BRCA mutations increase risk of reclassification in AS

April 11, 2019

"Patients with favorable-risk disease who have a DNA repair mutation should be counseled that there is a significantly increased risk of reclassification with AS," writes Stacy Loeb, MD, MSc.

Dr. Loeb,

a member of the

Urology Times 

Editorial Council, is assistant professor of urology and population health, New York University Langone and the Manhattan VA, New York.

Current guidelines recommend active surveillance (AS) as the preferred management for most patients with low-risk prostate cancer (bit.ly/prostateCaguide). Although its use has increased substantially over time, AS continues to be underutilized in the U.S. (JAMA 2015; 314:80-2). The reasons for this are multifactorial (BJU Int 2017; 120:32-9) and include uncertainty over the optimal patient selection and follow-up strategies.

There has been increasing recognition of the impact of germline mutations on prostate cancer risk and management decisions. In a study of men with metastatic disease, DNA repair gene mutations were identified in 11.8% (N Engl J Med 2016; 375:443-53). The 2018 NCCN prostate cancer guidelines recommend considering germline testing for all men with advanced and metastatic prostate cancer.

Related: Germline mutations linked to grade reclassification during AS

The prevalence of DNA repair mutations is lower in men with localized prostate cancer. For men with favorable-risk disease, the 2018 NCCN guidelines only recommend genetic testing if there is a strong family history (bit.ly/NCCNguide).

An important study by Carter et al evaluated the prevalence of germline DNA repair mutations in men with favorable-risk prostate cancer and their association with grade reclassification during AS (Eur Urol Oct. 8, 2018 [Epub ahead of print]). A total of 1,211 men on AS had a blood sample used for germline sequencing (three-gene panel). The overall frequency of germline mutations was low: BRCA1 in 11 patients (0.9%), BRCA2 in 11 (0.9%), and ATM in five (0.4%). Overall, 42% of men with mutations had grade reclassification vs. 23% of non-carriers (p=.04).

How genetic results should influence patient management has already been discussed at several consensus conferences. At the 2017 Philadelphia Prostate Cancer Consensus Conference, 64% of participants voted that BRCA2 mutation status should be factored into management discussions for early-stage/localized prostate cancer (J Clin Oncol 2018; 36:414-24). At the Advanced Prostate Cancer Consensus Conference, when asked whether the presence of a germline BRCA1, BRCA2, or ATM mutation would influence their treatment decisions for low-risk prostate cancer, 45% of panel members voted against AS, 35% voted for standard treatment options (including AS), and 20% voted for another treatment option (Eur Urol 2018; 73:178-211).

The study by Carter et al provides important new data addressing this clinical question. Patients with favorable-risk disease who have a DNA repair mutation should be counseled that there is a significantly increased risk of reclassification with AS.