Hsu Hung-Chih, Lapke Nina, Chen Shu-Jen, Lu Yen-Jung, Jhou Ren-Shiang, Yeh Chien-Yuh, Tsai Wen-Sy, Hung Hsin-Yuan, Hsieh Jason Chia-Hsun, Yang Tsai-Sheng, Thiam Tan Kien, You Jeng-Fu
Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan.
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan.
Cancers (Basel). 2018 Sep 6;10(9):314. doi: 10.3390/cancers10090314.
Bevacizumab-based regimens are used as standard treatments for colorectal cancer. Unfortunately, there are no established predictive markers for bevacizumab response.
Tumor samples from 36 metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy were analyzed by next-generation sequencing of all coding exons of more than 400 genes. Single gene and signaling pathway analyses were performed to correlate genomic data with response.
Among the genes most frequently mutated in our cohort, only mutations in , a phosphatase involved in signaling, were associated with response status, with deleterious mutations being enriched in non-responders. Pathway analysis revealed that deleterious mutations in genes of the pathway, namely in and the related gene , correlated with resistance. Mutations in , and pathways did not associate with response. Lack of response was observed in all patients with deleterious mutations or copy number loss of / ( = 10), compared to only 30.8% ( = 8) of patients without such alterations (relative risk, 3.25; 95% CI, 1.83⁻5.79, = 0.0003). Similarly, / deleterious alterations were associated with shorter progression-free survival, an association that was retained in multivariate analysis (HR, 3.33; 95% CI, 1.47⁻7.54; = 0.0038).
Deleterious alterations in / are potential biomarkers for bevacizumab resistance.
基于贝伐单抗的治疗方案被用作结直肠癌的标准治疗方法。不幸的是，目前尚无已确立的贝伐单抗反应预测标志物。
对36例接受贝伐单抗联合化疗的转移性结直肠癌患者的肿瘤样本进行了400多个基因的所有编码外显子的二代测序分析。进行单基因和信号通路分析以将基因组数据与反应相关联。
在我们队列中最常发生突变的基因中，只有参与信号传导的磷酸酶中的突变与反应状态相关，有害突变在无反应者中富集。通路分析显示，信号通路基因中的有害突变，即和相关基因中的突变，与耐药性相关。、和通路中的突变与反应无关。与无此类改变的患者中仅30.8%（ = 8）相比，所有具有/有害突变或拷贝数缺失的患者（ = 10）均观察到无反应（相对风险，3.25；95% CI，1.83⁻5.79， = 0.0003）。同样，/有害改变与无进展生存期缩短相关，这种关联在多变量分析中仍然存在（HR，3.33；95% CI，1.47⁻7.54； = 0.0038）。
/中的有害改变是贝伐单抗耐药的潜在生物标志物。
