Comprehensive analysis of AR alterations in cell free DNA from prostate cancer patients.

Abstract

314 Background: Somatic alterations identified in cfDNA may be associated with prognosis. Select AR alterations are associated with abiraterone/enzalutamide resistance in PCa. The goal was to characterize AR amplifications (amps) and somatic point mutations (muts) detected in cfDNA from PCa patients and to relate those changes to non-AR alterations detected in the cfDNA landscape. Methods: cfDNA data was obtained from a heterogeneous group of unique PCa pts who underwent Guardant360 testing (Guardant Health, Redwood City, CA). This assay includes next generation sequencing for full exonic coverage of 73 genes and amplifications in 18 genes. The AR amps/muts detected in cfDNA testing were reported. Results: Over 6,800 genomic alterations including AR amps/muts were identified in 892 PCa patients. Pts were a median age of 70 (range = 41-93) at testing. 49% (n = 436) had AR amp only, 32% (n = 283) had nonsynonymous (NS)-muts only, 18% (n = 165) had both amp and NS-muts; < 1% (n = 8) had synonymous AR muts only. AR amps had a mean absolute copy number of 3.3 (range = 1.2-165.2). Many patients had multiple AR muts; a total of 112 unique muts were identified in the AR gene, some of which are poorly characterized. The most prevalent AR muts were L702H (n = 220), T878A (n = 129), H875Y (n = 102), W742C (n = 75), W742L (n = 34), F877L (n = 19), and T878S (n = 14). The AR muts with the highest mutant allele fraction were H875Y, T878A, and L702H. Aside from AR, among these selected pts, amps/muts were identified in 74 other genes including TP53 50% (n = 449), MYC 34% (n = 301), BRAF 32% (n = 287), PIK3CA 29% (n = 259), MET 25% (n = 224), CDK6 26% (n = 229), EGFR 24% (n = 219), FGFR1 21% (n = 189), and APC 12% (n = 112). DNA repair gene alterations were detected in combination with AR alterations, BRCA2 8% (n = 69), BRCA1 5% (n = 42), and ATM 3% (n = 28). Conclusions: To our knowledge, this is the largest dataset ever reporting AR alterations in cfDNA. Both amps and muts, were frequently found in cfDNA from PCa pts. The common AR muts were L702H, T878A, H875Y and W742C/L, which are linked to resistance to abiraterone, enzalutamide or bicalutamide. Determining the association with other somatic cfDNA alterations and clinical outcomes may be critical for conceiving optimal treatment strategies.