been developed that either inhibit enzymes involved in androgen production or inhibit the androgen receptor, such as abiraterone and enzalutamide. Taxane chemotherapy with docetaxel or cabazitaxel may also be used after progression. Immunotherapy (sipuleucel-T) or radium 223 are options for select men.

Policy/
Coverage:
 
Use of gene expression analysis and protein biomarkers to guide management of prostate cancer is considered investigational in all situations.
 
Investigational services are Plan exclusions.
 
 
 
 
Coding
The following codes may be used to bill these services:  
 
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
 
81541 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
 
81542 Oncology (prostate) mRNA microarray gene expression profiling of 22 content genes, utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as metastasis risk score (Decipher Prostate) eff 01/01/20
 
0005U Oncology (prostate) gene expression profile by real-time RT-PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score
 
0047U Oncology (prostate), mRNA, gene expression profiling by real-time RT-PCR of 17 genes (12 content and 5 housekeeping), utilizing formalin-fixed paraffin-embedded tissue, algorithm reported as a risk score
 
81599 unlisted multianalyte assay with algorithmic analysis (MAAA)
 

Rationale:
This evidence review has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through October 11, 2023.
 
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.
 
INITIAL MANAGEMENT DECISION: ACTIVE SURVEILLANCE VS THERAPEUTIC INTERVENTION
 
Prolaris®
 
Prolaris is used to quantify expression levels of 31 cell cycle progression (CCP) genes and 15 housekeeper genes to generate a CCP score. This section reviews Prolaris for initial management decisions in newly diagnosed, localized cancer.
Three studies reporting clinical validity related to newly diagnosed men with clinically localized prostate cancer.
 
Cuzick et al (2012) examined the Prolaris prognostic value for prostate cancer death in a conservatively managed needle biopsy cohort. Cell cycle expression data were read blind to all other data. Patients were identified from 6 cancer registries in Great Britain and were included if they had clinically localized prostate cancer diagnosed by needle biopsy between 1990 and 1996; were younger than 76 years at diagnosis; had a baseline PSA measurement; and were conservatively managed. Potentially eligible patients who underwent RP, died, showed evidence of metastatic disease within six months of diagnosis, or received hormone therapy before diagnostic biopsy were excluded. The original biopsy specimens were retrieved and centrally reviewed by a panel of expert urologic pathologists to confirm the diagnosis and, where necessary, to reassign Gleason scores.44, Of 776 patients diagnosed by needle biopsy and for which a sample was available to review histology, needle biopsies were retrieved for 527 (68%), 442 (84%) of which had adequate material to assay. From the 442 samples, 349 (79%) produced a CCP score and had a complete baseline and follow-up information, representing 45% of 776 patients initially identified. The median follow-up time was 11.8 years. Ninety deaths from prostate cancer occurred within 2799 person-years.
 
Cuzick et al (2015) examined 3 U.K. cancer registries from 1990 to 2003 to identify men with prostate cancer who were conservatively managed following needle biopsy, with follow-up through December 2012. The authors stated that the samples did not overlap with Cuzick et al (2012). Men were excluded if they had undergone RP or RT within six months of diagnosis. A combination of the CCP and CAPRA scores (called the combined clinical cell cycle risk [CCR] score) was used to predict prostate cancer death. There were 989 men who fit eligibility criteria; CCP scores were calculable for 761 (77%), and combined CCP and clinical variables were available for 585 (59%). Median age at diagnosis was 70.8 years, and the median follow-up was 9.5 years. The prostate cancer mortality rate was 17% (n=100), with 29% (n=168) dying from competing causes. Higher CCP scores were associated with increased 10-year risk of prostate cancer mortality (see Table 5): 7% (CCP score <0), 15% (CCP score 0-1), 36% (CCP score 1-2), and 59% (CCP score >2). For the CCR score, the HR for 10-year prostate cancer mortality increased to 2.17 (95% CI, 1.83 to 2.57). The C statistic for the CAPRA score was 0.74; adding the CCP score increased the C statistic to 0.78 (no CIs for the C statistic were reported). Estimates with CIs for ten-year death rates for the CCR score are provided in a figure and given in Table 5 based on digitizing the figure. Note that the predictions appear to cross 100% for CCR of about 6. Treatment changes after 6 months were documented in only part of 1 of the 3 cohorts; at 24 months, 45% of the men in this cohort had undergone RT or prostatectomy.
 
