Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy in NSCLC  

作　　者：Wei Rao Yutao Liu Yan Li Lei Guo Tian Qiu Lin Dong Jianming Ying Weihua Li 

机构地区：[1]Department of Pathology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China [2]Department of Medical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China

出　　处：《Frontiers of Medicine》2023年第3期493-502,共10页医学前沿（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(No.81802294);the Beijing Hope Run Special Fund of Cancer Foundation of the People's Republic of China(No.LC2019L04).

摘　　要：Anaplastic lymphoma kinase(ALK)is the most common fusion gene involved in non-small cell lung cancer(NSCLC),and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors(ALK-TKIs).However,the clinical efficacy is highly variable.Pre-existing intratumoral heterogeneity(ITH)has been proven to contribute to the poor treatment response and the resistance to targeted therapies.In this work,we investigated whether the variant allele frequencies(VAFs)of ALK fusions can help assess ITH and predict targeted therapy efficacy.Through the application of next-generation sequencing(NGS),7.2%(326/4548)of patients were detected to be ALK positive.On the basis of the adjusted VAF(adjVAF,VAF normalization for tumor purity)of four different threshold values(adjVAF<50%,40%,30%,or 20%),the association of ALK subclonality with crizotinib efficacy was assessed.Nonetheless,no statistical association was observed between median progression-free survival(PFS)and ALK subclonality assessed by adjVAF,and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib.Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.

关 键 词：ALK fusion next-generation sequencing fluorescence in situ hybridization IMMUNOHISTOCHEMISTRY variant allele frequency intratumoral heterogeneity targeted therapy 

分 类 号：R730.5[医药卫生—肿瘤]