Special Report: Recent Developments in Prostate Cancer Genetics and Genetic Testing
EXECUTIVE SUMMARY
Background. Prostate cancer is the most common malignancy and second-leading cause of cancer death among males in the U.S. In 2007, there were approximately 218,000 new cases of prostate cancer and 27,000 deaths, with a man's lifetime risk of prostate cancer being 1 in 6. Prostate cancer is a heterogeneous disease with some cancers remaining asymptomatic and others behaving in an aggressive, often fatal, manner. A better understanding is needed of the biologic and genetic differences between these indolent and aggressive forms, as well as of the risk factors for development. Recent advances in the sequencing of the human genome and high-throughput analysis techniques have led to the identification of many potential biomarkers of prostate disease and risk assessment that are currently under investigation. Although proteomic profiling is also an emerging research field, it is not currently as far advanced as gene expression profiling and there have been issues of reproducibility; therefore, this report focuses on nucleic-acid-based markers.
Objective. This Special Report is intended to be a horizon-scanning catalog of nucleic-acid-based tests related to prostate cancer risk, detection, or prognosis that are currently available or are likely to be available in the near future. It does not address the question as to whether the TEC criteria are met.
Search Strategy. Gray literature for the period 2007 through September 2008 was routinely scanned for articles related to genetic testing and prostate cancer. MEDLINE® (via PubMed) was searched over the last 2 years for articles on genetic biomarkers and prostate cancer.
Selection Criteria. News articles from the gray literature were organized into specific topic groups.
Titles and abstracts of recent (2006–2008) journal publications were searched for studies of nucleic acid-based biomarkers investigated in clinical populations for use in prostate cancer risk assessment, diagnosis, or prognosis. Special attention was paid to the topic groups determined by the gray literature search. Topics not already identified by the gray literature search with a concentration of publications were also determined from the literature searches. Information on these additional topics was sought via Internet searches (e.g. for evidence of commercialization). Finally, full-length papers were requested for potentially relevant citations for each of the topic areas.
Discussion. Prostate cancer is a complex, heterogeneous disease. At the extremes of the spectrum, if left untreated, some prostate cancers behave aggressively, metastasize quickly, and cause mortality, while others are indolent and never progress to cause harm. While it would be desirable to screen for aggressive prostate cancer that is likely to cause morbidity and mortality, currently available biomarkers are incompletely sensitive, have poor specificity, and do not distinguish aggressive disease from indolent disease that need only be monitored. It is also not currently possible to predict in advance who is likely to develop aggressive disease. For those given curative treatment (e.g., prostatectomy for clinically localized disease), no biomarkers are available that accurately predict the risk of recurrence.
In response to the need for better biomarkers for risk assessment, diagnosis, and prognosis, a variety of exploratory research is ongoing. Some products of this work have already or are in the process of being translated into commercially available tests. This Special Report examines the state of the evidence for some of these tests. In general, the evidence addresses clinical validity i.e., the association of the test result with outcomes of interest, expressed in terms of clinical performance characteristics such as sensitivity, specificity, predictive value, and comparisons to current standards using receiver-operating curve (ROC) analysis and/or logistic regression. There is no evidence of clinical utility, i.e., that using a test will improve outcomes. Evidence was reviewed for the following tests:
Single-nucleotide polymorphisms (SNPs) for risk assessment. Several large population studies have identified SNPs that are repeatably highly significant predictors of prostate cancer risk, although the genes and biologic mechanisms behind these associations are as yet unknown. Several SNPs combined explain a significant proportion of prostate cancer, but by no means all. A few different groups are commercializing specific SNP panels, combined in one case with family history, as risk assessment tools presumably to identify those men who should start disease surveillance early and be monitored frequently. However, these tests do not predict certainty of disease, nor do they clearly predict aggressive versus indolent disease. While the monitoring of high-risk men may improve outcomes, it is also possible that these could be offset by the harms of identifying and treating additional indolent disease. Recent evidence regarding the safety of prevention with finasteride has not yet been incorporated into guidelines for cancer prevention in high-risk or general risk populations.
PCA3 for disease and diagnosis. PCA3 is overexpressed in prostate cancer and PCA3 mRNA can be detected in urine samples collected after prostate massage. When normalized using PSA to account for the amount of prostate cells released into the urine ("PCA3 Score") the test has significantly improved specificity compared to PSA and may better discriminate patients with eventual benign biopsies from those with malignant biopsy results.
One study suggests that PCA3 Score may also have value in identifying patients with less aggressive cancer who may only need surveillance. In general, however, PCA3 assay results to date are preliminary; interpretation of results has not been standardized and clinical utility studies of decision-making for initial biopsy, repeat biopsy or treatment have not been reported.
TMPRSS fusion genes for diagnosis and prognosis. TMPRSS2 is an androgen-regulated transmembrane serine protease that is preferentially expressed in normal prostate tissue. In prostate cancer, it may be fused to an ETS family transcription factor (ERG, ETV1, or ETV4), which modulates transcription of target genes involved in cell growth, transformation, and apoptosis. The result of gene fusion with an ETS transcription gene is that the androgen-responsive promoter of TMPRSS2 positively dysregulates expression of the ETS gene, suggesting a mechanism for neoplastic transformation. Fusion genes may be detected in tissue or urine. Evidence suggests that assays for fusion genes may offer specific disease detection, and that fusion genes are associated with a greater likelihood of biochemical recurrence. However, accurate fusion gene detection is complex, assays have not been standardized, and once they are, larger studies will be needed to determine clinical utility.
Candidate gene panels for prostate cancer diagnosis. Because no single gene markers have been found that are both highly sensitive and highly specific for diagnosing prostate cancer, particularly in men already known to have elevated PSA levels, some investigators are combining several promising markers into a single diagnostic panel. While promising in concept, only very limited evidence is available for these applications.
Gene hypermethylation for diagnosis and prognosis. Epigenetic changes, chromatin protein modifications that do not involve changes to the underlying DNA sequence but which can result in changes in gene expression, have been identified in specific genes in relation to prostate cancer. A review of recently published studies reveals an area of clinical research that has not yet identified the best markers for diagnosis and prognosis, nor the best way to measure them and in which sample type. Standardized assays and interpretation criteria have not yet been agreed upon to enable consistency and comparison of results across studies.
While these studies generate much useful information that may help elucidate the biologic mechanisms of prostate cancer and eventually help design treatments, the reviewed assays are in a developmental phase, currently without evidence of clinical utility.
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NOTICE OF PURPOSE: TEC Assessments are scientific opinions, provided solely for informational purposes. TEC Assessments should not be construed to suggest that the Blue Cross Blue Shield Association, Kaiser Permanente Medical Care Program or the TEC Program recommends, advocates, requires, encourages, or discourages any particular treatment, procedure, or service; any particular course of treatment, procedure, or service; or the payment or non-payment of the technology or technologies evaluated.
