Generally, age-standardized LCNS rates are higher among African American and Asian populations than among those of European descent.5  In the US, LCNS mortality is higher among African-Americans than among those of European descent.Survival is lower among Asian and Latina women in the US than among non-Hispanic white women.19  

Unique Pathologic and Genetic Features

Toxins in never-smokers appear to target peripheral tissue, with adenocarcinoma accounting for about 2 in 3 LCNS cases.7,15,16,17,20 For comparison, the ratio of adenocarcinoma to squamous cell carcinoma in never-smokers is 3.4:1 but in smokers is 0.4:1. 

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Genetically, patients with LCNS have fewer total somatic mutations than smokers with lung cancer.21 A unique pattern characterized by EGFR mutations, most commonly deletions in exon 19 and exon 21, is characteristic.10, 22,23  EGFR activating mutations are more common among never-smokers than smokers (Figure 2),10,18,21,24,25 but still represent a small portion of LCNS cases: 28% in a pooled analysis and 22% in a survey of patients at Massachusetts General Hospital.4,26 These mutations are highly associated with adenocarcinomas versus other lung cancer tumors, and also correlate with adenocarcinoma in situ (formerly bronchioloalveolar carcinoma) and the presence of well-differentiated tumors.18,22,24,25  Of the other EGFR family mutations, HER2 is found at a higher rate among never-smokers.10  

Adapted from Couraud et al, 2012.4

Figure 2. Pooled data on pattern of mutations by smoking status in American lung cancer patients4

EML4-ALK is created by fusion of the anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) genes. EML4-ALK is found in approximately 2% to 7% of NSCLC, but varies by population: 13% of non-Asians in a screened Massachusetts NSCLC sample carried the gene.22,26 EML4ALK-positive patients tend to be younger, male, and have more advanced NSCLC than EGFR-positive patients.22,26,27 EML4-ALK is associated with LCNS, with as many as one-third of EGFR-negative LCNS cases carrying the ALK rearrangement.4,26-28 Mutations such as KRAS and STK11, commonly found in smokers with NSCLC, are relatively rare in LCNS (Figure 2).10,18,21,24 In fact, EGFR activating mutations, other EGFR family mutations, KRAS mutations, and EML4ALK translocation are thought to be mutually exclusive.10,21,24,26 

Never-smokers are less likely than smokers to carry mutations in p53, and those mutations they carry differ. For example, a G to C transversion predominates in never-smokers versus G to T in smokers. Researchers have determined that different p53 mutations are associated with different exposure risks in LCNS.4,10 Other mutations, including reduced expression of the glypican 5 gene (GCP5), may increase LCNS risk.29,30 


Compared with former smokers or active smokers, never-smokers have a more favorable prognosis, with longer overall survival times usually reported. In two retrospective US studies done prior to the availability of TKI therapy, 5-year survival rates were higher in never-smokers than smokers, regardless of stage at diagnosis.13,14 In a WHO database of 26,957 lung cancer patients, never-smokers had longer median overall survival (OS) than former smokers (29.9 v 19.0 months, P<0.0001).20 However, a retrospective case-matched study, also pre-TKI, found no survival advantage for never-smokers versus smokers at 5 years,15 and a single-institution retrospective study from Johns Hopkins found little impact for never- versus former smoking on long-term survival after curative surgery.31