Understanding the Links Between Lung Cancer, COPD, and Emphysema: A Key to More Effective Treatment and Screening

Lung cancer has been linked to the changes in lung function characteristic of chronic obstructive pulmonary disease (COPD) and to the changes in lung morphology seen in emphysema. It seems that a common thread of smoking-induced lung injury can be traced to all three diseases. However, the association is not as straightforward as it may seem; for example, even never-smokers with emphysema have an increased risk of lung cancer. Whether lung cancer, COPD, and emphysema are linked by common genes, mechanisms, causes, or a combination thereof, understanding the associations between them has become a priority for research regarding tobacco-related illnesses. A better delineation of the relationships between these three entities may lead to significant improvements in the effectiveness of lung cancer screening programs, and to reductions in the morbidity and mortality associated with these deadly diseases.

Introduction

Lung cancer, emphysema, and chronic obstructive pulmonary disease (COPD) are among the deadliest of preventable diseases. Lung neoplasms are the leading cause of cancer deaths worldwide, outnumbering the combined death toll attributable to colon, prostate, and breast cancers.[1,2] COPD, characterized by persistent airflow limitation and chronic inflammation of the airways, is also a leading cause of death, second only to cardiovascular diseases.[3]

Lung cancer, COPD, and emphysema are all caused or aggravated by smoking. While the causal link with tobacco is obvious, and has been made clear by a plethora of scientific studies, the past decade has seen renewed interest in the links between lung cancer, COPD, and emphysema (a chronic lung disease resulting from damage to the alveoli and resulting in breathlessness). Recent evidence provided by screening studies has shown that patients with tobacco-related altered lung function (COPD) or altered morphology (emphysema) are particularly susceptible to lung cancer. Not surprisingly, chronic inflammation has been postulated as the obvious culprit linking COPD and lung cancer.[4] Inflammation causes cellular damage while promoting cell proliferation, hence providing a suitable environment for oncogenic mechanisms to prosper. However, the association between emphysema and lung cancer is not as intuitive, despite its being so powerful that even nonsmokers with emphysema are at risk for lung cancer.[5]

The challenge of finding common pathways is not only academic, but is a major concern in the current era of lung cancer screening, since screening programs are most effective when high-risk populations are selected. A better understanding of the common threads that link emphysema, COPD, and lung cancer might help us make lung cancer screening more cost-effective by enabling us to offer it to smokers with the greatest risk, but also simply make screening more effective-by including younger, less-exposed individuals who are nonetheless at risk, including some nonsmokers.

Evidence Linking Alterations in Lung Function and Morphology With Lung Cancer

The association between altered lung function and lung cancer was first described in the 1980s by Skillrud et al and Tockman et al.[6,7] It is now clear from a growing body of evidence, including a recent meta-analysis, that tobacco-related airflow obstruction conveys an independent two- to fourfold increase in lung cancer risk, even when the cohorts being compared are controlled for smoking.[8-12] This holds true for both men and women.[12] Interestingly, the timing of a COPD diagnosis and disease severity may play a role in the development of lung cancer, and not necessarily in the way one might expect.[13,14] In some studies, lung cancer appears to be more common in patients with a recent COPD diagnosis than in those with longstanding obstructive airway disease, and it may be two to three times more common in cases of mild to moderate obstruction than in more advanced disease-although the data about the latter association are mixed. An increased frequency of lung cancer in patients with less severe COPD seems especially common when screen-detected lung cancers are considered. In one screening study, the vast majority of lung cancers (94%) appeared in patients with early-stage COPD.[15] Even those with altered lung function, but with a forced expiratory volume in 1 second (FEV₁) exceeding 90% of predicted values, have twice the risk of smokers without COPD.[16] Indeed, existing evidence appears to support a survivor effect, suggesting that lung cancer may appear early on in the progression of COPD. This finding is important because it suggests that those who stand to benefit most from screening are precisely the ones who might tolerate invasive therapies with curative intent despite a COPD diagnosis. However, not all studies agree, and in any event, the survivor effect can only be partially responsible for this finding, since both the Pittsburgh Lung Screening Study (PLuSS) and data from the National Health and Nutrition Examination Survey suggest the opposite (ie, that lung cancer is more common in patients with moderate to severe airflow obstruction).[9,17]

