Prostate Cancer

WHAT MEN OVER 40 SHOULD KNOW

Robert Nam, winner of the George Armstrong-Peters Prize

Recently a large randomized trial demonstrated a significant 20% reduction in prostate cancer mortality among patients who underwent prostate cancer screening with a blood test called prostate specific antigen (PSA) (1). This finding coupled with another randomized trial demonstrating men undergoing radical prostatectomy versus watchful waiting had a 50% reduction in prostate cancer mortality would seem to suggest the pathway for success in prostate cancer is clear: screen aggressively with PSA and treat aggressively with surgery (2). However, as Dr. Nam points out, the solution may not be that clear.

PSA is not an ideal biomarker for screening. Initially after its inception in 1987 it was very effective. The 'cutoff ' of normal PSA at 4 ng/mL identified many of the men who were harbouring prostate cancer for years. However, since that harvest period, we've learned that prostate cancer is still prevalent even at low PSA values. The majority of cancers detected in 2009 occur in men with PSAs below 4.0 ng/mL.

Simply lowering the cutpoint for a normal PSA would certainly capture more prostate cancers, however it would mean many more men would undergo prostate biopsy in order to find these cancers. In his study of Ontario-wide data, Dr. Nam found the rate of complications after prostate biopsy is increasing, perhaps due to the increasing prevalence of drug-resistant bacterial strains. In 2006, 4% of men undergoing a prostate biopsy were subsequently admitted to hospital with sepsis, compared to 1% in 1996.

Given this screening conundrum, Dr. Nam suggests the medical community needs more refined 'selective screening' and prostate cancer genetic markers may help. He has worked extensively in developing a better screening instrument that incorporates PSA and other risk factors and tumour markers for prostate cancer. He developed a prostate cancer risk calculator that performs better than PSA alone. There have been several gene markers that have been associated with prostate cancer. A recent study demonstrated 5 single-nucleotide polymorphisms (SNPs) were strongly associated with prostate cancer (3). A man possessing all 5 SNPs has 9 times the risk of being diagnosed with prostate cancer compared to those without any of the 5 SNPs. In breast cancer our understanding of these genes is profound enough to make clinical decisions (e.g. offering prophylactic mastectomy for carriers of the BRCA-1 mutation); our understanding of genes in prostate cancer is not mature enough yet. For example, we don't know the biological function of the actual genes in which these SNPs reside; the predictive value of using the SNPs is not that much greater than our current conventional risk factors (age, family history, rectal exam and PSA); and the SNPs do not help delineate those harbouring high grade aggressive tumours.

The ability to distinguish those with high grade tumours versus those with low grade tumours is the key issue in prostate cancer. Those with high grade tumours are much more likely to die from prostate cancer. Dr. Nam has taken the concept of using genetic markers one step further. Using state of the art Genome Wide Associations Studies (GWAS) he identified several new SNPs associated in particular with high grade tumours. These SNPs at 10q26 and 15q21 are significantly associated with aggressive forms of prostate cancer.

Prostate Cancer Screening 2009

Combinations of these risk alleles were found to have a 3-fold increase in risk for aggressive prostate cancer. This is the first time SNPs have been found to be predictive of high grade prostate cancer. In a related research pathway, Dr. Nam is studying what happens when two genes, TMPRSS2 and ERG, fuse in a variable way. Variants in the TMPRSS2:ERG fusion transcript have been associated with prostate cancer, and in particular progression of cancer after surgical treatment. If TMPRSS2:ERG is identified in circulating tumour cells of men who present for screening, then they are at substantially increased risk of having an aggressive form of prostate cancer.

In summary, Dr. Nam feels we must work towards more selective screening and selective treatment to better identify men who will benefit from prostate biopsy and radical treatment of their cancer. This selective screening must begin with educating the primary care physicians to identify men at risk. Then an individual risk assessment must be done using traditional risk factors and eventually incorporating susceptibility genetic markers like the SNPs and circulating tumour cell profiles to maximize the yield of men undergoing prostate biopsy in hopes of identifying early those with high risk prostate cancer.

Robert Hamilton
PGY-5, Urology

1. Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 2009;360(13):1320-8.
2. Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352(19):1977-84.
3. Zheng SL, Sun J, Wiklund F, et al. Cumulative association of five genetic variants with prostate cancer. N Engl J Med 2008;358(9):910-9.