Germline mutations linked to grade reclassification during AS

Men with prostate cancer who are carriers of germline pathogenic mutations in the DNA repair genes BRCA1/2 and ATM are at increased risk for grade reclassification during active surveillance, according to research reported by H. Ballentine Carter, MD, at the 2018 AUA annual meeting in San Francisco.

“Active surveillance is often the preferred management for men with favorable-risk prostate cancer, but some men on active surveillance have adverse outcomes,” said Dr. Carter, Bernard L. Schwartz Distinguished Professor of Urologic Oncology and professor of urology, Johns Hopkins University, Baltimore.

“Our findings suggest that active surveillance may not be the preferred management option for men with germline pathogenic mutations in these DNA repair genes.”

Commentary: BRCA mutations increase risk of reclassification in AS

The study was published in European Urology (Oct. 8, 2018 [Epub ahead of print]) following its initial presentation at the AUA annual meeting.

The idea that germline pathogenic mutations in BRCA1/2 and ATM may independently identify men at risk for grade reclassification during active surveillance derived from recent evidence linking such mutations with metastatic and lethal prostate cancer.

To investigate the hypothesis, a study was conducted involving two independent cohorts of prostate cancer patients undergoing active surveillance. The study population comprised 882 men seen at Johns Hopkins and 329 men from the NorthShore University HealthSystem in suburban Chicago. All men had germline DNA samples that had been sequenced for 54 DNA repair genes, including BRCA1/2 and ATM. The sequencing was done at NorthShore using a targeted next-generation sequencing panel, and pathogenic mutations were defined according to American College of Medical Genetics guidelines.

At diagnosis, 97.6% of men were in grade group 1 (GG1, defined by a Gleason score of 3+3); 2.2% were in GG2 (Gleason score 3+4); and 0.2% were in GG3 (Gleason score 4+3). In surveillance biopsies obtained during a median follow-up of 3 years, 24% of men were reclassified (upgraded) from GG1 to a higher GG, and 8% were upgraded from GG1 to a GG >2.

Next: Carrier rate for mutations higher in reclassified menCarrier rate for mutations higher in reclassified men

The carrier rate for pathogenic mutations in any of the three genes was significantly higher in men who were reclassified compared to those whose GG remained unchanged (3.8 vs. 1.6%), and the cumulative incidence of upgrading was significantly higher for mutation carriers versus noncarriers (41% vs. 22%). In a multivariable analysis adjusting for age, PSA density, number of cores with cancer, and Eigenvalues (genetic background), mutation carriers had a statistically significant, twofold higher risk for upgrading than noncarriers, Dr. Carter reported.

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Analyses considering the three genes individually showed that men with a pathogenic mutation in BRCA2 had the greatest risk for reclassification. Fifty percent of men carrying a pathogenic mutation in BRCA2 were reclassified during follow-up compared with 22% of men without a pathogenic BRCA2 mutation. In the adjusted analysis, carrying a BRCA2 pathogenic mutation increased the risk of upgrading by 2.74-fold.

The cumulative incidence of upgrading from GG1 to GG ≥3 was also significantly higher for men with a pathogenic mutation in any of the three genes compared with noncarriers (20% vs. 8%), and in the adjusted analysis, mutation carriers had a 2.4-fold increased risk of upgrading from GG1 to GG ≥3.

A pathogenic mutation in BRCA2 was also associated with the strongest risk for upgrading from GG1 to GG ≥3. The incidence of upgrading from GG1 to GG ≥3 was 36% among men with a pathogenic mutation in BRCA2 and 8% in noncarriers. In the multivariable analysis, carriers of a pathogenic mutation in BRCA2 had a 5-fold increased risk for upgrading from GG1 to GG ≥3.