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Genetics of Prostate Cancer (PDQ®)

Health Professional Version
Last Modified: 08/18/2014

Interventions in Familial Prostate Cancer

Background
Screening
        Screening in BRCA mutation carriers
Chemoprevention of prostate cancer with finasteride and dutasteride in men at high risk
Summary



Background

Decisions about risk-reducing interventions for patients with an inherited predisposition to prostate cancer, as with any disease, are best guided by randomized controlled clinical trials and knowledge of the underlying natural history of the process. However, existing studies of screening for prostate cancer in high-risk men (men with a positive family history of prostate cancer and African American men) are predominantly based on retrospective case series or retrospective cohort analyses. Because awareness of a positive family history can lead to more frequent work-ups for cancer and result in apparently earlier prostate cancer detection, assessments of disease progression rates and survival after diagnosis are subject to selection, lead time, and length biases. (Refer to the PDQ Cancer Screening Overview summary for more information.) This section focuses on screening and risk reduction of prostate cancer among men predisposed to the disease; data relevant to screening in high-risk men are primarily extracted from studies performed in the general population.

Screening

Information is limited about the efficacy of commonly available screening tests such as the digital rectal exam (DRE) and serum prostate-specific antigen (PSA) in men genetically predisposed to developing prostate cancer. Furthermore, comparing the results of studies that have examined the efficacy of screening for prostate cancer is difficult because studies vary with regard to the cut-off values chosen for an elevated PSA test. For a given sensitivity and specificity of a screening test, the positive predictive value (PPV) increases as the underlying prevalence of disease rises. Therefore, it is theoretically possible that the PPV and diagnostic yield will be higher for the DRE and for PSA in men with a genetic predisposition than in average-risk populations.[1,2]

Most retrospective analyses of prostate cancer screening cohorts have reported PPV for PSA, with or without DRE, among high-risk men in the range of 23% to 75%.[2-6] Screening strategies (frequency of PSA measurements or inclusion of DRE) and PSA cutoff for biopsy varied among these studies, which may have influenced this range of PPV. Cancer detection rates among high-risk men have been reported to be in the range of 4.75% to 22%.[2,5,6] Most cancers detected were of intermediate Gleason score (5–7), with Gleason scores of 8 or higher being detected in some high-risk men. Overall, there is limited information about the net benefits and harms of screening men at higher risk of prostate cancer. In addition, there is little evidence to support specific screening approaches in prostate cancer families at high risk. Risks and benefits of routine screening in the general population are discussed in the PDQ Prostate Cancer Screening summary. On the basis of the available data, most professional societies and organizations recommend that high-risk men engage in shared decision-making with their health care providers and develop individualized plans for prostate cancer screening based on their risk factors. A summary of prostate cancer screening recommendations for high-risk men by professional organizations is shown in Table 12.

Table 12. Summary of Prostate Cancer Screening Recommendations for High-Risk Men
Screening Recommendation Source Population Test Age Screening Initiated Frequency Comments 
United States Preventive Services Task Force (2012) [7]No specific recommendation for high-risk populations (defined as black men and men with a prostate cancer family history).
American College of Physicians (2013) [8]African American men and men with first-degree relative diagnosed with prostate cancer, especially <65 yPSA≥45 yNo clear evidence to establish screening frequencyCounseling includes information about the uncertainties, risks, and potential benefits associated with prostate cancer screening.
No clear evidence to perform PSA test more frequently than every 4 y
Men with family history of multiple family members with prostate cancer diagnosed <65 yPSA≥40 y
PSA level >2.5 µg/L may warrant annual screening
American Urological Association (2013) [9]African American men and men with a strong prostate cancer family historyPSA>40 to <55 yIndividualized based on personal preferences and informed discussion regarding the uncertainty of benefit and associated harms.
American Cancer Society (2014) [10]African American men and/or men with a father or brother with prostate cancer diagnosed <65 yPSA with or without DREa≥45 yFrequency depends on PSA levelCounseling consists of a review of the benefits and limitations of testing so that a clinician-assisted, informed decision about testing can be made.
Men with multiple family members with prostate cancer diagnosed <65 yPSA with or without DREa≥40 yFrequency depends on PSA level
NCCN (2014) [11]African American men and men with family history of prostate cancerPSA with or without DREbBaseline age 45–49 yEvery 1–2 y if DRE within normal limits AND PSA level >1 ng/mLCounseling includes:
Repeat testing at age 50 y if DRE within normal limits AND PSA level ≤1 ng/mL– Screening purpose is to detect aggressive prostate cancer.
50–70 yEvery 1–2 y if DRE within normal limits AND PSA level <3 ng/mL– Screening usually identifies low risk cancers that can be managed through close surveillance.
>70 ycEvery 1–2 y if DRE within normal limits AND PSA level <3 ng/mL
NCCN (2014) [11,12]Men with BRCA1 deleterious mutationPSA with or without DREbConsider screening starting at age ≥40 yEvery 1–2 y
Men with BRCA2 deleterious mutationPSA with or without DREb≥40 yEvery 1–2 y

DRE = digital rectal exam; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen.
aDRE is recommended in addition to PSA test for men with hypogonadism.
bDRE not performed as a stand-alone screening exam. Performed in men with an elevated PSA and as a baseline exam in men with PSA levels within normal limits.
cScreening performed with caution and limited to men in good health with little or no comorbidities.

