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Genetics of Prostate Cancer (PDQ®) 3/3 –Health Professional Version - National Cancer Institute

Genetics of Prostate Cancer (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

Genetics of Prostate Cancer (PDQ®)–Health Professional Version



Screening and Prevention Interventions in Familial Prostate Cancer



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 cutoff 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 11.
Table 11. Summary of Prostate Cancer Screening Recommendations for High-Risk Men
ENLARGE
Screening Recommendation SourcePopulationTestAge Screening InitiatedFrequencyComments
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.
United States Preventive Services Task Force (2012) [7]N/AN/AN/AN/ANo 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 (2019) [11]African American men and men with family history of prostate cancerN/AN/AN/AThe panel states that it is reasonable for African American men to consider beginning shared decision-making about PSA screening with their providers at age 40 y and to consider screening at annual intervals rather than every other year.
NCCN (2019) [12]Men with BRCA1 pathogenic variantNot specifiedConsider screening starting at age ≥45 yNot specified
Men with BRCA2 pathogenic variantNot specified≥45 yNot specified
NCCN (2019) [11]Men with a personal or family history of high-risk germline pathogenic variantsBaseline PSA; strongly consider baseline DRE45–75 yEvery 2–4 y if PSA level <1 ng/mL, DRE normalAdditional recommendations for men with a PSA level >3 ng/mL or very suspicious DRE and men older than 75 y. (Refer to page PROSD-2 of the NCCN guidelines for more information.) Referral to a cancer genetics professional is recommended for those with a known or suspected cancer susceptibility gene.[11]
Every 1–2 y if PSA level 1–3 ng/mL, DRE normal
Level of evidence: 5

Screening in carriers of BRCA pathogenic variants

An international study that focused on prostate cancer screening in carriers of BRCA1/BRCA2 pathogenic variants 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 pathogenic variant 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 carriers of BRCA2 pathogenic variants, 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 carriers of BRCA pathogenic variants): 3

Chemoprevention of Prostate Cancer With Finasteride and Dutasteride

The benefits, harms, and supporting data regarding the use of finasteride and dutasteride for the prevention of prostate cancer in the general population are discussed in the PDQ summary on Prostate Cancer Prevention.


References
  1. Sartor O: Early detection of prostate cancer in African-American men with an increased familial risk of disease. J La State Med Soc 148 (4): 179-85, 1996. [PUBMED Abstract]
  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]
  3. Catalona WJ, Antenor JA, Roehl KA, et al.: Screening for prostate cancer in high risk populations. J Urol 168 (5): 1980-3; discussion 1983-4, 2002. [PUBMED Abstract]
  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]
  5. Narod SA, Dupont A, Cusan L, et al.: The impact of family history on early detection of prostate cancer. Nat Med 1 (2): 99-101, 1995. [PUBMED Abstract]
  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]
  9. Carter HB, Albertsen PC, Barry MJ, et al.: Early detection of prostate cancer: AUA Guideline. J Urol 190 (2): 419-26, 2013. [PUBMED Abstract]
  10. Smith RA, Manassaram-Baptiste D, Brooks D, et al.: Cancer screening in the United States, 2014: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin 64 (1): 30-51, 2014 Jan-Feb. [PUBMED Abstract]
  11. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 2.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed June 03, 2019.
  12. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 3.2019. Plymouth Meeting, Pa: National Comprehensive Cancer Network, 2019. Available online with free registration.Exit Disclaimer Last accessed June 20, 2019.
  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 66 (3): 489-99, 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 June 7, 2019.

