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Youfan Jiang
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.100 - Primary Drug Resistance to EGFR-TKIs by EGFR p.V1010M Germline Mutation Combined with EGFR p.L858R Somatic Mutation and its Pedigree Analysis (ID 2435)
00:00 - 00:00 | Presenting Author(s): Youfan Jiang
- Abstract
Introduction
Lung cancer is the world's leading tumor type in terms of morbidity and mortality, 85% of which is non-small cell lung cancer (NSCLC). Its pathogenesis can be divided into genetic factors and environmental factors, but previous studies have shown that the contribution of genetic factors isn’t significant, about 26%. EGFR is the most common driver gene mutation in Asian NSCLC patients, with mutation frequency up to 40-45%. This gene is closely related to the pathogenesis and treatment of NSCLC, and different mutant sites may lead to distinct therapeutic effects. It is mostly somatic variation in NSCLC, and there are few reports of germline variation. In this study, we reported for the first time a pedigree with EGFR p.V1010M germline mutation, and explored the correlation between V1010M germline mutation and NSCLC disease occurrence. Furthermore, the effect of the V1010M on the treatment of EGFR-TKIs was investigated through the treatment of the proband with simultaneous somatic mutation of EGFR p.L858R.
Methods
The families were screened by NGS and Sanger sequencing, and the genealogy was drawn to investigate the relationship between EGFR p.v1010m and the occurrence of NSCLC disease. To observe the treatment of EGFR-TKIs on the proband and explore the relationship between the mutation of V1010M and the therapeutic effect of TKIs, Schrödinger was used to predict the structural function of mutant amino acid sequence proteins.
Results
A total of 10 blood samples were collected from four generations of family members, many of whom suffered from lung cancer. And 6 positive carriers of EGFR p.V1010M were detected. Pedigree analysis showed that there was still no evidence of correlation between V1010M and disease occurrence. At the same time, the proband detected the somatic mutation of EGFR p.L858R, and the response after the treatment of gifitinib and afatinib was SD, which turned to PD one month later, suggesting that V1010M may be the primary drug-resistant mutation. Using Schrödinger to perform in-silico simulation of the EGFR structure, the results showed that the 1010th amino acid valine was located near the C terminal, and the variation to methionine had little effect on the structure of ligand-binding area, suggesting that there might be other reasons for drug resistance.
Conclusion
This study is the first report of a pedigree with EGFR p.V1010M germline mutation, which may not be a pathogenic mutation but may be associated with EGFR-TKIs resistance in NSCLC.
