Torquato Samantha, Pallavajjala Aparna, Goldstein Alexa, Toro Patricia Valda, Silberstein John L, Lee Justin, Nakazawa Mary, Waters Ian, Chu David, Shinn Daniel, Groginski Taylor, Hughes Robert M, Simons Brian W, Khan Hamda, Feng Zhaoyong, Carducci Michael A, Paller Channing J, Denmeade Samuel R, Kressel Bruce, Eisenberger Mario A, Antonarakis Emmanuel S, Trock Bruce J, Park Ben H, Hurley Paula J
Johns Hopkins School of Medicine, Baltimore, MD.
Johns Hopkins University, Baltimore, MD.
JCO Precis Oncol. 2019;3. doi: 10.1200/PO.18.00227. Epub 2019 Apr 3.
Androgen receptor () gene alterations, including ligand-binding domain mutations and copy number (CN) gain, have yet to be fully established as predictive markers of resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). The goal of this study was to validate gene alterations detected in cell-free DNA (cfDNA) as markers of enzalutamide and abiraterone resistance in patients with mCRPC.
Patients with mCRPC (N = 62) were prospectively enrolled between 2014 and 2018. Blood was collected before therapies-enzalutamide (n = 25), abiraterone (n = 35), or enzalutamide and abiraterone (n -and at disease progression. We used deep next-generation sequencing to analyze cfDNA for sequence variants and CN status in and 45 additional cancer-associated genes. Primary end points were prostate-specific antigen response, progression-free survival (PFS), and overall survival (OS).
Elevated tumor-specific cfDNA (circulating tumor DNA) was associated with a worse prostate-specific antigen response (hazard ratio [HR], 3.17; 95% CI, 1.11 to 9.05; = .031), PFS (HR, 1.76; 95% CI, 1.03 to 3.01; .039), and OS (HR, 2.92; 95% CI, 1.40 to 6.11; .004). ligand-binding domain missense mutations (HR, 2.51; 95% CI, 1.15 to 5.72; = .020) were associated with a shorter PFS in multivariable models. CN gain was associated with a shorter PFS; however, significance was lost in multivariable modeling. Genetic alterations in tumor protein p53 (HR, 2.70; 95% CI, 1.27 to 5.72; .009) and phosphoinositide 3-kinase pathway defects (HR, 2.62; 95% CI, 1.12 to 6.10; .026) were associated with a worse OS in multivariable models.
These findings support the conclusion that high circulating tumor DNA burden is associated with worse outcomes to enzalutamide and abiraterone in men with mCRPC. Tumor protein p53 loss and phosphoinositide 3-kinase pathway defects were associated with worse OS in men with mCRPC. status associations with outcomes were not robust, and additional validation is needed.
雄激素受体（AR）基因改变，包括配体结合域突变和拷贝数（CN）增加，尚未完全确立为转移性去势抵抗性前列腺癌（mCRPC）患者对恩杂鲁胺和阿比特龙耐药的预测标志物。本研究的目的是验证在游离DNA（cfDNA）中检测到的AR基因改变作为mCRPC患者对恩杂鲁胺和阿比特龙耐药的标志物。
2014年至2018年前瞻性纳入mCRPC患者（N = 62）。在接受恩杂鲁胺（n = 25）、阿比特龙（n = 35）或恩杂鲁胺与阿比特龙联合治疗（n = 2）前以及疾病进展时采集血液。我们使用深度二代测序分析cfDNA中AR及另外45个癌症相关基因的序列变异和CN状态。主要终点为前列腺特异性抗原反应、无进展生存期（PFS）和总生存期（OS）。
肿瘤特异性cfDNA（循环肿瘤DNA）升高与较差的前列腺特异性抗原反应（风险比[HR]，3.17；95%可信区间[CI]，1.11至9.05；P = 0.031）、PFS（HR，1.76；95%CI，1.03至3.01；P = 0.039）和OS（HR，2.92；95%CI，1.40至6.11；P = 0.004）相关。在多变量模型中，AR配体结合域错义突变（HR，2.51；95%CI，1.15至5.72；P = 0.020）与较短的PFS相关。AR CN增加与较短的PFS相关；然而，在多变量建模中该显著性消失。在多变量模型中，肿瘤蛋白p53的基因改变（HR，2.70；95%CI，1.27至5.72；P = 0.009）和磷酸肌醇3激酶途径缺陷（HR，2.62；95%CI，1.12至6.10；P = 0.026）与较差的OS相关。
这些发现支持以下结论，即高循环肿瘤DNA负荷与mCRPC男性患者对恩杂鲁胺和阿比特龙的较差预后相关。肿瘤蛋白p53缺失和磷酸肌醇3激酶途径缺陷与mCRPC男性患者较差的OS相关。AR状态与预后的关联并不稳健，需要进一步验证。
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