Lin et al (2018) validated a CCR cutoff of 0.8 using a subset of 585 conservatively managed men from the Cuzick (2015) cohort. Of the 585 men, 60 had CCR scores of 0.8 or less. Among the 284 men who were at low- or intermediate-risk by NCCN criteria, 59 had CCR scores of 0.8 or less. The text reports that the estimated 10-year prostate cancer mortality risk was 2.7% for men with CCR scores below the threshold and 3.3% (95% CI, 1.9% to 5.7%) at the threshold in the full cohort, and 2.3% below the threshold and 2.9% (95% CI, 1.3% to 6.7%) at the threshold in the cohort that excluded high-risk men. However, the Kaplan-Meier curves show an estimated prostate cancer mortality at ten years of 0% for men with CCR of 0.8 or less in both cohorts. The Kaplan-Meier curve estimated prostate cancer mortality at 10 years for men with CCR greater than 0.8 was 20% in the full cohort and 9% in the cohort excluding high-risk men.
 
Oncotype Dx® Prostate
The Oncotype DX Prostate assay includes 5 reference genes and 12 cancer genes that represent 4 molecular pathways of prostate cancer oncogenesis: androgen receptor, cellular organization, stromal response, and proliferation. The assay results are combined to produce a Genomic Prostate Score (GPS), which ranges from 0 to 100. Higher GPS scores indicate more risk.
 
Studies reporting clinical validity for Oncotype DX Prostate as follows.  
 
One publication by Klein et al (2014) compiled results for 3 cohorts: 2 in test development including a contemporary (1997-2011) group of patients in a prostatectomy study (n=441; Cleveland Clinic database, 1987-2004) and a biopsy study (n=167; Cleveland Clinic database, 1998-2007); the third was an independent clinical validation study cohort (n=395; University of California, San Francisco [UCSF] Database, 1998-2011). The Klein et al (2014) prostatectomy study, although used to identify genes to include in the GPS, provided estimates of clinical recurrence rates stratified by AUA criteria, compared with rates after further stratification according to the GPS from the validation study. The survival curves for clinical recurrence reached nearly 18 years based on the dates individuals in the cohort were entered into the database (1987-2004). The GPS groups are grouped by tertiles defined in the overall study. Absolute rates and precision estimates of clinical recurrence by GPS low-, intermediate-, and high-risk groups were not reported. These data would suggest the GPS can reclassify patient 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.
 
A retrospective cohort study by Cullen et al (2015) included men with NCCN-defined very low through intermediate-risk prostate cancer undergoing RP within 6 months of diagnosis.51, The sample was obtained from men enrolled in the Center for Prostate Disease Research longitudinal study at two U.S. military medical centers. A Gleason score of 4 or 5 with the non-organ-confined disease was considered adverse pathology. Biopsies were available for 500 (57.9%) of 864 eligible patients; 382 (44.2% of eligible) with both adequate tissues for gene expression analysis and available RP pathology were included in the analysis. Selected patients were older (61.0 years vs 59.7 years, p=0.013) and had both higher Gleason scores (p<0.001) and NCCN risk classification (29.8% vs 32.9% intermediate, p=0.035). Median follow-up was 5.2 years and biochemical recurrence (BCR) occurred in 62 (15.4%). Estimates of 5-year BCR by GPS score are shown in Table 12. Adverse pathology was noted in 163 (34%) men. In an analysis adjusted for baseline characteristics, the GPS was associated with BCR-free survival and adverse pathology following RP (see Table 13). The GPS improved the C statistic for adverse pathology over NCCN risk alone from 0.63 to 0.72 (CIs not reported). Comparisons with other predictors such as CAPRA or Gleason score alone were not reported. Study implications were limited by the low proportion of eligible men in the analysis and differences between excluded and included men.
 
Whalen et al (2016) prospectively evaluated the correlation between GPS and final pathology at RP in a clinical practice setting.52, Eligible men were 50 years of age and older with more than 10 years of life expectancy, PSA levels of 20 ng/mL or less, stage cT1c-cT2c newly diagnosed, untreated prostate cancer, and who met NCCN classifications as very low-risk, low-risk, or low-intermediate risk. Men were enrolled from May 2013 to August 2014 at an academic medical center. Genomic Health reclassified patients’ cancers as “less favorable,” “consistent with,” or “more favorable” than what would have been predicted by their NCCN risk group. Adverse pathology at RP was 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 a low-intermediate risk. Twenty-three (46%) of patients were reclassified using GPS.
 
