一项针对前列腺癌转移的全基因组前瞻性研究显示，wnt 通路激活和细胞周期增殖增加与醋酸阿比特龙-泼尼松的原发性耐药相关。
A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone.
机构信息
Division of Biomedical Statistics and Informatics, Department of Health Sciences, Rochester, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, USA; Department of Urology, University of Minnesota, Minneapolis, USA.
出版信息
Ann Oncol. 2018 Feb 1;29(2):352-360. doi: 10.1093/annonc/mdx689.
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.
背景
转移性去势抵抗性前列腺癌（mCRPC）存在基因组异常，但尚不清楚预测阿比特龙/泼尼松（AA/P）耐药的分子标志物。
方法
在一项前瞻性临床试验中，mCRPC 患者在开始 AA/P 治疗前，对转移灶活检标本进行全外显子组测序（n=82）和 RNA 测序（n=75），旨在鉴定与 AA/P 耐药相关的基因组改变。根据包括前列腺特异抗原（PSA）测定、骨和计算机断层扫描成像以及症状评估在内的进展标准，在治疗 12 周时确定原发性耐药。使用治疗改变时间（TTTC）终点来确定获得性耐药，定义为从入组到因疾病进展而改变治疗的时间。使用逻辑回归、Fisher 确切检验、单变量和多变量分析来确定基因组和转录组改变与原发性耐药的关系。使用 Cox 回归模型确定基因组和转录组改变与 TTTC 的关系。
结果
在队列中，有 32 名患者在 12 周时进展（无应答者）。中位研究随访时间为 32.1 个月，在此期间，有 58 名患者因进展而更换治疗。TTTC 的中位数为 10.1 个月（四分位距：4.4-24.1）。无应答者中 Wnt/β-连环蛋白通路的基因更频繁发生突变，Wnt/β-连环蛋白信号的负调控因子更频繁缺失或显示 mRNA 表达降低。此外，无应答者中细胞周期调节基因的 mRNA 表达增加。在多变量模型中，细胞周期增殖评分增加（≥50）与 TTTC 缩短相关（风险比=2.11，95%置信区间：1.17-3.80；P=0.01）。
结论
Wnt/β-连环蛋白通路激活和细胞周期增殖评分增加可作为预测 AA/P 治疗耐药的分子标志物。
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