Adenocarcinoma is the Lung Cancer Type Least Related to Smoking
Adenocarcinoma is the predominant histologic subtype of lung cancer in never-smokers and represents a distinct disease entity with specific molecular characteristics that differentiate it from smoking-related lung cancers. 1, 2
Key Epidemiologic Evidence
The evidence clearly establishes adenocarcinoma as the non-smoking-associated lung cancer:
Adenocarcinoma accounts for the vast majority of lung cancers in never-smokers, with approximately 19% of female and 9% of male lung cancers in the United States occurring in patients without any tobacco smoking history 1
Non-smoking-associated lung cancer is now recognized as a distinct disease entity with specific molecular and genetic tumor characteristics that differ fundamentally from tobacco-related cancers 1
The proportion of NSCLC patients who are never-smokers has been increasing, particularly in Asian countries, where approximately 500,000 deaths annually are attributed to lung cancer in lifetime never-smokers 1
Molecular and Genetic Distinctions
Adenocarcinoma in never-smokers demonstrates unique biological features:
EGFR mutations occur at significantly higher rates in never-smokers (approximately 10% in Caucasians, higher in East Asians), particularly in the adenocarcinoma subtype, women, and younger patients 1
ALK rearrangements are encountered more frequently in never-smokers with adenocarcinoma (approximately 5% of cases), representing younger patients with the adenocarcinoma subtype 1
Adenocarcinomas in never-smokers harbor single oncogene addictions (EGFR mutation, KRAS mutation, HER2 mutations, or ALK translocation) that occur in a mutually exclusive manner, making them particularly amenable to targeted therapy 3
These tumors demonstrate a lower incidence of overall genetic alterations (somatic mutations, loss of heterozygosity, and methylation) compared to smoking-related cancers 3
Clinical Implications for Testing
The molecular profile necessitates specific testing approaches:
EGFR mutation testing should be systematically analyzed in all advanced NSCLC with non-squamous histology, though testing is not recommended in squamous cell carcinoma except in never/former light smokers (<15 packs per year) 1
ALK rearrangement testing should be discussed in non-squamous histology, particularly in never/former light smokers, especially when EGFR and KRAS mutations are absent 1
Important Caveats
Do not use smoking status as an absolute screening criterion for molecular testing in clinical practice 4. While actionable driver mutations are more common in never-smokers with adenocarcinoma, a substantial proportion of patients with these mutations have previous smoking history, and conversely, many never-smokers harbor mutations traditionally associated with smoking 4.
Risk Factors Beyond Tobacco
Alternative etiologic factors for adenocarcinoma in never-smokers include:
Environmental exposures: radon, asbestos, arsenic, non-tobacco-related polycyclic aromatic hydrocarbons 1, 2
Indoor air pollution: coal-fueled stoves and cooking fumes, particularly contributing to the high burden in women in certain countries 1
Genetic susceptibility: familial risk with heritability estimated at 18%, with identified susceptibility loci including CHRNA3, CHRNA5, TERT, BRCA2, CHECK2, and HLA region 1