Van Den Eeden et al (2018) reported on a retrospective study using a stratified cohort sampling design including 279 of 6184 men who were diagnosed with prostate cancer within a registry between 1995 and 2010 and underwent RP within 12 months of diagnosis, with a median follow-up of 9.8 years. In an analysis adjusted for NCCN risk classifications, the GPS was associated with BCR-free survival, distant metastasis, and prostate cancer death following RP. Ten-year prostate cancer death by GPS score was displayed in a figure stratified by NCCN risk classification, which provides some information on potential reclassification. Ten-year prostate cancer death appears to be close to zero for men who are NCCN low-risk regardless of GPS score, indicating little useful reclassification of NCCN low-risk men based on GPS. For NCCN intermediate-risk, the risk of prostate cancer death ranges from approximately 0 for a GPS of less than 40 to close to 40% for a GPS of 100. It is unclear how many men with GPS less than 40 were NCCN favorable intermediate-risk.
 
Salmasi et al (2018) reported on a retrospective cohort from a UCLA institutional database of men with NCCN very low-, low-, or intermediate-risk prostate cancer treated with RP between 2010 and 2016 who had undergone simultaneous 3 Tesla multiparametric magnetic resonance imaging fusion targeted and systematic biopsies within the 6-month period prior to RP. The authors also reported an AUC for a model including Gleason score, GPS, and highest Prostate Imaging Reporting and Data System score determined by magnetic resonance imaging was 0.79 (95% CI, 0.71 to 0.87). The AUC of other models had overlapping CIs; the AUC of a model with Gleason score and highest Prostate Imaging Reporting and Data System score was 0.69 (95% CI, 0.59 to 0.78); and another model including Gleason score and PSA level was 0.68 (95% CI, 0.58 to 0.78).
 
In a systematic review, Brand et al (2016) combined the Klein et al (2014) and Cullen et al (2015) studies using a patient-specific meta-analysis. The GPS was compared with the CAPRA score, NCCN risk group, and AUA risk group. Reviewers tested whether the GPS added predictive value for the likelihood of favorable pathology above the clinical risk assessment tools. The model including the GPS and CAPRA score provided the best risk discrimination; the AUC improved from 0.68 to 0.73 by adding the GPS to the CAPRA score. The AUC improved from 0.64 to 0.70 by adding the GPS to the NCCN risk group. The improvements were reported to be significant but the CIs for AUC were not provided.
 
Decipher Biopsy
This section reviews Decipher for initial management decisions in men with newly diagnosed, localized prostate cancer.
 
Retrospective cohort studies reporting the clinical validity of Decipher Biopsy in men with newly diagnosed, localized prostate cancer has been published (Berlin et al, 2018; Nguyen et al, 2017; Tosoian et al, 2021).
 
ProMark™ Protein Biomarker Test
The ProMark assay includes eight biomarkers that predict prostate pathology aggressiveness and lethal outcomes: DERL1, PDSS2, pS6, YBX1, HSPA9, FUS, SMAD4, and CUL2. The assay results are combined using predefined coefficients for each marker from a logistic regression model to calculate a risk score. A risk score is a continuous number between 0 and 1, which estimates the probability of “non-GS 6” pathology.
 
Blume-Jensen et al (2015) reported on a study of 381 biopsies matched to prostatectomy specimens used to develop an 8-biomarker proteomic assay to predict prostate final pathology on prostatectomy specimen using risk scores.
 
Biomarker risk scores were defined as favorable if less than or equal to 0.33 and nonfavorable 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 systems¾NCCN 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 values 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 greater than 0.80, 77% had nonfavorable 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% of 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 in a second blinded validation study of 276 cases (see Table 19), also reported in Blume-Jensen et al (2015), to validate the assay’s ability to distinguish “favorable” pathology (defined as Gleason score on prostatectomy =3+4 and organ-confined disease) from “nonfavorable” pathology (defined as Gleason score on prostatectomy =4+3 or non-organ-defined disease). The second validation study separated favorable from nonfavorable pathology (AUC=0.68; 95% CI, 0.61 to 0.74).
 
