Uncommon EGFR mutations in lung adenocarcinoma: features and response to tyrosine kinase inhibitors

• Published in: Journal of thoracic disease 2020-09, Vol.12 (9), p.4643-4650
• Main Authors: Brindel, Aurélien, Althakfi, Wajd, Barritault, Marc, Watkin, Emmanuel, Maury, Jean-Michel, Bringuier, Pierre-Paul, Girard, Nicolas, Brevet, Marie
• Format: Article
• Language: English
• Subjects: Original
• ISSN: 2072-1439; 2077-6624
• DOI: 10.21037/jtd-19-3790

mutant non-small cell lung cancer (NSCLC) is a heterogeneous disease. The treatment for frequent mutations relies on tyrosine kinase inhibitors (TKIs); the clinical and therapeutic significance of uncommon EGFR mutations is uncertain. This is a single-center retrospective study of patients with -mutant lung cancer (2009-2017). Molecular analyses of exons 18-21 were performed. Only patients with uncommon mutations were included (p.Glu709X, p.Gly719X, p.Ala767_Val769 dup, p.Ser768Ile, and p.Leu861Gln). Among 6,747 tumor samples, 95 out 820 patients (11.6%) harbored 113 uncommon mutations. There were 50 metastatic NSCLC patients for whom the median OS was 18.0 months (95% CI: 15, 32). In this population, the p.Leu861Gln uncommon exon 21 mutation was associated with poor prognosis (HR: 2.96, 95% CI: 1.39, 6.31; P=0.003). Among those harboring a single uncommon mutation, median OS was 27.6 months (95% CI: 10.8, not attained) in patients who were treated by chemotherapy only (n=13) versus 6.0 months (95% CI: 2.4, not attained) in patients exclusively treated with a first or second- -TKI (n=9; HR: 0.27, 95% CI: 0.09, 0.78; P=0.01. In patients with a single uncommon mutation, first-line chemotherapy was associated with a better overall survival than TKIs (HR: 0.31, 95% CI: 0.15, 0.68; P=0.002). In patients who received first or second- -TKI as first-line treatment (n=26), OS was significantly better for those with two uncommon mutations than those with a single uncommon mutation (HR: 0.07, 95% CI: 0.009, 0.54; P=0.001). In conclusion, uncommon mutations may be associated with a poor outcome and the data challenge the use of first-generation TKI in such patients, however first-line TKI is more effective in cases of double uncommon mutations and such patients should be treated accordingly.