Concomitant genetic alterations are associated with response to EGFR targeted therapy in patients with lung
Hualin Chen1, Meilian Liu1, Zhiwei Dai1
1Department of Pulmonary Oncology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China.
Background:
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are considered to be more effective than chemotherapy in the treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, in addition to EGFR-sensitive mutations, the genetic factors that affect the prognosis of patients who receive TKI treatment are not yet clear.
Methods:
The clinical data of 36 NSCLC patients with EGFR mutation who received TKI treatment were retrospectively analyzed. Liquid re-biopsy with next generation sequencing (NGS) analysis was performed to analyze genetic alterations and potential resistance mechanisms.
Results:
All of the patients harbored actionable sensitive EGFR mutations by NGS, with the major types being 19del or 21L858R (52.78%, 19/36 and 55.56%, 20/36, respectively). The 3 most frequent accompanying somatic mutations were TP53 (12, 48.4%), KRAS (7, 19.44%) and PIK3CA (3, 8.33%). Concomitant mutations were present in 16 patients (44.44%). The occurrence of co-mutation was found to be significantly related to a history of smoking [87.5% (7 of 8) vs. 32.14% (9 of 28); Pearson chi-square, P=0.005]. Patients who received EGFR-TKIs treatment (P=0.0079) or third-generation EGFR-TKIs only (P=0.0468) had better progression-free survival (PFS). Concomitant mutations were significantly related to lower objective response rates (43.75% vs. 80.0%; P=0.024) and poorer PFS (P<0.001). Patients with concomitant genetic alterations had a worse response after receiving EGFR-TKIs treatment (P=0.0033).
Conclusions:
Our research underscores the importance of using multiple molecular profiles. Concomitant genetic alterations were significantly associated with response to EGFR targeted therapy in NSCLC. Therefore, research on multi-drug or sequential therapy to address the covariation that drives drug resistance is urgently needed.
Insights
Concomitant genetic alterations in EGFR-mutant non-small cell lung cancer (NSCLC) significantly impact treatment response and progression-free survival (PFS) for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) show superior efficacy over chemotherapy for EGFR-mutant advanced non-small cell lung cancer (NSCLC).
- The impact of genetic factors beyond EGFR-sensitive mutations on TKI treatment prognosis remains unclear.
Purpose of the Study:
- To investigate the clinical significance of concomitant genetic alterations in EGFR-mutant NSCLC patients receiving EGFR-TKI treatment.
- To identify genetic factors influencing treatment response and progression-free survival (PFS).
Main Methods:
- Retrospective analysis of clinical data from 36 NSCLC patients with EGFR mutations treated with TKIs.
- Liquid re-biopsy and next-generation sequencing (NGS) to identify genetic alterations and potential resistance mechanisms.
Main Results:
- Major EGFR mutations included 19del and 21L858R. TP53, KRAS, and PIK3CA were the most frequent co-occurring mutations.
- Concomitant mutations (44.44%) were associated with a history of smoking (P=0.005).
- Patients with concomitant genetic alterations exhibited lower objective response rates (P=0.024) and poorer PFS (P<0.001) compared to those without.
Conclusions:
- Concomitant genetic alterations significantly correlate with reduced response to EGFR-targeted therapy in NSCLC.
- The study highlights the importance of comprehensive molecular profiling for predicting treatment outcomes.
- Further research into multi-drug or sequential therapies is crucial to overcome drug resistance driven by co-mutations.
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