MANAGEMENT DECISION AFTER RADICAL PROTATECTOMY (RP)
 
Prolaris
This section reviews Prolaris for management after RP.
 
Four retrospective studies reporting clinical validity in the post-RP management setting have been identified. Three of these studies [Cuzick et al (2011), Cooperberg et al (2013), and Bishoff et al (2014)] reported on post-RP patients. Koch et al (2016) reported on post-RP patients with BCR. Freedland et al (2013), reported on post-RT patients but is included in this section for completeness.
 
Cuzick et al (2011) examined the potential use of the Prolaris CCP test combined with a clinical score following RP, using a retrospective cohort of archived samples from a tumor registry. The study also included a cohort of men with localized prostate cancer detected from specimens obtained during transurethral resection of the prostate, which is not a population of interest here, and so is not described. Men conservatively managed after RP between 1985 and 1995 were identified from a tumor registry (n=366 with CCP scores). The primary endpoint was time to BCR, and the secondary endpoint was prostate cancer death. Myriad Genetics assessed CCP scores blindly. The median age of patients was 68 years (median follow-up, 9.4 years). Gleason scores were 7 or lower in 96%, but margins were positive in 68%. Cancers were clinically staged as T3 in 34%; following RP, 64% was judged pathologic stage T3. CCP score was associated with BCR (see Table 15). Analyses of prostate cancer deaths in the RP cohort were problematic, due to only 12 (3%) deaths. The clinical score included PSA level, stage, positive surgical margins, and Gleason score. The AUC for BCR within 5 years in the RP cohort was 0.825 for the clinical score and 0.842 for the CCR score. Although the CCP increased the AUC by 2%, whether that improvement is clinically useful is unclear because reclassification data and analysis of net benefits are lacking.
 
Swanson et al (2021) published a reanalysis of 360 patients from the cohort first reported in Cuzick et al (2011). After a median follow-up of 16 years, 163 (45%) of the cohort developed BCR, 41 (11%) developed metastatic disease, and 33 (9%) died from prostate cancer. The CCR score (a combination of CAPRA-S and the CCP molecular score) was prognostic of prostate cancer death, but the estimate was imprecise (HR per unit score, 3.40; 95%CI, 1.52 to 7.59). The study authors illustrated the added value of CCR for predicting disease-specific mortality by comparing predicted risk using CCR to risk predicted by a CAPRA-S-only model in a Kaplan-Meier curve; however, precision estimates were not presented.
 
Cooperberg et al (2013) evaluated the CCP score in an RP cohort and the incremental improvement over the CAPRA-S score for predicting BCR using a prospective-retrospective design (conforming to a PRoBE study design). A prognostic model was developed from the RP cohort described by Cuzick et al (2011).76, The validation cohort was obtained from patients identified from the UCSF Urologic Oncology Database. Tissue sufficient to obtain a CCP score was available for 413 men (69% of the 600 eligible samples). Both UCSF and Myriad Genetics performed statistical analyses. In the validation cohort, 95% had Gleason scores of 7 or lower, 16% of samples had positive margins, 4% had seminal vesicle invasion, and 23% had extracapsular extension. BCR occurred in 82 (19.9%) men. The association with BCR is shown in Table 22. The AUC for BCR with CAPRA-S alone was 0.73, increasing to 0.77 for the combined CCR score.
 
Bishoff et al (2014) examined the prognostic ability of the CCP score in 3 cohorts: the Martini Clinic (n=283, simulated biopsies from formalin-fixed paraffin-embedded RP specimen), Durham Veterans Affairs Medical Center (n=176, diagnostic biopsies), and Intermountain Healthcare (n=123, diagnostic biopsies). The combined analysis included all 582 patients. Gleason scores were 7 or lower in 93% of men. In the combined cohorts, a unit increase in the CCP score increased the adjusted HR for BCR by 1.47 (see Table 22). Metastatic events (n=12) were too few to draw conclusions.
 
