Although there are a variety of causes and risk factors for lung cancer, none are more clearly defined than smoking, which is implicated in approximately 85% of all lung cancers (Larsen 2011). Overall, smokers are about 25 times more likely than nonsmokers to develop lung cancer (Larsen 2011; ACS 2013a; ACS 2014c). Over half of newly-diagnosed lung cancers in the United States, however, occur in people who have already quit smoking, a testament to the long-term damage caused by tobacco smoke (Larsen 2011). Those exposed to secondhand smoke are at increased risk of developing lung cancer as well; one study estimated that workers exposed to atypically high levels of secondhand smoke may have up to a 13-fold increased risk of dying from lung cancer (NCI 2014e; Mayo Clinic 2014; O'Hanlon 2013; Siegel 2003).
Tobacco smoke has been reported to contain over 6000 chemicals, more than 70 of which have been shown to be carcinogenic. These include arsenic, benzene, benzo(a)pyrene, cadmium, and formaldehyde (Sanders 2008; Health Canada 2011). When inhaled, these compounds contribute to DNA damage, resulting in the mutation of genes involved in controlling cellular growth (Landi 2006).
Fortunately, long-term smoking cessation mitigates lung cancer risk; after 10 years without smoking, the likelihood of developing lung cancer is decreased 30–50% (NCI 2013d). However, it is unclear if former smokers have a better prognosis than patients still smoking at diagnosis. It is clear, however, that smoking cessation after diagnosis improves outcomes (Parsons 2010).
In recent years, electronic cigarettes, or e-cigarettes, have become a popular alternative to traditional cigarettes (CDC 2013a; CDC 2013b). Advocates claim e-cigarettes are not only safer than regular cigarettes, but can serve as a smoking cessation tool (American Lung Association 2014a; Paradise 2013).
Despite claims of safety, recent evidence suggests that e-cigarettes can harm the lungs. Researchers from Greece evaluated the impact of e-cigarettes on 32 volunteers, of whom 8 never smoked. Some had healthy lungs, others had asthma or chronic obstructive pulmonary disease (COPD). After using one e-cigarette for 10 minutes, never smokers and regular smokers demonstrated a significant increase in airway resistance in response to e-cigarettes, although there was no change in those with lung disease (MNT 2013). In another study, researchers from the University of California conducted lab studies that showed the nicotine vapor enhanced the “aggressive” behavior of epithelial lung tissue that already contained mutations in the tumor-suppressor gene P53 or the KRAS gene (AACR 2014). Other studies found that e-cigarettes emit potentially harmful pollutants that could affect users and those who inhale the toxins through secondhand vapor (Schober 2013).
Although many findings suggest e-cigarettes are at least somewhat efficacious as tobacco-cessation aids, not all evidence supports this notion. More studies are needed before conclusive statements can be made about the ability of e-cigarettes to help tobacco smokers quit (Kasza 2013; Etter 2014; Bullen 2013; Siegel 2011).
Family History and Genetic Predisposition
Several large studies have identified inherited genetic variations that increase the risk of lung cancer, some of which also increase the risk of nicotine dependence (Larsen 2011). Studies have found at least 3 key chromosomal regions that in populations of European descent are associated with the risk of lung cancer: sequence variants within the nicotinic acetylcholine receptor genes on chromosome 15, which are associated with the number of cigarettes smoked per day, nicotine dependence, and smoking-related diseases; sequence variants in a region on chromosome 5, which includes the TERT and the CLPTM1L genes; and a region on chromosome 6. Neither of the two latter regions appeared to be associated with smoking behavior (Rafnar 2011). Having a first-degree relative with lung cancer is associated with a roughly 50% increased risk of acquiring the disease; the risk increases to about 80% when the affected relative is a sibling (Cote 2012).
Previous Lung Disease
Many lung diseases, including chronic bronchitis, emphysema, pneumonia, and tuberculosis are associated with lung cancer development (Brenner 2012; Koshiol 2009). Specifically, people with emphysema and chronic bronchitis have a 2.44-fold and 1.47-fold increased risk, respectively, of developing lung cancer. Never smokers with a history of emphysema, pneumonia, or tuberculosis demonstrate a higher risk of lung cancer than those without (Brenner 2012). These diseases are major sources of inflammation in lung tissue, which is thought to contribute to cellular changes resulting in malignancy (Brenner 2012; Koshiol 2009; Engels 2008).
