Genetics Of Prostate Cancer

    As with any disease process, decisions
    about risk-reducing interventions for patients with an inherited predisposition
    to prostate cancer are best guided by randomized controlled clinical trials, and
    by knowledge of the underlying natural history of the process. Unfortunately,
    little is known about either the natural history or the inherent biologic
    aggressiveness of familial prostate cancer compared with sporadic forms.
    Existing studies of the natural history of prostate cancer in men with a
    positive family history are predominantly based on retrospective case series.
    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 summary on
    Cancer Screening Overview for more information.

    Given the paucity of information on the
    natural history of prostate cancer in men with a hereditary predisposition,
    decisions about risk reduction, early detection, and therapy are currently based
    on the literature used to guide interventions in sporadic prostate cancer,
    coupled with the best clinical judgment of those responsible for the care of
    these patients, with the active participation of well-informed high-risk
    patients.

    Primary
    Prevention

    There are no definitive studies of primary
    prevention strategies in men with a hereditary risk of prostate cancer. Thus,
    there are no definitive recommendations that can be offered to these patients to
    reduce their risk for prostate cancer at the present time.

    The recently published Prostate Cancer
    Prevention Trial (PCPT), a prospective, randomized clinical trial of finasteride
    versus placebo, demonstrated a 25% reduction in prostate cancer risk among study
    participants receiving finasteride.[1] Finasteride administration produced
    statistically similar reductions in prostate cancer risk in
    family-history–positive (19% decrease) and family-history–negative (26%
    decrease) subjects. A subsequent PCPT publication suggested that end-of-study
    biopsies in asymptomatic men with serum prostate-specific antigen (PSA) values
    consistently lower than 4.0 ng/mL were more likely to detect prostate cancer in
    men with an affected first-degree relative (19.7%) versus those with a negative
    family history (14.4%).[1]

    Level of
    Evidence: Iaii

    Refer to the PDQ summary on Prevention of
    Prostate Cancer for a more detailed description of the prevention of prostate
    cancer in the general population. Information about ongoing prostate cancer
    prevention clinical trials is available from the NCI Web site.

    Screening

    There is little information about the net
    benefits and harms of screening men at higher risk of prostate cancer. There is
    no 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 summary on Screening for Prostate Cancer.

    There is limited information about the
    efficacy of commonly available screening tests such as the digital rectal
    examination (DRE) or serum PSA in men genetically predisposed to developing
    prostate cancer. Furthermore, comparing the results of studies examining the
    efficacy of screening for prostate cancer is difficult; 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
    [proportion of men with positive tests who have prostate cancer]) 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.[2,3]

    Currently, there are only a few
    case-control studies and no published randomized trials examining screening in
    men with an increased risk of prostate cancer. A 10-year longitudinal study of
    serum PSA and DRE every 6 to 12 months in high-risk men aged 40 years and older
    has been conducted.[4] Two high-risk categories (1,227 men with a family history
    of prostate cancer and 1,224 African American men) were compared with 15,964
    low-risk non–African American men without a family history of prostate cancer.
    Suspicious screening results were present in 7% of non–African American men with
    a family history of prostate cancer, 8% of the low-risk African American men,
    and 20% of African American men with a family history of prostate cancer. The
    PPV was inversely proportional to age for those who had an abnormal screening
    test and underwent biopsy. Among men aged 40 to 49 years, the PPV was 50% for
    non–African American men with a positive family history, 54% for African
    American men without a family history, and 75% among African American men with a
    family history, compared with 38%, 49%, and 52%, respectively, among men aged 50
    years and older. Of the 16 cancers detected in high-risk men younger than 50
    years, 15 were clinically significant, with intermediate Gleason scores (5–7),
    and three were not confined to the prostate.[4]

    One screening study of the relatives of 435
    men with prostate cancer measured serum PSA every 12 months for 2 years. Four
    hundred and forty-two participants were classified into two groups: sporadic,
    defined as only one first-degree relative with prostate cancer; or familial,
    with two or more cases of prostate cancer. PSA higher than 4 ng/mL was present
    in 0.8% in men aged 40 to 49 years, compared with 12.4% of men older than 50
    years. No differences in prostate cancer detection rates or elevated PSA levels
    were found between sporadic and familial groups. Of the ten prostate cancers
    detected in this study, nine were clinically localized and of intermediate
    Gleason scores (5–7).[5]

    In a Finnish prostate cancer screening
    study, family history of prostate cancer was obtained in 2,099 prostate cancer
    patients.[3] This resulted in the identification of 103 prostate cancer families
    with two or more affected first- or second-degree relatives having at least one
    living first-degree unaffected male. From those families, 209 of 226 eligible
    first-degree unaffected asymptomatic males aged 45 to 75 years were enrolled in
    a study involving a single serum PSA measurement. An elevated PSA (2.6–28.3
    mg/L) was identified in 21 (10%) of subjects. Subsequent biopsies revealed
    prostate adenocarcinoma in seven (3.3%), including one at an advanced stage, and
    prostatic intraepithelial neoplasia in two (1%). The mean age of PSA-detected
    cancers was 65.1 years, 7 years younger than the average age of prostate cancer
    diagnosis in Finland. In men with a family history of early-onset prostate
    cancer (mean age of diagnosis in the family, <60 years), the frequency of
    elevated PSAs was 28.6% and subclinical prostate cancer was 14.3%, significantly
    hi

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