Koch et al (2016) evaluated whether the CCP score could discriminate between systemic disease and local recurrence in patients with BCR after RP. All 60 patients given RP as primary therapy at an academic medical center between 1995 and 2010 for whom samples were available and who had a BCR and either developed metastatic disease or received salvage EBRT with at least 2 years of follow-up were eligible for retrospective analysis. Data from five patients were excluded for failing to meet clinical eligibility requirements (no clarification provided) or because data were incomplete; sample blocks from three patients contained insufficient tumor for assay and data from six patients were excluded due to lack of “passing” CCP scores. Forty-seven patients were included in the analysis. Outcomes were classified into 3 categories: (1) metastatic disease (n=22), (2) nonresponse to salvage 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 for metastatic disease or nonresponse was 3.72 (see Table 22). Multivariate analysis was performed; however, due to the very small number of participants in the durable response group, CIs were very wide.
 
Decipher® Prostate RP
 
Decipher used for initial management decisions was described in the previous section. This section reviews Decipher for management after RP.
 
The clinical validity of the Decipher test (GC) has been reported inmultiple studies to predict metastasis, mortality, or BCR after RP in men with postoperative high-risk features like pathologic stage T2 with positive margins, pathologic stage T3 disease, or a rising PSA level (Feng et al, 2021; Klein et al, 2015; Den et al, 2014; Cooperberg et al, 2015; Ross et al, 2014; Karnes et al, 2013; Erho et al, 2013; Ross et al, 2016; Freedland et al, 2016; Glass et al, 2016; Klen et al, 2016). 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 et al (2015) 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-dimensional conformal or IMRT). 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 1 of 2 academic centers between 1990 and 2009. The primary endpoint was metastatic disease (regional or distant) documented on computed tomography or bone scan. Adjuvant versus salvage RT was defined by PSA levels of 0.2 ng/mL or less and more than 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 or more. 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=0.002). In a multivariate analysis, GC and pre-RP PSA were independent predictors of metastasis (both p<0.01). In the low GC score group (score <0.4) there was no difference in cumulative incidence of metastasis compared with patients who received adjuvant or salvage RT (p=0.79), however, for patients with higher GC scores (=0.4), the cumulative incidence of metastasis at 5 years was 6% for patients treated with adjuvant RT compared to 23% treated with salvage RT (p<0.01). 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 et al (2015) 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. 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 more than 20, pathologic stage T3 or margin positive disease, or Gleason score of 8 or more, (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 et al (2015) 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 RP. Between the years 2000 and 2006, a cohort of 1010 patients at high risk of recurrence of prostate cancer after RP were treated at the Mayo Clinic. High-risk was defined by preoperative PSA more than 20 ng/mL, Gleason score of 8 or more, 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?mortality-free survival, including after adjusting for use of adjuvant therapy. Similarly, Karnes et al (2017) found that adding the GC to CAPRA improved the AUC from 0.73 to 0.76 with highly overlapping CIs.
 
Den et al (2014) 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. For the men classified as high-risk by Decipher, a median 4-year  SA 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 with 23% incidence of metastasis by 8 years in those who delayed treatment and received salvage radiation.
 
Spratt et al (2017) reported an individual patient-level data meta-analysis of five of the studies described in the previous section. Data from patients randomly selected from the case-cohort studies (total N=855 patients) were included. The pooled 10-year metastases incidence was 5.5%, 15.0%, and 26.7% for GC low, intermediate, and high risk, respectively (p<0.001, CIs not reported). The AUC for 10-year distant metastasis of the clinical model alone was 0.76, which increased to 0.81 with the inclusion of GC (CIs not reported).
 
Lin et al (2018) validated a CCR cutoff of 0.8 using a subset of 585 conservatively managed men from the Cuzick (2015) cohort. Of the 585 men, 60 had CCR scores of 0.8 or less. Among the 284 men who were at low or intermediate risk by NCCN criteria, 59 had CCR scores of 0.8 or less. The text reports that the estimated 10-year prostate cancer mortality risk was 2.7% for men with CCR scores below the threshold and 3.3% (95% CI, 1.9% to 5.7%) at the threshold in the full cohort, and 2.3% below the threshold and 2.9% (95% CI, 1.3% to 6.7%) at the threshold in the cohort that excluded high-risk men. However, the Kaplan-Meier curves show an estimated prostate cancer morality at 10 years of 0% for men with CCR of 0.8 or less in both cohorts. The Kaplan-Meier curve estimated prostate cancer mortality at 10 years for men with CCR greater than 0.8 was 20% in the full cohort and 9% in the cohort excluding high risk men.
 
