Curbing the burden of lung cancer

Abstract

Lung cancer contributes substantially to the global burden of disease and healthcare costs. New screening modalities using low-dose computerized tomography are promising tools for early detection leading to curative surgery. However, the screening and follow-up diagnostic procedures of these techniques may be costly. Focusing on prevention is an important factor to reduce the burden of screening, treatment, and lung cancer deaths. The International Agency for Research on Cancer has identified several lung carcinogens, which we believe can be considered actionable when developing prevention strategies. To curb the societal burden of lung cancer, healthcare resources need to be focused on early detection and screening and on mitigating exposure(s) of a person to known lung carcinogens, such as active tobacco smoking, household air pollution (HAP), and outdoor air pollution. Evidence has also suggested that these known lung carcinogens may be associated with genetic predispositions, supporting the hypothesis that lung cancers attributed to differing exposures may have developed from unique underlying genetic mechanisms attributed to the exposure of interest. For instance, smoking-attributed lung cancer involves novel genetic markers of risk compared with HAP-attributed lung cancer. Therefore, genetic risk markers may be used in risk stratification to identify subpopulations that are at a higher risk for developing lung cancer attributed to a given exposure. Such targeted prevention strategies suggest that precision prevention strategies may be possible in the future; however, much work is needed to determine whether these strategies will be viable.

Keywords

lung cancer / screening / risk factors / environmental

Introduction

For decades, lung cancer has been the most common form of malignancy worldwide [ 1]. The highest incidence rates of lung cancer are detected in North America and Europe for men and in the Asia-Pacific region, as well as North America and Europe, for women [ 2]. The high societal burdens of lung cancer are not restricted to any subgroup or region. Lung cancer treatment costs, including the individual and medical coverage costs, are considerable. In 2000, a 72-year-old patient diagnosed with lung cancer incurred monthly costs from US $2687 (no active treatment) for the first 6 months to US $9360 (chemo-radiotherapy), with variations based on stage at diagnosis and histologic type [ 3]. The patients are often responsible for up to 22% of these care costs, and this number is continuing to increase [ 3]. Large discrepancies in healthcare costs may occur depending on failure of initial treatment of patients, which can sometimes correlate to their stage at diagnosis. For example, if a lung cancer patient fails the initial treatment phase, the costs will markedly increase compared with those of lung cancer patients who only require initial treatment. Patients who failed initial therapy had total costs of US $120 650 as opposed to US $45 953 for those receiving initial therapy only [ 4]. Given that the cost of treatment and the burden of disease are increasing, finding new solutions for rectifying cost-effective strategies becomes imperative.

Lung cancer screening and prevention

Even with millions of lung cancer diagnoses each year, and decades of research on the disease, the prognosis of lung cancer remains poor with approximately 15% of cases surviving≥5 years [ 5]. Early detection of lung cancer may allow for curative surgical care. According to the National Lung Screening Trial (NLST), the use of low-dose computerized tomography (LDCT) in individuals from the general population aged 55–74 years old with≥30 pack-years of smoking resulted in a 20% reduction in lung cancer mortality and 7% reduction in all-cause mortality [ 6, 7]. The approach is cost effective [ 8], even though 27% of nodules≥4 mm at baseline (T₀) and 15%–30% of those detected during follow-up were subsequently determined to be benign. The significant findings reported by NLST encouraged several organizations to publish clinical guidelines for implementing LDCT screening programs in the general population; hence, this method has been rapidly applied in major medical centers [ 9]. However, given the high costs of LDCT and subsequent follow-ups, continued efforts should include prevention.

Society can decrease the lung cancer burden through strategies for prevention of known and suspected lung carcinogens. The leading cause of lung cancer is unequivocally tobacco smoking, with roughly 85% of lung cancer in men and 47% of lung cancer in women attributed to tobacco smoking [ 10]. A recent meta-analysis of 287 studies observed a strong association between smoking and lung cancer risk for ever smoking (RR= 5.50, 95%CI= 5.07–5.96), current-smoking (RR= 8.43, 95%CI= 7.63–9.31), and past-smoking (RR= 4.30, 95%CI= 3.93–4.71) subjects for all cancer types, including squamous-cell carcinoma and adenocarcinoma [ 11]. A meta-analysis of 55 studies observed an association between passive smoking and the development of lung cancer, particularly among never-smoking women exposed to passive smoking from their spouses (RR= 1.27, 95%CI= 1.17–1.37) [ 12]. The association of smoking and lung cancer has been investigated extensively, and tobacco legislation and smoking bans are often the focus of major public health policies.

Apart from smoking as the primary risk factor for lung cancer, other environmental and occupational exposures have also been deemed as risk factors [ 13]. The International Agency for Research on Cancer (IARC) is the governing body on cancer research of the World Health Organization. The working groups of IARC, consisting of the leading experts, met to assess the potential carcinogenicity of an agent or exposure circumstance in question. As of 2014, IARC had classified>100 agents and exposure circumstances as carcinogenic to humans (Group 1) [ 14, 15]. Group 1 lung carcinogens include agents such as tobacco smoking, environmental tobacco smoke, silica, asbestos, arsenic, polycyclic aromatic hydrocarbons (PAHs), engine exhaust, household air pollution (HAP) attributed to solid fuel use, outdoor air pollution, and radon.