Prostate Cancer Risk Assessment





The purpose of this section is to describe current approaches to assessing and counseling patients about susceptibility to prostate cancer. Genetic counseling for men at increased risk of prostate cancer encompasses all of the elements of genetic counseling for other hereditary cancers. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) The components of genetic counseling include concepts of prostate cancer risk, reinforcing the importance of detailed family history, pedigree analysis to derive age-related risk, and offering participation in research studies to those individuals who have multiple affected family members.[1,2] Genetic testing for prostate cancer susceptibility is not available outside of the context of a research study. Families with prostate cancer can be referred to ongoing research studies; however, these studies will not provide individual genetic results to participants.
Prostate cancer will affect an estimated one in nine American men during their lifetime.[3] Currently, evidence exists to support the hypothesis that approximately 5% to 10% of all prostate cancer is due to rare autosomal dominant prostate cancer susceptibility genes.[4,5] The proportion of prostate cancer associated with an inherited susceptibility may be even larger.[6-8] Men are generally considered to be candidates for genetic counseling regarding prostate cancer risk if they have a family history of prostate cancer. The Hopkins Criteria provide a working definition of hereditary prostate cancer families.[9] The three criteria include the following:
  1. Three or more first-degree relatives (father, brother, son), or
  2. Three successive generations of either the maternal or paternal lineages, or
  3. At least two relatives affected at or before age 55 years.
Families need to fulfill only one of these criteria to be considered to have hereditary prostate cancer. One study investigated attitudes regarding prostate cancer susceptibility among sons of men with prostate cancer.[10] They found that 90% of sons were interested in knowing whether there is an inherited susceptibility to prostate cancer and would be likely to undergo screening and consider genetic testing if there was a family history of prostate cancer; however, similar high levels of interest in genetic testing for other hereditary cancer syndromes have not generally been borne out in testing uptake once the clinical genetic test becomes available.


Risk Assessment and Analysis

Assessment of a man concerned about his inherited risk of prostate cancer should include taking a detailed family history; eliciting information regarding personal prostate cancer risk factors such as age, race, and dietary intake of fats and dairy products; documenting other medical problems; and evaluating genetics-related psychosocial issues.
Family history documentation is based on construction of a pedigree, and generally includes the following:
  • The history of cancer in both maternal and paternal bloodlines.
  • All primary cancer diagnoses (not just prostate cancer) and ages at diagnosis.
  • Race and ethnicity.
  • Other health problems including benign prostatic hypertrophy.[11]
(Refer to the Documenting the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for a more detailed description of taking a family history.)
Analysis of the family history generally consists of four components:
  1. Evaluation of the pattern of cancers in the family to identify cancer clusters, which might suggest a known inherited cancer syndrome. In addition to site-specific prostate cancer, other cancer susceptibility syndromes include prostate cancer as a component tumor (e.g., hereditary breast/ovarian cancer syndrome [associated with pathogenic variants in BRCA1 and BRCA2]).
  2. Assessment for genetic transmission. The pedigree should be assessed for evidence of both autosomal dominant and X-linked inheritance, which may be associated with a higher likelihood of an inherited susceptibility to prostate cancer. Autosomal dominant transmission is characterized by the presence of affected family members in sequential generations, with approximately 50% of males in each generation affected with prostate cancer. X-linked inheritance is suggested by apparent transmission of susceptibility from affected males in the maternal lineage. (Refer to the Analysis of the Family History section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
