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The causative association between tobacco use and lung cancer is a well-established fact. However, lung cancer also occurs, at surprisingly high rates, in lifelong never smokers. In fact, lung cancer in never smokers is among the leading causes of cancer-related mortality. This CCR Focus summarizes recent data, identifies knowledge deficits, and suggests future research directions with regard to this critically important subset of lung cancer patients.
Lung cancer caused by tobacco smoking is a well-documented public health tragedy. This highly fatal and largely avoidable cancer now causes more than 1 million deaths worldwide each year and more than 160,000 deaths annually in the United States (1). Lung cancer is responsible for more American deaths than colon cancer, breast cancer, and prostate cancer combined. An estimated 90% of cases are linked to cigarette smoking, based on the American Cancer Society’s Cancer Prevention Study II (CPS; ref. 2).
The exceptionally high risk for lung cancer in smokers has obscured the problem of lung cancer in never smokers. Not all cases of lung cancer can be attributed to current or former smoking, and several environmental risk factors for lung cancer other than smoking have been identified. Worldwide, clear estimates of the number of lung cancer cases in never smokers are not consistently available, but several populations have been described with particularly high rates that are not readily explained. In the United States, lung cancer in never smokers is almost as common a cause of death as atherosclerosis, and is among the most common causes of cancer mortality (see Fig. 1; refs. 3, 4).
The articles in this CCR Focus series were developed to summarize what is known about lung cancer in never smokers, covering multiple aspects of the problem: epidemiologic characteristics, risk factors, molecular and biological underpinnings, natural history, response to therapy, and outcome (5, 6). These articles are the products of a multidisciplinary workshop held at Johns Hopkins and supported by the Flight Attendant Medical Research Institute, with an international faculty representing public health, epidemiology, molecular biology, pathology, and oncology. They reflect the available literature across these disciplines along with recommendations developed from this workshop. The workshop was held in 2007; where appropriate, select key studies in the interim since the workshop have been incorporated into the articles and overview. Briefer and focused reviews of some of the individual topics covered here have been also published in recent years (7–9): a goal of this workshop, and of this issue of CCR Focus, is to provide a broad, current, and comprehensive summary of knowledge about this disease.
The workshop and the resulting articles were intentionally focused exclusively on evidence pertaining to lung cancer among never smokers. Studies pertaining to nonsmokers, which included former smokers, were therefore excluded from these analyses. For several of the studies that were included, the exposure status of nonsmoker was not clearly defined. Many of these studies were conducted among women living in countries with a very low prevalence of smoking among females, and we therefore considered their inclusion to be appropriate. Throughout the articles we specify whether the study subjects were never smokers (clearly defined) or nonsmokers (not clearly defined, or definitions vary).
Several general conclusions from the literature, and recommendations about future research on the issue of lung cancer in never smokers were derived from this workshop:
The following research needs were identified in the workshop:
The past decade has been notable for an emerging focus of interest in lung cancer in the never smoker across multiple disciplines including advocacy, epidemiology, clinical medicine, and bench sciences, reflected in increasing numbers of focused research publications addressing this patient population. This trend has been in part driven by a simple clinical observation: never smokers with lung cancer, especially those with EGFR mutations, show preferential benefit from a new class of anti-cancer drugs, the EGFR tyrosine kinase inhibitors. Continued interrogation of the biology of lung cancer in never smokers is likely to reveal additional therapeutic targets of relevance to smokers and never smokers alike.
Grant support: The workshop and resulting articles were supported by a grant from the Flight Attendant Medical Research Institute (FAMRI). The funding organization had no role in the preparation of the articles.
The authors of the articles in this issue of CCR Focus would like to thank Nicole Ammerman, Ting-Yuan (David) Cheng, and Nrupen Bhavsar for their technical assistance; Andrea Johnson and Charlotte Gerczak for editing assistance; and Carrie Mattson for her administrative support.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.