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Published on: August 11, 2017
Concomitant Mutations in EGFR 19Del/L858R Mutation and Their Association with Response to EGFR-TKIs in NSCLC Patients
Hengrui Liang1, Caichen Li1, Yi Zhao1
1Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, People's Republic of China.
Objective:
Differences in efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been observed between non-small cell lung cancer (NSCLC) patients with 19 exon deletion (19Del) and L858R mutation. We explored whether the total number or pattern of concomitant mutations of 19Del and L858R may explain their different sensitivities.
Patients And Methods:
This study contained the mutational profiles of EGFR-mutated NSCLC patients from two cohorts: Guangzhou (G1) and database (G2). Concomitant mutation status and EGFR-TKI response information were retrieved.
Results:
A total of 403 patients covered 283 genes in the G1 and 803 patients with a different gene set in the G2 were included. Similar prevalence of total concomitant mutation number was observed in both G1 (19Del 32.48% vs L858R 30.45%; P=0.68) and G2 (19Del 74.9% vs L858R 73.2%; P=0.65) cohorts. Only HGF/c-Met pathway same more related to L858R mutation. EGFR-TKI response information was recorded for 134 patients in the G2 cohort. 19Del showed a higher objective response (OR) rate compared with L858R, regardless of concomitant mutations. Compared to patients with OR, non-OR patients had more concomitant mutations, both in 19Del (53.8% vs 83.3%; P=0.021) and L858R (51.4% vs 77.8%; P=0.029). In particular, total concomitant mutations (OR=0.27; P=0.03), sensitive EGFR mutations (OR=2.21; P=0.04), and T790M (OR=0.244; P=0.02) significantly affected the TKI response.
Conclusion:
Concomitant mutations were widespread in 19Del and L858R and were associated with poorer OR to EGFR-TKIs. However, 19Del and L858R had similar numbers and patterns of concomitant mutations, which might not explain the different sensitivity to EGFR-TKI.
Insights
Concomitant mutations in EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are common in non-small cell lung cancer. While present in both 19 exon deletion (19Del) and L858R mutations, they do not fully explain differing EGFR-TKI sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are standard treatments for non-small cell lung cancer (NSCLC).
- Observed differences in EGFR-TKI efficacy exist between NSCLC patients with 19 exon deletion (19Del) and L858R mutations.
- The role of concomitant mutations in these differing sensitivities remains unclear.
Purpose of the Study:
- To investigate whether the number or pattern of concomitant mutations associated with 19Del and L858R EGFR mutations explain their differential response to EGFR-TKIs.
- To analyze the association between concomitant mutations and EGFR-TKI treatment outcomes in NSCLC patients.
Main Methods:
- Retrospective analysis of mutational profiles and EGFR-TKI response data from two cohorts of EGFR-mutated NSCLC patients (Guangzhou and database).
- Comparison of the prevalence and patterns of concomitant mutations between 19Del and L858R groups.
- Statistical analysis to determine the impact of concomitant mutations on objective response (OR) rates to EGFR-TKIs.
Main Results:
- No significant difference in the prevalence of total concomitant mutations was found between 19Del and L858R groups across both cohorts.
- The HGF/c-Met pathway was more frequently associated with the L858R mutation.
- In the database cohort, 19Del showed a higher OR rate than L858R, irrespective of concomitant mutations. Patients with non-OR had significantly more concomitant mutations than those with OR.
- Total concomitant mutations, sensitive EGFR mutations, and T790M mutations significantly impacted TKI response.
Conclusions:
- Concomitant mutations are prevalent in both 19Del and L858R NSCLC and are linked to poorer EGFR-TKI response.
- The similar number and patterns of concomitant mutations observed in 19Del and L858R suggest they may not be the primary drivers of differential sensitivity to EGFR-TKIs.
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