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Two Factors to ID Men at Highest Risk for Prostate Cancer Death

A family history of prostate cancer has long been one of the few universally accepted risk factors for the disease. New findings now provide evidence that risk stratification based on family history and inherited polygenic risk can identify men at highest risk of dying from the disease before age 75

Men in the upper quartile of polygenic risk score or who had a family history of prostate or breast cancer accounted for close to 100% of prostate cancer deaths by age 75. This strategy can also identify men at low risk for prostate cancer, potentially sparing them from intensive prostate cancer screening.

“This study provides compelling evidence for integrating a prostate cancer PRS [polygenic risk score] with information on family history of prostate and breast cancer in prostate cancer screening and risk assessment,” the authors conclude. “This is particularly relevant for assessing risk of dying from prostate cancer.”

The study results were published in Clinical Cancer Research.

Prior research has suggested that polygenic risk scores outperform family history in predicting prostate cancer risk.

A family history of prostate cancer can increase a person’s risk for the disease by a factor of 1.5 to 2, while a polygenic risk score can identify men with a nearly fourfold increased risk of prostate cancer. But polygenic risk scores do not fully explain the heritability of prostate cancer, nor do they include rare pathogenic germline variants.

In the current study, Anna Plym, PhD, from the Karolinska Institute, Stockholm, Sweden, and colleagues assessed the extent to which family history, combined with a polygenic risk score that involved 269 prostate cancer risk variants, could identify men at risk for prostate cancer and prostate cancer mortality across age groups.

The researchers followed 10,120 male participants from the Health Professionals Follow-up Study who had been genotyped as a part of multiple nested case-control studies, including a prostate cancer case-control study of 2000 case patients and control persons.

The median age of the men was 65.3 years at study entry; 2557 (25.3%) reported a family history of prostate or breast cancer (49.9% prostate cancer only, 42.4% breast cancer only, and 7.7% both). Participants with a family history of prostate or breast cancer had a higher polygenic risk score, and more reported having previously undergone prostate-specific antigen (PSA) testing, but they were otherwise similar in baseline characteristics to those without a family history.

During 20 years of follow-up, 1915 cases of prostate cancer and 166 related deaths occurred among the cohort. A family history of both breast and prostate cancer was associated with the highest risk of prostate cancer — 65% increased risk (hazard ratio [HR], 1.65); those with a family history of prostate cancer had a 58% higher risk of prostate cancer (HR, 1.58), and those with a family history of breast cancer had a 24% increased risk of prostate cancer (HR, 1.24).

Compared with men at lowest genetic risk for prostate cancer — those in the bottom polygenic risk score quartile who had no family history — those in the highest genetic risk — the top quartile with a family history of prostate or breast cancer — had nearly a sevenfold increased risk for prostate cancer and a 4.84 increased risk for prostate cancer death.

In addition, the authors found that men in the two upper quartiles (50% or above) or who had a family history of prostate or breast cancer accounted for 97.5% of prostate cancer deaths by age 75 years.

Results held when confounders such as PSA screening history, smoking, body mass index, diabetes, other cancers, and medication were added to the models.

The researchers concluded that combining a polygenic risk and family history “provides a better assessment of genetic risk of prostate cancer, and most importantly, prostate cancer death, than a traditional examination of family history alone.”

Plym and colleagues note that further research is needed to see whether being able to identify men at highest risk of dying from prostate cancer, in conjunction with appropriately tailored treatment, ultimately “translates to improved survival in the long-term.”

The study was funded by the National Cancer Institute at the National Institutes of Health, the Prostate Cancer Foundation, the Swedish Society for Medical Research, the Swedish Cancer Society, and donations from the DiNovi Family Foundation and William Casey. The authors have disclosed no relevant financial relationships.

Clin Cancer Res. Published online September 14, 2022. Abstract

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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