In 2011, the U.S Preventative Services Task Force published recommendations against the use of prostate-specific antigen (PSA)-based screening for prostate cancer(1). The contemporary USPSTF recommendations are based on five randomized controlled trials and two meta-analyses that found little or no reduction in prostate cancer mortality in 11-20 years of screening.
These trials found that early detection in the preclinical phase of prostate cancer does not guarantee better outcomes, especially since most men will die with their cancer rather than from it. There are also significant harms of screening and subsequent work-up. Models predict that 23-42% of screen-detected cancers are overdiagnosed, meaning they would not have caused symptoms or death had they remained undetected(2). Hematuria, infection, and hospitalization are appreciable risks of biopsy, and treating cancers that may never have resulted in death can cause unnecessary long-term incontinence and impotence. As well, the psychological impact of a cancer diagnosis should not be underestimated.
Screen-detected cancers must have better prognoses than clinically apparent cancers for screening to be useful. Biennial breast mammography is recommended in women aged 50-74 since meta-analyses have demonstrated it reduces disease specific mortality by 14% in the 50-59 age group (RR, 0.86 [95% CI; 0.75-0.96]), and by 32% in the 60-69 group (RR, 0.68 [95% CI; 0.54-0.87]), with little associated cost(3). PSA-based screening has not demonstrated a survival benefit, possibly because of the test’s low sensitivity (21% with a cut-off of 4ng/ml) and the highly curable nature of the disease(4). However, there are some prostate cancers that progress more quickly and have worse outcomes, so early detection from screening may improve survival if these subpopulations can be identified.
Research is beginning to indicate that BRCA mutation carriers may benefit from PSA-based screening. BRCA1 and BRCA2 mutation carriers are more likely to have worse clinical and pathological features than non-carriers (including higher rates of Gleason scores above 7, T3/4 stage, nodal involvement, and metastases at diagnosis) as well as poorer cause-specific survival outcomes(5). Prostate cancers in BRCA mutation carriers also occur at a younger age, which leaves more time for progression(5). The results of our study of screening characteristics in BRCA mutation carriers corroborate these findings(6). Preliminary results from a study investigating the role of targeted screening in BRCA mutation carriers have found that a prostate biopsy following a positive screen is more likely to detect intermediate- and high-risk cancer in BRCA2 carriers than in controls (PPV of 2.38% compared with 0.71% for controls, p=0.04)(7). It is important that targeted screening detects higher rates of intermediate- and high-risk disease and does not simply detect more low-risk cancers, since low-risk cancers are unlikely to benefit from early detection. While these preliminary data are based on numbers that are still too small to reach statistical significance for many of the study’s outcome measures, the authors hypothesize that differences between carriers and controls will reach significance towards the end of the study.
The purpose of screening is to reduce disease specific mortality, not to detect disease. While some trials demonstrate minor effects of screening versus non-screening on prostate cancer mortality, the majority have found no effect. However, some populations who may benefit from early detection should be considered for targeted screening. Unfortunately, many years of follow-up are needed to assess the value of screening approaches; it took nearly 20 years for PSA-based screening to be sufficiently evaluated. The role of targeted PSA-based screening for BRCA mutation carriers is not yet clear, but the idea is showing promise.
1. Lin K, Croswell JM, Koenig H, Lam C, Maltz A. Prostate-Specific Antigen-Based Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 [cited 2015 Apr 30]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK82303/
2. Draisma G, Etzioni R, Tsodikov A, Mariotto A, Wever E, Gulati R, et al. Lead time and overdiagnosis in prostate-specific antigen screening: importance of methods and context. J Natl Cancer Inst. 2009 Mar 18;101(6):374–83.
3. Nelson HD, Tyne K, Naik A, Bougatsos C, Chan B, Nygren P, et al. Screening for Breast Cancer: Systematic Evidence Review Update for the US Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009 [cited 2015 Apr 30]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK36392/
4. Wolf AMD, Wender RC, Etzioni RB, Thompson IM, D’Amico AV, Volk RJ, et al. American Cancer Society Guideline for the Early Detection of Prostate Cancer: Update 2010. CA Cancer J Clin. 2010 Mar 1;60(2):70–98.
5. Castro E, Goh C, Olmos D, Saunders E, Leongamornlert D, Tymrakiewicz M, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2013 May 10;31(14):1748–57.
6. Walker R, Louis A, Berlin A, Horsburgh S, Bristow RG, Trachtenberg J. Prostate cancer screening characteristics in men with BRCA1/2 mutations attending a high-risk prevention clinic. Can Urol Assoc J J Assoc Urol Can. 2014 Nov;8(11-12):E783–8.
7. Bancroft EK, Page EC, Castro E, Lilja H, Vickers A, Sjoberg D, et al. Targeted Prostate Cancer Screening in BRCA1 and BRCA2 Mutation Carriers: Results from the Initial Screening Round of the IMPACT Study. Eur Urol. 2014 Sep;66(3):489–99.
Richard Walker, Alyssa Louis, John Trachtenberg
Department of Surgical Oncology, University Health Network, Toronto, ON.