MANAGEMENT DECISION IN CASTRATION-RESISTANT PROSTATE CANCER
 
In men with metastatic castration-resistant prostate cancer (mCRPC), the purpose of protein biomarker assessment of circulating tumor cells (CTCs) is to inform a decision whether to administer androgen receptor signaling (ARS) inhibitors (eg, abiraterone, enzalutamide), or a taxane (eg, docetaxel).
 
Oncotype DX AR-V7 Nuclear Detect
 
Oncotype DX AR-V7 Nuclear Detectis used to detect nuclear-localized AR-V7 protein in CTCs of men with mCRPC who have failed first-line therapy and are considering additional ARS inhibitor therapy.
 
Scher et al (2018) reported results of a blinded validation study including 142 samples from patients with histologically confirmed, progressing mCRPC from 3 centers in the United States and the United Kingdom from 2012 to 2016. The samples were collected prior to administration of second-line or greater ARS inhibitors or taxanes. Median follow-up time in surviving men was not provided. Sixty-eight men were still in the risk set at 12 months. Numerically, men treated with ARS inhibitors had longest overall survival if they were AR-V7-negative and had shortest overall survival if they were AR-V7-positive. The unadjusted HR for overall survival for ARS inhibitors vs taxanes was statistically significantly greater than 1 (favoring ARS inhibitors) in the AR-V7-negative men while there was no statistically significant difference in overall survival (but with an unadjusted HR favoring taxanes) in AR-V7-positive men. A test of interaction for AR-V7 status by treatment was not provided. Analysis was further stratified by a binary prognostic risk score (high vs low) developed from the training cohort and including clinical biomarkers. However, the additional stratification resulted in the group that was AR-V7-positive and receiving ARS inhibitors including fewer than 10 men for both high and low risk.
 
Armstrong et al (2019) reported results of the PROPHECY trial, a prospective validation study of AR-V7 detection in men with high-risk mCRPC starting abiraterone or enzalutamide treatment.  Study population included 107 men with progressive, high-risk mCRPC initiating standard-of-care treatment with enzalutamide or abiraterone. Prior exposure to enzalutamide or abiraterone was permitted for men who were planning to receive the alternative agent. Detection of AR-V7 in CTCs was associated with shorter PFS and OS.
 