  3. Age at diagnosis of prostate cancer in the family. An inherited susceptibility to prostate cancer may be likely in families with early-onset (inconsistently defined) prostate cancer.[12] However, genetic research is also under way in families with an older age of prostate cancer onset. In the aggregate, the data are inconsistent relative to whether hereditary prostate cancer is routinely characterized by a younger-than-usual age at diagnosis.
  4. Risk assessment based on family and epidemiological studies. Multiple studies have reported that first-degree relatives of men affected with prostate cancer are two to three times more likely to develop prostate cancer than are men in the general population. In some studies, the relative risk (RR) of prostate cancer is highest among families who develop prostate cancer at an earlier age, consistent with other cancer susceptibility syndromes in which early age at onset is a common feature. It has been estimated that male relatives of men diagnosed with prostate cancer younger than 53 years have a 40% lifetime cumulative risk of developing prostate cancer.[13] A population-based case-control study of more than 1,500 cases and 1,600 controls, in which whites, African Americans, and Asian Americans were studied, reported an odds ratio of 2.5 for men with an affected first-degree relative after adjusting for age and ethnicity.[14] For men with a brother and father or son affected with prostate cancer, the RR was estimated to be 6.4.
A number of studies have examined the accuracy of the family history of prostate cancer provided by men with prostate cancer. This has clinical importance when risk assessments are based on unverified family history information. In an Australian study of 154 unaffected men with a family history of prostate cancer, self-reported family history was verified from cancer registry data in 89.6% of cases.[15] Accuracy of age at diagnosis within a 3-year range was correct in 83% of the cases, and accuracy of age at diagnosis within a 5-year range was correct in 93% of the cases. Self-reported family history from men younger than 55 years and reports about first-degree relatives had the highest degree of accuracy.[15] Self-reported family history of prostate cancer, however, may not be reliably reported over time,[16] which underscores the need to verify objectively reported prostate cancer diagnoses when trying to determine whether a patient has a significant family history.
The personal health and risk-factor history includes, but is not limited to, the following:
  • Family history.
  • Age.
  • Race.
  • Current and past diet history, including fat intake.
  • Current and past use of drugs that can affect prostatic growth, such as steroids (e.g., finasteride [Proscar]). (Refer to the PDQ summary on Prostate Cancer Prevention for more information about finasteride and prostate cancer.)
  • Current and past use of complementary and alternative medications (e.g., saw palmetto, PC-SPES).[17] (Refer to the PDQ summary on PC-SPES for more information.)
The most definitive risk factors for prostate cancer are age, race, and family history.[18] The correlation between other risk factors and prostate cancer risk is not clearly established. Despite this limitation, cancer risk counseling is an educational process that provides details regarding the state of the knowledge of prostate cancer risk factors. The discussion regarding these other risk factors should be individualized to incorporate the patient's personal health and risk factor history. (Refer to the Risk Factors for Prostate Cancer section of this summary for a more detailed description of prostate cancer risk factors.)
The psychosocial assessment in this context might include evaluation of the following:
  • Level of psychological distress.
  • Perceived risk of prostate cancer.
  • Past history of depression, anxiety, or other mental illness.
One study found that psychological distress was greater among men attending prostate cancer screening who had a family history of the disease, particularly if they also reported an overestimation of prostate cancer risk. Psychological distress and elevated risk perception may influence adherence to cancer screening and risk management strategies. Consultation with a mental health professional may be valuable if serious psychosocial issues are identified.[19]