The evidence linking emphysema and lung cancer is even more intriguing. The widespread availability of CT scanners and the advent of lung cancer screening using low-dose CT have provided ample evidence suggesting that the morphologic changes associated with emphysema may be the single most powerful predictor of lung cancer risk for any given individual. In a study by de Torres et al in patients enrolled in a lung cancer screening program, lung cancer was three times more likely in those with emphysema.[8] Similar results have been reported in other screening cohorts and even by the National Lung Screening Trial (NLST) investigators.[9,18] In the NLST, the presence of emphysema was clearly associated with an increased risk of death from lung cancer (hazard ratio, 1.56; 95% CI, 1.20–2.04). This finding has practical implications for screening, since restricting inclusion criteria by aiming at, for example, the 60% of individuals at highest risk for death from lung cancer would still account for almost 90% of CT-preventable lung cancer deaths while reducing both false-positives and the number needed to screen to prevent one lung cancer death. Unfortunately, the prevalence of both emphysema and COPD in the NLST was low (7% and 5%, respectively). It is likely that the use of emphysema as a screening criterion would provide an additional means of identifying at-risk individuals who might benefit from screening, as evidenced by a landmark study.[8] Emphysema is such a powerful predictor of risk that subjects not meeting NLST age or smoking criteria but who had emphysema might also benefit from screening.[19] Furthermore, it is quite clear from available epidemiologic evidence that even never-smokers with emphysema are at greater risk for lung cancer, suggesting that emphysema by itself, whether smoking-related or not, is a powerful risk factor.[5] Data from the International Early Lung Cancer Action Program (I-ELCAP) screening cohort have shown that never-smokers with emphysema have a sixfold increase in lung cancer risk compared with never-smokers without emphysema.[20] The combined emphysema–pulmonary fibrosis phenotype is also associated with a higher risk of lung cancer, although fibrosis appears to be more carcinogenic than emphysema in some series.[21]

The evidence in favor of emphysema as a putative risk factor for lung cancer independent of tobacco exposure can be contradictory. Some studies favor an association between emphysema severity and lung cancer risk, while others find no such link.[9,22,23] Of note, some studies in which emphysema severity has been determined by quantitative methods have failed to find an association with lung cancer.[10,24] Intriguingly, however, a recent meta-analysis reported that automated quantification of emphysema was inferior to visual assessment, suggesting that the association with lung cancer risk is qualitative, not quantitative.[25] The reasons for the differences between qualitative and quantitative assessments of emphysema and an association with lung cancer are not understood. One possibility is that automatic software quantitation is too sensitive, while visual emphysema determination only identifies areas of obvious parenchymal destruction. Perhaps, as was the case with advanced-stage COPD in some studies, patients with severe emphysema have outlived their chance of developing lung cancer, while it is those with traces of the morphologic changes on CT and preserved lung function who are at greatest risk. In any case, with current technology and knowledge, only visual qualitative determination of emphysema on low-dose CT has a role in assessing a patient’s risk for lung cancer.

The strength of the bond linking emphysema with lung cancer risk may also be dependent on regional lung differences. For example, lung nodules in the upper lobes are more likely to be cancer than those located in the lower lobes.[26] This finding may have more to do with upper lobe–predominant emphysema related to smoking than anything else. In fact, when lung cancer and emphysema coexist, the cancer tends to appear in an area affected by emphysema rather than in a healthier-appearing region of the lung.[27] This is an intriguing finding, given that there is less lung tissue in the emphysematous lung parenchyma for a cancerous clone to appear in than there is in healthier-appearing lung exposed to the same carcinogens. In our opinion, this seemingly counterintuitive finding lends support to the notion that the physiologic processes that are responsible for the morphologic changes typical of emphysema are also involved in lung carcinogenesis.

Finally, it should be noted that the severity of peritumoral emphysema may affect overall survival, suggesting that emphysema is not only associated with lung cancer, but may condition its biology as well.[28] Not surprisingly, recent research has revealed that interactions between lung cancer cells and the surrounding tumor stroma may be responsible for tumor progression and metastasis.[29] A recent study reported that matrix metalloproteinase-9 (MMP-9) expression in intratumoral stromal cells, typical of lung tumors arising in emphysematous lungs, is associated with more aggressive lung cancers. This might explain why lung cancer in a patient with underlying emphysema is associated with a worse prognosis.[30] It seems that emphysema provides the right kind of environment for tumors to develop and progress.

Mechanisms That Might Explain the Association Between Lung Cancer and Alterations in Lung Function and Morphology

Certain mechanistic aspects of the association between COPD, lung cancer, and emphysema have been touched on in the previous section, but much more is suggested by existing evidence (Table 1). Current research has unveiled multiple avenues for future investigation, centered around several hypotheses. Chief among these postulated mechanisms are: a common genetic susceptibility to all three tobacco-related diseases, DNA damage and repair, chronic inflammation, and a favorable milieu.

