Dynamic changes of acquired T790M mutation and small cell lung cancer transformation in a patient with EGFR-mutant adenocarcinoma after first- and third-generation EGFR-TKIs: a case report

Epithelial growth factor receptor (EGFR) T790M mutation and small cell lung cancer (SCLC) transformation are well-known resistance mechanisms acquired during treatment with EGFR tyrosine kinase inhibitors (TKIs). Various mechanisms sometimes coexist in patients. Here, we report a 57-year-old female diagnosed with stage IV lung adenocarcinoma, who harbored an EGFR exon 19 deletion mutation. This patient initially received gefitinib and progressed after 14 months. A repeat biopsy was performed, and the original EGFR exon 19 deletion and acquired exon 20 T790M mutation were identified. Then, pemetrexed plus carboplatin was administered as second-line and osimertinib as third-line treatment. Rapid progression and mixed response were observed after 2 months on osimertinib, with stable disease of the primary lung lesion but rapid growth of a right lower chest mass. The progressive chest lesion underwent biopsy, and the SCLC transformation was revealed. Furthermore, the patient was treated with etoposide and cisplatin, and she achieved disease control for 4 months. A fourth biopsy both for the primary lung lesion and the chest mass were finally conducted. Interestingly, the histopathology of the two different lesions showed adenocarcinoma and SCLC, respectively. The patient then rapidly suffered brain metastasis, and no EGFR mutations were detected in her cerebrospinal fluid (CSF). Overall survival (OS) of the patient was 29 months. This patient experienced concomitant resistance mechanisms of T790M mutation and SCLC transformation, which might have resulted from intra-tumor heterogeneity and drug-induced selection. Ultimately, this case reminds us that repeat biopsies are essential for patients receiving EGFR-TKIs in order to make appropriate treatment decisions according to the diverse mechanisms of acquired resistance.