Primary TKI resistance in advanced non-small cell lung cancer with EGFR mutation: an open question

The malignant behavior of non-small cell lung cancer (NSCLC) is caused by different driver mutations, which may include alterations in the epidermal growth factor receptor (EGFR) signaling pathway. Activating mutations in exons 19 or 21 of EGFR in NSCLC are associated with increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. However, approximately 10% of NSCLC patients show primary resistance to TKIs, and the resistance mechanism is poorly understood. We report the case of a 72-year-old nonsmoking Caucasian woman who underwent pulmonary segmentectomy for right peripheral T1N0M0 NSCLC. The tumor was an adenocarcinoma, with a point mutation in exon 21 of EGFR and with negative ALK gene rearrangement. Postoperative CT scan revealed right pleural effusion and abundant ascites without metastases to parenchymal organs. After paracentesis with positive cytology for adenocarcinoma, the patient started therapy with oral gefitinib 250 mg/day. CT scan after 2 months revealed disease progression with an increase in the pleural effusion (right and left) and ascites, as well as the appearance of solid tissue involving the right main bronchus and bronchus intermedius. Gefitinib was stopped and the patient died 1 month later of progressive NSCLC. The peculiarities of our case are the site of the metastatic disease and the complete lack of a response to gefitinib in a patient with an activating mutation in EGFR exon 21.