BRCA1/2 Linked to Poor Prognosis in Prostate Cancer

Elena Castro, MD, and David Olmos, MD, PhD, Spanish National Cancer Research Centre

A new study suggests that germline mutations of BRCA1/2 could play a significant role in more-aggressive cases of prostate cancer. Additionally, BRCA2 mutations were specifically linked to poor overall survival.

Excluding advanced age, family history of prostate cancer is the strongest risk factor for the disease. Genomewide association studies have identified more than 70 DNA sequences associated with a risk of developing prostate cancer. Previous research has found that BRCA1 and BRCA2 mutations are relatively rare in prostate cancer, occurring in only 0.44% and 1.2% of cases, respectively. However, that still amounts to thousands of patients, since more than 900,000 new cases of prostate cancer are diagnosed worldwide annually.

“Whilst the majority of patients with prostate cancer have an excellent prognosis, one of the biggest challenges we face in daily clinical practice is the difficulty of identifying those patients in which the illness can be fatal,” said David Olmos, MD, PhD, head of the Prostate Cancer and Genitourinary Tumours Clinical Research Unit at the Spanish National Cancer Research Centre (CNIO), in a statement. Olmos worked with Elena Castro, MD, another member of the unit and lead author of the study.

In this retrospective analysis, patients from two ongoing prospective studies, the United Kingdom Genetic Prostate Cancer study (UKGPCS) and Epidemiological Study of BRCA1/2 Mutation Carriers (EMBRACE), were analyzed. A total of 2019 patients with prostate cancer were eligible, which included 18 BRCA1 mutation carriers, 61 BRCA2 mutation carriers, and 1940 noncarriers. Researchers used the Kaplan-Meier method and Cox regression analysis to evaluate the association between BRCA1/2 status and overall survival, cause-specific overall survival (CSS), CSS in localized prostate cancer (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M₁).

The researchers found that prostate cancer with germline BRCA1/2 mutations were more frequently associated with a Gleason score ≥8 (P = .00003), T3/ T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than in prostate cancer in patients who did not exhibit those mutations. Additionally, CSS was longer in noncarriers than in carriers (15.7 years vs 8.6 years; multivariable analysis [MVA] P = .015; hazard ratio [HR] = 1.8). Patients with localized prostate cancer had significantly higher 5-year CSS and MFS if they were noncarriers compared with carriers (96% vs 82%; MVA P = .01; HR = 2.6; and 93% vs 77%; MVA P = .009; HR = 2.7, respectively).

A subgroup analysis was performed with patients whose disease had not spread at diagnosis. This analysis found that 23% of BRCA1/2 carriers developed metastases over the following 5 years compared with 7% of noncarriers. At 5 years postdiagnosis, 19% of patients with early-stage disease with the BRCA2 mutation had died compared with 4% of noncarriers. No significant difference in survival was observed between patients with a BRCA1 mutation and noncarriers.

“These data turn the BRCA2 gene into the first genetic factor for prostate cancer prognosis,” Castro said in a statement. “The results of this study suggest the need for a paradigm shift in the clinical management of patients with prostate cancer who are carriers of mutations in the BRCA genes; current treatment standards for these patients appear to be insufficient and there are no specific action guidelines.”

Olmos added that the next step is to explore adequate treatment options for patients who have these mutations.

Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer [published online ahead of print April 8, 2013]. J Clin Oncol. doi:10.1200/JCO.2012.43.1882.