American Association for Cancer Research
10780432ccr142666-sup-139263_1_supp_2835014_nqnjnz.docx (14.98 kB)

Supplementary Table 5 from Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer

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journal contribution
posted on 2023-03-31, 18:29 authored by Arun A. Azad, Stanislav V. Volik, Alexander W. Wyatt, Anne Haegert, Stephane Le Bihan, Robert H. Bell, Shawn A. Anderson, Brian McConeghy, Robert Shukin, Jenny Bazov, Jack Youngren, Pamela Paris, George Thomas, Eric J. Small, Yuzhuo Wang, Martin E. Gleave, Colin C. Collins, Kim N. Chi

Supplementary Table 5. Univariate and multivariate analysis examining association between pre-treatment clinico-pathological factors and progression-free survival (radiographic and/or clinical) in patients switched onto enzalutamide after collection of circulating cell-free DNA (n = 39)



Purpose: Although novel agents targeting the androgen–androgen receptor (AR) axis have altered the treatment paradigm of metastatic castration-resistant prostate cancer (mCRPC), development of therapeutic resistance is inevitable. In this study, we examined whether AR gene aberrations detectable in circulating cell-free DNA (cfDNA) are associated with resistance to abiraterone acetate and enzalutamide in mCRPC patients.Experimental Design: Plasma was collected from 62 mCRPC patients ceasing abiraterone acetate (n = 29), enzalutamide (n = 19), or other agents (n = 14) due to disease progression. DNA was extracted and subjected to array comparative genomic hybridization (aCGH) for chromosome copy number analysis, and Roche 454 targeted next-generation sequencing of exon 8 in the AR.Results: On aCGH, AR amplification was significantly more common in patients progressing on enzalutamide than on abiraterone or other agents (53% vs. 17% vs. 21%, P = 0.02, χ2). Missense AR exon 8 mutations were detected in 11 of 62 patients (18%), including the first reported case of an F876L mutation in an enzalutamide-resistant patient and H874Y and T877A mutations in 7 abiraterone-resistant patients. In patients switched onto enzalutamide after cfDNA collection (n = 39), an AR gene aberration (copy number increase and/or an exon 8 mutation) in pretreatment cfDNA was associated with adverse outcomes, including lower rates of PSA decline ≥ 30% (P = 0.013, χ2) and shorter time to radiographic/clinical progression (P = 0.010, Cox proportional hazards regression).Conclusions: AR gene aberrations in cfDNA are associated with resistance to enzalutamide and abiraterone in mCRPC. Our data illustrate that genomic analysis of cfDNA is a minimally invasive method for interrogating mechanisms of therapeutic resistance in mCRPC. Clin Cancer Res; 21(10); 2315–24. ©2015 AACR.

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