Genetic Testing

Multigene (panel) tests for variants in genes associated with prostate cancer susceptibility are currently available and are increasingly being used in the clinic. (Refer to the Multigene [Panel] Testing in Prostate Cancer section for more information.) Although routine genetic testing of high-risk prostate cancer patients for inherited variants associated with the disease is not standard, many centers are studying the clinical utility of germline genetic testing and counseling in these patients.


References
  1. Nieder AM, Taneja SS, Zeegers MP, et al.: Genetic counseling for prostate cancer risk. Clin Genet 63 (3): 169-76, 2003. [PUBMED Abstract]
  2. Bruner DW, Baffoe-Bonnie A, Miller S, et al.: Prostate cancer risk assessment program. A model for the early detection of prostate cancer. Oncology (Huntingt) 13 (3): 325-34; discussion 337-9, 343-4 pas, 1999. [PUBMED Abstract]
  3. American Cancer Society: Cancer Facts and Figures 2019. Atlanta, Ga: American Cancer Society, 2019. Available onlineExit Disclaimer. Last accessed June 7, 2019.
  4. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 17 (4): 337-47, 1990. [PUBMED Abstract]
  5. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992. [PUBMED Abstract]
  6. Lesko SM, Rosenberg L, Shapiro S: Family history and prostate cancer risk. Am J Epidemiol 144 (11): 1041-7, 1996. [PUBMED Abstract]
  7. Grönberg H, Damber L, Damber JE, et al.: Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146 (7): 552-7, 1997. [PUBMED Abstract]
  8. Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62 (6): 1425-38, 1998. [PUBMED Abstract]
  9. Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993. [PUBMED Abstract]
  10. Bratt O, Kristoffersson U, Lundgren R, et al.: Sons of men with prostate cancer: their attitudes regarding possible inheritance of prostate cancer, screening, and genetic testing. Urology 50 (3): 360-5, 1997. [PUBMED Abstract]
  11. Pienta KJ, Esper PS: Risk factors for prostate cancer. Ann Intern Med 118 (10): 793-803, 1993. [PUBMED Abstract]
  12. Giovannucci E: How is individual risk for prostate cancer assessed? Hematol Oncol Clin North Am 10 (3): 537-48, 1996. [PUBMED Abstract]
  13. Neuhausen SL, Skolnick MH, Cannon-Albright L: Familial prostate cancer studies in Utah. Br J Urol 79 (Suppl 1): 15-20, 1997. [PUBMED Abstract]
  14. Whittemore AS, Wu AH, Kolonel LN, et al.: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141 (8): 732-40, 1995. [PUBMED Abstract]
  15. Gaff CL, Aragona C, MacInnis RJ, et al.: Accuracy and completeness in reporting family history of prostate cancer by unaffected men. Urology 63 (6): 1111-6, 2004. [PUBMED Abstract]
  16. Weinrich SP, Faison-Smith L, Hudson-Priest J, et al.: Stability of self-reported family history of prostate cancer among African American men. J Nurs Meas 10 (1): 39-46, 2002 Spring-Summer. [PUBMED Abstract]
  17. Barqawi A, Gamito E, O'Donnell C, et al.: Herbal and vitamin supplement use in a prostate cancer screening population. Urology 63 (2): 288-92, 2004. [PUBMED Abstract]
  18. Stanford JL, Stephenson RA, Coyle LM, et al., eds.: Prostate Cancer Trends 1973-1995. Bethesda, Md: National Cancer Institute, 1999. NIH Pub. No. 99-4543. Also available online. Last accessed June 7, 2019.
  19. Taylor KL, DiPlacido J, Redd WH, et al.: Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Cancer 85 (6): 1305-12, 1999. [PUBMED Abstract]

Psychosocial Issues in Familial Prostate Cancer



Introduction

Research to date has included survey, focus group, and correlation studies on psychosocial issues related to prostate cancer risk. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about psychological issues related to genetic counseling for cancer risk assessment.) Genetic testing for pathogenic variants in genes with some association with prostate cancer risk is now available and has the potential to identify those at increased risk of prostate cancer. Having an understanding of the motivations of men who may consider genetic testing for inherited susceptibility to prostate cancer can help clinicians and researchers anticipate interest in testing. Further, these data may inform the nature and content of counseling strategies for men and their families, including consideration of the risks, benefits, decision-making issues, and informed consent for genetic testing.

Risk Perception

Knowledge about risk of prostate cancer is thought to be a factor influencing men’s decisions to pursue prostate cancer screening and, possibly, genetic testing.[1] A study of 79 African American men (38 of whom had been diagnosed with prostate cancer and the remainder who were unaffected but at high risk of prostate cancer) completed a nine-item telephone questionnaire assessing knowledge about hereditary prostate cancer. On a scale of 0 to 9, with 9 representing a perfect score, scores ranged from 3.5 to 9 with a mean score of 6.34. The three questions relating to genetic testing were the questions most likely to be incorrect. In contrast, questions related to inheritance of prostate cancer risk were answered correctly by the majority of subjects.[2] Overall, knowledge of hereditary prostate cancer was low, especially concepts of genetic susceptibility, indicating a need for increased education. An emerging body of literature is now exploring risk perception for prostate cancer among men with and without a family history. Table 12 provides a summary of studies examining prostate cancer risk perception.
Table 12. Summary of Cross-Sectional Studies of Prostate Cancer Risk Perception
Study PopulationSample SizeProportion of Study Population That Accurately Reported Their RiskOther Findings
FDR = first-degree relative.
Unaffected men with a family history of prostate cancer [3]120 men aged 40–72 y40%
FDR of men with prostate cancer [4]105 men aged 40–70 y62%
Men with brothers affected with prostate cancer [5]111 men aged 33–78 yNot available38% of men reported their risk of prostate cancer to be the same or less than the average man.
FDR of men with prostate cancer and a community sample [6]56 men with an FDR with prostate cancer and 100 men without an FDR with prostate cancer all older than 40 y57%29% of men with an FDR thought that they were at the same risk as the average man, and 14% believed that they were at somewhat lower risk than average.
Study conclusions vary regarding whether first-degree relatives (FDRs) of prostate cancer patients accurately estimate their prostate cancer risk. Some studies found that men with a family history of prostate cancer considered their risk to be the same as or less than that of the average man.[5,6] Other factors, including being married, have been associated with higher prostate cancer risk perception.[7] A confounder in prostate cancer risk perception was confusion between benign prostatic hyperplasia and prostate cancer.[3]

