PRE-PROOF Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation PRE-PROOF Copyright Chronic Obstructive Pulmonary Diseases: Journal of the COPD

Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are common global causes of morbidity and mortality. Because both diseases share several predisposing risks, the two diseases may occur concurrently in susceptible individuals. The diagnosis of COPD has important implications for the diagnostic approach and treatment options if lesions concerning for LC are identified during screening. Importantly, the presence of COPD has significant implications on prognosis and management of patients with LC. In this monograph, we review the mechanistic linkage between LC and COPD, the impact of LC screening in patients at risk, and the implications of the presence of COPD on the approach to the diagnosis and treatment of LC. This manuscript succinctly reviews the epidemiology and common pathogenetic factors for the concurrence of COPD and LC. Importantly for the clinician, it summarizes the indications, benefits, and complications of LC screening in patients with COPD, and the assessment of risk factors for patients with COPD undergoing consideration of various treatment options for LC. PRE-PROOF Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation PRE-PROOF Copyright Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation ©2022 Published online June 29, 2022 doi: https://doi.org/10.15326/jcopdf.2022.0296 Introduction Chronic obstructive pulmonary disease (COPD) and lung cancer (LC) are common global causes of morbidity and mortality. COPD has a worldwide prevalence of 7-19% and is the 3rd leading cause of death. Over 65 million people suffer from COPD worldwide; COPD caused 3.23 million deaths in 2019.(1) LC is one of the most frequently diagnosed cancers worldwide (11.6% of all cancers) (2) and is the most common cancer diagnosed in men and third most common cancer diagnosed in women (Table1). LC is the leading cause of all cancer deaths at 1.74 million (18.4%), a number expected to reach 2.45 million patients worldwide by 2030, a 39% increase since 2016. Tobacco smoking causes LC in 80% of cases, but exposures to biomass fuels, radon and asbestos also contribute. Because COPD and LC share similar risks, both diseases may concur in susceptible patients. Lung cancer is an important comorbidity of COPD that contributes to increased mortality. (3, 4) Conversely COPD is associated with reduced overall survival in patients with lung cancer and COPD compared to those without COPD, especially in those with an emphysematous predominant component.(5) Smokers with COPD have a 6-fold risk of LC compared to smokers without airflow limitation(6) and LC incidence increases as FEV1 declines regardless of cigarette smoke exposure.(7, 8) Emphysema also increases LC risk.(9) In the Danish LC Screening Trial, patients with airflow limitation, emphysema, age > 70 yrs. and > 35 pack-years smoking had a twofold greater LC risk. (10) The diagnosis and severity of COPD has important diagnostic and therapeutic implications for the population undergoing low dose chest CT (LDCT) for LC screening. This monograph reviews the mechanistic linkage between LC and COPD, the impact of LC screening and the implications of COPD on the diagnosis and treatment of LC. Pathobiological factors linking LC and COPD LC is caused by mutations in oncogenes leading to an uncontrolled proliferation of cells and tumor formation.(11) Pathophysiological links between COPD and LC has been elusive due to heterogeneity in responses to chronic inflammation and lung reparative processes.(12) Possible PRE-PROOF Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation PRE-PROOF Copyright Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation ©2022 Published online June 29, 2022 doi: https://doi.org/10.15326/jcopdf.2022.0296 common pathobiological processes includes: chronic inflammation, genetic predisposition, epigenetic changes, telomere shortening, protease and anti-protease imbalance, mitochondrial dysfunction, premature aging and aberrant reparative processes. (Figure.1) Inflammation and cancer are closely linked; most cancerous tissue shows inflammation.(13-15) Tobacco smoking, a shared risk between lung cancer and COPD, is a major factor contributing to lung carcinogenesis since smoking-related inflammation is superimposed upon the presence of tobacco smoke carcinogens.(16) It is also feasible that chronic lung inflammation in COPD predisposes to LC.(17) A reduction in mucociliary clearance may enable carcinogens to reside longer in the lung.(8) The COPD lung microbiome differs from healthy individuals and may induce inflammatory changes that promotes LC development.(18, 19) Cigarette smoke may also induce release of VEGF from epithelial cells causing angiogenesis which facilitates the progression, invasion, and metastasis of lung cancer.