Prostate news article, November 2009

SCREENING FOR PROSTATE CANCER: THE WAY AHEAD   Article by:   Professor Roger Kirby, Chairman, Prostate UK

Prostate cancer already claims more than 10,000 lives per annum in the British Isles and many more than that internationally. Men dying from advanced disease often suffer intractable bone pain and debilitating lower urinary tract symptoms and consequently suffer significant quality of life impairment. In the absence of a breakthrough in the treatment of metastatic disease, earlier diagnosis and effective eradication of clinically significant disease currently seem to afford the best opportunity of stemming the tide.

Recently, prostate specific antigen (PSA) population screening has been evaluated in two major randomised, controlled studies. The European Randomised Study of Prostate Cancer Screening (ERSPC) reported a 20% reduction in the risk of prostate cancer death with screening¹. By contrast, the US based Prostate, Lung Colorectal and Ovarian (PLCO) screening study showed no significant difference in prostate cancer mortality between the two groups². The latter study was however flawed by the inclusion of almost 50% of individuals in the control “unscreened” group who had in fact been tested for PSA values outside the study – a reflection of the pre-existing high level of public awareness of prostate cancer screening by PSA in the USA.

Another difference between the ERSPC and the PLCO studies was the PSA cut-point selected for further investigation, usually biopsy. While the PLCO study selected a 4.0 ng/ml value, the ERSPC selected a 3.0 ng/ml value, although some study sites ordered additional diagnostic tests for men with a PSA value of 2.5 – 3.9 ng/ml. Very recently, Holmstrom et al³ have reported a case-control study assessing the utility of PSA in predicting a subsequent prostate cancer diagnosis by record linking to the regional cancer registry. They matched 540 cases and 1034 controls from the Northern Swedish Health and Disease Cohort by age and date of blood sampling. The positive likelihood ratios were 4.5, 5.5 and 6.4 for PSA cut-off values of 3ng/ml, 4 ng/ml and 5 ng/ml respectively. None of these likelihood ratios provides strong evidence to rule in the disease in the event of a positive test. This is a reflection of the high prevalence of benign prostatic hyperplasia (BPH) as a cause of a mildly elevated PSA. The results echo previous findings indicating that a cut-off value of 4ng/ml increases the specificity of the test but reduces the sensitivity. Lowering the cut-off value to 3 ng/ml increases the sensitivity but reduces its specificity⁴.

In clinical practice the lack of a clear cut-off value that differentiates men who do have prostate cancer from those who do not is clearly problematic. Lowering the cut-off value to 3 ng/ml would undoubtedly diagnose more cancers at an earlier, potentially curable phase, but would also expose more men to unnecessary (ie false positive) biopsies, the side-effects of which are sometimes not trivial.

The above-mentioned limitations of the PSA test as a screening tool has driven research into other potential biomarkers for screening for prostate cancer⁵. The PCA3 test, which is based on the analysis of a urine sample taken immediately after prostatic massage, looks promising in terms of sensitivity and specificity, and may also preferentially identify less well-differentiated, higher risk cancers, rather than those which are clinically insignificant⁶. More clinical trials are required to increase the evidence-base surrounding this marker however before its widespread introduction.