Genetic susceptibility

The obvious argument in favor of a shared genetic susceptibility linking COPD, emphysema, and lung cancer is based on the facts that only a minority of smokers develop any of these diseases while most are spared, and that susceptibility runs in families.[31] Patients who are genetically susceptible to the development of emphysema, such as individuals with α₁-antitrypsin deficiency, also have a higher risk of lung cancer, probably due to an imbalance in elastase activity.[32] Similarly, genome-wide association studies investigating the link between obstructive airway disease and lung cancer have identified a locus on chromosome 15q25, responsible for encoding nicotinic acetylcholine receptors, as a potential culprit, although the obvious link to nicotine dependence clouds the significance of this finding.[33-36]

Shortened telomeres have also been implicated in the development of lung cancer, emphysema, and COPD[37-39] and may be associated with a worse lung cancer prognosis.[40] Telomere length is controlled by a group of specialized enzymes known collectively as telomerase reverse transcriptases, or TERTs. A TERT gene polymorphism, rs2736100, was linked in a recent meta-analysis with the risk for lung cancer.[41]

Vascular endothelial growth factor receptor 1 (VEGFR1), which promotes inflammation and tumor progression and is one of several promising targets for novel lung cancer treatments, has been implicated in both COPD and lung cancer.[42] VEGFR1 is encoded by FLT1, an oncogene instrumental in the control of cell differentiation and proliferation. Not surprisingly, genetic alterations in mediators of inflammation such as interleukin (IL)-7R, IL-1α, and IL-10 have also been the focus of attention. Interestingly, cytokine alterations in lung cancer may vary by altered lung function, as well as by race, gender, and smoking history.[43] Genetic variants of the FAM13A gene, heavily expressed in the lung, have also been implicated in the common susceptibility to both COPD and lung cancer, although the mechanism by which this family of genes is involved is uncertain, with tumor suppressor activity being the most likely.[44]

DNA damage and repair

Further evidence linking COPD and lung cancer can be found in epigenetics, an important mediator between genetic variation and environmental exposure. DNA methylation profiles associated with smoking and COPD have been described in seemingly normal lung tissue from patients with lung cancer and may have prognostic implications.[45] A recently published study of methylation profiles for two well-defined cohorts of COPD patients identified 349 CpG sites (regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide) significantly associated with the presence and severity of altered lung function. Several of the sites linked to COPD in that study have also been implicated in lung tumorigenesis. A subsequent epigenetic study identified 2 genes, CCDC37 and MAP1B, with methylation patterns associated with both COPD and lung cancer susceptibility.[46] In COPD, reduced expression of CCDC37, which is expressed by bronchial epithelium, and of MAP1B, a microtubule assembly mediator, might predispose the CCDC37 and MAP1B genes to hypermethylation and ultimately to involvement in lung cancer tumorigenesis through as yet unknown mechanisms.

Finally, common messenger RNA profiles have also been studied in this regard. The similarities found between patterns in patients with COPD and lung cancer are noteworthy when compared with patterns in a control group of healthy individuals.[47]

Chronic inflammation

Chronic inflammation has been implicated in a host of human cancers. A number of inflammation-related mediators, including nuclear factor kappa B (NF-κB), oxygen and nitrogen radicals, cytokines, prostaglandins, and microRNAs, may be responsible for this well-known association.[48] Because COPD and emphysema are also related to inflammation, it is only logical to postulate that proinflammatory mediators play a pivotal role in the link between all three tobacco-related diseases. Genetic alterations in cytokines implicated in the pathogenesis of both COPD and lung cancer have already been mentioned, but other cytokines also play a role. For example, proinflammatory IL-17 may contribute to disease progression in patients with severe COPD.[49] In lung cancer, however, its role is confusing: mechanisms that have been proposed include protumoral cell proliferation, angiogenesis, metastasis, immune system evasion, and chemotherapy resistance.[50,51] Human non–small-cell lung cancer cells have been shown to produce type 2 cytokines, which contribute to an oncogenic stroma. IL-4, for example, has been linked to tumor growth and the appearance of metastasis in lung cancer.[52,53] While COPD has been traditionally considered a type 1 cytokine–producing disease, recent evidence suggests that protumoral type 2 inflammatory cytokines may play a crucial role as well, providing further evidence in favor of a mechanistic link between COPD and lung cancer.[54] This is a key finding because Th1 cell infiltration is associated with a better prognosis in non–small-cell lung cancer, while infiltration by type 2 cytokines favors tumor progression.[55]

NF-κB, a regulator of genes that control cell proliferation and cell survival, and a modifier of Th2 proinflammatory cytokines, has been implicated in the development of both lung cancer and COPD.[56] NF-κB expression is stimulated by smoking, and has been linked to COPD pathogenesis, as well as to chronic inflammation–related carcinogenesis and muscle wasting in smokers.[57-59] It may also induce carcinogenesis by a p53-related mechanism.

