Transformation or tumor heterogeneity: Mutations in EGFR, SOX2, TP53, and RB1 persist in the histological rapid conversion from lung adenocarcinoma to small-cell lung cancer

The transformation from non-small-cell lung cancer (NSCLC) to small-cell lung cancer (SCLC) is one of the mechanisms of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) resistance. Previous studies exhibited that the median transformation time was 17.8 months for NSCLC to SCLC. Here we introduced a case of lung adenocarcinoma (LADC) with EGFR19 exon deletion mutation in which the pathological transformation emerged only 1 month after lung cancer surgery and receiving EGFR-TKI inhibitor. Eventually, the pathological examination confirmed the patient experienced a transformation from LADC to SCLC with EGFR, tumor protein p53 (TP53), RB transcriptional corepressor 1 (RB1), and SRY-box transcription factor 2 (SOX2) mutation. Although the transformation of LADC with EGFR-mutant into SCLC after targeted therapy was frequent, the pathological results of most patients were only biopsy specimens, which cannot rule out the existence of mixed pathological components of the primary tumor. In this case, the patient's postoperative pathology was sufficient to exclude the probability of mixed tumor components, confirming that the patient's pathological change was indeed transformation from LADC to SCLC. In addition, primary drug resistance in such a short time after surgery and osimertinib-targeted therapy has not been reported before. We detected the molecular state of this patient before and after SCLC transformation through targeted gene capture and high-throughput sequencing, and also found for the first time that the mutations of EGFR, TP53, RB1, and SOX2 continue to exist before and after transformation, but the mutation abundance is different. In our paper, the occurrence of small-cell transformation is affected largely by these gene mutations.