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Updated: Jan 20, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Co-occurring genetic alterations predict distant metastasis and poor efficacy of first-line EGFR-TKIs in EGFR-mutant
Li-Li Deng1, Ge Gao1, Hong-Bin Deng2
1Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, Heilongjiang, People's Republic of China.
Purpose:
To determine the frequency of co-occurring genes in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation and the predictive effect of co-mutations on the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs).
Methods:
54 patients with advanced NSCLC were tested for 422 clinically relevant genes by next-generation sequencing (NGS) before treatment. Among them, patients with EGFR mutation received first-line treatment of EGFR-TKIs. Progression-free survival (PFS) and objective response rate (ORR) were evaluated using Kaplan-Meier methods and compared between two groups using log-rank test.
Results:
Among 24 EGFR mutant and 30 EGFR wild-type patients, co-mutation rate was lower in patients with EGFR mutation (62.5% [15/24] vs 93.3% [28/30], p = 0.005). There was lower frequency for co-alterations in BRAF (0% [0/24] vs 20% [7/30], p = 0.033), NF1 (4.2% [1/24] vs 30% [9/30], p = 0.038) and RAS-RAF-MAPK pathway genes (16.6% [4/24] vs 56.7% [17/30], p = 0.003) in EGFR mutation group. 24 patients with EGFR mutation received first-line treatment of gefitinib or erlotinib, with an ORR of 83.3% and a median PFS of 12.3 months (95% CI 10.00-14.60). Co-mutation was associated with shorter median PFS (10.2 months [95% CI 5.20-15.20] vs 15.3 months [95% CI 12.09-15.81]; HR 0.29 [95% CI 0.10-0.82]; p = 0.014) in EGFR mutation cohort. Among patients with EGFR mutation and distant metastasis, median PFS was decreased in those with co-mutations (6.3 months [95% CI 3.25-9.35] vs 22.0 months[95% CI 12.10-31.90]; HR 0.12 [95% CI 0.00-5.87]; p = 0.007) and frequency of PIK3CA (0% [0/12] vs 41.7% [5/12], p = 0.037) and PI3K/AKT/mTOR pathway genes (0% [0/12] vs 50% [6/12], p = 0.014) was lower.
Conclusion:
The presence of co-mutations was lower in the EGFR mutation patients and reduces the efficacy of EGFR-TKI, especially in patients with distant metastases. Lower frequency of co-mutation in PIK3CA and PI3K/AKT/mTOR pathway genes may be responsible for promoting metastasis and limiting the efficacy of EGFR-TKIs.
Insights
Co-occurring gene mutations are less frequent in non-small cell lung cancer (NSCLC) patients with EGFR mutations and negatively impact EGFR tyrosine kinase inhibitor (EGFR-TKI) efficacy, particularly in those with distant metastases.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide.
- Epidermal growth factor receptor (EGFR) mutations are key drivers in a subset of NSCLC patients.
- EGFR tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized NSCLC treatment, but resistance remains a challenge.
Purpose of the Study:
- To investigate the frequency of co-occurring gene mutations in NSCLC patients with EGFR mutations.
- To evaluate the impact of these co-mutations on the efficacy of first-line EGFR-TKIs.
- To identify specific co-mutated genes associated with treatment outcomes.
Main Methods:
- Next-generation sequencing (NGS) was used to analyze 422 clinically relevant genes in 54 advanced NSCLC patients.
- Patients with EGFR mutations received first-line treatment with EGFR-TKIs (gefitinib or erlotinib).
- Progression-free survival (PFS) and objective response rate (ORR) were assessed and compared between groups.
Main Results:
- Co-mutation rates were lower in EGFR-mutant NSCLC patients (62.5%) compared to EGFR wild-type (93.3%).
- EGFR-mutant patients showed lower frequencies of BRAF, NF1, and RAS-RAF-MAPK pathway co-alterations.
- Co-mutations were associated with significantly shorter median PFS (10.2 vs. 15.3 months) and reduced efficacy in patients with distant metastases.
Conclusions:
- Co-occurring gene mutations are less frequent in EGFR-mutant NSCLC but significantly reduce EGFR-TKI efficacy.
- The presence of co-mutations, particularly in PIK3CA and PI3K/AKT/mTOR pathways, may promote metastasis and limit treatment response.
- Targeting co-mutations could potentially improve outcomes for NSCLC patients receiving EGFR-TKIs.
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