Another mediator of inflammation implicated in both COPD and lung cancer is the phosphatidylinositol 3-kinase (PI3K) pathway, a key promoter of tumorigenesis, as well as tumor proliferation and survival.[60] Interestingly, inhaled PI3K inhibitors have been developed as promising new therapies for COPD.[61]

Aberrant expression of the epidermal growth factor receptor (EGFR) and Wnts may also be involved in a common pathway leading to both COPD and lung cancer.[62] The EGFR signaling pathway is a key regulator of airway mucus production and secretions, a salient feature of the chronic bronchitis phenotype of COPD. A possible role for EGFR in connecting the dots between COPD and lung cancer is intriguing, since, as most clinicians know, lung cancers in smokers with COPD rarely manifest EGFR mutations amenable to tyrosine kinase inhibitor treatment.[63] EGFR may play an indirect role, since the proinflammatory mediators that induce EGFR expression in diseased airways are most likely type 2 protumoral cytokines.[64]

The Wnt–β-catenin pathway has been linked to both COPD and lung cancer in animal models.[65,66] Wnt–β-catenin alterations are prominent in human malignancies.[67] Furthermore, decreased Wnt signaling is involved in parenchymal tissue destruction and impaired repair capacity in emphysema.[68]

Finally, chronic inflammation has been indirectly linked to both COPD and lung cancer by the repair mechanisms it triggers, notably epithelial-mesenchymal transitions (EMTs).[69,70] Five major EMT regulatory genes have been identified: SNAI1, SLUG, ZEB1, ZEB2, and TWIST1. A recent study investigating the role of one of them (SNAI1) in the common origins of lung cancer and COPD found a clear association.[71] SNAI1 has been implicated in the promotion of EMT-like changes, cell migration, and invasion. In that study of more than 7,000 persons, including patients with lung cancer, patients with COPD, and controls, an exon variant of SNAI1 was associated with a decreased risk for both lung cancer and COPD. Interestingly, the effect on lung cancer risk appeared to be mediated indirectly by COPD.

Clinical Implications

Lung cancer in patients with COPD

Lung cancer and COPD not only go hand in hand in some patients, they also seem to be synergistic insofar as their combined impact on mortality is concerned. Lung cancer appears to be especially deadly in patients with COPD and/or emphysema. A recent meta-analysis found that COPD is associated with stage-independent poor overall and disease-free survival, while emphysema in lung cancer patients predicts worse overall survival.[72] The NLST investigators also found that lung cancer in patients with altered lung function is more aggressive.[73] This finding, common to other screening studies, including the Danish Lung Cancer Screening Trial (DLCST), suggests that screening-related overdiagnosis is less common in patients with COPD; since overdiagnosis is a frequently noted pitfall of screening, this finding arguably makes lung cancer screening more effective in patients with altered lung function.[74]

COPD and emphysema as selection criteria for lung cancer screening

Most recommendations regarding lung cancer screening rely on the NLST’s age and pack-year entry criteria, with only slight variations in smoking abstinence (Table 2).[75-80] However, concerns about the cost of screening so many at-risk individuals or missing cancers in younger, lighter smokers, especially women, have been raised. After all, the NLST entry criteria were arbitrary, not based on scientific evidence. That notwithstanding, current estimates suggest that as many as 7 million US adults are NLST-eligible.[81] Screening all of them is an expensive proposition. Making matters worse is the fact that many cancers are diagnosed in patients who do not meet NLST entry criteria.[19,81,82] In one study alone, less than 50% of lung cancers diagnosed in Olmsted County, Minnesota, between 2005 and 2011 occurred in NLST-eligible patients.[81] Furthermore, only 37% of women with lung cancer in that cohort would have been offered lung cancer screening if current recommendations were complied with, suggesting that a significant proportion of lung cancers may be missed by existing screening programs. Because the NLST and other studies have shown that a considerable number of screening-detected cancers are found in patients with altered lung function or morphology, it is only rational to assume that both emphysema and COPD may be considered clinically useful in this regard.[83] In fact, it is rare for a patient with lung cancer to have neither. In some studies, almost 80% of screened patients with lung cancer had COPD, emphysema, or both.[8]

