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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Mutation Profiling of Lung Cancers with Long-Term Response to Gefitinib Therapy
Oliver Gautschi1, Carola Stadelmann, Franziska Aebersold-Keller
1Tumorzentrum, Luzerner Kantonsspital, Lucerne, Switzerland.
Background:
The role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) and unknown EGFR mutation status has recently been questioned.
Patients And Methods:
We conducted a retrospective study of patients with unknown EGFR mutation status and long-term response (LTR) to gefitinib in the Swiss Iressa expanded access program (EAP). We assessed patient characteristics, and performed Sanger sequencing and next generation sequencing on archived tumor tissue. We hypothesized that EGFR mutations are prevalent in patients with LTR.
Results:
Of 430 patients in the EAP, 18 (4%) fulfilled our definition of LTR, and 16 of them had archived tumor tissue. Patient characteristics were as expected for age, sex, and smoking history. Median duration of therapy was 38 months (range 24-142 months). Sanger sequencing revealed EGFR exon 18-21 mutations in 6 (38%) of the tumors. Next generation sequencing revealed no further EGFR-mutated cases, but reported in 15 (94%) of the tumors mutations in other genes (ALK, BRAF, DDR2, KEAP1, MET, PTEN, STK11) previously associated with NSCLC.
Conclusion:
Larger studies are needed to define the prognostic values of different driver mutations in patients with NSCLC.
Insights
Epidermal growth factor receptor (EGFR) mutations were found in 38% of advanced non-small cell lung cancer (NSCLC) patients with long-term response to gefitinib. Other gene mutations were also common in these NSCLC patients.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- The efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) with unknown EGFR mutation status is under scrutiny.
- This study investigates the genetic landscape of patients with long-term response to gefitinib.
Purpose of the Study:
- To determine the prevalence of EGFR mutations in non-small cell lung cancer (NSCLC) patients exhibiting long-term response (LTR) to gefitinib.
- To explore other co-occurring mutations in NSCLC patients with LTR to gefitinib.
Main Methods:
- Retrospective analysis of patients from the Swiss Iressa expanded access program (EAP) with unknown EGFR mutation status and LTR to gefitinib.
- Sanger sequencing and next-generation sequencing (NGS) were performed on archived tumor tissues.
- Patient characteristics and treatment duration were assessed.
Main Results:
- Of 430 patients, 18 (4%) achieved LTR; 16 had available tumor tissue.
- EGFR mutations (exons 18-21) were identified in 6 (38%) of the tumors via Sanger sequencing.
- NGS revealed mutations in other NSCLC-associated genes (e.g., ALK, BRAF, MET) in 94% of tumors, with no additional EGFR mutations.
Conclusions:
- EGFR mutations are present in a significant subset of advanced NSCLC patients with long-term response to gefitinib.
- Co-occurring mutations in other driver genes are highly prevalent in this patient group.
- Further research is required to establish the prognostic significance of various driver mutations in NSCLC.
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