The very recent identification of 27 genetic variants (Fig 1) that predispose towards prostate cancer offer another, more targetted, opportunity to reduce the death toll of this increasingly prevalent disease^7-10. Linkage studies in multiple case families have shown linkage to some regions, but searches for definitive genetic mutations arising from candidate gene screening in such regions have yielded conflicting results. Several research groups are now using candidate gene screening for rare variants and genome-wide association approaches to identify common variants. From the former of these types of studies, rare but high/moderate risk variants have been found in genes in the DNA repair pathway. A recent genome wide association study in DNA samples from prostate cancer cases and controls from the UK and Australia found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk and confirmed previous reports of SNPs associated with prostate cancer risk on chromosomes 8 and 17. A worldwide consortium of 21 groups (PRACTICAL) has been created to follow up results from genome-wide association studies. Blood DNA from 7370 prostate cancer cases and 5742 control men were analysed using genotyping assays. Odds ratios associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs from the initial UK study showed clear evidence of association with prostate cancer (p=.0007 – p=10-17). For each of these 6 SNPs the estimated per allele odds ratio was similar to those previously reported and ranged from 1.12 to 1.25. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported (per allele OR 1.08 (95%CI 1.00-1.16), p=.06 versus 1.18 (1.06-1.31)). The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1 fold increased risk relative to general population rates. A further paper⁷ has found a further 7 SNPs which has raised the percentage of the familial risk explained to 21%. The top 1% of the population risk distribution as a result has a 3.4-fold increased risk of prostate cancer compared with the average of the whole population. These discoveries raise the possibility of the identification of a sub-group of men who are especially susceptible to prostate cancer, in the same way that women who harbour certain genetic mutations are particularly prone to breast cancer. These men could in theory be carefully scrutinised for evidence of prostate cancer along the lines of the recently published PSA Best Practice Statement¹¹ by PCA3 testing and template prostate biopsies taken via the trans-perineal route to reduce the risk of serious infection. A new trial has just started at The Institute of Cancer Research and Royal Marsden in which men with a family history of prostate cancer are offered primary biopsy and will be retrospectively SNP profiled to try to determine if in retrospect such genetic profiling would have been helpful to target screening and increased its positive predictive value.

We are currently a long way away from eliminating the scourge of prostate cancer in men of middle age and beyond, but recent clinical and genetic advances do offer the prospect of urologists and other clinicians being able to identify those susceptible men whose natural life-span is likely to be curtailed by the disease, while not over-treating individuals with non-life threatening cancers. Moreover, recent advances in treatment modalities for localised disease, such as robotically-assisted laparoscopic radical prostatectomy (RALP), now offer improved chances of cure with less morbidity, quicker recovery and possibly lower risks of collateral damage in the form of persistent stress incontinence and erectile dysfunction¹².

References:
1. Schroder F, Hugosson J, Roobol M, et al. Screening and prostate cancer mortality in a randomised European study. N Engl J Med 2009; 360:1320-8.
2. Andriole G, Crawford E, Grubb R et al. Mortality results from a randomised prostate-cancer screening trial. N Engl J Med 2009;360:1310-9.
3. Holmstrom B, Johansson M, Bergh A et al. Prostate specific antigen for early detection of prostate cancer: longitudinal study BMJ 2009:339-b3537.
4. Thompson I, Ankerst D, Chi C et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.9 ng/ml or lower JAMA 2005;294:66-70.
5. Lin D, Beyond PSA: utility of novel tumour markers in the setting of elevated PSA Urol Oncol 2009; 27:315-21.
6. Kirby RS, Fitzpatrick JM, Irani J. Prostate cancer diagnosis in the new millennium: strengths and weaknesses of prostate-specific antigen and the discovery and clinical evaluation of prostate cancer gene 3 (PCA3). BJU Int. 2009;103:441-5.
7. Eeles RA, Kote-Jarai Z, Al Olama AA Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet. 2009;41:1116-21.
8. Al Olama AA, Kote-Jarai Z, Giles GG et al. Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat Genet. 2009; 41:1058-60.
9. Gudmundsson J, Sulem P, Gudbjartsson DF et al. Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nature Genet. 2009; 41:1122-6.
10. Yeager M, Chatterjee N, Ciampa et al Identification of a new prostate cancer susceptibility fous on chromosome 8q24. Nature Genet. 2009; 41:1055-7.
11. Greene KL, Albertsen PC, Babaian RJ et al. Prostate Antigen Best Practice Statement, J Urol 2009;182:2232-41.
12. Dasgupta P, Kirby RS. The current status of robot-assisted radical prostatectomy. Asian J Androl. 2009;11:90-3