||Gene Expression Profiling Tests for Prostate Cancer
||November 13, 2017
||November 13, 2017
Gene expression profiles (GEPs) evaluate the expression of several genes using one sample. Gene expression is determined through RNA analysis, using either reverse transcriptase (RT) polymerase chain reaction (PCR) or DNA microarrays.
This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.
|Policy Position Coverage is subject to the specific terms of the member’s benefit plan.|
Decipher Prostate Cancer Classifier, OncotypeDX Genomic Prostate Score, Prolaris, and ProMark Proteomic Prognostic Test are considered experimental/investigational (E/I) and therefore non-covered.
- E/I molecular and genomic (MolGen) tests refer to assays involving chromosomes, DNA, RNA, or gene products that have insufficient data to determine the net health impact, which typically means there is insufficient data to support that a test accurately assesses the outcome of interest (analytical and clinical validity), significantly improves health outcomes (clinical utility), and/or performs better than an existing standard of care medical management option. Such tests are also not generally accepted as standard of care in the evaluation or management of a particular condition.
- In the case of MolGen testing, FDA clearance is not a reliable standard given the number of laboratory developed tests that currently fall outside of FDA oversight and FDA clearance often does not assess clinical utility.
Decipher® Prostate Cancer Classifier (GenomeDX Biosciences, Inc.).
- According to the manufacturer, the Decipher test is a tissue-based tumor genomic test that predicts the probability of metastasis within 5 years of RP, and provides an independent assessment of tumor aggressiveness, information that is distinct from that provided by the Gleason score or PSA.
- Decipher analyzes a small tissue sample removed during surgery that is routinely archived or stored by the pathology lab. This test is intended for PC patients with stage T2 disease with positive margins, stage T3 disease, or rising serum PSA after RP. The test evaluates the expression of 1.4M RNA (44,000 genes) using RNA extracted from formalin-fixed paraffin-embedded (FFPE) tumor specimens of the index lesion, defined as the highest tumor stage or Gleason score.
- The Decipher test result is expressed as a continuous risk score; a genomic classifier (GC) that ranges from 0 (lowest) to 1 (highest). Each score is associated with the probability of 5-year metastasis.
Oncotype DX® Genomic Prostate Score (GPS) (Genomic Health)
- According to the manufacturer, Oncotype DX prostate cancer assay is a multi-gene expression profiling assay that produces a genomic prostate score (GPS), ranging from 0-100, representing tumor aggressiveness. The Oncotype DX GPS provides risk stratification to properly classify patients. This test is designed to help patients with newly diagnosed, early-stage PC make informed treatment decisions, including active surveillance.
- Oncotype DX GPS uses quantitative RT-PCR for 12 prostate cancer-related genes and 5 control genes (total of 17 genes). It was developed for use with fixed paraffin-embedded (FPE) diagnostic prostate needle biopsies (≥1 mm prostate tumor).
Prolaris® (Myriad® Genetics)
- According to the manufacturer, Prolaris is a genomic test developed to predict PC-specific mortality in PC patients after needle biopsy, as well as post-RP patients to assess the risk of BCR. This test is designed to assist clinicians with predicting tumor aggressiveness combined with clinical and pathologic variables (Gleason score, PSA).
ProMark Proteomic Prognostic Test (Metamark®)
- According to the manufacturer, ProMark uses an 8-protein signature to predict PC aggressiveness (adverse prostate pathology of Gleason > or = 4+3 and/or non-organ confined disease [T3a, T3b, N1, or M1]) in patients with biopsy Gleason Scores of 3+3 and 3+4. It is designed to provide a personalized prediction regarding if PC can be managed with or without aggressive forms of treatment.
- ProMark scores range from 0 to 1 score, reflecting the probability of adverse pathology at radical prostatectomy.
|Professional Statements and Societal Positions|
The National Comprehensive Cancer Network (NCCN) 2017 Clinical Practice Guidelines on Prostate Cancer state the following regarding molecular assays:
- “Men with clinically localized disease may consider the use of tumor-based molecular assays. Retrospective case cohort studies have shown that molecular assays performed on biopsy or prostatectomy specimens provide prognostic information independent of NCCN risk groups. These include, but are not limited to, likelihood of death with conservative management, likelihood of biochemical progression after radical prostatectomy or external beam therapy, and likelihood of developing metastasis after radical prostatectomy or salvage radiotherapy.”
- “Several tissue-based molecular assays have been developed in an effort to improve decision-making in newly diagnosed men considering active surveillance and in treated men considering adjuvant therapy or treatment for recurrence.”
