AUA 2013 - Session Highlights: Molecular markers for risk, diagnosis, and prognosis in prostate cancer

SAN DIEGO, CA USA (UroToday.com) - In the wake of last year’s USPSTF PSA-screening statement and the results of the PIVOT (Prostate Cancer Intervention Versus Observation Trial) trial, there has been a reduction in the number of men undergoing prostate needle biopsy (PNBx) and treatment. Recent studies estimate that 10-15% fewer men are getting PSA testing by primary care physicians, there has been a 25-30% reduction in PNBx, and there has been a 15-20% reduction in RP. In a panel discussion moderated by Dr. Edward Messing, MD, Professor of Urology at the University of Rochester Medical Center, experts addressed the role of molecular markers in prostate cancer diagnosis, staging, and management.

auaMolecular markers have the potential to predict men at risk for prostate cancer (especially aggressive prostate cancer), improve performance of screening over PSA alone, predict men on AS who will progress, and, preferentially, identify men with higher-risk disease who may benefit from more aggressive management.

Dr. Alan Partin (Johns Hopkins) reviewed the current state of prostate cancer molecular biomarkers, including the prostate health index (PHI), PCA3, TMPRSS2-ERG, and single nucleotide polymorphisms (SNPs). PHI can be calculated from pro-, free-, and total PSA measurements ((proPSA/free PSA)x √PSA). Higher PHI values are associated with an increased risk of PCa, and relative risk increases linearly with increases in PHI. By increasing specificity, the use of PHI may reduce unnecessary biopsies by 27%.

PCA3 is a prostate-specific noncoding RNA that is over expressed in PCa. A reverse transcriptase PCR assay is utilized to quantitate the ratio of PCA3/PSA mRNA collected from a urine specimen. For patients undergoing an initial prostate biopsy, a high PCA3 score (> 60) has a PPV of cancer detection of 80%. When used in patients with an initial negative prostate needle biopsy (PNBx) who require repeat biopsy due to persistent clinical risk, a low PCA3 score (< 20) has a NPV of 88% and may be used to spare more men from unnecessary repeat PNBx.

The TMPRSS2-ERG gene fusion is an androgen-regulated transcription factor on chromosome 21 that is a key prostate cancer oncogene. A linear increase in the predictive ability of prostate biopsy is seen in the presence of the gene fusion. Combining gene fusion analysis and PCA3 scoring can help predict men at highest risk for cancer detection prior to PNBx.

Finally, single nucleotide polymorphisms, or SNPs, represent substitution of a single nucleotide in the DNA strand. SNPs can alter protein function, gene expression, or have no effect at all. Several PCa SNPs have been identified as potential biomarkers on chromosomes 8 and 17. As the number of SNPs accrued increases, the probability of PCa increases as well. If ≥ 5 SNPs are identified, patients have an approximately 9-fold increased risk of PCa. In a genome-wide analysis of over 300 000 SNPs in 23 000 Finnish men and 15 000 American men, the absence of SNPs was associated with a 5% risk of PCa, whereas the presence of 8 SNPs was associated with an 80% risk of PCa. At present over 50 SNPs have been identified in prostate cancer. Although there is no FDA-approved SNP assay at this time, both PHI and PCA3 have obtained FDA approval.

Dr. Daniel Lin (UW-Seattle) commented that biomarkers might also be used in men on active surveillance to prompt treatment. There are currently no validated biomarkers for men on AS, but there are a number of excited candidate markers. Prolaris-31 is a gene-cell cycle-progression signature which may have a role in improved stratification of disease risk. Oncotype DX is a 17-gene genomic prostate score that can predict adverse pathology at the time of prostatectomy. Finally, Decipher is a 22-gene multi-pathway signature that can predict the development of metastatic disease after RP.

Presented by Edward M. Messing, MD, Daniel W. Lin, MD, Alan W. Partin, MD, and Theo H. Van der Kwast, MD at the American Urological Association (AUA) Annual Meeting - May 4 - 8, 2013 - San Diego Convention Center - San Diego, California USA

 

Reported for UroToday.com by Zhamshid Okhunov, MD, University of California, Irvine, Department of Urology

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