## Molecular Features of Lung Adenocarcinoma **Key Point:** KRAS mutations in adenocarcinoma are generally associated with resistance to EGFR-TKIs and represent a distinct molecular subtype with poor prognosis. Unlike EGFR or ALK alterations, KRAS-mutant tumours do NOT respond to conventional tyrosine kinase inhibitors. ### Comparison of Actionable Mutations in Lung Adenocarcinoma | Mutation | Frequency | TKI Sensitivity | Demographics | Prognosis | |----------|-----------|-----------------|--------------|----------| | EGFR | 10–15% (Asian > Western) | High (erlotinib, gefitinib) | Non-smokers, females, Asian | Better with TKI | | ALK | 3–5% | High (crizotinib, alectinib) | Younger, non-smokers | Better with ALK-TKI | | KRAS | 25–30% (Western) | **Resistant to EGFR-TKI** | Smokers, older | Worse; limited targeted options | | ROS1 | 1–2% | High (crizotinib) | Non-smokers | Better with ROS1-TKI | **High-Yield:** KRAS mutations are a **negative predictive marker** for EGFR-TKI response. They are often mutually exclusive with EGFR mutations and define a chemotherapy-dependent phenotype (until recent KRAS G12C inhibitors like sotorasib). ### Why the Other Options Are Correct 1. **EGFR mutations > adenocarcinoma:** True. EGFR mutations occur in ~40% of Asian adenocarcinomas but <15% of squamous cell carcinomas. [cite:Robbins 10e Ch 15] 2. **ALK rearrangement + young/non-smoker:** True. ALK-positive tumours are enriched in younger patients and those with minimal smoking history, distinct from KRAS-driven tumours. 3. **PD-L1 and checkpoint response:** True. High PD-L1 expression (≥50%) predicts better response to anti-PD-1/PD-L1 monotherapy in adenocarcinoma. **Clinical Pearl:** The presence of KRAS mutation should prompt consideration of chemotherapy (pemetrexed-based) as first-line, or enrollment in trials of newer KRAS-targeted agents, rather than empiric EGFR-TKI.
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