- “Uncertainty about the risk of disease progression can be reduced if such molecular assays can provide accurate and reproducible prognostic or predictive information beyond NCCN risk group assignment and currently available life expectancy tables and nomograms. Retrospective case cohort studies have shown that these assays provide prognostic information independent of NCCN risk groups, which include likelihood of death with conservative management, likelihood of biochemical recurrence after radical prostatectomy or radiotherapy, and likelihood of developing metastasis after operation or salvage radiotherapy. No randomized controlled trials have studied the utility of these tests.”
- According to NCCN, the Molecular Diagnostic Services Program (MolDX) recommendations stated the following:
- Decipher: “Cover post-RP for 1) pT2 with positive margins; 2) any pT3 disease; 3) rising PSA (above nadir).”
- Prolaris: “Cover post-biopsy for NCCN very-low and low-risk prostate cancer at diagnosis with at least 10 years life expectancy.”
- Oncotype DX: “Cover post-biopsy for NCCN very-low and low-risk prostate cancer at diagnosis with at least 10-20 years life expectancy.”
- ProMark: Not reviewed.
- Decipher Literature Review:
- There is currently limited evidence in the peer-reviewed literature to support the widespread use of the Decipher tests to accurately provide prognostic risk stratification among patients with prostate cancer who have undergone RP in routine clinical practice. The relatively large evidence base, published primarily by the test manufacturer, consists of retrospective case-control and retrospective cohort studies evaluating the strength of the association between the Decipher score and incidence of disease recurrence (e.g., biochemical recurrence, metastasis) or PC-associated mortality. Hazard and odds ratios from univariate and multivariate logistic regression analyses show significant associations between the test and clinical endpoint. Also, study results indicate that Decipher consistently discriminates between men at 5-year risk of metastatic disease progression after RP and men without disease progression with reasonable AUC and c-index estimates. Several studies reported reclassification rates using the Decipher test, indicating that patient risk could be stratified differently based on Decipher results. These types of reclassification calculations are useful since the clinical usefulness of a prognostic test has been reported to be reliant on its ability to categorize patients into different and more accurate prognostic groups, providing accurate predictions about their future disease state, and ultimately guiding optimal treatment regimens. However, these various estimates may be subject to bias and confounders given the several limitations that weaken the quality of the individual studies, including publication bias; patient overlap; insufficient follow-up periods and small number of metastatic event cases; bias associated with retrospective analyses; lack of observer or investigator blinding; missing or flawed registry data; Decipher sampling issues; and considerable heterogeneity between cases and controls for various demographic, disease risk factors, and treatment regimens. Most importantly, it is not clear how results of the Decipher test will impact patient disease management and treatment strategies, and if any changes will translate into improved morbidity and mortality for high-risk PC patients. Ongoing prospective clinical trials indicate that clinical utility studies of Decipher for PC patients are forthcoming in 2017. Results of new peer-reviewed studies of clinical utility will potentially provide higher quality evidence to better inform clinicians regarding patient selection criteria and appropriate use of the Decipher test among high-risk PC patients who are weighing the risk and benefits of various treatment options.
- Ongoing clinical trials:
- Three ongoing clinical trials, identified on ClinicalTrials.gov are currently undergoing patient recruitment or have completed recruitment and are ongoing.
- Observational prospective cohort study (NCT02723734): A Validation Study on the Impact of Decipher® Testing on Treatment Recommendations in African-American and Non-African American Men with Prostate Cancer (VANDAAM Study).
- Observational patient registry study (NCT02609269): Decipher Genomics Resource Information Database (GRID).
- Prospective cohort study sponsored by GenomeDx (estimated completion date, March 2017) to study the influence of the Decipher test on urologist and patient treatment plan choices immediately after RP, and at the time of PSA risk or BCR (NCT02080689): Prospective Clinical Utility Study to Assess the Impact of Decipher on Treatment Decisions
After Surgery (PRO-IMPACT).
- Prolaris Literature Review:
- Although clinical studies suggest that Prolaris may have potential prognostic value following RP in patients with prostate cancer, a number of limitations characterizing the evidence base weaken the strength of these findings. The available studies focused on primarily evaluating associations between results of Prolaris and the incidence of disease recurrence or mortality, which represents a preliminary stage of development of prognostic tests. The most appropriate clinical decisions to be made based on Prolaris test results have not been clearly established since there are no published studies that have reported the ability of the Prolaris test to prospectively predict patient-relevant health outcomes by virtue of prognostic risk assessment or changes made to treatment recommendations. The evidence base may possibly be subject to publication bias. With one exception, the reviewed studies with consistently positive or favorable results were sponsored or funded by the test manufacturer. The single study not funded by the manufacturer reported that 20 of 52 patients were misclassified by the Prolaris test, indicating that use of the test may be misleading in some cases.