Anticipated Interest in Genetic Testing for Risk of Prostate Cancer

A number of studies summarized in Table 13 have examined participants' interest in genetic testing, if such a test were available for clinical use. Factors found to positively influence the interest in genetic testing include the following:
  • Advice of their primary care physician.[8]
  • Combination of emotional distress and concern about prostate cancer treatment effects.[9]
  • Having children.[10]
Findings from these studies were not consistent regarding the influence of race, education, marital status, employment status, family history, and age on interest in genetic testing. Study participants expressed concerns about confidentiality of test results among employers, insurers, and family and stigmatization; potential loss of insurability; and the cost of the test.[8] These concerns are similar to those that have been reported in women contemplating genetic testing for breast cancer predisposition.[11-16] Concerns voiced about testing positive for a pathogenic variant in a prostate cancer susceptibility gene included decreased quality of life secondary to interference with sex life in the event of a cancer diagnosis, increased anxiety, and elevated stress.[8]
Table 13. Summary of Cross-Sectional Studies of Anticipated Interest in Prostate Cancer Susceptibility Genetic Testing
Study PopulationSample SizePercent Expressing Interest in Genetic TestingOther Findings
FDR = first-degree relative; PSA = prostate-specific antigen.
Prostate screening clinic participants [17]342 men aged 40–97 y89%28% did not demonstrate an understanding of the concept of inherited predisposition to cancer.
General population; 9% with positive family history [8]12 focus groups with a total of 90 men aged 18–70 yAll focus groups
African American men [18]320 men aged 21–98 y87%Most participants could not distinguish between genetic susceptibility testing and a prostate-specific antigen blood test.
Men with and without FDRs with prostate cancer [9]126 men aged >40 y; mean age 52.6 y24% definitely; 50% probably
Swedish men with an FDR with prostate cancer [3]110 men aged 40–72 y76% definitely; 18% probably89% definitely or probably wanted their sons to undergo genetic testing.
Sons of Swedish men with prostate cancer [10]101 men aged 21–65 y90%; 100% of sons with two or three family members affected with prostate cancer60% expressed worry about having an increased risk of prostate cancer.
Healthy outpatient males with no history of prostate cancer [19]400 men aged 40–69 y82%
Healthy African American males with no history of prostate cancer [20]413 African American men aged 40–70 y87%Belief in the efficacy of and intention to undergo prostate cancer screening was associated with testing interest.
Healthy Australian males with no history of prostate cancer [21]473 adult men66% definitely; 26% probably73% reported that they felt diet could influence prostate cancer risk.
Males with prostate cancer and their unaffected male family members [22]559 men with prostate cancer; 370 unaffected male relatives45% of men affected with cancer; 56% of unaffected menIn affected men, younger age and test familiarity were predictors of genetic testing interest. In unaffected men, older age, test familiarity, and a PSA test within the last 5 y were predictors of genetic testing interest.
Overall, these reports and a study that developed a conceptual model to look at factors associated with intention to undergo genetic testing [23] have shown a significant interest in genetic testing for prostate cancer susceptibility despite concerns about confidentiality and potential discrimination. These findings must be interpreted cautiously in predicting actual prostate cancer genetic test uptake once testing is available. In both Huntington disease and hereditary breast and ovarian cancers, hypothetical interest before testing was possible was much higher than actual uptake following availability of the test.[24,25]
In a sample comprised of undiagnosed men with and without a prostate cancer–affected FDR, older age and lower education levels were associated with lower levels of prostate cancer–specific distress (as measured by the 11-item Prostate Cancer Anxiety Subscale of the Memorial Anxiety Scale for Prostate Cancer); higher distress was associated with having more urinary symptoms.[26] In the same study, men with a prostate cancer–affected FDR who perceived their relative’s cancer as more threatening and who had a relative deceased from the disease reported higher distress. In general, prostate cancer–specific distress levels were low for both groups of men.

