基于液体活检基因组图谱的ALK和ROS−1阳性非小细胞肺癌患者治疗方法
肺癌是全球癌症相关死亡的主要原因。间变性淋巴瘤激酶（anaplastic lymphoma kinase，ALK）和ROS−1基因重排分别发生在约5%和1%~2%的晚期非小细胞肺癌患者中，主要发生在肺腺癌中。
靶向ALK和ROS−1的酪氨酸激酶抑制剂（tyrosine kinase inhibitors，TKI）已成为晚期ALK和ROS−1阳性非小细胞肺癌患者一线治疗的新标准方案。由于目前可及的TKI类药物有若干种，在疾病进展时使用最佳的ALK和ROS−1 TKI序贯治疗策略会对患者的预后产生影响。
几乎三分之一的晚期非小细胞肺癌患者没有足够的肿瘤组织进行基因组分析。采用液体活检的方式进行循环肿瘤DNA分析（circulating tumor DNA analysis，ctDNA）可以提供关于个性化治疗后疾病分子进化的实时信息。目前，下一代测序（next generation sequencing，NGS）被认为是检测ctDNA中ALK和ROS−1突变的最佳方法。
尽管酪氨酸激酶内ALK突变是ALK TKI药物获得性耐药的主要机制，但基于所选的不同ALK TKI药物，存在初步的特异性的耐药突变谱和后续的治疗指征。在第一代ALK TKI药物克唑替尼难治性肿瘤中，下一代ALK TKI药物（布加替尼、恩沙替尼、色瑞替尼、劳拉替尼）的疗效与获得性ALK突变的发生无关。然而，第二代ALK TKI药物（艾乐替尼、布加替尼）或第三代ALK TKI药物（劳拉替尼）的前期给药对目前临床医生指导的盲法序贯治疗策略提出了挑战。
通过药理学或生物学机制可产生对ROS−1 TKI药物的获得性耐药，主要包括获得ROS1激酶结构域中的次级点突变、旁路通道的激活和表型变化。一线ROS−1 TKI药物克唑替尼治疗进展后，可以用洛普替尼或劳拉替尼克服二次突变。然而，对于新的一线药物恩曲替尼和其他正在开发的新药，其耐药模式有待深入的了解，这将对随后的治疗产生影响。
考虑到继发性的ALK和ROS−1耐药突变对于选择最佳的序贯TKI药物具有关键预后和预测价值，连续ctDNA分析可以提供有关ALK和ROS−1 TKI药物治疗后疾病分子进化的实时信息。临床上，获得性耐药的机制特征将与发展用于克服耐药的新个体化治疗策略息息相关。
Acknowledgments
Funding: None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Precision Cancer Medicine for the series “ALK and ROS-1 NSCLC Patients Treatment Approach Based on Genomic Profile by Liquid Biopsy”. The article did not undergo external peer review.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pcm.amegroups.com/article/view/10.21037/pcm-21-36/coif). The series “ALK and ROS-1 NSCLC Patients Treatment Approach Based on Genomic Profile by Liquid Biopsy” was commissioned by the editorial office without any funding or sponsorship. JC, EN and LM served as the unpaid Guest Editors of the series. JC serves as an unpaid editorial board member of Prevision Cancer Medicine from April 2020 to March 2022. EN and LM serve as unpaid editorial board members of Prevision Cancer Medicine from March 2020 to February 2022. JC and EN receive consulting fees from AstraZeneca, Pfizer, Boehringer, MSD, Takeda, Roche, Lilly and Bristol-Myers. LM reports research grant/funding (self): Bristol Myers Squibb, Boehringer Ingelheim, Amgen, Stilla, Inivata; Advisory/Consultancy: Roche, Takeda; Honoraria (self): Bristol Myers Squibb, Roche, Takeda; Travel/Accommodation/Expenses: Roche, BMS, AstraZeneca. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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陈一瑜
复旦大学附属肿瘤医院（更新时间：2023-05-05）
（本译文仅供学术交流，实际内容请以英文原文为准。）
Cite this article as: Nadal E, Mezquita L, Corral J. ALK and ROS-1 NSCLC patients treatment approach based on genomic profile by liquid biopsy. Precis Cancer Med 2022;5:1.
