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Technology Evaluation
Center (TEC)

Gene Expression Analysis for Prostate Cancer Management

Executive Summary


Prostate cancer is the second most common cancer diagnosed among men in the U.S. According to the National Cancer Institute, nearly 240,000 new cases are expected to be diagnosed in the U.S. in 2013, and associated with around 30,000 deaths. Localized prostate cancers may appear clinically very similar at diagnosis. 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 prostate-specific antigen (PSA) titers, Gleason grade, or tumor stage. This creates uncertainty whether or not to treat immediately. A patient may choose definitive treatment comprising radiotherapy, surgery, chemotherapy, or androgen deprivation. Alternatively, the patient may forgo immediate therapy and continue regular monitoring until signs or symptoms of disease progression are evident, at which point curative treatment is instituted. This approach is referred to as “active surveillance.”

Given the unpredictable behavior of early prostate cancer, additional prognostic tests are under investigation. These include gene expression profiling using RTPCR-based technology. Gene expression profiling refers to analysis of mRNA expression levels of many genes simultaneously in a tumor specimen.

Two gene expression profiling tests are now offered, intended to biologically stratify prostate cancers: Prolaris® (Myriad Genetics, Salt Lake City, UT) and Oncotype Dx® Prostate Cancer Assay (Genomic Health, Redwood City, CA). Both use archived tumor specimens as the mRNA source, reverse transcriptase polymerase chain reaction amplification, and a low density RTPCR array platform. 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 (median 1.03, interquartile range 0.41–1.74) and GPS (range 0–100) are combined in proprietary algorithms with clinical risk criteria (PSA, Gleason grade, tumor stage) to generate new risk categories (i.e., reclassification) intended to reflect biological indolence or aggressiveness of individual lesions, and thus inform management decisions.


The purpose of this Assessment is to examine the evidence available on Prolaris® (Myriad Genetics, Salt Lake City, UT) and Oncotype Dx® Prostate (Genomic Health, Redwood City, CA). The main question addressed is: What is the incremental value of gene expression tests for discriminating men with aggressive and indolent disease to guide treatment decisions that improve net health outcomes? The evidence assessment was organized around the analytic validity, clinical validity, and clinical utility of each test.

Search Strategy

We searched the National Library of Medicine MEDLINE® database (via PubMed) with no date restrictions through June 25, 2013, to identify published literature on the use of Prolaris® and Oncotype Dx® Prostate, as follows:

“Prostatic Neoplasms” [MeSH] OR ((prostate OR prostatic) AND (cancer OR cancers OR carcinoma* OR neoplasms)) AND “pathology” [Subheading] OR pathology OR biopsy OR biopsies OR tissue AND “Prognosis”[MeSH] OR prognosis OR prognostic OR indolent OR aggressive OR stratification AND (genomic* OR genome OR genomes) AND (Prostate OR Prostatic) in the title AND Filters: Humans; English

The search included primary studies, review articles, systematic reviews, and editorials published in English. We consulted the websites for the 2 tests under consideration for further background and clinical information, as well as the U.S. Food and Drug Administration (FDA) website for regulatory information. Test developers were also contacted to identify publications either not identified in the search or in press.

Selection Criteria

The primary study selection criterion was to include any peer-reviewed, full-length publication that reported evidence related to the analytic validity, clinical validity, or clinical utility of either test, using human prostate tumor specimens obtained by needle biopsy according to the Patient Indications and Specific Assessment Question presented below. Review articles, systematic reviews, and other materials were sources of information for the Background, Discussion, and Future Research Needs sections.

Main Results

Analytic Validity

We did not find specific information on the analytic validity of Prolaris® or Oncotype Dx® Prostate in the peer-reviewed literature, through an Internet search for grey literature, or on the developers’ websites. The FDA website does not contain specific information on either test. The performance of gene expression analysis platforms, including the TaqMan platform (Applied Biosystems, Foster City, CA) used in Prolaris, has been addressed in the MicroArray Quality Control (MAQC) project. In the MAQC project, expression data were gathered for 4 titration pools from 2 distinct reference RNA samples generated at multiple test sites on 7 microarray-based and 3 alternative technology platforms. They found very similar performance across array platforms, with a median coefficient of variation of 5% to15% for the quantitative signal and 80% to 95% concordance for the qualitative detection call between sample replicates. Thus, although we have no direct evidence on the analytic validity of either test in analysis of prostate cancer specimens, the MAQC project results on the TaqMan arrays may be a reasonable surrogate for test performance.

