Germline BRCA Mutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer

Abstract

A B S T R A C T PurposeTo analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes. Patients and MethodsThis study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M 0 ), metastasis-free survival (MFS), and CSS from metastasis (CSS_M 1 ). ResultsPCa with germline BRCA1/2 mutations were more frequently associated with Gleason Ն 8 (P ϭ .00003), T3/T4 stage (P ϭ .003), nodal involvement (P ϭ .00005), and metastases at diagnosis (P ϭ .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P ϭ .015; hazard ratio [HR] ϭ 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P ϭ .01; HR ϭ 2.6%; and 93% v 77%; MVA P ϭ .009; HR ϭ 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup. ConclusionOur results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.

Prostate cancer screening characteristics in men with BRCA1/2 mutations attending a high-risk prevention clinic

“…11 Indeed, Castro and colleagues analyzed the clinicpathological characteristics of prostate cancers in BRCA1 and BRCA2 carriers and found carriers more frequently had high Gleason scores (8 or above), T3/4 stage, nodal involvement, metastases at diagnosis, and found that cause specific survival was shorter compared to non-carriers. 12 Other similar studies corroborate these findings. [13][14][15][16] Until recently, reports on the screening outcomes of male BRCA1/2 carriers have been scarce and often limited to specific founder mutations studied in a select population.…”

Erratum: Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition

“…However, there were no differences in median PSAV between carriers and noncarriers. Given the possibility that higher PSAV may associate with aggressive PrCa (D'Amico et al, 2004; D'Amico et al, 2005), we would expect BRCA2 carriers who are at risk of aggressive disease would exhibit higher PSAVs (Castro et al, 2013;Castro et al, 2015). BRCA2 carriers in this group may be too young to demonstrate this trend at this point of follow up.…”

“…This may help delineate PSAV among men diagnosed with PrCa with low PSA values (Carter et al, 1992; Kitagawa et al, 2014). A strength of this study is the unique patient cohort of men with a genetic predisposition to PrCa, in particular BRCA2 carriers who are predisposed to aggressive PrCas (Mitra et al, 2008;Narod et al, 2008;Castro et al, 2013;Castro et al, 2015). Within the group of BRCA2 carriers, PSAV proved predictive of any grade cancer, however, given the low number of cancers diagnosed overall it was not possible to assess whether PSAV was associated with high grade cancer and BRCA2 status.…”

“…There remains debate about whether there is an increased risk of PrCa associated with BRCA1 mutations, with some studies reporting no increased risk to those reporting a 1.8-3.75 fold increased risk (Thompson et al, 2002;Leongamornlert et al, 2012;Moran et al, 2012). A number of studies have reported that BRCA2 mutation carriers have more aggressive disease, suggested by their younger age at diagnosis, higher rates of lymph node involvement and distant metastasis at diagnosis, and higher mortality rates compared with non-carriers (Tryggvadóttir et al, 2007;Mitra et al, 2008;Edwards et al, 2010;Gallagher et al, 2010;Thorne et al, 2011;Castro et al, 2013). There is increasing evidence that BRCA1 mutation carriers may also harbour more aggressive disease (Giusti et al, 2003;Gallagher et al, 2010;Castro et al, 2013).…”

“…A number of studies have reported that BRCA2 mutation carriers have more aggressive disease, suggested by their younger age at diagnosis, higher rates of lymph node involvement and distant metastasis at diagnosis, and higher mortality rates compared with non-carriers (Tryggvadóttir et al, 2007;Mitra et al, 2008;Edwards et al, 2010;Gallagher et al, 2010;Thorne et al, 2011;Castro et al, 2013). There is increasing evidence that BRCA1 mutation carriers may also harbour more aggressive disease (Giusti et al, 2003;Gallagher et al, 2010;Castro et al, 2013). Furthermore, BRCA2-mutant localised prostate cancer demonstrates increased genomic instability and a mutational profile that more closely resembles metastastic than localised disease, therefore supporting early detection in this at risk patient population (Taylor et al, 2017).…”