De novo exon 18 G724S point mutation may be sensitive to Gefitinib

Abstract

Osimertinib has been approved for lung cancer patients with acquired T790M point mutations after 1st or 2nd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, resistance may develop after osimertinib treatment due to various mutations including G797X, L718Q, S768I, G724S alone, or coexisting with T790M. G724S mutation in the P-loop of the EGFR kinase domain has been identified as one of the acquired resistant mechanisms after progression to osimertinib. Most G724S mutation was acquired and standard therapy for lung cancer harboring G724S is still controversial. Herein, we present a patient with advanced lung adenocarcinoma harboring de novo G724S mutation who was susceptible to gefitinib and demonstrated a long-term response. This 54-year-old female was a never smoker and was diagnosed with lung adenocarcinoma via bronchoscopic biopsy, T4N2M1a stage 4A. An EGFR mutation examination utilized amplification refractory mutation specific (ARMS) polymerase chain reactions (PCRs) and Scorpion technologies for detection; direct sequencing was performed if a negative result was found in the ARMS PCR. The report disclosed an exon 18 G724S mutation. Initially, chemotherapy was encouraged but she refused. Therefore, Gefitinib was prescribed in December 2011. The tumor shrank slightly under gefitinib treatment and the duration of response persisted to September 2015 (Figure 1). She did not undergo further tissue biopsy and EGFR mutation testing again after resistance developed and she refused salvage cytotoxic chemotherapy. She died in June 2016. To the best of our knowledge, this is the first report of de novo exon 18 G724S in a lung adenocarcinoma patient who demonstrated a long-term response to gefitinib. Most exon 18 G724S point mutations are acquired. Li et al. reviewed 1170 lung cancer patients who received EGFR tests and only five had G724S mutations (0.43%), all G724S mutations were acquired after first-generation TKI treatment. Oztan et al. reported acquired G724S clone increased significantly after progression of osimertinib treatments in EGFR mutant adenocarcinomas. Furthermore, Fassunke et al. reported four cases with G724S mutations, two of which occurred after osimertinib treatment with the other two cases being detected after gefitinib or erlotinib treatment failure. They showed the G724S mutation is resistant to osimertinib both in vitro