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

Abstract

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.

Keywords

ALK fusion / next-generation sequencing / fluorescence in situ hybridization / immunohistochemistry / variant allele frequency / intratumoral heterogeneity / targeted therapy

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81802294) and the Beijing Hope Run Special Fund of Cancer Foundation of the People’s Republic of China (No. LC2019L04).

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-022-0946-x and is accessible for authorized users.

Compliance with ethical guidelines

Wei Rao, Yutao Liu, Yan Li, Lei Guo, Tian Qiu, Lin Dong, Jianming Ying, and Weihua Li declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

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