An estimated 226,160 new cases of lung cancer and 160,340 associated deaths will occur in the United States in 2012, the vast majority of them being non-small cell lung cancer (NSCLC).1 As many as 10% to 15% of NSCLC cases occur in people who have never smoked, defined as having smoked <100 cigarettes over a lifetime.2-4 Lung cancer in never-smokers (LCNS) occurs in numbers similar to leukemia and endometrial cancer, and is thought to be the sixth most common cause of cancer death in Americans.3,5 In the Cancer Prevention Study II, age-standardized death rates per 100,000 person-years from LCNS were 17.1 for men and 14.7 for women.6  Risk for LCNS appears not to be increasing over time, but there are conflicting data and the long-term trend is uncertain.5,7

Primary risk factors for LCNS are exposure to second-hand smoke (SHS), radon, asbestos, or indoor air pollution, and history of radiation therapy to the upper chest.1,3,8 Risk factor predominance varies by geographic area and to some extent by sex, as in many countries women are more frequently exposed to SHS and men to occupational toxins.4,9 As in most cancer, family history plays a role: never smokers are more likely than smokers to report having a first-degree relative with NSCLC, especially one whose disease occurred before age 50 years.8,10,11 History of previous inflammatory pulmonary disease, such as tuberculosis or pneumonia, increases LCNS risk.12 Less well-established is a relationship between LCNS and hormones in women. Estrogen-receptor-ß is more frequently expressed in LCNS and correlates with EGFR mutations and response to EGFR tyrosine kinase inhibitors (TKIs). Additional risk factors still being explored include the role of menopausal hormone replacement, oral contraceptives, viral infections, and diabetes mellitus.4

Epidemiology of LCNS

Compared with smokers, never-smokers with lung cancer are more likely to be women,  symptomatic, and have poorly differentiated tumors at the time of diagnosis.13-15 In the United States and Europe, patients with LCNS tend to be older than smokers, but in Asian studies they tend to be younger.4,14,16  In prospective cohort studies from the United States, the lowest incidence of LCNS among women was higher than the highest among men (Figure 1).17  The overrepresentation of women may reflect lower smoking rates among women in most of the studies rather than some inherent gender difference.18

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NA indicates no data for men or women in that study. NHS=Nurses Health Study; HPFS=Health Professionals Follow-Up Study; CTS=California Teachers Study; MEC=Multiethnic Cohort; NHEFS=National Health and Nutrition Examination Survey Epidemiologic Follow-Up Study. Adapted from Wakelee et al, 2007.17

Figure 1. Age-adjusted incidence of lung cancer in never-smokers: US cohort studies17