- In some cases, study follow-up was very short, and may was not sufficiently long enough to capture metastatic event data. In addition, the total number of identified cases in each study was relatively small, which limited the power of the analysis to properly assess diagnostic accuracy. Other flaws in study design that weaken the overall quality of the evidence base include the retrospective design aspect; the lack of investigator or observer blinding; presence of missing or flawed data in registry studies; sampling and specimen processing issues; and the presence of heterogeneity between cases and controls in terms of high risk PC features, and risk factors for metastasis. All of these introduce the possibility of bias and confounding, which weaken the overall confidence in the estimate of prognostic accuracy of the Prolaris test.
- Ongoing clinical trials:
- Two ongoing clinical trials, identified on ClinicalTrials.gov are currently undergoing patient recruitment or have completed recruitment and are ongoing.
- Behavioral Registry Study to Measure the Impact of Adding Genomic Testing (NCT02454595): Outcome measures: the impact of genomic test results towards selecting a first-line therapy option for newly diagnosed, localized, prostate cancer patients (recruiting).
- Open Registry Measuring Impact of Genomic Testing on Treatment Decision after Biopsy in Newly Diagnosed Prostate Cancer Patients (NCT02209584). Outcome measures: Percentage change from the recorded PRE-Prolaris® test treatment option versus the ACTUAL treatment option of genomic risk assessment testing (Prolaris®); Percentage change from the recorded PRE-Prolaris® test treatment option versus the POST-Prolaris® test treatment plan (prior to patient consultation) (active, not recruiting).
- OncotypeDX Prostate Literature Review:
- Oncotype DX may be useful to assist RP patients in deciding whether or not they should receive early adjuvant therapy after RP, and may be useful to assist AS patients in predicting the probability of adverse pathology that would help guide the need for subsequent intervention or AS. Oncotype DX was found to predict adverse prostate cancer pathology beyond currently used clinical parameters and nomograms in patients with very low, low-, and intermediate risk disease. Despite these preliminary clinical studies suggesting the potential benefit of Oncotype DX, additional well-designed studies are still needed to adequately determine if the test can allow for clinicians to offer active surveillance safely, thereby minimizing the risk of underestimating the risk of metastasis or local tumor spread. In addition, clinical utility studies in real-world urologic clinical practice are needed to evaluate if treatment practices change with test use, and if these changes result in improved patient-important outcomes.
- Ongoing clinical trials:
- One ongoing clinical trial, identified on ClinicalTrials.gov is currently undergoing patient recruitment.
- Engaging Newly Diagnosed Men About Cancer Treatment Options (NCT02668276): Outcome measures: effect of adding Oncotype DX prostate cancer assay to usual counseling (standard NCCN counseling using recommendations based on currently accepted treatment approaches for cancer) on the proportion of men adopting active surveillance. Time frame: 3 to 6 months after making a treatment decision (recruiting).
- ProMark Literature Review:
- One clinical validity study suggests that the ProMark risk score offers additional prognostic information for patients compared with NCCN risk categories alone. However, the current evidence base consists of one clinical validity study and one analytical validity study, both published by the manufacturer. Additional clinical studies are needed to showcase consistency of ProMark test results to accurately predict disease severity following RP. Use of the test in clinical practice will shed light on whether test information is considered sufficient by the medical community to change treatment decision-making and if such changes result in improvement in patient-relevant outcomes, including morbidity and survival.
|Place of Service: Inpatient/Outpatient|
Experimental/Investigational (E/I) services are not covered regardless of place of service.
Gene expression profiling tests for prostate cancer are typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.
|The policy position applies to all commercial lines of business|
Services that do not meet the criteria of this policy will be considered experimental/investigational (E/I). A network provider can bill the member for the experimental/investigational service. The provider must give advance written notice informing the member that the service has been deemed E/I. The member must be provided with an estimate of the cost and the member must agree in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.
Medical policies do not constitute medical advice, nor are they intended to govern the practice of medicine. They are intended to reflect Highmark's reimbursement and coverage guidelines. Coverage for services may vary for individual members, based on the terms of the benefit contract.
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