Family History is the Greatest Risk Factor for Lethal Prostate Cancer
Family history of prostate cancer is the strongest risk factor associated with lethal prostate cancer, with men having multiple affected first-degree relatives facing up to a 5.3-fold increased risk of dying from prostate cancer. 1
Key Risk Factors for Lethal Prostate Cancer
Family History
- Men with one first-degree relative with prostate cancer have a 2.49-fold increased risk of lethal prostate cancer 1
- Risk increases dramatically with multiple affected relatives:
- Family history remains significant even when no first-degree relatives are affected but multiple second or third-degree relatives have had lethal prostate cancer 1
- Maternal and paternal family histories confer equivalent risks 1
Genetic Factors
- Having two or more genetic risk factors (family history, high polygenic risk score, rare variants in DNA repair genes) increases odds of early lethal disease by 3.5-fold 2
- BRCA2 mutations are associated with a 2-6 fold increase in prostate cancer risk and are linked to more aggressive disease 3
- Approximately 9% of prostate malignancies are due to inherited predisposition 3
- Chromosomes 1,8,10,16,17,20, and X have been associated with prostate cancer, with chromosome 1 most strongly linked 3
Age Considerations
- More than 70% of prostate cancer patients are older than 65 years at diagnosis 3
- Median age at diagnosis is 71 years; median age at death is 78 years 3
- More than 90% of deaths from prostate cancer occur in men older than 65 years 3
- Early-onset prostate cancers (diagnosed before age 55) are more likely to be inherited, with approximately 42% having a hereditary component 3
Race and Ethnicity
- African American men have:
- However, stage and grade-adjusted mortality rates are similar between races, suggesting access to care may play a role 3
Clinical Implications
Risk Assessment
- Baseline PSA value is a stronger predictive factor than family history or African American heritage, but family history remains crucial for risk stratification 3
- Men with a family history of prostate cancer are significantly more likely to undergo biopsy, even when controlling for PSA and digital rectal examination findings 3
- Familial prostate cancers generally follow a more aggressive course, with higher grade and stage at diagnosis and increased risk of death 3
Screening Recommendations
- Consider earlier and more intensive screening for men with:
- Family history assessment should be thorough at the time of prostate cancer diagnosis to help identify patients at risk for more aggressive disease 4
Second Primary Cancers
- Prostate cancer patients with family history have a 37% increased risk of developing second primary cancers compared to 10% without family history 4
- In patients with second primary cancers, these malignancies account for half of all deaths, while only 12.77% die from the original prostate cancer 4
- Family history increases risk of specific second cancers, including colorectal, lung, kidney, bladder, and skin cancers 4
Common Pitfalls and Caveats
- Relying solely on PSA testing without considering family history may miss high-risk individuals 3
- Failure to account for 5-alpha reductase inhibitors (finasteride, dutasteride) when interpreting PSA results - these medications reduce PSA by approximately 50% 3, 5
- Starting screening before any prostate cancers are diagnosed in a family may be counterproductive 6
- Not all prostate cancers require treatment - careful risk stratification is essential to avoid overtreatment 3
- Focusing only on first-degree relatives may miss significant family history in second and third-degree relatives 1