INTRODUCTION

Uncommon epidermal growth factor receptor (EGFR) mutations include single and complex mutations. However, the association of the smoking status of patients with uncommon and complex mutations remains unclear.

METHODS

This retrospective study evaluates the spectrum of uncommon mutations and investigates the influence of smoking status on the frequency of various uncommon mutations using a multi-institutional medical database.

RESULTS

Between 2010 and 2019, 5,608 non-small cell lung cancer (NSCLC) patients were analyzed. mutations were detected in 3,155 (56.3%) patients. Among the 399 (12.6%) patients with uncommon mutations, 198 had single uncommon and 201 complex mutations, including 87 exon 20 insertions, 79 T790M, 70 complex common, and 52 complex uncommon mutations. For comparison, we also included 402 patients with common mutations. The percentage of ever-smokers was significantly higher in patients with uncommon mutations than in patients with common mutations (25.8% vs. 17.4%, = 0.005). Furthermore, the percentage of ever-smokers was higher in those with a complex mutation than in those with a single uncommon mutation (30.3% vs. 21.2%, = 0.040). Among patients carrying uncommon mutations, ever-smokers had significantly more complex uncommon mutations than never-smokers (22.3% vs. 9.8%, = 0.002). Among patients carrying G719X, L861Q, and S768I, ever-smokers tended to have complex mutations more frequently than never-smokers (64.7% vs. 28.7%, 50.0% vs. 18.7%, 88.9% vs. 81.2%, respectively).

CONCLUSIONS

Our study demonstrates not only a comprehensive spectrum of uncommon mutations, but also a positive relationship between smoking status and uncommon mutation frequency, especially complex uncommon mutations. The results suggest that smoking contributes to the development of complex mutations.