Three15 148 Epidemiology, etiology and prevention of prostate cancer screening

  1. Risk factors for prostate cancer?
    Genetic factors  - RR is 2-3 times

    Environmental factors - Chronic inflammation leading to cellular hyperproliferation to replace damaged tissue appears to contribute to the development of prostate cancer. 

    Histologic evidence of inflammation, as manifested by proliferative inflammatory atrophy (PIA), is common in prostate cancer and may represent a key pathobiologic process in its development.

    Androgen exposure of the prostate plays an important but incompletely defined role in prostate carcinogenesis.

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    • Since 2008, the incidence of prostate cancer in the United States has been consistently decreasing.
    • African American men have one of the highest reported incidences of prostate cancer in the world.
    • Incidence of prostate cancer is highest in countries with the highest rates of screening.
  2. Obesity and prostate cancer risk?
    Higher body mass index has been associated with increased biologic measures of oxidative stress, lower circulating androgen levels, lower serum PSA (perhaps as a consequence of lower circulating androgens), higher serum-free IGF-1 levels, and worse cancer specific survival after radical prostatectomy.

    Obese men have lower PSA levels and larger prostates, which together may lead to fewer biopsies and more sampling error, potentially contributing to an increased risk of highgrade disease
  3. BRCA and prostate cancer?
    • There is clear evidence that both BRCA1 and BRCA2 carriers are at increased risk for prostate cancer, especially
    • early-onset disease.
    • BRCA1 has been estimated to increase risk by 1.8- to 3.5-fold and BRCA2 from 4.6- to 8.6-fold in men younger than 65 years of age. BRCA associated cancers, especially for BRCA2, are also more likely to present with higher-grade, locally advanced, and metastatic disease and have poorer cancer-specific and metastasis-free survival after prostatectomy
  4. SPOP mutation and prostate cancer?
    Tumors with SPOP mutations account for about 10% of primary prostate cancers and have average levels of methylation. A subclass of SPOP mutated tumors that overexpress the SPINK1 gene occur more commonly in African Americans and are associated with higher Gleason scores, and may in part underlie the increased incidence and mortality of prostate cancer in this group.
  5. Epigenetic events in prostate cancer?
    Epigenetic events affect gene expression without altering the actual sequence of DNA, and in prostate cancer, the following listed mechanisms are important

    • a. chromatin remodeling
    • b. promoter hypo- and hypermethylation
    • c. microRNAs that lead to gene silencing
    • d. long noncoding RNAs

    HOXB13 and BRCA are two genes that substantially increase individual risk. BRCA-related tumors present with more aggressive clinical features.

    Primary prostate cancer has a distinct molecular taxonomy characterized by seven distinct subtypes, including four defined by gene fusions and three by mutations. Variations in gene methylation profiles further distinguish the molecular subtypes of prostate cancer.
  6. PLCO trial 2009?
    Prostate, Lungs, Colorectal and Ovarian cancer screening trial

    To compare prostate cancer specific mortality among screened and unscreened arms 

    Annual screening for 6 years (screening interval of 4 years in ERSPC) 

    PSA and DRE screening - no benefit on survival, even at 13 yrs follow up

    • Criticism
    • - Approximately 40% of participants had been prescreened with PSA
    • - In the screening arm, most patients with abnormal screening results did not undergo prompt biopsy. 
    • - higher PSA cutoff value 4 (in ERSPC is 3)
    • - 52% contamination by ad hoc screening in the control arm 

    However, in subset analysis, 44% decrease in cancer-specific death was observed in screening arm in men with no or minimal comorbidity.
  7. ERSPC 2009?
    European randomized study on screening prostate cancer 

    ERSPC was twice as large and had less contamination with opportunistic screening of the control arm (PSA testing was not as widespread in Europe as in the United States at the time)

    20% Reduction of cancer-specific mortality

    To prevent one cancer death, 781 men need to be screened

    PSA screening reduces prostate cancer mortality; however, the absolute effect is small relative to the number needed to screen and treat to cure a single individual.
  8. PCPT Trial?
    Clinical Question - Does daily finasteride therapy reduce prostate cancer development when compared to placebo?

    Inclusion criteria - normal DRE, PSA level of 3 ng/dl orless 

    • Results
    • - 25% reduction in the period prevalence of prostate cancer in men taking finasteride (18.4%) compared to placebo (24.4%) 
    • - significant increase in the prevalence of biopsy Gleason score 7-10 cancers was observed in men receiving finasteride compared to placebo. 

    • Bottom Line
    • - Finasteride reduces the incidence of prostate cancer but causes sexual side effects and increases the incidence of high-grade prostate cancer when compared to placebo for primary prevention.
    • - Finasteride-treated glands were also 28% smaller on average compared to those in the placebo arm, and data suggest that having a smaller prostate enhances the detection of cancer and proportionately more diagnosed cancers are high grade
    • - There is no safe PSA threshold that can rule out prostate cancer at any age range. Risk of prostate cancer is continuous as PSA increases. 