(20) Immune cell composition and function is important in non-small cell LC (NSCLC) as well as COPD. COPD severity has been related to CD4+ T cell content and differentiation status (Thelper type -1cells, TH17, regulator t cells (Treg) with increases in CD4+ TH1 as the disease progresses.(21)IL-17 drives protumor inflammatory responses and facilitate tumor growth in animal models.(22) (21) COPD has increased sensitivity of CD8+ tumor-infiltrating T lymphocytes to tumor mediated immune escape mechanisms suggesting higher sensitivity to PD1 blockade. (21) In NSCLC, immune cell composition is heterogenous and varies between adenocarcinomas and squamous cell carcinomas.(12) In stage I non-squamous NSCLC a more favorable gene signature for survival (FAIM3 ) was predominantly expressed in tumorinfiltrating leukocytes.(23) Patients with COPD and lung cancer are reported to have a decline in IgG-secreting plasma cell levels but not in other cell types compared to patients with lung cancer but without COPD.(24) Aging of the lung may represent a common thread between LC and COPD.(25) The failure of organs to repair DNA caused by oxidative stress and telomere shortening drives aging and occurs PRE-PROOF Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation PRE-PROOF Copyright Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation ©2022 Published online June 29, 2022 doi: https://doi.org/10.15326/jcopdf.2022.0296 in COPD. (26) Cigarette smoking decreases telomere length; LC and COPD are both associated with shortened telomere length. (27-29) Oxidative stress plays a role in LC and COPD through DNA damage and leads to carcinogenic mutations.(11) (30, 31) In COPD, nitration of histone deacetylase (HDAC) leads to its inactivation and enhances further inflammation. Oxidants inactivate other proteins making them auto-antigenic and thereby immunoinflammatory. (32) Extensive exposure to nicotine is also common to patients with COPD and those that develop lung cancer. Nicotine promotes tumor growth by increasing proliferation, angiogenesis, migration, epithelial to mesenchymal transition, and stimulates tumor growth.(33) It is also the principal compound that drives smoking addiction. Genetic predisposition to LC and COPD has been localized to chromosome 6. (34-36) genomewide association study (GWAS) studies have implicated loci at cholinergic receptor nicotinic alpha subunit (CHRNA) 3 and CHRNA5 single nucleotide polymorphisms (SNPs) and regions at 4q31, 4q24 and 5q. (37) Genetic polymorphism of IL10 in peripheral blood mononuclear cells (PBMC) was found to be associated with increased rates of COPD and LC.(13, 38) Epigenetic changes (DNA methylation, micro-RNA expression, covalent histone modifications and nucleosome remodeling) may play roles in COPD and LC.(39, 40) COPD patients with LC have hypermethylation of tumor suppressor and other gene promoters than COPD patients without LC.(11) Clinical Features of COPD that increase LC risk The presence and severity of airflow limitation and/or emphysema (diagnosed using computerized chest tomography [CT] or diffusing capacity for carbon monoxide [DLCO]) are important risks for LC development.(7, 9, 41-43) Studies in smokers and nonsmokers report a relationship between severity of airflow limitation and LC risk.(7, 41, 44) (Table. 2) In a post hoc subset analysis of the National Lung Screening Trial (NLST), subjects with COPD had a twofold increase in LC incidence. (45) Others, however, report the opposite relationship, that severity of airflow limitation is inversely related to LC risk. (46, 47) In 2,517 patients with COPD followed over 60 months, LC occurred in those with less severe airflow limitation (GOLD stages I and II), lower body mass index (BMI) and DLCO < 80%. (48) Others report emphysema may be a greater risk factor for LC compared to airflow limitation.(9, 42) The Pamplona International Early LC Detection Program and the Pittsburgh Lung Screening Study PRE-PROOF Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation PRE-PROOF Copyright Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation ©2022 Published online June 29, 2022 doi: https://doi.org/10.15326/jcopdf.2022.0296 databases showed (49) that emphysema was independently associated with increased LC risk using a risk stratification score (range,0-10 points). In both cohorts, the risk of LC was 3.5-fold higher in the high (7-10) vs. the low (0-6) risk group. Severity of emphysema was related to greater likelihood of developing and dying from LC even after adjustment for age and smoking history. (50) Others report no impact of emphysema severity on LC risk.(44) The histology and localization of LC is linked to the regional presence and degree of emphysema. Squamous cell carcinoma is more common when COPD and emphysema are present (48, 51). A link exists between LC location and degree of emphysema.(52) A lower emphysema burden is found with central tumors while a greater emphysema burden is associated with peripheral lesions.(51) The aggressiveness of tumors is associated with the extent of emphysema and