Sequential small cell transformation and T790M mutation in an epidermal growth factor‐mutant lung adenocarcinoma: A rare occurrence with significant management implications

Background Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) resistance may be acquired via genotypic and/or phenotypic transformations. Herein, we report an extremely uncommon case with sequential small cell transformation and EGFR T790M mutation, in an elderly female with EGFR exon 21 L858R‐mutant lung adenocarcinoma, following treatment with a first‐generation EGFR‐TKI. Case A 67‐year‐old female never‐smoker presented with a cough and dyspnoea of 2 months' duration. Computerised tomography revealed a 39 mm lesion in the upper lobe of the right lung with pleural effusion. Pleural fluid cytology revealed metastatic lung adenocarcinoma, and EGFR testing revealed exon 21 L858R mutation. She was started on gefitinib. After a progression‐free survival of 31 months, she presented with disease progression and multiple extra‐thoracic metastases. Fine needle aspiration cytology of a chest wall lesion revealed metastatic small cell carcinoma. EGFR testing on this aspirate revealed persistent L858R mutation only. In view of small cell transformation, chemotherapy (etoposide and carboplatin) was administered. After 4 months, ascitic fluid cytology revealed metastatic adenocarcinoma with persistent L858R mutation and an acquired T790M mutation (both detected on liquid biopsy as well) indicating amplification of the adenocarcinoma clone and regression of the small cell carcinoma clone. She was then initiated on osimertinib. Conclusions The index case highlights the significance of serial EGFR genotyping along with repeated tissue and/or blood sampling in the prompt detection of genetic and phenotypic resistance mechanisms to EGFR‐TKIs. Furthermore, it lends evidence in support of the upfront treatment approaches targeting the heterogeneity of acquired EGFR‐TKI resistance mechanisms. Most EGFR‐mutated patients develop EGFR‐TKI resistance, but sequential development of multiple resistance mechanisms is rare. Nonetheless, its detection is crucial as it requires significant management changes for better patient outcomes.