At least 12 different genetic tests for prostate cancer are under development. The two tests currently available are Oncotype DX (Genomic Health, Redwood City, California) and Prolaris (Myriad Genetic Laboratories, Salt Lake City). Both tests can identify which low-risk patients are “truly” at low risk and can be managed by active surveillance and which ones should seek immediate treatment.

Genomic Prostate Score

The Oncotype DX prostate cancer assay can determine whether men with newly diagnosed low-risk prostate cancer (ie, Gleason score of 6) are appropriate candidates for watchful waiting or harbor more aggressive disease sugesting the need for primary treatment with surgery or radiotherapy.

Recently launched by Genomic Health Inc, the Oncotype DX prostate cancer assay is similar (in the sense that it assays gene expression) to the Oncotype DX breast cancer assay used to determine whether women with node-negative early breast cancer should be treated with chemotherapy and whether women with ductal carcinoma in situ should receive radiation.

Oncotype DX for prostate cancer is a biopsy-based assay of the levels of expression of 17 genes that can predict the aggressiveness of prostate cancer. A genomic prostate score ranging from 0 to 100 is derived from the prostate specimen to determine the level of risk.

 “The [genomic prostate score] helps assign men with newly diagnosed low-risk prostate cancer to active treatment or not. It also might be appropriate for a subset of intermediate-risk men with low-volume disease who might be assigned to active surveillance,” said H. Jeffrey Lawrence, MD, Senior Director of Medical Affairs at Genomic Health, at ASCO.

Dr. Lawrence and colleagues found that the 17-gene expression patterns that predict prostate cancer aggressiveness are similar in tumor and normal prostate tissue.¹ The genomic prostate score derived from tumor-based gene expression patterns in the tumor was also associated with clinical tumor recurrence when assessed in adjacent normal prostate tissue, but the strength of the association was less robust than in tumor. The genes associated with the strongest predictive value of the genomic prostate score in normal tissue were those representing stromal response and androgen signaling.

“These results suggest the presence of an underlying field effect within the tumor-containing prostate gland that is associated with the development and presence of aggressive prostate cancer,” Dr. Lawrence stated.

Validation Study

The clinical validation study of the Oncotype DX prostate cancer assay was presented at the 2013 meeting of the American Urological Association in San Diego.² The test, developed jointly by investigators at UCSF and the Cleveland Clinic, significantly predicted the aggressiveness of disease (P = .002) beyond clinical factors (including prostate-specific antigen [PSA] level and Gleason Score obtained at biopsy.

“Use of the test tripled the number of patients who were good candidates for active surveillance and identified a smaller number of patients who despite low-risk status had more aggressive disease and were candidates for immediate treatment,” stated principal investigator Peter R. Carroll, MD, MPH, Professor and Chair of the Department of Urology at the University of California (UCSF), San Francisco in a news release from Genomic Health.

The percentage of patients identified as having very low risk disease went from 5% to 10% based on PSA level and Gleason score to 26% when the genomic prostate score was factored into the assessment. These patients could be confident about active surveillance. However, about 10% of patients originally classified as low or very low risk by clinical factors were identified as having more aggressive disease when the genomic prostate score was added to PSA level and Gleason score, and these patients should be considered for immediate treatment.

Dr. Carroll stated that the use of the genomic prostate score may significantly increase the use of active surveillance. “In the past, use of active surveillance has been limited to some extent by the absence of a validated genomic tool to more accurately distinguish between low- and high-risk diseases at the time of biopsy,” he added.

The test is estimated to cost about $3,800. Genomic Health is in the process of building a dossier of evidence for insurers. “We are familiar with this type of dossier from experience with Oncotype DX for breast cancer, which is now reimbursed by Medicare and 90% of other insurers. We are optimistic that the same will be true for the prostate cancer assay,” said Eric A. Klein, MD, Cleveland Clinic, lead author of the study on the Oncotype DX prostate cancer test presented at the Annual Meeting.

Prolaris: Retrospective Studies

Like Oncotype DX, Prolaris can identify which patients are “truly” at low risk and can be managed by active surveillance, potentially reducing overtreatment of prostate cancer. Prolaris is also being marketed as a test for the postprostatectomy patient with high-risk features after surgery; it is intended to estimate the risk of tumor recurrence and to guide the adjustment of therapy accordingly.

A retrospective review of studies of the Prolaris test found that the cell-­cycle progression score (CCP) was able to predict prostate cancer outcomes in multiple patient cohorts and in diverse clinical settings.³

“The [cell-cycle progression score] provides independent information above and beyond traditional PSA levels and Gleason scores. Right now, it is useful in low-risk patients to determine who needs therapy and who should be assigned to active surveillance,” stated Jack Cuzick, PhD, Director of
Cancer Research at the UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, London, who presented the study at the ASCO Annual Meeting.

He reviewed results of five retrospective studies to show the usefulness of the cell-cycle progression score. The score is calculated by measuring the average RNA expression of 31 cell-cycle progression genes normalized by the average expression of 15 housekeeping genes as quantitated by reverse transcriptase–polymerase chain reaction. “We use so many genes, because if one fails, we still have enough information for prognostic value,” he said.

Key Findings

A 1-unit change in cell-cycle progression score score represents a doubling of the expression of the 31 genes. The five studies included patients undergoing transurethral resection of the prostate, needle biopsy with conservative management, radical prostatectomy (two studies), and external-beam radiation therapy. The first two studies reported prostate cancer death, and the last three studies used biochemical tumor recurrence as an endpoint. The median follow-up was over 10 years.

A similar distribution of cell-cycle progression scores was found in all five studies. “This shows that the distribution is largely independent of the circumstances in which the test is used,” he said.

The cell-cycle progression score emerged as a significant predictor in both univariate and multivariate analyses. Dr. Cuzick added, “The predictive value of the [cell-cycle progression score] almost wiped out the predictive value of the Gleason score.” He also said, however, that the endpoints of the study are different, and this gives an indication of broad applicability, but they can’t strictly be combined. ■

Disclosure: Dr. Lawrence is an employee of Genomic Health. Dr. Klein receives a consulting fee from Genomic Health but does not own stock in the company and has no other financial interest in Oncotype Dx or Genomic Health. Dr. Cuzick receives honoraria and research funding from Myriad Genetics. Dr. Carroll reported no potential conflicts of interest.

References

1. Klein EA, Falzarano SM, Zhang N, et al: Evidence for a field effect in early prostate cancer: gene expression profiles in normal-appearing prostate tissue adjacent to tumor are predictors of clinical outcome. 2013 ASCO Annual Meeting. Abstract 5029. Presented June 1, 2013.

2. Cooperberg M, Simko J, Falzarano S, et al: Development and validation of the biopsy-based prostate score (GPS) as a predictor of high-grade or extracapsular to improve patient selection for active surveillance. American Urological Association Annual Meeting. Abstract 2131. Presented May 8, 2013.

3. Brawer MK, Cuzick J, Cooperberg MR, et al: Prolaris: A novel genetic test for prostate cancer prognosis. 2013 ASCO Annual Meeting. Abstract 5005. Presented June 2, 2013.