Background Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/β-catenin pathway were more frequently mutated and negative regulators of Wnt/β-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions Wnt/β-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

中文翻译：

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一项针对前列腺癌转移的全基因组前瞻性研究表明，wnt途径激活和细胞周期增殖增加与对醋酸阿比特龙酯-泼尼松的主要耐药性相关。

背景技术在转移性去势抵抗性前列腺癌（mCRPC）中已经确定了基因组畸变，但是尚不清楚对醋酸阿比特龙酯/泼尼松（AA / P）治疗具有抗性的分子预测因子。患者和方法在一项前瞻性临床试验中，mCRPC患者在开始AA / P之前接受了转移活检的全基因组测序（n = 82）和RNA测序（n = 75），目的是鉴定与抗AA / P相关的基因组改变。 P. 在治疗12周时，使用包括血清前列腺特异性抗原测量，骨骼和计算机断层扫描成像和症状评估在内的进展标准确定原发性耐药。使用治疗变化的终点时间（TTTC）确定获得的耐药性，定义为从入组到进展性疾病改变治疗的时间。基因组和转录组变异与原发性耐药的相关性通过逻辑回归，Fisher精确检验，单变量和多变量分析确定。使用Cox回归模型确定TTTC的基因组和转录组改变的关联。结果在第12周，该队列中有32名患者进展（无反应）。中位研究随访时间为32.1个月，当时58位患者因病情转行了治疗。TTTC中位数为10.1个月（四分位间距：4.4-24.1）。Wnt /β-catenin途径中的基因更经常发生突变，Wnt /β-catenin信号传导的负调控因子更经常被删除或在无应答者中mRNA表达降低。此外，细胞周期调节基因的mRNA表达在无反应者中增加。在多变量模型中，增加的细胞周期增殖评分（≥50）与较短的TTTC相关（危险比= 2.11，95％置信区间：1.17-3.80； P = 0.01）。结论Wnt /β-catenin途径的激活和细胞周期进程评分的增加可作为预测AA / P治疗耐药性的分子标志。