The availability of prognostic molecular tests for localized prostate cancer opens a range of possibilities, and at the same time is confusing for providers and patients. What are the differences among these tests? Are these new tests clinically useful? Will they change management beyond existing guidelines? Should they be ordered routinely or under specific circumstances?
Currently, these questions cannot be answered, and although all but one of the multigene tests have been validated retrospectively, prospective studies are needed to establish the role of multigene testing. Additionally, head-to-head comparisons of available molecular tests are warranted but probably will not be performed because of competing marketing forces, explained Ashley E. Ross, MD, PhD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
Dr. Ross, Assistant Professor of Urology, Oncology, and Pathology, reviewed the evidence supporting the validity of currently available molecular prognostic tests for localized prostate cancer. He noted that the field is moving toward developing predictive (vs prognostic) tests indicating whether a patient will respond to a particular therapy, and he said that predictive tests will undoubtedly be more clinically useful.
“Last year, NCCN incorporated molecular testing into the NCCN Guidelines for Prostate Cancer for the first time. This was not a hard recommendation, and the wording said to ‘consider’ available tests under certain circumstances,” Dr. Ross explained. The NCCN Guidelines recommendation states: “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.”
“Localized prostate cancer is characterized by extraordinary genomic complexity, with various copy number alterations—including deletions and amplifications—chromosomal rearrangements, and, to a lesser extent, point mutations,” Dr. Ross said. “The hope is that molecular tests can aid in treatment selection and in deciding which patients need treatment intensification.” Available molecular tests for localized prostate cancer are summarized in Table 1.
Cell cycle abnormalities are common in localized prostate cancer, and Prolaris (Myriad Genetics, Inc., Salt Lake City, UT) and immunohistochemistry from Ki-67 are specific to the cell cycle, whereas PTEN, ProMark (Metamark Genetics, Inc., Cambridge, MA), Decipher (GenomeDx Biosciences, San Diego, CA), and Oncotype DX (Genomic Health, Inc., Redwood City, CA) tests are based on molecular features of prostate cancer. PTEN and Ki-67 assays cost approximately $100 each and are not commercially marketed. ProMark, Decipher, Prolaris, and Oncotype DX tests cost approximately $3,000 to $4,000 per test.
PTEN loss is an early and important event in prostate cancer, and it can be detected in 15% to 40% of primary cancers and in approximately 50% of metastatic cancers. “Loss of PTEN is correlated with stage and grade [of prostate cancer],” he said. “Loss of PTEN puts low-risk disease into a high-risk category, whereas in high-risk disease, loss of PTEN does not have much significance.” Ki-67, assayed by immunohistochemistry, has independent prognostic significance, Dr. Ross noted, but is not readily quantitative and may not robustly capture the proliferative status of cells.
Prolaris, a quantitative polymerase chain reaction (PCR) test based on 31 cell cycle genes normalized to 15 housekeeping genes, has use in all risk categories of prostate cancer and provides “added prognostic information,” Dr. Ross said. In one study, an increased Prolaris cell cycle proliferation (CCP) score correlated with an increase in prostate cancer biochemical recurrence after radical prostatectomy and prostate cancer death in patients managed with watchful waiting.1 These findings were validated in a second study in which an increased CCP score resulted in decreased survival after radical prostatectomy in patients at low, intermediate, and high risk.2
Two studies validated Prolaris in needle biopsy cohorts after radical prostatectomy3 and after radiation.4 After prostatectomy, an increased CCP score predicted biochemical recurrence and increased the risk of metastasis (hazard ratio [HR], 1.5 and 4.2, respectively) per unit increase in score on multivariate analysis. Further, in a group of men conservatively managed undergoing needle biopsy in the Prostate Cancer Transatlantic Consortium, the HR for death per unit of CCP increase was approximately 2.5 Therefore, Cuzick et al5 suggested that the CCP score can identify men who can be managed conservatively.
Cuzick J, Swanson GP, Fisher G et al.. Prognostic value of an FRNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer. Lancet Oncol 2011:12:21–19.
Cooperberg MR, Simko JP, Cowan JE et al.. Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol 2013;31:1428–1434.
Bishoff JT, Freedland SJ, Gerber L et al.. Prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy. J Urol 2014;192:409–414.
Freedland SJ, Gerber L, Reid J et al.. Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation. Int J Radiat Oncol Biol Phys 2013;86:848–853.
Cuzick J, Stone S, Fisher G et al.. Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer 2015;113:382–389.
Brand TC, Zhang N, Crager MR et al.. Patient-specific meta-analysis of 2 clinical validation studies to predict pathologic outcomes in prostate cancer using the 17-gene Genomic Prostate Score. Urology 2016;89:69–75.
Blume-Jensen P, Berman DM, Rimm DL et al.. Development and clinical validation of an in situ biopsy-based multimarker assay for risk stratification in prostate cancer. Clin Cancer Res 2015;21:2591–2600.
Karnes RJ, Bergstrath EJ, Davicioni E et al.. Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol 2013;190:2047–2053.
Ross AE, Johnson MH, Yousefi K et al.. Tissue-based genomics augments post-prostatectomy risk stratification in a natural history cohort of intermediate- and high-risk men. Eur Urol 2016;69:157–165.
Klein EA, Yousefi K, Haddad Z et al.. A genomic classifier improves prediction of metastatic disease within 5 years after surgery in node-negative high-risk prostate cancer patients managed by radical prostatectomy without adjuvant therapy. Eur Urol 2015;67:778–786.
Cooperberg MR, Davicioni E, Crisan A et al.. Combined value of validated clinical and genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prostatectomy cohort. Eur Urol 2015;67:326–333.
Freedland SJ, Choeurng V, Howard L et al.. Utilization of a genomic classifier for prediction of metastasis following salvage radiation therapy after radical prostatectomy [published online ahead of print January 21, 2016]. Eur Urol, doi: 10.1016.j.eururo.2016.01.008.
Alam R, Carter HB, Landis P et al.. Conditional probability of reclassification in an active surveillance program of prostate cancer. J Urol 2015;193:1950–1955.