Genome-wide association study (GWAS) of response to androgen deprivation therapy (ADT) and survival in metastatic prostate cancer (PCa).

1540 Background: Inherited genetic factors are among the variables influencing PCa outcome and response to treatment. We conducted a GWAS to identify germline genetic polymorphisms associated with time to ADT resistance and overall survival (OS). Methods: DNA isolated from blood from 1,048 subjects with metastatic hormone-sensitive PCa were genotyped for approximately one million single nucleotide polymorphisms (SNPs) with minor allele frequency ≥ 0.05 (1,037 samples with call rate > 85%). Among these, 687 patients were treated with ADT alone and were included in this study. An additional 80 million SNPs per sample were imputed using data from the 1000 Genomes Project. Time to castration-resistant prostate cancer (CRPC) was defined as duration between ADT start and either i) the first of two documented rises in PSA, or ii) start of medication for CRPC. Time to CRPC and OS were treated as time-to-event data in the analysis. Results: Median time to CRPC from start of ADT was 13.3 months. Median OS from ADT start was 4.5 years. The SNPs most highly associated with time to CRPC were polymorphisms residing in intronic regions of the genes FHIT (p-value, 1.73x10-7), PSD3 (p-value, 1.70x10-6), SARDH (p-value, 2.18x10-6). The SNPs most highly associated with OS resided in intergenic regions approximately 70 kilobases (kb) upstream of ETV6 (p-value, 2.99x10-7) and 500 kb from GUSBP4 (p-value, 1.51x10-6), and in an intronic region of HEATR5B (p-value, 1.46x10-6). Conclusions: This study is among the most extensive interrogations of the germline genetic underpinnings of PCa hormone responsiveness and lethality. Reproducibility is being assessed in an independent cohort. Proven associations with ADT response will provide novel insights into ADT resistance as well as potential clinical biomarkers.