Targeting rare oncogenic mutations in resectable non-small cell lung cancer: emerging perioperative strategies

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Rare oncogenic alterations (e.g., EGFR exon 20 insertions, MET exon 14 skipping, RET, ROS1, NTRK fusions, BRAF V600E, KRAS G12C, HER2 mutations) are actionable in non-small cell lung cancer (NSCLC).
• These alterations represent approximately 20% of NSCLC cases, but evidence for perioperative treatment is limited.
• Traditional chemoimmunotherapy may be less effective in certain genotypes due to an immune-cold tumor microenvironment.

Purpose of the Study:

• To review current knowledge and ongoing research on neoadjuvant and adjuvant strategies for resectable NSCLC with rare mutations.
• To explore the potential utility of targeted therapies in perioperative settings for NSCLC.
• To discuss the role of biomarkers like circulating tumor DNA and minimal residual disease in guiding perioperative treatment.

Main Methods:

• Literature review synthesizing current evidence and ongoing research.
• Analysis of clinical efficacy data for targeted therapies in advanced NSCLC.
• Exploration of preliminary data on molecular subtype-specific perioperative approaches.

Main Results:

• Targeted therapies demonstrate clinical efficacy in advanced NSCLC and hold potential for perioperative use.
• Molecular subtype-specific approaches may optimize outcomes in NSCLC patients with rare mutations.
• Circulating tumor DNA and minimal residual disease are emerging biomarkers for perioperative treatment guidance.

Conclusions:

• Biomarker-directed perioperative strategies are critical for improving outcomes in NSCLC patients with rare targetable alterations.
• Prospective clinical trials enriched for specific genotypes are needed to validate these approaches.
• Challenges include the lack of randomized perioperative trials and uncertainty in pathological response assessment and surrogate endpoints.