Lethal Prostate Cancer Linked to BRCA1/2, ATM Mutations

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Mutation carrier status was associated with earlier death and among lethal prostate cancer patients (age 67 vs 72 in non-carriers) and shorter survival.
Mutation carrier status was associated with earlier death and among lethal prostate cancer patients (age 67 vs 72 in non-carriers) and shorter survival.

Germline mutations in the BRCA2 gene are linked to development of prostate cancer (PCa) and suggests BRCA1/2 and ATM mutation carrier status may help distinguish lethal from indolent PCa, a new study confirms.

Based on previous research findings, an international team led by Jianfeng Xu, MD, DrPH, of North Shore University Health System in Evanston, Illinois, William Isaacs, PhD, of Johns Hopkins University in Baltimore, and Qiang Ding, MD, of Fudan University in Shanghai, compared carrier rates for mutations in any of the 3 DNA repair genes among 313 men who died with lethal metastatic PCa and 486 men with localized, low-risk disease. The investigators analyzed germline DNA in 3 populations: men of European, African, and Chinese ancestry.

The combined carrier rate for the inherited mutations was higher in patients with aggressive versus localized PCa: 6.07 vs 1.44%, according to results published online ahead of print in European Urology. The rate differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% among patients who died at age 60 years or younger and 61–65, 66–70, 71–75, and over 75 years, respectively, and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died 5 years or less and 6–10, and more than 10 years after PCa diagnosis, respectively).

After performing a survival analysis on the entire population, the investigators determined that carrier status independently predicted lethal PCa. Race, age, PSA, and Gleason score at the time of diagnosis did not attenuate risk.

“The study results have an important translational impact because they clearly demonstrate germline mutations in these three well-established genes can be used to predict risk for lethal prostate cancer and time to death,” Dr Xu stated in a press release. “This confirms major findings from previous studies and provides further direct evidence of the important role of genetic testing in prostate cancer screening and treatment.”

Guidelines recommend clinicians inquire about a family history of BRCA1/2 mutations. The researchers recommend that clinicians also ask patients whether a family member died of PCa before age 75. Mutation carrier status also may be an important factor for patients considering active surveillance.

References

1. Na R, Zheng SL, Han M, et al. Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. Eur Urol. doi: 10.1016/j.eururo.2016.11.033.

2. New study affirms the role of inherited genetic mutations in helping distinguish potentially deadly prostate cancer from benign forms of the disease. [press release]. North Shore Health Systems; December 15, 2016.

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