Prostate cancer is the most common male malignancy in North America but follows an indolent course in most men — only ~16% of those diagnosed ultimately die of it, and the most common cause of death in men with prostate cancer is cardiac disease. Its incidence has been driven heavily by PSA screening, and a substantial minority of cases are hereditary.
Epidemiology
Incidence:
- Worldwide — the 2nd most common visceral malignancy in men; highest in countries with the most screening (estimated 1,414,259 cases in 2020).
- US — the most common male malignancy (lung/bronchus second); estimated 299,010 in 2024 (288,300 in 2023; 268,490 in 2022). About 1 in 8 males is diagnosed in his lifetime. (A projected 2040 incidence of 66,000 is cited in the source — see Corrections; this appears inconsistent with the rising trend.)
- Canada — the most common male malignancy, followed by lung/bronchus (13.2%) and colorectal (12.9%); estimated 23,300 in 2020. (In Canadian females the most common cancers are breast 25%, lung 13.5%, colorectal 10.9%.)
Trends: PSA was discovered in 1979 and FDA-licensed as a test in 1986; incidence then rose sharply, peaking in 1992 (~5 years after PSA), declined until 1995 (screen-detection depleting the source population), then rose again at a pre-PSA rate, fluctuating since 2001 until the 2011 draft USPSTF recommendation against PSA screening (grade D). Median age at diagnosis is 67; men <50 account for 2% of cases.
Mortality (US): estimated 34,700 in 2023 — the 2nd most common cause of cancer death (lung first); cause of death in ~3% of men. Mortality has been decreasing since 2001; the average age at death is 77, and mortality in African-Americans is ~2.4× that of Caucasians.
Stage at diagnosis (SEER): ~80% localized, ~12% regional, ~5% metastatic.
Pathogenesis and Risk Factors
Inherited (germline): the frequency of germline DNA-repair-gene mutations rises with disease burden — metastatic 12%, localized 5%, general population 2.7%. True hereditary disease is defined as >3 cases in one family, prostate cancer in 3 successive generations, or >2 men diagnosed <55 years; it has earlier onset (by 6–7 years) but is not more aggressive.
- BRCA1/BRCA2 — a 2–6× lifetime risk, with higher-grade, locally advanced, and metastatic disease and worse cancer-specific and metastasis-free survival after prostatectomy; BRCA2 is more strongly associated than BRCA1; systematic PSA screening is indicated. Part of hereditary breast and ovarian cancer (HBOC) syndrome — associated cancers: breast (male and female), ovarian, prostate, pancreatic, melanoma.
- Lynch syndrome (HNPCC) — from mismatch-repair gene mutations (MLH1, MSH2, MSH6, PMS2, EPCAM); associated cancers: colorectal, gastric, ovarian, small bowel, urologic (upper-tract urothelial, bladder, prostate), biliary tract, pancreatic, brain (glioblastoma), sebaceous adenomas, keratoacanthomas.
- Other mutations (require further study): ATM, MLH1, MSH2, MSH6, PMS2, HOXB13, NBS1, CHEK2.
Family history — ~15% of patients have the familial/hereditary form (defined as >2 first- or second-degree relatives on the same side). Relative risk by affected relative:
| Affected relative | Relative risk |
|---|---|
| Father | 2.2× |
| Brother | 3.4× |
| First-degree relative, age <65 at diagnosis | 3.3× |
| >2 first-degree relatives | 5.1× |
| Second-degree relative | 1.7× |
A "strong" family history = ≥1 brother/father or ≥2 male relatives diagnosed <60, who died of prostate cancer, or who had metastatic disease; or ≥2 HBOC/Lynch-spectrum cancers in the family. Patients with a strong family history should ideally be genotyped (BRCA1/2, Lynch, ATM, CHEK2, and other DNA-repair mutations).
Ethnicity: incidence is Blacks > Whites > Hispanics > Asian-Americans (Blacks ~1.7× Whites and ~2× Hispanics); Asian-Americans have higher risk than Asians in Asia, suggesting dietary/lifestyle/environmental factors.
Age (autopsy prevalence): <30 years 5%; 70–79 years 36% (Caucasians) and 51% (African-Americans); >79 years 59%.
External factors: inflammation (triggered by dietary carcinogens from cooked meats, estrogens, and infections — STI/prostatitis data are mixed); polymorphisms in the androgen receptor, 5-alpha reductase type 2, and testosterone-biosynthesis genes; the insulin-like growth factor axis; low-activity vitamin-D-receptor polymorphisms; and smoking (worse biochemical recurrence, metastasis, and cancer-specific mortality). Alcohol data are mixed.
