Prostate CancerGermline DNA-repair Gene Mutations and Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Receiving First-line Abiraterone and Enzalutamide
Introduction
While prostate cancer is known to be one of the most heritable human malignancies [1], the prevalence of high-penetrance cancer-susceptibility alleles in prostate cancer patients has only recently begun to be elucidated. To this end, current estimates suggest that inherited germline mutations in DNA-repair genes may be found in 7–12% of men with metastatic prostate cancer; approximately 60–75% of these involve the BRCA1, BRCA2, and ATM genes (absolute prevalence in metastatic prostate cancer of 5–8%) [2], [3]. It is now known that germline mutations in certain DNA-repair genes (particularly BRCA2) are associated with early-onset prostate cancers with higher Gleason grades and higher recurrence rates following definitive local therapy [4]. In addition, our group has recently shown that germline BRCA2 and ATM mutations distinguish lethal from indolent prostate cancers, and are associated with shorter survival times and earlier age at death [5].
What is less clear is the prognostic significance of germline DNA-repair gene alterations in the context of systemic therapies for metastatic castration-resistant prostate cancer (mCRPC) [6]. Early reports suggest that mCRPC patients with germline BRCA2 mutations may respond more favorably to poly ADP-ribose polymerase (PARP) inhibitors as well as platinum-based chemotherapies [7], [8], although these observations require confirmation. In addition, a recent publication suggested that patients with germline DNA-repair defects demonstrate poorer responses to first-line androgen deprivation therapy as well as next-generation hormonal therapies (abiraterone, enzalutamide) compared to those without germline mutations [3]. By contrast, a separate study evaluating germline and/or somatic DNA-repair mutations found that patients carrying mutations had superior responses to first-line abiraterone treatment than patients with the wild-type counterparts [9]. Therefore, the clinical impact of germline DNA-repair alterations in mCRPC patients receiving next-generation hormonal therapy remains uncertain [10].
To shed additional light on this issue, we conducted an analysis investigating the clinical significance of germline DNA-repair gene mutations on the efficacy of next-generation hormonal therapy (NHT) among 172 mCRPC patients beginning treatment with first-line abiraterone or enzalutamide. Given the role of the androgen receptor (AR) in mediating and promoting DNA repair functions [11], [12], we hypothesized that AR-targeted therapies would induce a “synthetic lethality” in patients with an inherited DNA repair–deficient state, resulting in superior responses to abiraterone and enzalutamide in men harboring germline DNA-repair gene mutations compared to those without germline mutations. We further hypothesized that this difference in outcomes would be driven primarily by mutations in BRCA1/BRCA2/ATM rather than other DNA-repair gene alterations, given the predominant role played by these genes in terms of both disease susceptibility and prognosis.
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Patients
This study included 172 consecutive men with mCRPC who were beginning NHT using enzalutamide or abiraterone: 115 men were prospectively enrolled at the time of first-line NHT, and 57 men were prospectively enrolled at the time of second-line NHT (requiring retrospective first-line NHT data). Patients were not selected based on prior knowledge of germline/somatic mutations, and thus this sample was not artificially enriched for DNA-repair alterations. Patients had to have histologically
Patients and germline DNA-repair status
A total of 172 patients with germline DNA available and who began first-line NHT treatment between October 2011 and December 2015 were included in this analysis. Of these, 22/172 (12.8%) had a germline DNA-repair gene mutation (any), and 9/172 (5.2%) had a germline BRCA/ATM mutation. The median follow-up for OS among the alive patients was 34.5 mo (42.6 and 34.4 mo for those with and without BRCA/ATM mutations, respectively). Table 1 shows the distribution and types of DNA-repair mutations
Discussion
While inherited DNA-repair gene mutations are relatively prevalent in patients with mCRPC [2], their clinical significance in the setting of NHT (abiraterone and enzalutamide) is uncertain [10]. Here, we report that the presence of particular germline mutations (in BRCA1, BRCA2, and ATM), but not mutations in other DNA-repair genes, is associated with better PSA response rates (≥90% declines) as well as longer PSA-PFS, radiographic PFS, and OS. Importantly, we report statistically significant
Conclusions
In conclusion, our study suggests that mCRPC patients with germline DNA-repair gene alterations have superior clinical outcomes to first-line NHT treatment (abiraterone, enzalutamide), and that this improvement in prognosis is likely driven by mutations in BRCA1/BRCA2/ATM rather than other DNA-repair genes. However, owing to conflicting results in the literature, these findings will require prospective validation in larger patient cohorts.
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Cited by (0)
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These authors contributed equally to this work.