Medical Policy: 02.04.57
Original Effective Date: June 2016
Reviewed: May 2017
Revised: May 2017
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in American men. In 2017, it is estimated that 161,360 men will be diagnosed with prostate cancer and 26,730 will die of this disease. Gene expression profile analysifs 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 regarding active surveillance versus therapeutic intervention, or after radical prostatectomy (RP) to guide radiotherapy use.
Prolaris® (Myriad Genetics, Salt Lake City, UT) and Oncoytpe DX® Prostate Cancer Assay (Genomic Health, Redwood City, CA) are gene expression profiling tests each intended to be used in combination with accepted clinical criteria (Gleason score, prostate-specific antigen (PSA), clinical stage) to stratify needle biopsy-diagnosed localized prostate cancer according to biological aggressiveness, and direct initial patient management.
Decipher® (GenomeDx Biosciences, Vancouver, BC) 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 patient 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 developing metastasis.
ProMark™ is an automated quantitative imaging method to measure 8 protein biomarkers (DERL1, PDSS2, pS6, YBX1, HSPA9, FUS, SMAD4, and CUL2) using immunofluorescence and automated quantitative images in intact biopsy tissue to risk stratify patients to active surveillance or therapeutic intervention. The assay results are combined using predefined coefficients for each marker from a logistic regression model to calculate a risk score and the risk score is continuous number between 0 and 1 which stratify the patient into a favorable or less favorable risk score.
Localized prostate cancers may appear very similar clinically at diagnosis. However, they often exhibit diverse risk of progression that may not be captured by clinical risk categories or prognostic tools that are based on clinical findings, including PSA titers, Gleason grade, or tumor stage. 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% to 20% to perhaps 27% at 20-year follow up. Among elderly men (ages > 70 years) with low risk disease, comorbidities typically supervene as a cause of death; these men will die with prostate cancer present, rather than from the cancer itself. Other very similar appearing low risk tumors may progress unexpectedly rapidly, quickly disseminating and becoming incurable.
In men newly diagnosed with clinically localized prostate cancer, the purpose of gene expression profiling and protein biomarkers tests is to inform decisions whether to undergo immediate therapy versus forego immediate therapy and begin active surveillance.
The divergent behavior of localized prostate cancers creates uncertainty whether or not to treat immediately. A patient may choose potentially curative treatment upfront. Surgery including radical prostatectomy (RP) or external beam radiotherapy (EBRT) are most commonly used to treat patients with localized prostate cancer.
The American Urological Association (AUA) guideline suggests patients with low risk localized prostate cancer and select patients with favorable intermediate-risk localized prostate cancer have the option of “active surveillance”, which is determined through a shared decision making process considering cancer severity (risk category), patient values and preferences, life expectancy, pre-treatment general functional and genitourinary symptoms, expected post treatment functional status, and potential for salvage treatment. With this approach the patient will forgo immediate therapy and continue regular monitoring until signs and symptoms of disease progression are evident, at which point curative treatment is instituted. Given the unpredictable behavior of early prostate cancer additional prognostic methods to biologically stratify this disease are being investigated to include if gene expression profiling and protein biomarkers compared with clinicopathologic risk stratification or when used with clinicopathologic risk stratification, there is improved outcomes in newly diagnosed men with clinically localized prostate cancer.
Clinicopathologic risk stratification is currently being used to make decisions about prostate cancer management. Clinical characteristics (e.g. stage, biopsy Gleason grade, serum PSA) and demographic characteristics (e.g. age, life expectancy) are combined to classify men according to risk. National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) provide treatment recommendations based on risk stratification. Prospective active surveillance cohorts now comprise >10,000 patients, thousands of whom have been followed for >10 years. Clinical parameters (e.g. PSA, PSA density, extent of disease on biopsy, race, T-stage) allow for stratification for risk of co-existent higher grade disease. Monitoring low risk patients on surveillance is associated with low risk of prostate cancer specific mortality. Therefore, the benefit to most patients of a biomarker to further stratify patients according to the risk of progression is modest. Per the American Urological Association (AUA)/American Society of Radiation Oncology (ASTRO) and Society Urologic Oncology (SUO) 2017 guideline for clinically localized prostate cancer states, “that tissue based genomic biomarkers have not shown a clear role in active surveillance for localized prostate cancer and are not necessary for follow up (Expert Opinion).”
