Expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed small cell lung cancer

Authors：Zhang, Shi-Ling; Zhang, Chan -Yuan; Chen, Yu-Qing; Li, Yu -Fa; Xie, Zhi; Zhang, Xu-Chao; Zhou, Qing; Zhong, Wen-Zhao; Huang, Jie; Sun, Hao; Zheng, Ming-Ying; Xiao, Fa-Man; Yan, Hong-Hong; Lu, Dan-Xia; Lv, Zhi-Yi; Wu, Yi-Long; Chen, Hua-Jun^*; Yang, Jin-Ji^*

Source：Journal of Thoracic Disease, 2023, 15(9).

DOI：10.21037/jtd-23-161

• Epidermal growth factor receptor-mutant proteins (EGFR-mutant proteins)
• genomic evolution
• resistance
• small cell lung cancer (SCLC)
• histologic transformation

Background: The transformation of epidermal growth factor receptor (EGFR )-mutant lung adenocarcinoma (LUAD) into small cell lung cancer (SCLC) accounts for 3-14% of the resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs). At present, there is no relevant research to explore the dynamic expression of EGFR-mutant proteins and genomic evolution in EGFR-mutant transformed SCLC/neuroendocrine carcinoma (NEC). Methods: Genetic analysis and protein level analysis by next-generation sequencing (NGS), Wholeexome sequencing (WES) and immunohistochemistry were performed to explore expression of EGFRmutant proteins and genomic evolution in EGFR-mutant transformed SCLC. The research used three patient-derived organoids (PDOs) to explore the efficacy of combo [chemotherapy (chemo) plus TKI or bevacizumab] treatment. According to the subsequent treatment regimens after SCLC/NEC transformation, 35 patients were divided into chemo (n=21) and combo (n=14) groups. Results: EGFR L858R and EGFR E746-750 del protein expression by immunohistochemistry was 80.0% (4/5) and 100% (6/6), respectively (P=0.455) in initially-transformed tissues. Meanwhile, EGFR-mutant proteins were expressed in 85.7% (6/7) of dynamic rebiopsy tissues or effusion samples after the first transformation. Then, by the pathway enrichment analysis of tissue and plasma NGS, the EGFR-related pathways were still activated after SCLC/NEC transformation. Moreover, WES analysis revealed that transformed SCLC shared a common clonal origin from the baseline LUAD. The drug sensitivity of three PDOs demonstrated potent anti-cancer activity of EGFR-TKIs plus chemo, compared with chemo or TKI alone. There were significant differences in objective response rate (ORR) between the combo and chemo groups [42.9 % vs. 4.8%, P=0.010, 95% confidence interval (CI): 1.5-145.2]. Furthermore, the median posttransformation progression-free survival (pPFS) was significantly prolonged in the combo group, with 5.4 Conclusions: EGFR 19del or L858R-mutant proteins could be constantly expressed, and EGFR pathway still existed in EGFR-mutant transformed SCLC/NEC with a common clonal origin from the baseline LUAD. Taking together, these molecular characteristics potentially favored clinical efficacy in transformed SCLC/NEC treated with the combo regimen.

• Institution
  南方医科大学; 广东省人民医院