Mengli Qiu,1 Peiwen Guo,1 Jieheng Lin,2 Sisi Wang,2 Wenping Wang,2 Jianying Yang,3 Zhongming Huang,4 Yang Cao2 

1The First Clinical School, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 2Department of Oncology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, People’s Republic of China; 3Department of Oncology, The 928rd Hospital of the Chinese People’s Liberation Army Joint Logistic Support Force, Haikou, People’s Republic of China; 4Department of Oncology, Cancer Hospital of Shantou University Medical College, Shantou University, Shantou, People’s Republic of China

Correspondence: Yang Cao, Department of Oncology, The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, 510000, People’s Republic of China, Tel +86 028-13802945884, Email caoyang0342@gzucm.edu.cn Zhongming Huang, Department of Oncology, Cancer Hospital of Shantou University Medical College, Shantou University, Shantou, 515000, People’s Republic of China, Tel +86 028-13060033385, Email 576737943@qq.com

Abstract: Lung adenocarcinoma (ADC) harboring epidermal growth factor receptor (EGFR) mutations rarely transforms into squamous cell carcinoma (SCC) following resistance to targeted therapy. Here, we present a case of EGFR-positive ADC that transformed into EGFR-negative SCC after developing resistance to EGFR tyrosine kinase inhibitors (TKIs). The patient experienced progressive disease after one cycle of chemotherapy and subsequently underwent five courses of tislelizumab combined with chemotherapy. Although the primary tumor showed a partial response to this combined regimen, intracranial metastases continued to progress, ultimately leading to the patient’s death. Notably, the patient survived for 8 months after SCC transformation with immuno-chemotherapy, a significantly longer duration than the previously reported median survival of 3.5 months. This case underscores the occurrence of genomic instability, histological transformation, and dissociated response (DR) following treatment with EGFR-TKIs in EGFR-positive lung ADC. We hypothesize that these phenomena may be driven by tumor heterogeneity and the dynamic variability within the tumor microenvironment (TME).

Keywords: immunotherapy, chemotherapy, brain metastases, epidermal growth factor receptor, dissociated response, histological transformation