Screening for Prostate Cancer in Individuals at Increased Familial Risk

The proportion of prostate cancers attributed to hereditary causes is estimated to be 5% to 10%,[27] and the risk of prostate cancer increases with the number of blood relatives with prostate cancer and young age at onset of prostate cancer within families.[28] There is considerable controversy in prostate cancer about the use of serum prostate-specific antigen (PSA) measurement and digital rectal exam for prostate cancer early detection in the general population, with different organizations suggesting significantly different screening algorithms and age recommendations. (Refer to the PDQ summary on Prostate Cancer Treatment for more information about prostate cancer in the general population and the Interventions section of this summary for more information about inherited prostate cancer susceptibility.) This variation is likely to add to patient and provider confusion about recommendations for screening by members of hereditary cancer families or FDRs of prostate cancer patients. Psychosocial questions of interest include what individuals at increased risk understand about hereditary risk, whether informational interventions are associated with increased uptake of prostate cancer screening behaviors, and what the associated quality-of-life implications of screening are for individuals at increased risk. Also of interest is the role of the primary care provider in helping those at increased risk identify their risk and undergo age- and family-history–appropriate screening.

Screening behaviors

In most cancers, the goal of improved knowledge of hereditary risk can be translated rather easily into a desired increase in adherence to approved and recommended (if not proven) screening behaviors. This is complicated for prostate cancer screening by the lack of clear recommendations for men in both high-risk and general populations. (Refer to the Screening section of this summary for more information.) In addition, controversy exists with regard to the value of early diagnosis of prostate cancer. This creates uncertainty for patients and providers and challenges the psychosocial factors related to screening behavior.
Several small studies have examined the behavioral correlates of prostate cancer screening at average and increased prostate cancer risk based on family history; these are summarized in Table 14. In general, results appear contradictory regarding whether men with a family history are more likely to be screened than those not at risk and whether the screening is appropriate for their risk status. Furthermore, most of the studies had relatively small numbers of subjects, and the criteria for screening were not uniform, making generalization difficult.
Table 14. Summary of Studies of Behavioral Correlates for Prostate Cancer Screening
Study PopulationSample SizePercent Undergoing ScreeningPredictive Correlates for Screening Behavior
AAHPC = African American Hereditary Prostate Cancer Study Network; DRE = digital rectal exam; FDR = first-degree relative; NHIS = National Health Interview Survey; PSA = prostate-specific antigen.
Unaffected men with at least one FDR with prostate cancer [29]82 men (aged ≥40 y; mean age 50.5 y)PSA:Aged >50 y.
Annual income ≥ U.S. $40,000.
50% reported PSA screening within the previous 14 mo.History of PSA screening before study enrollment.
Higher levels of self-efficacy and response efficacy for undergoing prostate cancer screening.
Sons of men with prostate cancer [30]124 men (60 men with a history of prostate cancer aged 38–84 y, median age 59 y; 64 unaffected men aged 31–78 y, median age 55 y)PSA:39.4% patient request.
— Unaffected men: 95.3% reported ever having a PSA test.
— Affected men: 71.7% reported ever having a PSA test before diagnosis.
DRE:
— Unaffected men: 96.9% reported ever having a DRE.
— Affected men: 91.5% reported ever having a DRE before diagnosis.35.6% physician request.
Both PSA and DRE:
— Unaffected men: 93.8% had both procedures.
— Affected men: 70.0% reported having both procedures before diagnosis.
Unaffected men with and without an FDR with prostate cancer [6]156 men aged ≥40 y (56 men with an FDR; 100 men without an FDR)PSA:Older age.
63% reported ever having a PSA test.
FDRs reported higher disease vulnerability and less belief in disease prevention, but this did not result in increased prostate cancer screening when compared with those without an FDR.
DRE:
86% reported ever having a DRE.
Unaffected Swedish men from families with a 50% probability of carrying a pathogenic variant in a dominant prostate cancer susceptibility gene [3]110 men aged 50–72 y68% of men aged ≥50 y were screened for prostate cancer.More relatives with prostate cancer.
Low score on the avoidance subscales of the Impact of Event Scale.[31]
Brothers or sons of men with prostate cancer [32]136 men aged 40–70 y (72% were African American men)PSA:More relatives with prostate cancer.
72% reported ever having a PSA test.
— 73% within 1 y.Older age.
— 23% 1–2 y ago.
— 4% >2 y ago.
DRE:Urinary symptoms.
90% reported ever having had a DRE.
— 60% within 1 y.
— 23% 1–2 y ago.71% reported their physician had spoken to them about prostate cancer screening.
— 17% >2 y ago.
Unaffected men with and without an FDR with prostate cancer [33]166 men aged 40–80 y (83 men with an FDR; 83 men with no family history)PSA:Family history of prostate cancer.
— FDR: 72% reported ever having had a PSA test.
— No family history: 53% reported ever having had a PSA test.Greater perceived vulnerability to developing prostate cancer.
French brothers or sons of men with prostate cancer [34]420 men aged 40–70 yPSA:Younger age.
More relatives with prostate cancer.
Increased anxiety.
88% adhered to annual PSA screening.Married.
Higher education.
Previous history of prostate cancer screening.
Data from unaffected African American men participating in AAHPC and data from the 1998 and 2000 NHIS [35]Unaffected men aged 40–69 y:PSA:Younger age.
AAHPC Cohort:
— 45% reported ever having had a PSA test.
— AAHPC Cohort: 134 menAfrican American men in 2000 NHIS:
— 65% reported ever having had a PSA test.
DRE:
— NHIS 1998 Cohort: 5,583 men (683 African American, 4,900 white)AAHPC Cohort:Fewer relatives with prostate cancer.
— 35% reported ever having had a DRE.
African American men in 1998 NHIS:
— NHIS 2000 Cohort: 3,359 men (411 African American, 2,948 white)— 45% reported ever having had a DRE.
Unaffected African American men who participated in the 2000 NHIS [36]736 men aged ≥45 yPSA:Older age (≥50 y).
Private or military health insurance.
48% reported ever having had a PSA test.Fair or poor health status.
Family history of prostate cancer.

