Prostate Cancer: Epidemiology and Pathogenesis

Epidemiology

Incidence

• Worldwide[1]
  • 2nd most common visceral malignancy in men
  • Highest in countries with the highest rates of screening
  • Estimated incidence 2020: 1,414,259
• US[2]
  • Most common malignancy in men
    • Lung and bronchus cancer second most common
  • Estimated incidence 2023: 288,300[3] (2022: 268,490)
    • ≈1/8 males are diagnosed with prostate cancer during their lifetime
  • Projected incidence 2040: 66,000[4]
• Canada[5]
  • Most common malignancy in males
    • Followed by lung and bronchus (13.2%) and colorectal (12.9%)
    • In females, most common cancers are breast (25%), lung and bronchus (13.5%), and colorectal (10.9%)
  • Estimated incidence 2020: 23,300
• Trends in incidence
  • PSA was discovered in 1979 and was licensed as a test by the FDA in 1986. Thereafter, the incidence of prostate cancer increased significantly, peaking in 1992, ≈5 years after the introduction of the PSA test.
  • Incidence then declined until 1995 (screening responsible for decrease i.e. there were now fewer people with prostate cancer in the source population as they had been screen-detected)
  • Since 1995, incidence increased at a rate similar to pre-PSA screening era, and fluctuated year-to-year since 2001 until 2011 when the draft of the 2012 US Preventative Services Task Force recommendations (see Prostate Cancer Screening) came out recommending against PSA screening in all males (grade D).
• Median age at diagnosis: 67
  • Incidence has increased in younger males and decreased in older males, largely account for by PSA screening
  • Men with prostate cancer younger than 50 years account for 2% of all cases

Mortality

• US
  • Estimated mortality 2023: 34,700[6]
    • Second most common cause of cancer-related death
      • Lung and bronchus cancer are most common cause of cancer-related death
    • Cause of death in ≈3% of US men
      • Only ≈16% of males diagnosed with prostate cancer ultimately die of it, demonstrating the indolent course of most prostate cancers
      • Most common cause of mortality in males with prostate cancer is cardiac disease[7]
• Trends in Mortality
  • Decreasing since 2001
• Average age of death from prostate cancer is 77 years
• Mortality in African-Americans 2.4x higher than Caucasians

Trends in stage

• There has been clinical and pathological stage migration over time largely due to PSA screening
• At the time of diagnosis[8]
  • ≈80% present with localized disease
  • ≈12% present with regional disease
  • ≈ 5% present with metastatic disease

Pathogenesis

• Risk factors (5 (first 3 mentioned in AUA Early Detection of Prostate Cancer Guidelines):
  1. Ethnicity
     • Incidence in Blacks > Whites > Hispanics > Asian-Americans
       • Estimated incidence in Blacks is 1.7x higher than Whites and 2x higher than HIspanics[9]
     • Males of Asian descent living in the US have a lower incidence compared to white Americans, but their risk is higher than that of Asians living in Asia, suggesting a dietary, lifestyle, environmental factor
  2. Germline mutations
     • Frequency of germline mutations in genes mediating DNA-repair processes by population:[10]
       • Metastatic prostate cancer: 12%
       • Localized prostate cancer: 5%
       • General population: 2.7%
     • BReast CAncer Genes (BRCA)
       • BRCA1 and BRCA2 variants have increased risks of both prostate cancer incidence and progression.
         • More likely to present with higher grade, locally advanced, and metastatic disease, and have worse cancer-specific survival and metastasis-free survival after prostatectomy
         • 2-6x increased lifetime risk
         • Increased risk of metastasis and prostate cancer-specific mortality[11]
         • Stronger association between BRCA2, compared to BRCA1, with both incidence and aggressive cancer
         • Systematic PSA screening is indicated
       • Hereditary breast and ovarian cancer syndrome
         • Most commonly associated with mutations in either the BRCA1 or BRCA2 gene
         • Associated cancers (5):[12]
         1. Breast (male and female)
         2. Ovarian
         3. Prostate
         4. Pancreatic
         5. Melanoma
     • Lynch syndrome[13]
       • Also known as hereditary non-polyposis colorectal cancer (HNPCC)
       • Due to inherited mutations in genes (MLH1, MSH2, MSH6, PMS2, and EPCAM) that affect DNA mismatch repair
       • Associated cancers (10)[14]
         1. Colorectal
         2. Gastric
         3. Ovarian
         4. Small bowel
         5. Upper tract urothelial carcinoma
         6. Biliary tract
         7. Pancreatic
         8. Brain cancers (glioblastoma)
         9. Sebaceous gland adenomas
         10. Keratoacanthomas
     • Other mutations
       • ATM, MLH1, MSH2, MSH6, PMS2, HOXB13, NBS1, and CHEK2
         • These mutations need further study to evaluate their role in prostate cancer incidence and aggressiveness
  3. Family history
     • ≈15% of prostate cancer patients have the familial or hereditary form
     • Risk varies according to the number of affected family numbers, their degree of relatedness, and the age at which they were affected
       • Father affected: relative risk (RR) 2.2x
       • Brother affected: RR 3.4x
       • First-degree family member affected, age <65 at diagnosis: RR 3.3x
       • >2 first-degree relatives affected: RR 5.1x
       • Second-degree relative affected: RR 1.7x
     • Criteria for "strong" family history (2):*#*#≥1 brother or father OR ≥2 male relatives with one of the following (3):
       1. 1. Diagnosed with prostate cancer at age <60 years
          2. Any of whom died of prostate cancer
          3. Any of whom had metastatic prostate cancer.
       2. Family history of other cancers with ≥2 cancers in hereditary breast and ovarian cancer syndrome or Lynch syndrome spectrum.
          • See associated cancers above
     • Patients with a "strong" family history should ideally be genotyped[15]
       • Genotype is to ascertain whether there is presence of a pathogenic variant (e.g., BRCA1/2, Lynch Syndrome, ATM, CHEK2) or one or more of a growing set of identified germline DNA damage-repair mutations found in patients with metastatic prostate cancer diagnoses.
  4. Age
     1. Prevalence of prostate cancer from autopsy series in males aged[16][17]
        1. <30: 5%
        2. 70-79: 36% of Caucasians and 51% of African-Americans
        3. >79: 59%
  5. Inflammation
     • Likely contributes to development and progression of early-stage disease
     • Potential triggers for inflammation include dietary carcinogens (especially from cooked meats), estrogens, and infectious agents
     • Studies assessing the association between infection and prostate cancer have shown mixed results; some data suggest that history of STIs and prostatitis is associated with increased risk of prostate cancer
  • Polymorphisms in both synthetic and metabolic genes, including the androgen receptor (AR), the 5-alpha reductase type 2 isoenzyme, and genes involved in testosterone biosynthesis, have been reported to affect risk
  • Insulin-like growth factor axis is important in prostate cancer risk and progression
  • Polymorphisms conferring lower vitamin D receptor activity are associated with increased risk for prostate cancer; vitamin D and its interaction with its receptor modulates disease aggressiveness
  • Smoking increases risk and is associated with worse biochemical recurrence, metastasis, and cancer-specific mortality
  • Mixed results with alcohol

