Exploratory cohort study and meta-analysis of deletion polymorphism in patients with epidermal growth factor receptor-mutant non-small-cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors.

BACKGROUND

Non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor () mutations might develop primary and secondary resistance to tyrosine kinase inhibitors (TKIs). The proapoptotic protein Bcl-2-like 11 (BIM) is a key modulator of apoptosis triggered by EGFR-TKIs. The recent studies have indicated that some patients with positive mutations were refractory to EGFR-TKIs if they harbored a deletion polymorphism. The purpose of this study was to investigate whether polymorphism predicts treatment efficacy of EGFR-TKIs in Chinese NSCLC patients.

PATIENTS AND METHODS

A cohort of advanced NSCLC patients with mutations and treated with EGFR-TKIs (gefitinib or erlotinib) were recruited. We drew peripheral blood to determinate deletion status and then compared patients' clinical outcomes according to the deletion status. Additionally, we electronically searched eligible cohort studies and conducted a meta-analysis to pool event risk.

RESULTS

The exploratory cohort study included 140 patients. Patients with and without the deletion polymorphism had similar objective response rates (ORRs, 48.5 vs 63.0%, =0.16), disease control rate (DCR, 93.9 vs 97.0%, =0.60) and adverse reactions. Similar progression-free survival (PFS) and overall survival (OS) were noted in overall population (=0.27 for PFS and =0.61 for OS) and prespecified patient subgroups. The meta-analysis included 10 eligible cohort studies involving 1,317 NSCLC patients. It showed the positive BIM deletion was associated with shorter PFS (hazard ratio =1.45; =0.02). Nonsignificant differences existed for ORR, DCR and OS.

CONCLUSION

The expanded meta-analysis results demonstrated the positive deletion predicts shorter PFS in NSCLC patients after treatment with EGFR-TKIs while other clinical measures do not. A large multicenter well-designed cohort study involving other concurrent genetic alterations is warranted.