    - Some investigators have recommended against referring to PSA as elevated or abnormal.

    [@ PCPT - Proscar, reDuce - Dutasteride]
  9. REDUCE Trial?
    Dutasteride versus placebo in terms of their ability to prevent prostate cancer

    Inclusion criteria - PSA 2.5 to 10 ng/dl, prior negative biopsy within 6 months of enrollment, prostate volume 80 ml or less 

    • Results - 
    • 23% reduction in prostate cancer
    • Small increase in Gleason 8+ cancers in the treatment arm

    [@ Dutasteride Reduce prostate cancer, PCPT = FCFT - Finasteride reduce prostate cancer]
  10. Screening of prostate cancer
    Population or mass screening is defined as the ‘systematic examination of asymptomatic men (at risk)’. 

    Overall, when DRE and PSA tests are used in prostate cancer screening, detection rates are higher with PSA testing than with DRE and highest with the tests together. 

    • AUA recommendation - 
    • Men with a life expectance of >10 years with LUTS
    • Based on informed decision making
    • The greatest benefit is for men with age 55-69 years
    • Interval - 2 years 

    • EAU 2020
    • Offer an individualised risk-adapted strategy for early detection to a well-informed man and a life expectancy of at least 10 to 15 years.
    • Don't offer without counselling risk and benefit. 
    • Offer early PSA testing to well-informed men at elevated risk of having PCa:
    • • men > 50 years of age;
    • • men > 45 years of age and a family history of PCa;
    • • men of African descent > 45 years of age;
    • • men carrying BRCA2 mutations > 40 years of age.

    • Offer a risk-adapted strategy (based on initial PSA level), with follow-up intervals of 2 years for those initially at risk:
    • • men with a PSA level of > 1 ng/mL at 40 years of age;
    • • men with a PSA level of > 2 ng/mL at 60 years of age;
    • Postpone follow-up to 8 years in those not at risk.

    Stop early diagnosis of PCa based on life expectancy and performance status; men who have a life-expectancy of < 15 years are unlikely to benefit. 

    Some others reject on performing PSA based screening in asymptomatic man

    Although prostate cancer screening remains controversial, men who present for periodic health examinations should be made aware of the availability of the PSA test so that they can make an informed decision whether to be screened. (C11-2602)

    • If PSA >10 and DRE negative - Rate of high-grade cancer in biopsy - 19.4%
    • If PSA >10 and DRE positive - Rate of high-grade cancer in biopsy - 50.5%

    Do not use mpMRI as an initial screening tool. Strong (EAU 2020)

    [@ 40,45,50,55 yrs]
  11. What to do for incidentally raised PSA?
    • The AUA does not recommend giving empiric antibiotics for an elevated PSA.
    • Repeating an abnormal test after a period of observation is a good practice.
  12. Finding of SELECT trial?
    Findings of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) -  increased risk of prostate cancer in those taking vitamin E alone
  13. G8 scoring system?
    The G8 Score is a screening tool containing 8 questions. The total G-8 score lies between 0 and 17. A higher score indicates a better health status.

    G8 should be used as a screening tool to identify patients in need for a further assessment and appropriate care. Score of 14 or lower should undergo full geriatric evaluation

    • Evaluation of health status in Prostate cancer - EAU 2020
    • Use the Geriatric-8 and mini-COG tools for health status screening. 
    • Perform a full specialist geriatric evaluation in patients with a G8 score < 14. Strong
    • Offer symptom-directed therapy alone to frail patients. Strong

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  14. Differential diagnosis of hard prostate? ref?
    • Carcinoma prostate 
    • Granulomatous prostatitis
    • Metastasis to prostate - Liver, lung, melanoma, Bone, Kidney, ureter [@ LLMB KU]  - ref
  15. Granulomatous prostatitis?
    • It is a form of prostatitis, resulting from
    • - infection (bacterial, viral, or fungal), 
    • - BCG vaccine
    • - malacoplakia or
    • - systemic granulomatous diseases 

    • Diagnosed incidentally on histopathology
    • Broadly classified as nonspecific, specific, postsurgical (post-transurethral resection), or secondary to other rare systemic granulomatous diseases.

    • Typically presents with pain, dysuria and tendern prostate - 
    • Prostate is hard, but is not nodular - ref? bhojraj dai

    • The major concern lies in the fact that it simulates prostate malignancy on clinical as well as radiological fronts leading to overtreatment.
    • Diagnosis of granulomatous prostatitis is based on histological detection of epitheloid granulomas with or without other inflammatory cells.
Card Set
Three15 148 Epidemiology, etiology and prevention of prostate cancer screening
Prostate cancer