Initial Management Decision: Active Surveillance and Therapeutic Intervention
For individuals who have clinically localized prostate cancer who receive Prolaris, the evidence includes 1 study of analytic validity and retrospective cohort studies of clinical validity using archived samples and a decision curve analysis. No direct evidence is available to support the clinical utility of Prolaris for improving net outcomes of patients with localized prostate cancer to include when following radical prostatectomy. The indirect chain of evidence is also incomplete. Decision-curve analysis did not provide convincing evidence of meaningful improvement in net benefit in biochemical recurrence (BCR) by incorporating the cell cycle progression (CCP) score. Prolaris CCP score may have an association with BCR but disease-specific survival outcomes were not reported. A larger number of disease-specific survival events and precision estimates for discrimination measures are needed. There is insufficient evidence in the peer reviewed medical literature demonstrating Prolaris testing has a role in clinical decision making or has a beneficial effect on net health outcomes. Further studies are needed to determine the clinical utility for Prolaris gene expression profiling in the management of prostate cancer. The evidence is insufficient to determine the effects of this testing on net health outcomes and therefore, is considered investigational.
In November 2015, the Food and Drug Administration’s (FDA) office of Public Health Strategy and Analysis published a document on public health evidence for FDA oversight of LDTs. FDA argued that many tests need more FDA oversight then the regulatory requirements of CLIA. CLIA standards related 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 meaningfully improve clinical outcomes.
For individuals who have clinically localized prostate cancer who receive Oncotype DX Prostate, the evidence includes 2 studies of analytic validity, case-cohort and retrospective cohort studies of clinical validity using archived samples, and a decision curve analysis examining indirect evidence of clinical utility. The evidence on clinical validity for Oncotype DX Prostate has suggested the genomic prostate score (GPS) can reclassify a patient’s risk of recurrence based on a biopsy specimen. However, whether these findings support a conclusion that the GPS could predict the biological aggressiveness of a tumor or disease-specific survival, based solely on the level of pathology in a biopsy specimen is unclear. Generalizing the evidence to a true active surveillance population for which most in the study would be eligible is difficult because all of the patients had elective radical prostatectomy. Therefore, the findings do not reflect a clinical scenario of predicting risk of 10-year distant recurrence in untreated patients under active surveillance. Also, there is no direct evidence of clinical utility found for Oncotype DX Prostate in active surveillance because all patients regardless of clinical criteria elected radical prostatectomy within 6 months of diagnostic biopsy. Further studies are needed to determine the clinical utility of Oncotype DX Prostate gene expression profiling in the management of prostate cancer. There is insufficient evidence in the peer reviewed medical literature demonstrating that Oncotype DX Prostate has a clinical role in decision making or a has a beneficial effect on net health outcomes and therefore, is considered investigational.
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 of clinical validity using archived samples, and no published studies on clinical utility were identified. There is insufficient evidence in the peer reviewed medical literature demonstrating that ProMark protein biomarker testing has a role in clinical decision making or has a beneficial effect on net health outcomes. Further studies are needed to determine the clinical utility of this test. The evidence is insufficient to determine the effects of this testing on net health outcomes and therefore, is considered investigational.