Level of evidence: 5

Screening in BRCA mutation carriers

An international study that focused on prostate cancer screening in BRCA1/2 mutation carriers versus noncarriers reported initial screening results.[13] The study recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 noncarriers; 731 BRCA2 carriers, 428 BRCA2 noncarriers). A total of 199 men (8%) presented with PSA levels higher than 3.0 ng/mL, which was the study PSA cutoff for recommending a biopsy. The overall cancer detection rate was 36.4% (59 prostate cancers diagnosed among 162 biopsies). Prostate cancer by BRCA mutation status was as follows: BRCA1 carriers (n = 18), BRCA1 noncarriers (n = 10); BRCA2 carriers (n = 24), BRCA2 noncarriers (n = 7). Using published stage and grade criteria for risk classification,[14] intermediate- or high-risk tumors were diagnosed in 11 of 18 BRCA1 carriers (61%), 8 of 10 BRCA1 noncarriers (80%), 17 of 24 BRCA2 carriers (71%), and 3 of 7 BRCA2 noncarriers (43%). The PPV of PSA with a biopsy threshold of 3.0 ng/mL was 48% in BRCA2 mutation carriers, 33.3% in BRCA2 noncarriers, 37.5% in BRCA1 carriers, and 23.3% in BRCA1 noncarriers. Ninety-five percent of the men were white; therefore, the results cannot be generalized to all ethnic groups. Follow-up for this study is ongoing.

Level of evidence (screening in BRCA mutation carriers): 3

Chemoprevention of prostate cancer with finasteride and dutasteride in men at high risk

The benefits, harms, and supporting data regarding the use of finasteride and dutasteride for the prevention of prostate cancer are discussed more extensively in the PDQ summary on Prostate Cancer Prevention. Here, the reported benefits and harms and the use in men at high risk of prostate cancer are summarized.

Finasteride and dutasteride were studied for the prevention of prostate cancer in randomized controlled trials. The Prostate Cancer Prevention Trial (PCPT) studied finasteride and included 9,060 participants in the reported analysis;[15] the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial evaluated dutasteride and included 8,231 participants.[16] A small subset of the participants in these studies were men with a family history of prostate cancer or men of African descent. Men with a family history of prostate cancer represented 16.7% of participants in the PCPT and 13% of participants in the REDUCE trial. African American men represented 3.3% of PCPT participants and 2.3% of REDUCE participants. Overall, finasteride and dutasteride reduced the incidence of prostate cancer, but the evidence is inadequate to determine whether there is a reduction in mortality with these agents.[15,16] In the PCPT trial, absolute reduction in incidence for more than 7 years with finasteride was 6% (24.4% with placebo and 18.4% with finasteride); relative risk reduction (RRR) for incidence was 24.8% (95% confidence interval [CI], 18.6%–30.6%). There was no difference in the number of men who died from prostate cancer in the two groups, although the number of deaths was low. In the REDUCE trial, absolute risk reduction with dutasteride was 5.1% at 4 years, and the RRR was 22.8% (95% CI, 15.2%–29.8%; P < .001). There was no difference in prostate cancer–specific or overall mortality, although the number of deaths was low. Subgroup analysis from the PCPT by race/ethnicity, age, and family history of prostate cancer showed no difference in efficacy of finasteride within any of these subgroups.

Harms of finasteride and dutasteride include increased rates of erectile dysfunction, loss of libido, decreased volume of ejaculate, and gynecomastia. Both finasteride and dutasteride were associated with increased rates of high-grade prostate cancer (finasteride study: 6.4% in finasteride group vs. 5.1% in placebo group; years 3 through 4 of dutasteride study: 0.5% in dutasteride group vs. <0.1% in placebo group). In the dutasteride study, evaluating rates of high-grade prostate cancer over all 4 years revealed no significant difference by study arm (0.9% in dutasteride group vs. 0.6% in placebo group). Table 13 summarizes the findings from these two studies.