Clinical Validity


One retrospective validation study on Prolaris® is based on patients (n=349) culled from 6 cancer registries in Great Britain. The study was designed to examine the clinical validity of the test showing association between a CCP gene expression score combined with clinical risk factors (PSA, Gleason score), and risk of prostate cancer death at 10 years postdiagnosis. The test was performed using microdissected tissue prepared from archived tumor specimens obtained through needle biopsy. A primary univariate analysis suggests that a 1-unit increase in CCP score was associated with a 2-fold increase in the hazard ratio for death from prostate cancer (hazard ratio=2.02, 95% confidence interval: 1.62 to 2.53, p

We examined 3 other studies of the Prolaris® CCP gene expression test. Two used archived pathological specimens obtained from patients who underwent radical prostatectomy or transurethral resection of the prostate. The role of CCP analysis in those studies was to prognosticate for biochemical recurrence or prostate-specific mortality following treatment or watchful waiting, respectively. A third study reported results of CCP analysis as adjunct to clinical criteria to predict biochemical recurrence in men who underwent external-beam radiotherapy. The patients and management approaches in these studies do not represent the population of interest or address the primary question asked in this Assessment.

Oncotype Dx® Prostate

We did not identify any full-length peer-reviewed publications on the Oncotype Dx® Prostate test in our electronic literature search; nor did we locate any studies via an Internet search and search of the FDA website. The developer’s website contains information on a validation study to evaluate this test in needle biopsy specimens in a cohort of men in the United States. This study was presented at the 2013 annual meeting of the American Urological Association, but slides are not available (see abstract 2131 at It evaluated the test in men who could be considered for active surveillance, and who would be representative of patients in contemporary practice. They report that a combination of the GPS from the test and clinical findings (i.e., PSA level, Gleason score) identified patients in specific risk categories and allowed reclassification between groupings as shown in Table A. 


However, the number of patients correctly or incorrectly reclassified between all 3 categories cannot be ascertained. Clinical Utility We did not identify any published evidence on the clinical utility of the Prolaris® or Oncotype Dx® Prostate test.

Author’s Conclusions and Comment

Two RTPCR-based gene expression analysis tests—Prolaris® and Oncotype Dx® Prostate—are commercialized. The test results are intended to be used in combination with accepted clinical criteria (Gleason score, 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.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel (MAP) made the following judgments about whether gene expression analysis meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria to guide management of patients with newly diagnosed prostate cancer.

1. The technology must have final approval from the appropriate governmental regulatory bodies.

Neither Prolaris® nor Oncotype Dx® Prostate Cancer Assay is cleared for marketing by the U.S. Food and Drug Administration (FDA). Each is available under auspices of the Clinical Laboratory Improvement Act (CLIA). Clinical laboratories may develop and validate tests in-house (laboratory- developed tests [LDTs]; previously called “home-brew”) and market them as a laboratory service; LDTs must meet the general regulatory standards of the CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. Although FDA has technical authority to regulate LDTs, to date there has been no active oversight, with the exception of a more recently described category, “in vitro diagnostic multivariate index assay” (IVDMIA) devices. Neither gene expression profile test in this Assessment has been publicly classified by FDA as an IVDMIA.

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

The analytic validity has not been rigorously shown for either test under consideration here; it 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

We identified no peer-reviewed, published evidence on the clinical validity of Oncotype Dx® Prostate. No evidence is available on the clinical utility of either test for any clinical end point.

3. The technology must improve the net health outcome.

Evidence is insufficient to determine whether Prolaris® or Oncotype Dx® Prostate testing affects the net health outcome.

4. The technology must be as beneficial as any established alternatives.

Evidence is insufficient to determine the incremental value of either Prolaris® or Oncotype Dx® Prostate gene expression test compared with clinical criteria for discriminating men with aggressive and indolent disease to guide treatment decisions that improve the net health outcome.

5. The improvement must be attainable outside the investigational settings.

Evidence is insufficient to determine whether Prolaris® or Oncotype Dx® Prostate testing improves health outcomes in the investigational setting.

Based on the above, neither the Prolaris® nor Oncotype Dx® Prostate gene expression test meets the TEC criteria.

Full Study


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genome; prognosis; prognostic; biomarker; predictive; active surveillance; AUA; American Urological Association; biopsy; prostatectomy; Gleason; scoring; archived; proliferation genes;