Inflammation and Lung Cancer
Inflammatory signaling is involved in many aspects of lung cancer biology. The proliferation and survival of cancer cells, growth of new blood vessels to supply a tumor (angiogenesis), spread of cancer (metastasis), and tumor responses to a variety of chemotherapeutic drugs are all, to varying degrees, dependent upon inflammatory reactions (Gomes 2014; Hanahan 2011). Accordingly, several studies have linked elevated levels of inflammatory markers with increased lung cancer risk.
A study published in 2013 evaluated 68 biomarkers associated with inflammation in 526 lung cancer patients and 592 healthy controls. Eleven biomarkers were found to correlate with lung cancer risk; pro-inflammatory markers (eg, CRP) were linked to increased risk of lung cancer, whereas anti-inflammatory markers (eg, interleukin-1 receptor antagonist) were associated with a decreased risk (Shiels 2013). A systematic analysis of data on 1918 lung cancer cases from 10 studies revealed a statistically significant association between rising CRP levels and lung cancer risk: each 1 mg/L unit increase in CRP was associated with a 28% increased risk (Zhou 2012). Another inflammatory marker – interleukin-6 (IL-6) – was associated with a significantly increased risk of lung cancer in an analysis of data from two studies. In one of the two studies, subjects whose serum levels of IL-6 fell within the top 25% of the distribution were 3.29 times more likely to have lung cancer than subjects with lower IL-6 levels. Similarly, the second study revealed a 1.48-fold increased risk for lung cancer among those in the top 25% of the distribution for IL-6 levels (Pine 2011).
In addition to the role of inflammation in predicting lung cancer risk, measuring inflammation in lung cancer patients may help determine prognosis. In a study on 173 patients with metastatic NSCLC, researchers developed an inflammatory index based upon anthropomorphic measures, albumin levels, and the ratio of neutrophils to lymphocytes. This index was termed the Advanced Lung Cancer Inflammation Index (ALI), and it was found to be a strong predictor of overall and progression-free survival time. Patients whose ALI score denoted high systemic inflammation had an overall survival time of 3.4 months, but those whose ALI score indicted lower inflammation survived for a median 8.3 months (Jafri 2013).
The powerful link between inflammation and lung cancer is further evidenced by studies showing that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced lung cancer risk (Gomes 2014). The relationship between NSAIDs and lung cancer risk is further discussed later in this protocol, in the Novel and Emerging Strategies section.
Carcinogenic Environmental Factors and Toxins
Several environmental factors are associated with lung cancer development, including exposure to asbestos, diesel engine exhaust, air pollution, pesticides, and heavy metals such as cadmium and nickel (Vermeulen 2014; Raaschou-Nielsen 2013; Clapp 2008; Offermans 2014; Wild 2009).
Radon, a radioactive gas released from the decay of uranium, thorium, and radium, can damage epithelial lung cells, leading to cancer. In fact, exposure to radon is the second leading cause of lung cancer in the United States, after smoking (NCI 2011).
Viruses and Bacteria – Potential Associations with Lung Cancer
Certain types of the human papillomavirus (HPV) increase the risk of cervical, vulvar, anal, oral, and head and neck cancers. It also appears that infection with HPV, particularly HPV-16 and HPV-18, may be associated with lung cancer development, although the evidence is mixed (Zandberg 2013).
People infected with HIV also have a higher risk of lung cancer – 2 to 4 times higher than the general population, even after accounting for smoking status. Several factors may contribute to this association, including the cancer-promoting properties of the virus itself, increased risk of recurrent pulmonary infections in this population, and HIV-related immune system abnormalities (Mani 2012).
An emerging hypothesis suggests that Helicobacter pylori (H. pylori) bacteria, the underlying cause of most gastric ulcers, may also increase lung cancer risk. Epidemiologic evidence appears to suggest lung cancer may be more prevalent in those infected with H. pylori, and studies have found evidence of the bacteria in upper respiratory tract tissue. However, more studies are needed to conclusively link the two (Deng 2013).