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Updated: Jul 11, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
The impact of oncogenic driver mutations on neoadjuvant immunotherapy outcomes in patients with resectable non-small
Ziyun Shen1,2, Meixin Teng3, Lu Han1
1Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Shanghai, 200433, China.
Background:
Neoadjuvant immunotherapy has been demonstrated to be effective and safe in resectable non-small cell lung cancer (NSCLC) patients. However, the presence of different oncogenic driver mutations may affect the tumor microenvironment and consequently influence the clinical benefit from immunotherapy.
Methods:
This retrospective study included consecutive NSCLC patients (stage IIA to IIIB) who underwent radical surgery after receiving neoadjuvant immunotherapy at a single high-volume center between December 2019 and August 2022. Pathological response and long-term outcomes were compared based on the driver oncogene status, and RNA sequencing analysis was conducted to investigate the transcriptomic characteristics before and after treatment.
Results:
Of the 167 patients included in this study, 47 had oncogenic driver mutations. KRAS driver mutations were identified in 28 patients, representing 59.6% of oncogenic driver mutations. Of these, 17 patients had a major pathological response, which was significantly higher than in the non-KRAS driver mutation group (60.7% vs. 31.6%, P = 0.049). Multivariate Cox regression analysis further revealed that the KRAS driver mutation group was an independent prognostic factor for prolonged disease-free survival (hazard ratio: 0.10, P = 0.032). The median proportion of CD8+ T cells was significantly higher in the KRAS driver mutation NSCLCs than in the non-driver mutation group (18% vs. 13%, P = 0.030). Furthermore, immune-related pathways were enriched in the KRAS driver mutation NSCLCs and activated after immunotherapy.
Conclusion:
Our study suggests that NSCLC patients with KRAS driver mutations have a superior response to neoadjuvant immunotherapy, possibly due to their higher immunogenicity. The findings highlight the importance of considering oncogenic driver mutations in selecting neoadjuvant treatment strategies for NSCLC patients.
Insights
Non-small cell lung cancer (NSCLC) patients with KRAS driver mutations show improved responses to neoadjuvant immunotherapy. This suggests KRAS mutations may indicate higher immunogenicity, guiding future treatment strategies.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- Neoadjuvant immunotherapy is effective for resectable non-small cell lung cancer (NSCLC).
- Oncogenic driver mutations can influence the tumor microenvironment and immunotherapy response.
Purpose of the Study:
- To investigate the impact of oncogenic driver mutations on pathological response and long-term outcomes in NSCLC patients receiving neoadjuvant immunotherapy.
- To explore the transcriptomic characteristics associated with different driver oncogene statuses.
Main Methods:
- Retrospective analysis of 167 NSCLC patients (stage IIA-IIIB) treated with neoadjuvant immunotherapy and surgery.
- Comparison of pathological response and outcomes based on driver oncogene status (KRAS vs. non-KRAS).
- RNA sequencing to analyze pre- and post-treatment transcriptomic profiles.
Main Results:
- Patients with KRAS driver mutations (n=28) had a significantly higher major pathological response rate (60.7%) compared to non-KRAS groups (31.6%).
- KRAS mutation was an independent predictor of prolonged disease-free survival (HR=0.10, P=0.032).
- Higher CD8+ T cell infiltration and enrichment of immune-related pathways were observed in KRAS-mutated NSCLCs post-immunotherapy.
Conclusions:
- NSCLC patients with KRAS driver mutations exhibit a superior response to neoadjuvant immunotherapy, potentially due to increased immunogenicity.
- Oncogenic driver mutation status, particularly KRAS, is crucial for tailoring neoadjuvant treatment strategies in NSCLC.
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