SUMMARY OF EVIDENCE
 
Initial Management Decision: Active Surveillance vs Therapeutic Intervention
For individuals who have clinically localized untreated prostate cancer who receive Prolaris, the evidence includes retrospective cohort studies of clinical validity using archived samples in patients of mixed risk categories. The relevant outcomes include OS, disease-specific survival, QOL, and treatment-related morbidity. For the low-risk group, the ProtecT trial showed 99% 10-year disease-specific survival in mostly low-risk patients receiving active surveillance. The low mortality rate estimated with tight precision makes it unlikely that a test intended to identify a subgroup of low-risk men with a net benefit from immediate treatment instead of active surveillance would find such a group. For the intermediate-risk group, the evidence of improved clinical validity or prognostic accuracy for prostate cancer death using Prolaris Cell Cycle Progression score in patients managed conservatively after a needle biopsy has shown some improvement in areas under the receiver operating characteristic curve over clinicopathologic risk stratification tools. 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 untreated prostate cancer who receive Oncotype DX Prostate, the evidence includes case-cohort and retrospective cohort studies of clinical validity using archived samples in patients of mixed risk categories, and a decision-curve analysis examining indirect evidence of clinical utility. The relevant outcomes include OS, disease-specific survival, QOL, 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 after RP. The validity of using tumor pathology as a surrogate for the risk of progression and cancer-specific death is unclear. It is also unclear whether results from an RP population can be generalized to an active surveillance population. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have clinically localized untreated prostate cancer who receive Decipher Biopsy, the evidence includes retrospective cohort studies of clinical validity using archived samples in intermediate-risk patients and no studies of clinical utility. The relevant outcomes include OS, disease-specific survival, QOL, and treatment-related morbidity. For intermediate-risk men, a test designed to identify men who can receive active surveillance instead of RP or RT would need to show very high NPV for disease-specific mortality at ten years and improvement in prediction compared with existing tools used to select such men. Clinical validity studies of Decipher Biopsy reported prostate cancer metastases at five years but did not report survival outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have clinically localized untreated prostate cancer who receive the ProMark protein biomarker test, the evidence includes a retrospective cohort study of clinical validity using archived samples and no studies of clinical utility. The relevant outcomes include OS, disease-specific survival, QOL, and treatment-related morbidity. Current evidence does not support improved outcomes with ProMark given that only a single clinical validity study is available. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Management Decision After RP
For individuals who have localized prostate cancer treated with RP who receive Prolaris, the evidence includes retrospective cohort studies of clinical validity using archived samples. The relevant outcomes include OS, disease-specific survival, QOL, and treatment-related morbidity. Evidence of improved clinical validity or prognostic accuracy for prostate cancer death using the Prolaris Cell Cycle Progression score in patients after prostatectomy has shown some improvement in areas under the receiver operating characteristic curve over clinicopathologic risk stratification tools. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
For individuals who have localized prostate cancer who are treated with RP and who receive the Decipher prostate cancer classifier, the evidence includes a study of analytic validity, prospective and retrospective studies of clinical validity using overlapping archived samples, decision-curve analyses examining indirect evidence of clinical utility, and prospective decision-impact studies without pathology or clinical outcomes. The relevant outcomes include OS, disease-specific survival, QOL, 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 RP. Studies reported some incremental improvement in discrimination. However, it is unclear whether there is consistently improved reclassification-particularly to higher risk categories-or whether the test could be used to predict which men will benefit from radiotherapy. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
Management Decision in Castration-Resistant Prostate Cancer
For individuals who have mCRPC who receive the Oncotype DX AR-V7 Nuclear Detect, the evidence includes one prospective cohort study, one retrospective cohort study of clinical validity using archived samples, and no studies of clinical utility. The relevant outcomes include OS, disease-specific survival, QOL, and treatment-related morbidity. Current evidence does not support improved outcomes with Oncotype DX AR-V7 Nuclear Detect, given that only two clinical validity studies meeting inclusion criteria were available. The evidence is insufficient to determine the effects of the technology on health outcomes.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of online site ClinicalTrials.gov registry identified several currently unpublished trials that might influence this policy.
 
PRACTICE GUIDELINES AND POSITION STATEMENTS
 
American Society of Clinical Onclology (ASCO)
In 2020, the American Society of Clinical Onclology (ASCO) published a guideline on molecular biomarkers in localized prostate cancer (Eggener et al, 2020). The guidelines state, "Currently, there are no strong data or expert guidelines to support active surveillance in otherwise healthy men with Grade Group 3 or higher cancer; therefore, we would consider the use of genomic biomarkers only in situations in which the assay result, when considered as a whole with routine clinical factors, is likely to affect a physician’s recommendation or a patient’s choice for surveillance versus treatment, but they should not be used routinely."
 
Specific recommendations included the following:
 
Molecular biomarkers to identify patients with prostate cancer who are most likely to benefit from active surveillance:
    • Recommendation 1.1. Commercially available molecular biomarkers (i.e. Oncotype Dx Prostate, Prolaris, Decipher, and ProMark) may be offered in situations in which the assay result, when considered as a whole with routine clinical factors, is likely to affect management. Routine ordering of molecular biomarkers is not recommended (Type: Evidence based; Evidence quality: Intermediate; Strength of recommendation: Moderate).
    • Recommendation 1.2. Any additional molecular biomarkers evaluated do not have sufficient data to be clinically actionable or are not commercially available and thus should not be offered (Type: Evidence based; Evidence quality: Insufficient; Strength of recommendation: Moderate).
Molecular biomarkers to diagnose clinically significant prostate cancer:
    • Recommendation 2.1. Commercially available molecular biomarkers (i.e. Oncotype Dx Prostate, Prolaris, Decipher, and ProMark) may be offered in situations in which the assay result, when considered as a whole with routine clinical factors, is likely to affect management. Routine ordering of molecular biomarkers is not recommended (Type: Evidence based; Evidence quality: Intermediate; Recommendation: Moderate). Recommendation
    • 2.2. Any additional molecular biomarkers evaluated do not have sufficient data to be clinically actionable or are not commercially available and thus should not be offered (Type: Evidence based; Evidence quality: Insufficient; Strength of recommendation: Moderate).
Molecular biomarkers to guide the decision of post prostatectomy adjuvant versus salvage radiation:
    • Recommendation 3.1. The Expert Panel recommends consideration of a commercially available molecular biomarker (eg, Decipher Genomic Classifier) in situations in which the assay result, when considered as a whole with routine clinical factors, is likely to affect management. In the absence of prospective clinical trial data, routine use of genomic biomarkers in the postprostatectomy setting to determine adjuvant versus salvage radiation or to initiate systemic therapies should not be offered (Type: Evidence based; Evidence quality: Intermediate; Strength of recommendation: Moderate).
 
