Elsevier

European Urology

Volume 68, Issue 2, August 2015, Pages 186-193
European Urology

Platinum Priority – Prostate Cancer
Editorial by Ola Bratt and Niklas Loman on pp. 194–195 of this issue
Effect of BRCA Mutations on Metastatic Relapse and Cause-specific Survival After Radical Treatment for Localised Prostate Cancer

https://doi.org/10.1016/j.eururo.2014.10.022Get rights and content

Abstract

Background

Germline BRCA mutations are associated with worse prostate cancer (PCa) outcomes; however, the most appropriate management for mutation carriers has not yet been investigated.

Objective

To evaluate the response of BRCA carriers to conventional treatments for localised PCa by analysing metastasis-free survival (MFS) and cause-specific survival (CSS) following radical prostatectomy (RP) or external-beam radiation therapy (RT).

Design, setting, and participants

Tumour features and outcomes of 1302 patients with local/locally advanced PCa (including 67 BRCA mutation carriers) were analysed. RP was undergone by 535 patients (35 BRCA); 767 received RT (32 BRCA). Median follow-up was 64 mo.

Outcome measurements and statistical analysis

Median survival and 3-, 5-, and 10-yr survival rates were estimated using the Kaplan-Meier method. Generated survival curves were compared using the log-rank test. Cox regression analyses were used to assess the prognostic value of BRCA mutations.

Results and limitations

A total of 67 BRCA carriers and 1235 noncarriers were included. At 3, 5, and 10 yr after treatment, 97%, 94%, and 84% of noncarriers and 90%, 72%, and 50% of carriers were free from metastasis (p < 0.001). The 3-, 5- and 10-yr CSS rates were significantly better in the noncarrier cohort (99%, 97%, and 85%, respectively) than in carriers (96%, 76%, and 61%, respectively; p < 0.001). Multivariate analysis confirmed BRCA mutations as an independent prognostic factor for MFS (hazard ratio [HR]: 2.36; 95% confidence interval [CI], 1.38–4.03; p = 0.002) and CSS (HR: 2.17; 95% CI, 1.16–4.07; p = 0.016).

Conclusions

BRCA carriers had worse outcomes than noncarriers when conventionally treated for local/locally advanced PCa.

Patient summary

Prostate cancer patients with germline BRCA mutations had worse outcomes than noncarriers when conventionally treated with surgery or radiation therapy.

Introduction

Advances in prostate cancer (PCa) diagnosis and treatment during the last 25 yr have improved patients’ survival [1], and the focus is now shifting towards individualising treatment options according to disease biology.

Several predictive tools have been developed to estimate the risk of relapse following the main standard treatment options for localised PCa [2]. However, PCa is very heterogeneous, and some patients who a priori have good prognostic features still relapse and succumb to the disease. This is particularly applicable to men who harbour germline mutations in the BRCA1 or BRCA2 genes. We recently demonstrated that BRCA2 germline mutations not only confer a high risk of PCa (8.6-fold in men ≤65 yr) [3] but are also an independent prognostic factor for cause-specific survival (CSS) in all stages of PCa including localised disease [4].

BRCA1 and BRCA2 play central roles in DNA repair by homologous recombination, which is the mechanism that cells use to repair double-strand breaks induced, for instance, by platinum-based chemotherapeutic agents or ionising radiation. Previous studies have demonstrated that BRCA1 and BRCA2 mutations are predictive factors for response to platinum-based chemotherapy in breast and ovarian cancer, respectively [5], [6]. However previous studies in breast cancer have failed to show a relevant difference in local relapse or toxicity following radiation therapy (RT) compared with noncarriers [7], [8], [9].

We hypothesise that BRCA status may have prognostic implications when considering radical treatment options for localised PCa. We have compared the outcomes of PCa patients (BRCA carriers and noncarriers) who underwent radical prostatectomy (RP), and separately, the outcomes of those who received external-beam RT to treat localised or locally advanced PCa.

Section snippets

Study design

In this retrospective analysis the outcomes of local/locally advanced PCa patients known to be BRCA mutation carriers or noncarriers were compared. Briefly, 67 BRCA mutation carriers with PCa treated with curative intent were identified from two studies: the United Kingdom Genetic Prostate Cancer Study [UKGPCS] (NIHR869) and the Epidemiological Study of BRCA1/2 Mutation Carriers [EMBRACE] (NIHR1358) study (Fig. 1). These numbers include 55 carriers previously reported [4] and 12 new cases

Results

A total of 1302 patients were included in the study, of which 67 carried a germline BRCA mutation (18 BRCA1 and 49 BRCA2). These mutations were spread throughout the coding regions of both genes and not clustered in specific regions. No differences were seen between carriers and noncarriers in age at diagnosis and PSA pretreatment levels (median age: 57 yr; median PSA: 10 ng/ml). Overall, 9% of carriers had T1 tumours, 48% had T2, and 34% had T3, compared with 26%, 39%, and 28% of noncarriers

Discussion

We have previously demonstrated that BRCA mutation carriers have a worse prognosis than noncarriers when diagnosed with PCa at any stage without considering treatment modality [4]. In this study, we have shown that those carriers who were treated at diagnosis with curative intent using conventional radical treatment modalities (RT or RP) developed metastasis earlier and had shorter survival than noncarriers, independent of other prognostic factors. This is the first genetic event proven to be a

Conclusions

Our study demonstrates that BRCA carriers treated for localised PCa have worse outcomes than noncarriers because they relapse and progress earlier to lethal metastatic disease. Pending future studies confirming the biologic role of BRCA genetic alterations in this setting, our results support closer follow-up of these patients and the need for clinical trials to tailor the best radical/adjuvant treatments.

Presented in part at the 48th annual meeting of the American Society of Clinical Oncology

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    *

    These authors contributed equally to this work as senior authors.

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