Potential unreliability of <i>ALK</i> variant allele frequency in the efficacy prediction of targeted therapy in NSCLC

doi:10.1007/s11684-022-0946-x

Front. Med.

2023, Vol. 17

Issue (3) : 493-502 https://doi.org/10.1007/s11684-022-0946-x

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

Wei Rao¹, Yutao Liu², Yan Li¹, Lei Guo¹, Tian Qiu¹, Lin Dong¹, Jianming Ying¹(

), Weihua Li¹(

)

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

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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

Corresponding Author(s): Jianming Ying,Weihua Li

Just Accepted Date: 20 December 2022 Online First Date: 07 April 2023 Issue Date: 28 July 2023

Cite this article:

Wei Rao,Yutao Liu,Yan Li, et al. Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy in NSCLC[J]. Front. Med., 2023, 17(3): 493-502.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-022-0946-x
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I3/493

Fig.1 Analysis of ALK fusions in a large cohort of Chinese NSCLC patients through different ALK testing methods. (A) Frequency of ALK fusions detected by NGS, FISH, and IHC. (B) Different methods applied to identify ALK-positive cases. In particular, 145, 201, and 551 cases were identified ALK positive only by one method (NGS, FISH, or IHC); 277 cases were identified ALK positive by two different platforms (NGS&FISH, IHC&FISH, or NGS&IHC); 16 cases were concurrently tested by three methods (NGS&FISH&IHC) due to discordant results.

Tab.1 Survival analysis according to different subclonality threshold values in the 85 ALK-positive NSCLC patients who received first-line crizotinib therapy

Fig.2 Correlation analysis between ALK adjVAF and the clinical outcomes in patients who received ALK-TKIs. (A) Flow diagram showing the ALK-positive patients included in the analysis. (B) Distribution of ALK adjVAF in 321 cases determined by NGS. The black line represents the median value (49.4%). (C) Correlation analysis between ALK adjVAF and PFS in first-line crizotinib treatment.

Fig.3 Correlation analysis between ALK VAF and FISH break-apart ratio, IHC-positively stained cell ratio, and VAF determined by other NGS platform in the same sample. (A) There was no correlation between ALK VAF and FISH break-apart ratio in the same sample. (B) There was no correlation between ALK VAF and IHC-positively stained cell ratio in the same sample. (C) Significantly different VAFs were observed between two oncopanels (panels A and B) in the same sample.

Fig.4 Genetic characteristics of three patients with concurrent ALK fusion and other actionable alterations identified by IHC and NGS. (A) Genetic feature of a patient with concurrent ALK fusion and ROS1 fusion. (B) Genetic feature of a patient with concurrent ALK fusion and EGFR mutation. (C) Genetic feature of a patient with concurrent ALK fusion and KRAS mutation. a, ALK IHC-positive area; b, ALK IHC-negative area.

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