A 58-year-old male smoker presents with a peripheral lung nodule on CT chest. Bronchoscopy and biopsy confirm adenocarcinoma of the lung. Regarding the molecular and pathological features of lung adenocarcinoma, all of the following are true EXCEPT:

Question

Accepted Answer

C. KRAS mutations typically confer sensitivity to tyrosine kinase inhibitors. ## 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.

Answer

A. PD-L1 expression correlates with response to immune checkpoint inhibitors

Answer

B. EGFR mutations are more common in adenocarcinoma than in squamous cell carcinoma

Answer

D. ALK rearrangement is associated with younger age and non-smoking history

A 58-year-old male smoker presents with a peripheral lung nodule on CT chest. Bronchoscopy and biopsy confirm adenocarcinoma of the lung. Regarding the molecular and pathological features of lung adenocarcinoma, all of the following are true EXCEPT:

Explanation

Molecular Features of Lung Adenocarcinoma

Comparison of Actionable Mutations in Lung Adenocarcinoma

Why the Other Options Are Correct

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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