Table 13. Randomized Controlled Trials (RCTs) Examining the Efficacy of 5-Alpha-Reductase Inhibitors in Prostate Cancer Chemopreventiona
 PCPT (Finasteride) [15] REDUCE (Dutasteride) [16] 
Duration of RCT 7 y4 y
No. of participants included in analysis 9,0608,231
– % with FH of prostate cancer16.7%13.0%
– % African American3.3%2.3%
Benefits
– Absolute risk reduction in incidence6%5.1%
– Relative risk reduction in incidence24.8%22.8%
– Prostate cancer mortalityNo differenceNo difference
Harms
– Incidence of high-grade prostate cancerb6.4% (finasteride) vs. 5.1% (placebo)0.9% (dutasteride) vs. 0.6% (placebo)
– Side effectsDecreased volume ejaculateDecreased volume ejaculate
Decreased libidoDecreased libido
Erectile dysfunctionErectile dysfunction
GynecomastiaGynecomastia

FH = family history; PCPT = Prostate Cancer Prevention Trial; REDUCE = Reduction by Dutasteride of Prostate Cancer Events trial.
aThis table summarizes the first two RCTs of finasteride and dutasteride in prostate cancer chemoprevention.
bHigh-grade prostate cancer is defined as a Gleason score ≥7 in PCPT and a Gleason score ≥8 in REDUCE.

The American Society of Clinical Oncology and the American Urological Association issued joint recommendations regarding the use of 5-alpha-reductase inhibitors (5-ARIs) (i.e., finasteride and dutasteride) for prostate cancer prevention after a systematic literature review.[17] The guidelines state that asymptomatic men with a PSA level of 3.0 ng/mL or lower who regularly undergo PSA screening or men who anticipate undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of the benefits of taking 5-ARIs for 7 years for the prevention of prostate cancer and its potential risks (including the possibility of high-grade prostate cancer) to enable them to make a better-informed decision. Men who are taking 5-ARIs for benign conditions associated with lower urinary tract symptoms may also benefit from a similar discussion. Points recommended to include in the physician-patient discussions were: (1) inform the men who are considering using 5-ARIs that these agents reduce the incidence of prostate cancer but do not reduce the risk of prostate cancer to zero; (2) discuss the elevated rate of high-grade cancer and inform men of the potential explanations; (3) make it known to men that no information about the long-term effects of 5-ARIs on prostate cancer incidence exists beyond approximately 7 years, and that whether or not a 5-ARI reduces prostate cancer mortality or increases life expectancy remains unknown; (4) inform men of possible but reversible sexual adverse effects; and (5) inform men of the likely improvement in lower urinary tract symptoms. No specific recommendations were made for high-risk men based on the evidence review.

Level of evidence: 3aii

Summary

On the basis of available evidence and guidelines, men with a family history of prostate cancer and men of African descent may benefit from engaging in shared decision-making regarding prostate cancer screening. Optimal screening strategies for high-risk men are yet to be determined. Although high-risk men may consider 5-ARIs for prostate cancer prevention, it is important to note that the U.S. Food and Drug Administration has not approved finasteride or dutasteride for the indication of prostate cancer prevention, and an in-depth discussion of the risks and benefits is warranted.

References
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  2. Matikainen MP, Schleutker J, Mörsky P, et al.: Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. Clin Cancer Res 5 (6): 1275-9, 1999.  [PUBMED Abstract]

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  4. Valeri A, Cormier L, Moineau MP, et al.: Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives. J Urol 168 (2): 483-7, 2002.  [PUBMED Abstract]

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  6. Giri VN, Beebe-Dimmer J, Buyyounouski M, et al.: Prostate cancer risk assessment program: a 10-year update of cancer detection. J Urol 178 (5): 1920-4; discussion 1924, 2007.  [PUBMED Abstract]

  7. Moyer VA; U.S. Preventive Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 157 (2): 120-34, 2012.  [PUBMED Abstract]

  8. Qaseem A, Barry MJ, Denberg TD, et al.: Screening for prostate cancer: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 158 (10): 761-9, 2013.  [PUBMED Abstract]

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  11. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 1.2014. Rockledge, PA : National Comprehensive Cancer Network, 2014. Available online with free subscription. Last accessed June 17, 2014. 

  12. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2014. Rockledge, PA: National Comprehensive Cancer Network, 2014. Available online with free registration. Last accessed June 17, 2014. 

  13. Bancroft EK, Page EC, Castro E, 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.  [PUBMED Abstract]

  14. National Collaborating Centre for Cancer (UK): Prostate Cancer: Diagnosis and Treatment. Cardiff, UK: National Collaborating Centre for Cancer, 2008. Available online. Last accessed July 17, 2014. 

  15. Thompson IM, Goodman PJ, Tangen CM, et al.: The influence of finasteride on the development of prostate cancer. N Engl J Med 349 (3): 215-24, 2003.  [PUBMED Abstract]

  16. Andriole GL, Bostwick DG, Brawley OW, et al.: Effect of dutasteride on the risk of prostate cancer. N Engl J Med 362 (13): 1192-202, 2010.  [PUBMED Abstract]

  17. Kramer BS, Hagerty KL, Justman S, et al.: Use of 5-alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline. J Clin Oncol 27 (9): 1502-16, 2009.  [PUBMED Abstract]