Management Decision After Radical Prostatectomy
The purpose of gene expression profiling and protein biomarkers tests in patients who have prostate cancer and who have undergone radical prostatectomy is to inform management decisions. For example, the optimal timing of radiation therapy after radical prostatectomy is a debate. Adjuvant radiation therapy may maximize cancer control outcomes; however, salvage radiation therapy can maximize overtreatment and still lead to acceptable oncologic outcomes. Several analyses have shown conflicting conclusions whether adjuvant radiation therapy is favored over salvage radiation therapy (salvage radiation therapy it is typically initiated at a post-radical prostatectomy PSA level of 0.3 to 0.6 ng/mL). Clinicopathologic risk stratification is currently being used to make decisions about prostate cancer management following radical prostatectomy. Clinical characteristics (e.g. stage, biopsy Gleason grade, serum PSA, surgical margin, disease involvement) and demographic characteristics (e.g. age, life expectancy) are combined to classify men according to risk. As described previously National Comprehensive Cancer Network (NCCN) and American Urological Association (AUA) provide risk-stratification guidelines. Per the American Urological Association (AUA)/American Society of Radiation Oncology (ASTRO) and Society Urologic Oncology (SUO) 2017 guideline for clinically localized prostate cancer states, “for post-treatment follow-up, clinicians should monitor localized prostate cancer patients post therapy with PSA, even though not all PSA recurrences are associated with metastatic disease and prostate cancer specific death.” This guideline does not indicate the use of gene expression profiling or protein biomarker testing in regards to management decisions following radical prostatectomy.
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 of clinical validity using archived samples, decision curve analyses examining indirect evidence of clinical utility, and prospective decision impact studies without pathology or clinical outcomes. 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, results did not consistently demonstrate meaningful improvement in reclassification, most importantly to higher risk categories. The performance over clinicopathologic predictors did not appear consistent and meaningfully improved. Further studies are needed to determine clinical utility. There is insufficient evidence in the peer reviewed medical literature demonstrating that Decipher prostate cancer classifier has a role in clinical decision making or has a beneficial effect on health outcomes, and therefore, is considered investigational.
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 provided accurate and reproducible prognostic or predictive information beyond NCCN risk group assignment and currently available life expectancy tables and namograms. Retrospective case cohort studies have shown that these assays provide prognostic information independent of NCCN risk groups, which include likelihood of biochemical recurrence after radical management, likelihood of biochemical recurrence after radical prostatectomy or radiotherapy, and likelihood of developing metastasis after operation of salvage radiotherapy. No randomized controlled trials have studied the utility of these tests.
Although full assessment of their clinical utility requires prospective randomized clinical trials, which are unlikely to be done, the panel believes that men with clinically localized disease may consider the use of tumor-based molecular assays at this time. Future comparative effectiveness research may allow these tests and others like them to gain additional evidence regarding their utility for better risk stratification of men with prostate cancer.
Table 1. Lists these tests in alphabetical order and provides an overview of each test, population where each test independently predicts outcomes, and supporting references (See NCCN guideline for detailed information). Available Tissue Based Tests for Prostate Care Prognosis – includes the following:
In 2007, the American Urological Association issued the guideline for management of clinically localized prostate cancer which included the following:
The Panel has identified a number of opportunities for investment in research, clinical trials, and reporting of results that would provide the foundation for useful updates of this evidence-based guideline:
Determining which prostate cancers require therapy:
In 2017, American Urological Association (AUA)/American Society of Radiation Oncology (ASTRO) and Society Urologic Oncology (SUO) issued a guideline for clinically localized prostate cancer, which states the following:
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 Cancer Assay 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 has chosen not to require any regulatory review of this test.
Not applicable
See Related Medical Policies
Use of gene expression analysis and protein biomarker to guide management of prostate cancer is considered investigational in all situations. This includes but is not limited to the following:
Gene Expression Analysis
Protein Biomarker test
Based on review of the peer reviewed medical literature there is insufficient evidence demonstrating that these tests have a role in clinical decision making or have a beneficial effect on net health outcomes. Further studies are needed to determine the clinical utility of these tests. Therefore, the use of gene expression analysis and protein biomarkers to guide management of prostate cancer is considered investigational in all situations.
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