HAP is a non-tobacco lung carcinogen of major public health concern [ 16]. HAP is responsible for nearly 4 million deaths per year [ 17], among the approximately 3 billion people exposed to HAP [ 18]. HAP exposures and subsequent burden of disease are anticipated to increase as rural residents of western countries increasingly rely on wood as a low-cost, renewable heating source [ 19]. HAP consists of smoke attributed to solid fuel use (i.e., coal, wood) for heating and cooking, increasing the household levels of carcinogens, such as PAHs [ 20]. A meta-analysis of 25 studies found in-home coal use to be associated with lung cancer risk (OR= 2.15; 95%CI= 1.61–2.89) [ 21]. A pooled analysis of 7 studies from the International Lung Cancer Consortium (5105 cases and 6535 controls) also observed an association between coal use and lung cancer risk [ 22]. HAP exposure mitigation programs have shown some promise. In Xuanwei, China, a retrospective cohort study of approximately 42 000 farmers [ 23], who were coal users and underwent stove improvement from unvented stationary stoves to portable stoves, observed a significant reduction in risk of lung cancer mortality (men: 39%; women: 59%) [ 24]. Improving to a stove with a chimney also reduced lung cancer risk (men: 41%; women: 46%) [ 23]. Recent studies on stove improvement at the individual level have experienced challenges with adoption and adherence [ 25– 28], limiting the health impacts. However, community-wide stove change programs have shown promise in terms of PM_2.5 reduction [ 29, 30].

Genetic predisposition

Apart from environmental exposures, a systematic review of 52 studies observed that a positive family history of lung cancer was also associated with a significant, nearly twofold increase in risk of lung cancer, even when restricted to studies evaluating never smokers only [ 31], indicating that genetic predispositions may play an important role in lung cancer. Large-scale multinational genome-wide association studies (GWASs) initially found that the 5p15.33, 6p21.33, and 15q25 regions were associated with lung cancer risk [ 32– 35]. These GWASs found that genetic variation on chromosome 15q, which contains nicotinic acetylcholine receptors genes, was the strongest association with lung cancer risk [ 32, 33]. Given that the aforementioned studies were conducted on Caucasian smoking populations, it may not be surprising that the variants most strongly associated with lung cancer were related to nicotine use and dependence. To identify genetic markers associated with lung cancer in the absence of tobacco smoking, GWASs have also been conducted on non-smoking populations. Similar to the previous GWASs, a multistage GWAS on lung cancer in Asian never smoking women was conducted. A total of 5510 cases and 4544 controls were scanned, and follow-up genotyping of SNPs at P<5×10^-6 was conducted in an additional 1099 cases and 2913 controls [ 36]. Interestingly, novel regions including 10q25.2, 6q22.2, and 6p21.32 were associated with lung cancer risk in those who had never smoked [ 36]. The previously observed association at 15q25 in smokers was not statistically significant in never smokers. Coupling the novel regions observed in never smokers with the lack of association at 15q among never smokers suggests that the risk variants for nonsmoking-related lung cancer are distinct from those for smoking-related lung cancer. Interestingly, among the a priori regions identified by the GWAS of never smokers, significant gene-environment interactions with HAP (HLA Class II rs2395185, P = 0.02; TP63 rs4488809 (rs4600802), P = 0.04) were identified, thus suggesting that the risk of lung cancer associated with HAP exposure varied with the respective alleles for those regions [ 37]. To date, the weight of evidence suggests that populations who have differing environmental exposures, such as tobacco smoking and HAP, may be susceptible to lung cancer attributed to the unique underlying mechanisms of pathogenesis. As with many genomic applications, however, researchers should replicate these findings in additional populations prior to considering translation to the clinic or public health action. Understanding the underlying mechanism of lung carcinogenesis may lead to better targeted prevention strategies related to exposures other than tobacco and may significantly affect the global burden of disease.

Conclusions

Prevention strategies and screening modalities are vital to curb the global burden of lung cancer. Existing methods for preventing lung cancer, in conjunction with early detection to enable curative surgery, must be improved by mitigating human exposures to lung carcinogens. Among heavy smokers, LDCT screening and smoking cessation programs and interventions for current smokers have shown promise. Notably, incorporating smoking cessation interventions into LDCT screening improves the cost effectiveness of LDCT screening by 20%–45% [ 38]. Apart from focusing on smoking, prevention strategies must also focus on individuals with high environmental exposures (i.e., HAP), particularly identifying those exposures and how to reduce or eliminate them. Further research is also needed to determine how genomic patterns can be used for risk stratification and to identify the patients at risk earlier for prevention and early detection. Although the utilization of genomics for risk stratification is currently not cost effective or commonly accepted in medical practice, research in this area will help support the development of a tool for healthcare providers to eventually identify subpopulations at high risk of lung cancer. Finally, our proposed all-encompassing prevention and screening strategies must be critically evaluated for their sustainable viability.

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