Familial History of Prostate Cancer Strongly Linked With Early-Onset Disease

Jennifer Beebe-Dimmer, MPH, PhD

While the risk of prostate cancer varies by family history, it is strongly associated with early onset of disease, according to results of a large, population-based, family database study published in the Journal of Clinical Oncology.

Findings showed that family history of hereditary prostate cancer posed the greatest relative risk (RR) for all prostate cancer subtypes combined (RR, 2.30; 95% CI, 2.22-2.40). This was followed by hereditary breast and ovarian cancer, as well as Lynch syndrome, which were all statistically significant (both 1

Investigators gathered the results from the database in an effort to understand and target high-risk populations that would benefit from genetic screening and enhanced surveillance.

“The observation in our study that men with either 3 first-degree relatives with [prostate cancer] or 2 first- or second-degree relatives diagnosed with early-onset [prostate cancer] had a more than 8-fold increase in the diagnosis of early-onset [prostate cancer] is important and merits replication in other studies, because this confirmation would affect the age at which [prostate cancer] screening should be initiated,” Jennifer Beebe-Dimmer, MPH, PhD, of Wayne State University, and co-investigators wrote.

Data were collected from the Utah Population Database (UPDB), which provides family history information from the Genealogical Society of Utah, state records, and the Utah Cancer Registry.

Through the UPDB, investigators identified a total of 619,630 men, aged ≥40 years, whose family history included ≥3 consecutive generations. Each man was evaluated for family history of hereditary prostate cancer, breast and ovarian cancer, and Lynch syndrome, as well as his own prostate cancer status. Prostate cancer occurrences (n = 36,360) were classified into 3 subtypes: early-onset, lethal, and/or clinically significant.

At the time of the study in August 2018, 68.1% of men identified (n = 421,827) were alive. The median age of those alive was 57.5 years (interquartile range [IQR], 48.1-66.9 years) and the median age at time of death was 75.5 years (IQR, 64.6-83.9 years). Occurrence of prostate cancer was found in 5.9% of the cohort; 7.0% of patients met the criteria for early-onset disease, 11.1% for lethal disease, and 41.8% for clinically significant disease. The median age at time of diagnosis was 69.0 years (IQR, 63.0-76.0 years).

Investigators defined 3 forms of hereditary prostate cancer that affected risk: ≥3 first-degree relatives with prostate cancer, ≥3 affected relatives spanning 3 generations to third-degree relatives, and ≥2 first- or second-degree relatives diagnosed with prostate cancer at age ≤55 years. The most common form of hereditary prostate cancer was ≥3 affected relatives spanning 3 generations (n = 11,104); other forms were uncommon. Men with ≥3 affected first-degree relatives (n = 2618; RR, 8.72; 95% CI, 6.60-11.5) or men with >1 first-degree and/or second- degree relative with prostate cancer (n = 893; RR, 8.92; 95% CI, 6.07-13.1) experienced an increased risk for early-onset prostate cancer.

More than 70% of men in the study were diagnosed with organ-confined disease and approximately 6% were first diagnosed with metastatic disease. Seventy-one percent of patients were missing information on their Gleason score; however, among those patients with information on their Gleason score (n = 10,523 men), 46.7% were diagnosed with a Gleason score of ≤6; 39.0% with a score of 7; and 14.3% with a score of ≥8.

Family history of prostate cancer (RRs, 1.81; 95% CI, 1.76-1.86), hereditary breast and ovarian cancer (RRs, 1.47; 95% CI, 1.43-1.50), and Lynch syndrome (RRs, 1.16; 95% CI, 1.12-1.19) were also all associated with an increased risk. Hereditary prostate cancer was associated with a 4-fold increase in risk for early-onset prostate cancer (RR, 3.93; 95% CI, 3.33-4.61).

Moreover, hereditary prostate cancer was also associated with higher risks for both lethal prostate cancer (RR, 2.21; 95% CI, 1.95-2.50) and clinically significant disease (RR, 2.32; 95% CI, 2.17-2.48). Less severe elevations in risk were found in Lynch syndrome at a 34% increased risk for early-onset disease (RR, 1.34; 95% CI, 1.18-1.52) and clinically significant disease (RR, 1.15; 95% CI, 1.10-1.21).

Future studies should utilize the 3 identified subtypes to discover new genes of prostate cancer that can be used in genetic screening and risk assessment, the investigators concluded.

Beebe-Dimmer JL, Kapron AL, Fraser AM, et al. Risk of prostate cancer associated with familial and hereditary cancer syndromes [published on March 24, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.02808