References for this Review were identified through searches of PubMed. Publication date or language restrictions were not applied. Search terms “prostate cancer”, “risk factors”, “screening”, “early detection”, and “prevention” were used. Articles identified through searches of the authors' own files were used. The reference list is based on originality and relevance to the broad scope of this Review. Additional references are listed in the appendix.
ReviewPrevention and early detection of prostate cancer
Introduction
Prostate cancer is a common malignancy in men, and its incidence continues to rise in many countries.1 Screening for, and management of, early prostate cancer is one of the most challenging and controversial issues in medicine. In this Review, we discuss the evidence regarding risk assessment, early detection, and management of early prostate cancer, and identify the key issues for further research (figure). Improved identification of risk factors to guide risk-adapted screening and preventive interventions is important. This Review also focuses on potentially modifiable lifestyle factors, and preventive therapies that might reduce risk. Prostate-specific antigen (PSA) screening for prostate cancer is controversial, and results from the CAP/ProtecT trial,2 which is investigating PSA screening and three different methods for treating early screen-detected lesions, are eagerly anticipated. Work is in progress to assess new tests that might be offered either as part of primary screening, or for the triage of men with high PSA concentrations, and we discuss these tests in detail. Management strategies for low-grade cancers and for men with high PSA concentrations but negative biopsies are discussed. We assess new tests based on serum markers or tissue from needle biopsies and the role of multiparametric MRI, and outline the need for improved diagnostic methods. We conclude with a research agenda of areas most in need of further development and investigation.
Section snippets
Risk factors and biomarkers
Risk factors can be divided into non-modifiable factors (including known genetic mutations or polymorphisms, or specific genes not yet identified), and external factors (including lifestyle factors when modification might be possible). Blood-based markers, such as androgen levels or IGF-1, are not well established but are affected by both genetic and environmental factors.
Age, race, and geography
Age is the most important non-modifiable factor. In unscreened populations, prostate cancer has the
PSA screening
The value of PSA screening is contentious. Five screening trials have been completed, but three are not of adequate quality to be informative;33 the other two are of higher methodological quality. These two large trials, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)34 and the European Randomized Study on Screening for Prostate Cancer (ERSPC),35 have reported different results36 possibly because of differences in design.
The PLCO trial was done in the USA, where PSA
Management of men with raised PSA concentrations
An important issue is how best to manage men with raised PSA concentrations who have had negative biopsies. Study findings60, 61 show a high incidence of prostate cancer during follow-up after negative biopsy. The Göteborg sub-cohort of the ERSPC trial showed a 26% incidence within 4 years,61 whereas 10% of such men in the PLCO trial developed prostate cancer within 3 years of negative biopsy.60 The placebo group of the Prostate Cancer Prevention Trial (PCPT) had high positive rates (15%
Management of low-grade prostate cancer
An equally important issue is the management of men with low-grade (eg, Gleason score 6) cancer. Gleason 6 is poorly defined, and its natural history and the appropriate active surveillance protocols need to be refined and clinically validated.
Role of 5α-reductase inhibitors
The use of 5α-reductase inhibitors either for prevention or management of early disease has produced complex outcomes. The PCPT64 investigated finasteride in men with low PSA (≤3 mg/mL) and no evidence of disease. Biopsies were recommended at the end of the study or if digital rectal examination was abnormal and PSA exceeded 4·0 ng/mL in the control group or 2·0 ng/mL (1·75 ng/mL after first 4 years) to allow for the reduction of PSA level with this drug. After 7 years of follow-up, a 24·8%
Research and policy agenda
Research should focus on developing better biomarkers for identification of aggressive disease. Urinary markers such as PCA3 and TMPRSS2–ERG are the most developed, but still require further validation. Multiparametric MRI has potential to identify the highest grades of lesion and guide biopsies to be taken from the most aggressive regions, especially in men with high PSA concentrations, but further studies are needed. Once a biopsy sample has been taken, expression profile panels such as the
Conclusions
Evidence for several of the modifiable prostate cancer risk factors is uncertain. However, lifestyle modifications such as smoking cessation and exercise can decrease the risk of developing prostate cancer. Although associated with an increased number of high-grade prostate cancers, 5α-reductase inhibitors reduce overall prostate cancer burden. In the absence of any detrimental effect on survival, these agents can be cost effective for the prevention of prostate cancer. Several other
Search strategy and selection criteria
References (85)
- et al.
International variation in prostate cancer incidence and mortality rates
Eur Urol
(2012) - et al.
A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk
Eur Urol
(2014) - et al.
Androgenetic alopecia and risk of prostate cancer: a systematic review and meta-analysis
J Am Acad Dermatol
(2013) - et al.
Effect of physical activity and sedentary behavior on serum prostate-specific antigen concentrations: results from the National Health and Nutrition Examination Survey (NHANES), 2003-2006
Mayo Clin Proc
(2013) - et al.
Does physical activity reduce the risk of prostate cancer? A systematic review and meta-analysis
Eur Urol
(2011) - et al.
Low testosterone and risk of biochemical recurrence and poorly differentiated prostate cancer at radical prostatectomy
Urology
(2008) - et al.
A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range
J Urol
(2011) - et al.
Toward the detection of prostate cancer in urine: a critical analysis
J Urol
(2013) - et al.
Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer
Eur Urol
(2014) - et al.
Increased gene copy number of ERG on chromosome 21 but not TMPRSS2-ERG fusion predicts outcome in prostatic adenocarcinomas
Mod Pathol
(2011)