    • Recommendation 3.2. Any additional molecular biomarkers evaluated do not have sufficient data to be clinically actionable or are not commercially available and thus should not be offered (Type: Evidence based; Evidence quality: Insufficient; Strength of recommendation: Moderate).
National Comprehensive Cancer Network (NCCN)
The National Comprehensive Cancer Network guidelines for prostate cancer (v.2023) provide a table of tissue-based tests for prostate cancer prognosis.
 
The guidelines include the following statements related to risk stratification:
    • Patients with low or favorable intermediate-risk disease and life expectancy >10 years may consider the use of Decipher, Oncotype DX Prostate, Prolaris, or Promark during initial risk stratification.
    • Patients with unfavorable intermediate- and high-risk disease and life expectancy >10 years may consider the use of Decipher or Prolaris.
    • Decipher may be considered to inform adjuvant treatment if adverse features are found after radical prostatectomy and during workup for radical prostatectomy PSA persistence or recurrence (category 2B for the latter setting)
The panel noted that full assessment of the clinical utility of these molecular biomarker tests requires prospective randomized controlled trials, but these studies are unlikely to be done.
The panel also recommended that "the use of AR-V7 tests in circulating tumor cells can be considered to help guide selection of therapy in the post-abiraterone/enzalutamide metastatic castration-resistant prostate cancer setting."
 
National Institute for Health and Care Excellence
In 2019, the National Institute for Health and Care Excellence updated its guidance on the diagnosis and management of prostate cancer.  The guidance did not address gene expression profile testing.
 
American Urological Association and American Society for Radiation Oncology
The American Urological Association and American Society for Radiation Oncology published guidelines on clinically localized prostate cancer (Eastham et al, 2022).
The guidelines included the following statements on risk assessment:
    1. "Clinicians should use clinical T stage, serum PSA, Grade Group (Gleason score), and tumor volume on biopsy to risk stratify patients with newly diagnosed prostate cancer.(Strong Recommendation; Evidence Level: Grade B)"
    2. "Clinicians may selectively use tissue-based genomic biomarkers when added risk stratification may alter clinical decision-making. (Expert Opinion)"
    3. "Clinicians should not routinely use tissue-based genomic biomarkers for risk stratification or clinical decision-making. (Moderate Recommendation; Evidence Level: Grade B)"
In 2018, the American Urological Association published guidelines for castration-resistant prostate
Cancer (Lowrance et al, 2018). The guidelines do not mention AR-V7 assays.
 
U.S. Preventive Services Task Force Recommendations
Not applicable.
 
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 Amendments (CLIA). Prolaris® (Myriad Genetics, Salt Lake City, UT), Oncotype DX® Prostate and Oncotype DX AR-V7 (Genomic Health, Redwood City, CA), and Decipher® gene expression profiling test (GenomeDx Biosciences, Vancouver, BC), and the ProMark™ protein biomarker test (Metamark Genetics, Cambridge, MA) 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 LDTs. The FDA argued that many tests need more FDA oversight than the regulatory requirements of the CLIA. The 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 report asserted that patients are potentially receiving inappropriate prostate cancer care because there is no evidence that results from the test meaningfully improve clinical outcomes.
 

CPT/HCPCS:
0005UOncology (prostate) gene expression profile by real time RT PCR of 3 genes (ERG, PCA3, and SPDEF), urine, algorithm reported as risk score
0011MOncology, prostate cancer, mRNA expression assay of 12 genes (10 content and 2 housekeeping), RT PCR test utilizing blood plasma and 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
81542Oncology (prostate), mRNA, microarray gene expression profiling of 22 content genes, utilizing formalin fixed paraffin embedded tissue, algorithm reported as metastasis risk score
81599Unlisted multianalyte assay with algorithmic analysis

ICD9:

ICD10:

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