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Landscape of Concomitant Driver Alterations in Classical EGFR-Mutated Non-Small Cell Lung Cancer
Huaying Wang1, Lie Lin2, Chuqiao Liang3
1Department of Respiratory and Critical Care Medicine, The Affiliated People's Hospital of Ningbo University, Ningbo Yinzhou People's Hospital, Ningbo, Zhejiang, China.
Purpose:
Next-generation sequencing (NGS) has enabled the detection of concomitant driver alterations in non-small cell lung cancer (NSCLC). However, the magnitude and clinical relevance of concomitant drivers remain to be explored.
Methods:
We profiled concomitant driver alterations of EGFR+ NSCLC by using targeted NGS. The associated genomic and clinical features were analyzed and validated in an independent The Cancer Genome Atlas cohort of patients with EGFR+ NSCLC.
Results:
Out of the total patient population, 334 patients had EGFR mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing EGFR mutations include KRAS at 53.9%, followed by ERBB2 at 24.3%, MET at 16.5%, and BRAF at 3.3%. KRAS mutations in concomitant drivers were frequently hyperexchange mutations (25.6% v 8.2%, P < .001), compared with KRAS single drivers. EGFR/ERBB2 drivers exhibited a higher incidence of ERBB2 amplification (40.7% v 16.5%, P < .001) and p.S310F/Y mutations (44.4% v 4.3%, P < .001) compared with ERBB2 alone. EGFR/MET drivers had a higher frequency of MET amplification (71.4% v 43.3%) than MET single drivers. At the genomic level, the median number of additional concurrent mutations was four, with TSC2 (4%), CD274 (1%), and TP53 (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that EGFR mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant MET amplification exhibited worse prognosis.
Conclusion:
These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies.
Insights
Concomitant driver mutations in EGFR-mutant non-small cell lung cancer (NSCLC) are present in 3.09% of patients. These co-occurring alterations, particularly MET amplification, are associated with a worse prognosis and may guide combination therapy selection.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Next-generation sequencing (NGS) advances have enabled the detection of concurrent driver alterations in non-small cell lung cancer (NSCLC).
- The clinical significance and impact of these concomitant drivers require further investigation.
Purpose of the Study:
- To profile and analyze concomitant driver alterations in EGFR-mutant NSCLC.
- To explore the genomic and clinical relevance of these co-occurring mutations.
Main Methods:
- Targeted NGS was employed to identify concomitant driver alterations in EGFR-mutant NSCLC.
- Genomic and clinical features were analyzed and validated using The Cancer Genome Atlas (TCGA) cohort.
Main Results:
- 3.09% of patients with EGFR-mutant NSCLC harbored concomitant driver mutations, with KRAS (53.9%), ERBB2 (24.3%), MET (16.5%), and BRAF (3.3%) being most frequent.
- EGFR/MET drivers showed increased MET amplification (71.4%), and concomitant drivers, especially MET amplification, were linked to poorer prognosis.
- Clonality analysis revealed EGFR mutations as clonal events, while co-drivers were often subclonal.
Conclusions:
- Concomitant driver alterations in EGFR-mutant NSCLC are clinically relevant and impact prognosis.
- These findings can inform the selection of targeted therapies and the development of novel combination treatments for NSCLC.
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