Neuroendocrine transformation from EGFR/ALK-wild type or TKI-naïve non-small cell lung cancer: An under-recognized phenomenon
Xiao Chu, Yuyin Xu, Ye Li, Yue Zhou, Li Chu, Xi Yang, Jianjiao Ni, Yida Li, Tiantian Guo, Zhiqin Zheng, Qiang Zheng, Qianlan Yao, Yuan Li, Xiaoyan Zhou, Zhengfei Zhu, Xiao Chu, Yuyin Xu, Ye Li, Yue Zhou, Li Chu, Xi Yang, Jianjiao Ni, Yida Li, Tiantian Guo, Zhiqin Zheng, Qiang Zheng, Qianlan Yao, Yuan Li, Xiaoyan Zhou, Zhengfei Zhu
Abstract
Introduction: Neuroendocrine transformation (NET) is a resistance mechanism for epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). We aimed to elucidate whether NET develops in TKI-naïve NSCLC by using molecular fingerprinting in paired pre- and post-NET tissues.
Patients and methods: NET cases were identified based on the following criteria: the pre- and post-NET lesions must harbor mutual somatic mutations; neuroendocrine component should be absent in the sampled specimens of pre-NET lesions; and re-biopsy should be performed in either previously biopsied baseline lesions or newly developed lesions, but not in baseline-existing non-biopsied lesions, excluding synchronous neuroendocrine malignancy. p53 and Rb expression were evaluated via immunohistochemistry. Clinical characteristics, treatments, and outcomes were recorded and analyzed.
Results: Fifteen NET cases were identified, including five EGFR/ALK wild-type, three EGFR-mutant TKI-naïve, and seven TKI-treated cases. All cases harbored mutual somatic mutations in paired pre- and post-NET lesions. Recurrent pre-NET mutations were detected in TP53 (44.4%), RB1 (33.3%), and PDGFRA (33.3%), but two of the three PDGFRA mutations were lost after NET, whereas pre-NET TP53 and RB1 mutations were retained in the corresponding post-NET lesions. Immunohistochemistry revealed inactivated p53/Rb in 90.9% and 72.7% of the pre-NET lesions, respectively.
Conclusions: This proof-of-concept study demonstrated that NET develops in NSCLCs without TKI targets or treatments. This phenomenon could be under-recognized, because re-biopsy was less frequently performed in these patients. Tissue re-biopsy should be preferred over liquid biopsy at the time of progression to account for histology transformation. p53/Rb IHC should be considered in addition to genomic TP53/RB1 evaluation for NET risk prediction.
Keywords: Drug resistance; Histology transformation; Molecular fingerprinting; Neuroendocrine transformation; Next-generation sequencing; Non-small cell lung cancer.
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
Source: PubMed