Molecular Genetics

• Biologic functions of known prostate cancer susceptibility genes include:
  1. Control of the inflammatory response
  2. Homeobox genes
  3. DNA repair mechanisms
  4. Susceptibility to infection
• Most common gene fusion identified in localized prostate cancer involves TMPRSS2 or other promoters (SLC45A3, HERPUD1, or NDRG) fused to ERG (ETS-related gene)
  • The TMPRSS2 gene is prostate specific, and is expressed in both benign and malignant prostatic epithelium;
  • TMPRSS2:ERG fusion gene is detected in ≈50% of prostate cancers
  • TMPRSS2-ERG fusion gene is present in prostate stem cells
  • TMPRSS2 expression has been shown to be induced by androgens
  • TRMPSS2-related gene fusions are highly specific for the presence of prostate cancer
• Most common point mutations in prostate cancer are mutations in SPOP, which encodes a subunit of ubiquitin ligase
• Current evidence suggests that most prostate cancer is polygenic in origin. GWAS studies have identified more than 70 risk alleles and chromosomal loci, many of which occur in non-coding areas of the genome. A variety of genes implicated in prostate cancer initiation and progression include
  • Hypermethylation of
    • Hormonal response genes (ERαA, ERβ, and RARβ)
    • Genes controlling the cell cycle (CyclinD2 and 14-3-3σ)
    • Tumor cell invasion/tumor architecture genes (CD44)
    • DNA repair genes (GSTpi, GPX3, and GSTM1)
    • Tumor suppressor genes (APC, RASSF1α, DKK3, p16INK4?−α, E-cadherin, and p57WAF1)
    • Signal transduction genes (EDNRB and SFRP1)
    • Inflammatory response genes (PTGS/COX2)
  • Hypomethylation of CAGE, HPSE, and PLAU
  • Histone hypoacetylation of CAR, CPA3, RARB, and VDR
  • Histone methylation of GSTP1 and PSA
• Epigenetic mechanisms active in prostate cancer include:
  1. Chromatin remodeling
  2. Promoter hypomethylation and hypermethylation
  3. MicroRNAs that lead to gene silencing
  4. Long non-coding RNAs

Questions

1. What proportion of US males are diagnosed with prostate cancer during their lifetime?
2. Which germline mutations are associated with increased risk of prostate cancer?
3. What are the BRCA2 related cancers?
4. Which 5 ARI subtype (type 1 vs 2) is predominantly in the prostate? Also found in the brain?
5. What is the most common gene fusion identified in localized prostate cancer?

Answers

1. What proportion of US males are diagnosed with prostate cancer during their lifetime?
   • ≈1/7-1/9
2. Which germline mutations are associated with increased risk of prostate cancer?
   • HOXB13 and BRCA2
3. What are the BRCA2 related cancers?
   • Breast, ovarian, prostate, pancreatic, melanoma
4. Which 5 ARI subtype (type 1 vs 2) is predominantly in the prostate? Also found in the brain?
   • Type 2 is primarily in the prostate and other genital tissues such as the epididymis, genitalia, seminal vesicle, testis, but also in liver, uterus, breast, hair follicles, and placenta
   • Type 1 is primarily in the non-genital skin and liver, and also found in the prostate, testis, and brain
5. What is the most common gene fusion identified in localized prostate cancer?
   • TMPRSS2 fused to ERG

Additional references

Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 107