Neuroendocrine transformation from EGFR/ALK-wild type or TKI-naïve non-small cell lung cancer: An under-recognized phenomenon

•Neuroendocrine transformation (NET) in TKI-naïve NSCLCs was controversial in clinic.•Molecular fingerprinting revealed NET development from TKI-naïve NSCLC.•Immunohistochemistry evaluation of p53 and Rb is an economic surrogate marker for NET prediction.•Tissue re-biopsy over liquid biopsy at progression/relapse to account for under-recognized histology transformation. 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. 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. 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. 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.