Psychosocial outcomes of screening in individuals at increased familial risk

Concern about developing prostate cancer: Although up to 50% of men in some studies who were FDRs of prostate cancer patients expressed some concern about developing prostate cancer,[5] the level of anxiety reported is typically relatively low and is related to lifetime risk rather than short-term risk.[3,5] The concern is also higher in men who are younger than his FDR was at the time when their prostate cancer was diagnosed.[5] Unmarried FDRs worried more about developing prostate cancer than did married men.[5] Men with higher levels of concern about developing prostate cancer also had higher estimates of personal prostate cancer risk and had a larger number of relatives diagnosed with prostate cancer.[5] In a Swedish study, only 3% of the 110 men surveyed said that worry about prostate cancer affected their daily life “fairly much,” and 28% said it affected their daily life "slightly."[3]
Baseline distress levels: Among men who self-referred for free prostate cancer screening, general and prostate cancer–related distress did not differ significantly between men who were FDRs of prostate cancer patients and men who were not.[37] Men with a family history of prostate cancer in the study had higher levels of perceived risk. In a Swedish study, male FDRs of prostate cancer patients who reported more worry about developing prostate cancer had higher Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores than men with lower levels of worry. In that study, the average HADS depression and anxiety scores among FDRs was at the 75th percentile. Depression was associated with higher levels of personal risk overestimation.[3]
Distress experienced during prostate cancer screening: A study measured the anxiety and general quality of life experienced by 220 men with a family history of prostate cancer while undergoing prostate cancer screening with PSA tests.[32] In this group, 20% of the men experienced a moderate deterioration in their anxiety scores, and 20% experienced a minimal deterioration in health-related quality of life (HRQOL). The average period between assessments was 35 days, which encompassed PSA testing and a wait for results that averaged 15.6 days. Only men with normal PSA values (4 ng/mL or less) were assessed. Factors associated with deterioration in HRQOL included being age 50 to 60 years, having more than two relatives with prostate cancer, having an anxious personality, being well-educated, and having no children presently living at home. These authors stress that analysis of the impact of screening on FDRs should not rely solely on mean changes in scores, which may “mask diversity among responses, as illustrated by the proportion of subjects worsening during the screening process.” Given that these were men receiving what was considered a normal result and that a subset of men experienced screening-associated distress, this study suggests that interventions to reduce screening-related distress may be needed to encourage men at increased hereditary risk to comply with repeated requests for screening.
A study in the United Kingdom assessed predictors of psychological morbidity and screening adherence in FDRs of men with prostate cancer participating in a PSA screening study. One hundred twenty-eight FDRs completed measures assessing psychological morbidity, barriers, benefits, knowledge of PSA screening, and perceived susceptibility to prostate cancer. Overall, 18 men (14%) scored above the threshold for psychiatric morbidity, consistent with normal population ranges. Cancer worry was positively associated with health anxiety, perceived risk, and subjective stress. However, psychological morbidity did not predict PSA screening adherence. Only past screening behavior was found to be associated with PSA screening adherence.[38]


