A Higher Proportion of the EGFR T790M Mutation May Contribute to the Better Survival of Patients with Exon 19 Deletions Compared with Those with L858R

Increasing evidence has demonstrated that exon 19 deletions (Del19) and L858R mutation in EGFR have different prognostic and predictive roles in NSCLC. We aimed to investigate whether these two mutations produced differences in mechanisms of resistance to EGFR tyrosine kinase inhibitors. Consecutive...

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Published in:Journal of thoracic oncology 2017-09, Vol.12 (9), p.1368-1375
Main Authors: Ke, E-E, Zhou, Qing, Zhang, Qiu-Yi, Su, Jian, Chen, Zhi-Hong, Zhang, Xu-Chao, Xu, Chong-Rui, Yang, Jin-Ji, Tu, Hai-Yan, Yan, Hong-Hong, Zhang, Yi-Chen, Niu, Fei-Yu, Wu, Yi-Long
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Drug Resistance, Neoplasm
Exon 19 deletions
Exons
Female
Humans
L858R mutation
Lung Neoplasms - enzymology
Lung Neoplasms - genetics
Male
Middle Aged
Mutation
Prognosis
Protein Kinase Inhibitors - pharmacology
Receptor, Epidermal Growth Factor - genetics
Resistance mechanisms
Sequence Deletion
Survival Analysis
T790M mutation
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Summary:Increasing evidence has demonstrated that exon 19 deletions (Del19) and L858R mutation in EGFR have different prognostic and predictive roles in NSCLC. We aimed to investigate whether these two mutations produced differences in mechanisms of resistance to EGFR tyrosine kinase inhibitors. Consecutive patients with advanced EGFR-mutant NSCLC who acquired resistance to EGFR tyrosine kinase inhibitors and underwent postprogression biopsy were enrolled. Mechanisms including T790M mutation, mesenchymal-epithelial transition proto-oncogene (MET) amplification, and histological transformation, as well as KRAS, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation, and anaplastic lymphoma receptor tyrosine kinase gene (ALK) fusion, were analyzed. The prevalence of T790M mutation was significantly higher in the Del19 subgroup than that in L858R subgroup (50.4% versus 36.5%, p = 0.043). Apart from this, there was no difference in other mechanisms including MET amplification and histological transformation. The median overall survival (OS) of patients with T790M mutation was 36.0 months (95% confidence interval [CI]: 30.9–41.2), which was significantly longer than the 26.5 months (95% CI: 24.0–29.0) in MET-positive patients, 19.7 months (95% CI: 18.2–21.2) in patients with histological transformation, and 23.0 months (95% CI: 17.4–28.6) in the KRAS/PIK3CA/ALK-altered population (p = 0.021). The hazard ratios of the MET-amplification subgroup and subgroup with histological transformation were 1.809-fold and 2.370-fold higher than that in T790M-positive subgroup. The median OS times were months 33.3 (95% CI: 28.9–37.7) in the Del19 subgroup and 26.4 months (95% CI: 23.2–29.6) in the L858R subgroup (p = 0.028). However, in multivariable analysis adjusted for T790M genotype, the EGFR mutation subtype was no longer found to be significant. Significant OS benefit was observed in patients with T790M mutation, suggesting that a larger proportion of T790M mutation might contribute to the better survival of patients with Del19.
ISSN:1556-0864
1556-1380
DOI:10.1016/j.jtho.2017.05.018