Why do non-smokers (NS) develop lung cancer (LC)?

Why Non-Smokers Develop Lung Cancer

Non-smokers develop lung cancer through multiple distinct pathways including environmental carcinogen exposure (secondhand smoke, radon, occupational agents, air pollution), genetic susceptibility with family history conferring 1.8-fold increased risk, and specific molecular alterations (EGFR mutations in 43%, ALK rearrangements in 12%) that define this as a biologically distinct disease entity from smoking-related lung cancer. 1, 2, 3

Environmental Risk Factors

Secondhand Smoke Exposure

• Secondhand smoke increases lung cancer risk by 24% (RR 1.24,95% CI 1.13-1.36) in adults living with smokers, with workplace exposure conferring similar risk (RR 1.22,95% CI 1.13-1.33). 1
• A dose-response relationship exists between years of secondhand smoke exposure and lung cancer risk, though this association is weaker than active smoking. 1

Occupational Carcinogens

• Eight specific lung carcinogens—arsenic, chromium, asbestos, nickel, cadmium, beryllium, silica, and diesel fumes—confer a mean relative risk of 1.59 for lung cancer development. 1
• These occupational exposures account for a substantial proportion of non-smoking-related lung cancers, particularly in industrial settings. 1

Radon Exposure

• Residential radon exposure demonstrates a linear relationship with lung cancer risk, with meta-analysis showing RR of 1.14 (95% CI 1.0-1.3), though the risk is substantially lower than occupational uranium miner exposure. 1
• Radon represents a significant risk factor only with documented sustained and substantially elevated exposure levels. 1

Indoor and Outdoor Air Pollution

• Indoor air pollution from coal-fueled stoves and cooking fumes contributes significantly to the high burden of lung cancer in never-smoking women, particularly in Asian countries. 1, 2
• Non-tobacco-related polycyclic aromatic hydrocarbons from various environmental sources represent additional etiologic factors. 1, 2

Genetic and Host Factors

Family History

• First-degree relatives of lung cancer patients have an 1.8-fold increased risk (95% CI 1.6-2.0) even after adjusting for age, gender, and smoking habits. 1
• Risk increases further with multiple affected family members or cancer diagnosis at young age, though no high-penetrance inherited syndrome has been identified. 1
• Genetic susceptibility loci including CHRNA3, CHRNA5, TERT, BRCA2, CHECK2, and HLA region have been identified, with heritability estimated at 18%. 2

Prior Cancer History

• Patients previously treated with chest irradiation have a 13-fold increased risk for new primary lung cancer, while those treated with alkylating agents have RR of 9.4. 1
• Survivors of Hodgkin lymphoma have RR of 4.2-5.9 depending on treatment modality, and small cell lung cancer survivors have 3.5-fold increased risk for new primary cancers. 1

Molecular and Biological Distinctions

Unique Molecular Profile

• EGFR mutations occur in approximately 43% of lung cancers in never-smokers compared to only 11% in smokers, with higher prevalence in women, adenocarcinoma histology, and East Asian populations. 1, 4, 2, 5, 3
• ALK rearrangements are present in 12% of never-smoker lung cancers versus 2% in smokers, representing a therapeutically actionable target. 1, 2, 5, 3
• Tumor mutation burden is dramatically lower in never-smokers (0-3 mutations/megabase) compared to smokers (0-30 mutations/megabase), indicating fundamentally different carcinogenic mechanisms. 3

Histologic Patterns

• Adenocarcinoma accounts for 60-80% of lung cancers in never-smokers, with squamous or adenosquamous representing 10-20% and small cell lung cancer less than 10%. 2, 3
• This histologic distribution differs substantially from smoking-related lung cancer, where squamous cell carcinoma is more prevalent. 1

Epidemiologic Considerations

Population Burden

• Lung cancer in never-smokers represents 15-20% of all lung cancer cases worldwide, with annual US incidence of 14.4-20.8 per 100,000 person-years in females and 4.8-12.7 per 100,000 person-years in males. 3, 6
• If considered separately, lung cancer in never-smokers would rank among the top 10 causes of cancer mortality in the United States (16,000-24,000 deaths annually). 7
• The proportion of never-smoker lung cancer patients has been increasing, particularly in Asian countries where approximately 500,000 annual deaths occur in lifetime never-smokers. 1, 2

Gender Disparities

• Women are disproportionately affected, with 19% of female lung cancers versus 9% of male lung cancers occurring in never-smokers in the United States. 1, 2
• Women are overrepresented among younger patients, raising questions about gender-specific susceptibility to lung carcinogens. 1

Clinical Implications

The recognition that lung cancer in never-smokers represents a distinct disease entity has critical therapeutic implications, as these patients have dramatically improved survival when treated with targeted therapies (median survival exceeding 3-5 years with actionable mutations versus 1-2 years without). 3

Comprehensive molecular testing for EGFR mutations and ALK rearrangements should be performed immediately upon diagnosis in all never-smokers with advanced non-squamous NSCLC, as these actionable alterations occur in over 50% of cases combined and dictate first-line treatment selection. 4, 5, 3