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Changes to This Summary (10/04/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Introduction
Revised text to state that in one Swedish study of 80,449 men with prostate cancer, 6,396 developed a second primary malignancy. Also added text to state that those with a family history of cancer were found to have an increased risk for a second primary cancer with the greatest risk consisting of colorectal cancer, lung cancer, kidney cancer, bladder cancer, melanoma, squamous cell skin cancer, and leukemia (cited Chattopadhyay et al. as reference 47).
Identifying Genes and Inherited Variants Associated With Prostate Cancer Risk
The Clinical study of genome-wide association studies (GWAS) findings subsection was renamed from Clinical application of GWAS findings.
Revised text to state that as increasing numbers of risk single nucleotide polymorphisms have been discovered, they have been applied to clinical cohorts alongside traditional variables such as prostate-specific antigen and family history, although the clinical utility of this information has not been established.
Added text to state that research focused on the associated risk of prostate cancer and the predictability of polygenic risk scores is under way (cited Li-Sheng Chen et al. as reference 120).
Clinical Application of Genetic Testing for Inherited Prostate Cancer
Updated National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology: Prostate Cancer as reference 4.
The Multigene (Panel) Testing in Prostate Cancer subsection was extensively revised.
Added text to state that a study of 1,133 primary prostate adenocarcinomas and 43 neuroendocrine prostate cancers conducted screening by MSH2 immunohistochemistry with confirmation by next-generation sequencing (cited Guedes et al. as reference 56). Overall, 8% of adenocarcinomas with primary Gleason pattern 5 had MSH2 loss compared with 0.4% of tumors with any other Gleason scores. Three patients had germline variants in MSH2, of whom two had a primary Gleason score of 5. Pending further confirmation, these findings may support universal mismatch repair screening of prostate cancer with a Gleason score of 9 to 10 to identify men who may be eligible for immunotherapy and germline testing.
Added text to state that genetic results are increasingly informing treatment and management strategies for prostate cancer. Confirmation of somatic mutations through germline testing is needed so that additional recommendations can be made regarding cancer risk for patients and families.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary



Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Genetics of Prostate Cancer are:
  • Kathleen A. Calzone, PhD, RN, AGN-BC, FAAN (National Cancer Institute)
  • Veda N. Giri, MD (Thomas Jefferson University)
  • Suzanne M. O'Neill, MS, PhD, CGC
  • Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
  • Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
  • Mark Pomerantz, MD (Dana-Farber Cancer Institute)
  • Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
  • Catharine Wang, PhD, MSc (Boston University School of Public Health)
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”
The preferred citation for this PDQ summary is:
PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Prostate Cancer. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/prostate/hp/prostate-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389227]
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