In light of this, some medical societies have proposed modified inclusion criteria for screening, suggesting that NLST-ineligible smokers with at least one additional risk factor should also be offered screening.[77,78] This strategy was put to the test in three combined hypothetical cohorts from US and Spanish screening programs employing the I-ELCAP protocol in patients older than 40 years of age with at least a 10-pack-year smoking history.[19] Had screening been offered only to NLST-eligible patients in those cohorts, a large number of cancers would have been missed. However, if emphysema detected on a baseline CT scan had been used in order to recommend ongoing screening for those not meeting NLST criteria, most of the screening-detected lung cancers would have been included in a hypothetical cohort formed by emphysematous and NLST-compliant subjects. This strategy would not only improve lung cancer screening results, but might also limit the number of patients considered at-risk who do not meet current screening recommendations. Kovalchik’s study highlighting the importance of emphysema in the NLST cohort has already been mentioned.[18] In that study, a risk-based strategy for lung cancer screening of NLST-ineligible smokers was thought to be a rational starting point for expanded criteria.[18] Pursuant to this and other considerations, a lung cancer screening score has been proposed for COPD patients in order to identify those at greatest risk for lung cancer.[84] The score, known as the COPD-LUCSS, blends traditional lung cancer screening criteria, such as age and tobacco exposure, with alternative criteria, including emphysema and body mass index, in order to stratify COPD patients by risk. High-risk patients (COPD-LUCSS ≥ 7 points) identified using this score have a threefold increase in lung cancer risk compared with those who have the lowest scores (COPD-LUCSS = 0–6 points). Diffusing capacity for carbon monoxide (DLCO) measurements in patients with COPD may be an alternative criterion when CT phenotyping is not available, since DLCO correlates with the presence of emphysema in those patients.[85] Although the correlation may not be robust in asymptomatic smokers, an alternative score that incorporates DLCO, known as the COPD-LUCSS-DLCO, can also help clinicians select those COPD patients at highest risk.[86,87] It is important to keep in mind that lung cancer is especially deadly in patients with COPD. Contrary to what some believe, existing evidence suggests that COPD patients stand to benefit most from lung cancer screening, despite the risks and premature mortality associated with obstructive airways disease.[11] de Torres et al reported that lung cancer mortality in patients with COPD is dramatically reduced by screening this patient population: 0.08 vs 2.48 deaths per 100 person-years in screened and control cohorts, respectively.[88] Similar findings were reported by the DLCST investigators, who could only demonstrate a benefit for screening in their cohort of persons with COPD, proving that a screening strategy based solely on age and tobacco exposure and eschewing key inclusion criteria such as COPD and emphysema may be flawed.[74] In fact, validated simulations have shown that a lower pack-year threshold for screening eligibility may benefit COPD patients.[11]

Finally, it is worth mentioning that lung cancer screening programs may offer a unique opportunity to improve COPD underdiagnosis rates. A myriad of studies have demonstrated that tobacco-related alterations in lung function are not only deadly, but common and frequently missed.[89-91] Lung cancer screening–eligible patients share the combination of age and risk factors that might help identify COPD in otherwise seemingly healthy current or former smokers.[92] An Australian study found that symptoms may be an appropriate surrogate for spirometry when determining the presence of COPD in this population.[93] Low-dose CT imaging is also an excellent tool capable of detecting not only emphysema, but COPD as well.[94] Low-dose CT performed in the context of lung cancer screening has a 63% sensitivity and an 88% specificity for the diagnosis of COPD.[95] Visual scoring of chest CT findings can also characterize the presence, pattern, and progression of early emphysema, showing that continued smoking leads to progression of that disease.[96] In any case, future recommendations should stress the need for combined lung cancer and COPD screening.

Conclusions

The links between lung cancer and tobacco-related alterations in lung function and lung morphology are strong, and research is ongoing to determine how far-reaching they may be. Current interest in lung cancer screening and the widespread availability of CT imaging continue to nurture a growing body of evidence supporting the existence of ties binding these deadly diseases together, as well as new strategies for fighting them. Ongoing cost-effectiveness studies will tell us whether a strategy of expanded inclusion criteria for screening that incorporates altered lung function and/or emphysema is viable. Meanwhile, more studies are needed in order to determine whether the NLST entry criteria should be set in stone, or whether the current age and tobacco exposure criteria can be modified in order to screen all persons at risk. In our opinion, all patients with CT-detected emphysema, as well as COPD patients with high COPD-LUCSS scores, should be offered lung cancer screening, irrespective of age or smoking history.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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