Molecular Genetics
Known susceptibility genes control the inflammatory response, homeobox functions, DNA repair, and infection susceptibility. The most common gene fusion in localized disease is TMPRSS2:ERG (~50% of cancers) — TMPRSS2 is prostate-specific, androgen-induced, and present in prostate stem cells (it may also fuse to SLC45A3, HERPUD1, or NDRG promoters). The most common point mutation is in SPOP (a ubiquitin-ligase subunit). Prostate cancer is largely polygenic (GWAS has identified >70 risk alleles), with epigenetic mechanisms including chromatin remodeling, promoter hyper-/hypomethylation, histone modification, microRNAs, and long non-coding RNAs.
Prevention
No agent is recommended for prostate-cancer chemoprevention. The 5-alpha reductase inhibitors reduce overall cancer detection but raise concern about high-grade disease, and antioxidant supplements have shown no benefit (vitamin E may be harmful).
5-Alpha Reductase Inhibitors
Randomized trials (PCPT and REDUCE) showed 5-ARIs give a ~5% reduced risk of cancer detection but a slight increase in high-grade cancer — thought to reflect easier detection of a high-grade focus in a drug-shrunken gland. The FDA concluded 5-ARIs do not have a favourable risk-benefit profile for chemoprevention (for every 150–200 men treated, 1 additional high-grade cancer would be diagnosed to avert 3–4 low-grade cancers).
- PCPT (Thompson 2003) — n=18,882, age ≥55, normal DRE, PSA ≤3.0; finasteride 5 mg vs placebo, with end-of-study (7-year) or for-cause biopsy. Finasteride gave a 6% absolute risk reduction in incident cancer (18.4% vs 24.4%) but a 15% absolute increase in biopsy Gleason 7–10 among those biopsied (37% vs 22%). Long-term follow-up showed no effect on cancer-specific survival (Goodman 2019).
- REDUCE (Andriole 2010) — n=8,231, age 50–75, negative prior biopsy, PSA 2.5–10, prostate ≤80 cc; dutasteride vs placebo with mandated biopsies at 2 and 4 years. Dutasteride gave a 5% absolute risk reduction (19.9% vs 25.1%); no overall difference in Gleason 7–10, but an increased risk of Gleason 8–10 in years 3–4.
Selenium and Vitamin E (SELECT, Lippman 2009)
n=35,533 with normal DRE, PSA ≤4, and normal blood pressure, randomized to selenium, vitamin E, both, or placebo. The trial was stopped early for no effect; follow-up showed dietary vitamin E supplementation increased prostate-cancer risk.
Lycopene and Others
- Lycopene — a carotenoid in tomatoes; an animal model showed a protective effect for calorie restriction and tomato powder but not pure lycopene, and a meta-analysis of 3 RCTs found no association with prostate-cancer risk.
- HGPIN trials: selenium + vitamin E + soy did not reduce risk; green tea catechin reduced risk (n=60); toremifene did not reduce risk at 3 years (n=1,467).
Self-Test
1. What proportion of US males are diagnosed with prostate cancer in their lifetime? About 1 in 8 (≈1/7–1/9).
2. Which germline mutations are associated with increased prostate-cancer risk? HOXB13 and BRCA2 (also BRCA1, ATM, CHEK2, and the Lynch mismatch-repair genes).
3. What are the BRCA2-related cancers? Breast, ovarian, prostate, pancreatic, and melanoma.
4. Which 5-alpha reductase subtype predominates in the prostate, and which is also found in the brain? Type 2 predominates in the prostate and other genital tissues (epididymis, genitalia, seminal vesicle, testis; also liver, uterus, breast, hair follicles, placenta). Type 1 is mainly in non-genital skin and liver, and is also found in the prostate, testis, and brain.
5. What is the most common gene fusion in localized prostate cancer? TMPRSS2 fused to ERG.
6. Describe the PCPT trial. n=18,882 men ≥55 with normal DRE and PSA ≤3.0 randomized to finasteride 5 mg vs placebo for 7 years (biopsy at study end or for cause). Finasteride reduced incident cancer by 6% absolute (18.4% vs 24.4%) but increased biopsy Gleason 7–10 disease; no effect on cancer-specific survival.
7. List the benefits of 5-ARIs. ~5% reduced prostate-cancer detection, plus the general benefits: reduced acute urinary retention and BPH-related surgery, reduced prostatitis, and improved PSA/DRE sensitivity for cancer detection.
8. List the side effects of 5-ARIs. Reduced ejaculate volume, erectile dysfunction, reduced libido, and gynecomastia.