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Polygenic risk score and family history combined improve prostate cancer risk stratification

Combing the polygenic risk score and family history data enables a much better risk stratification for prostate cancer mortality

The use of an inherited polygenic risk score and an individual’s family history of prostate or breast cancer provides a much better method for risk stratification for disease mortality according to the findings of a study by US researchers.

Prostate cancer is the second most frequent cancer diagnosis made in men and the fifth leading cause of death worldwide. Moreover, global data suggests that in 2020 there were 1,414,259 new cases and 375,304 deaths from the cancer. The importance of family history as a risk factor has been known for several decades and a 1990 case-control study found that men with a father or brother affected by the cancer were twice as likely to develop prostate cancer compared to men without affected relatives.

Given the higher risk for men with a family history of the cancer, in recent years, genome-wide association studies have been used to identify a polygenic risk score (PRS) and which influences prostate cancer susceptibility. In fact, the PRS can be used to identify a substantial proportion of men at high-risk for prostate cancer.

Interestingly, some evidence indicates that men with a family history of breast or prostate cancer had elevated prostate cancer risks, including the risk of lethal disease. With both a PRS and the presence of a family history able to evaluate an individual’s risk of developing prostate cancer, for the present study, the US researchers wondered about the prognostic value of combining these two risk scores.

The researchers used data from the Health Professionals Follow-up Study (HPFS) in which information on a family history of prostate and breast cancer had been collected. In addition, men in the HPFS study were invited to provide a blood or buccal sample for genotyping.

The US team then collated data for men who had genotyped samples and who were prostate cancer free. They defined genetic risk in terms of a family history (Yes/No) of either prostate or breast cancer and divided the polygenic risk score into quartiles. The primary outcomes were prostate cancer and prostate cancer-specific death and the researchers used regression models to assess the association between PRS, family history and the risk of developing prostate cancer and of dying from the cancer.

Polygenic risk score and prostate cancer

Data were available for 10,120 men with a median age of 65.3 years at entry into the study of whom 49.9% reported a family history of prostate cancer and 7.7% had a history of both prostate and breast cancer.

A total of 1,915 cases of prostate cancer and 166 fatal prostate cancers were detected during a median follow-up of 18.3 and 23.2 years respectively.

When researchers considered a family history of prostate cancer, this was associated with a 58% higher risk of developing the cancer (Hazard ratio, HR = 1.58, 95% CI 1.38 – 1.81) and a 60% higher risk of prostate cancer-related death (HR = 1.60, 95% CI 1.06 – 2.42). In addition, using the top quartile polygenic risk score, the hazard ratio for prostate cancer was 5.29 (95% CI 4.47 – 6.27) and 3.68 (95% CI 2.29 – 5.90) for mortality.

But when both the PRS and a family history of prostate or breast cancer were included in a model, the hazard ratio increased to 6.95 (95% CI 5.57 – 8.66) and the associated hazard ratio for prostate cancer mortality was 4.84 (95% CI 2.59 – 9.03) compared to men in the lowest quartile and without a family history of either prostate or breast cancer. Overall, men within the upper two PRS quartiles (i.e., 50 to 100%) and who had a family history or prostate, or breast cancer accounted for 97.5% of prostate cancer deaths by age 75.

The authors concluded that using both the polygenic risk score and the presence of a family history, can enable the identification of men who at the highest risk of dying from prostate cancer before the age of 75.

Citation
Plym A et al. Family history of prostate and breast cancer integrated with a polygenic risk score identifies men at highest risk of dying from prostate cancer before age 75 years. Clin Cancer Res 2022

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