Cancer development in COPD patients: retrospective analysis of the National Health Insurance Service-National Sample Cohort in Korea

Background COPD is a well-known risk factor for lung cancer, independent of smoking behavior. By investigating the retrospective National Health Insurance Service-National Sample Cohort (NHIS-NSC) in Korea, this study attempted to prove our hypothesis that COPD is a risk factor for major cancers developing outside of the lungs. We also aimed to investigate the environmental factors associated with the development of lung cancer in COPD patients. Methods This study analyzed data from the NHIS-NSC over a 12-year period. Among the 514,795 subjects in the NHIS-NSC, 20,837 patients who were diagnosed with any cancer from 2002 to 2003 were excluded. Finally, this cohort enrolled four arms, the healthy control group (N=127,884), never-smokers with COPD (N=29,799), former smokers with COPD (N=3,267), and smokers with COPD (N=8,335). Our study provides a comprehensive analysis of COPD as a risk factor for major in the Korean population. Our data revealed that COPD in the Korean population was an independent risk factor contributing to the development of lung cancer but was not linked to the development of other major cancers, irrespective of smoking status. In this analysis of a national cohort representative of the Korean population with up to 12 years of follow-up, multivariate analysis demonstrated that male gender, lower BMI, and exercise status, along with smoking and COPD diagnosis, were independent risk factors for the development of lung cancer.

Background COPD is a well-known risk factor for lung cancer, independent of smoking behavior. By investigating the retrospective National Health Insurance Service-National Sample Cohort (NHIS-NSC) in Korea, this study attempted to prove our hypothesis that COPD is a risk factor for major cancers developing outside of the lungs. We also aimed to investigate the environmental factors associated with the development of lung cancer in COPD patients.

Methods
This study analyzed data from the NHIS-NSC over a 12-year period. Among the 514,795 subjects in the NHIS-NSC, 20,837 patients who were diagnosed with any cancer from 2002 to 2003 were excluded. Finally, this cohort enrolled four arms, the healthy control group (N=127,884), neversmokers with COPD (N=29,799), former smokers with COPD (N=3,267), and smokers with COPD (N=8,335).

Results
Over a 12-year period, lung cancer developed in 1.27% of the never-smokers with COPD, 2.97% of the former smokers with COPD, and 4.79% of smokers with COPD much higher than in 0.63% of the healthy control group (p < 0.001). Multivariate analyses showed that COPD, regardless of smoking status, contributed to the development of lung cancer but was not linked with any other major cancers, including stomach cancer, colorectal cancer, liver cancer and acute myeloid leukemia (p < 0.01). Age, male gender, lower BMI, low exercise level, smoking, and COPD were independent factors associated with the development of lung cancer (p< 0.01)

Conclusion
Our data suggest that COPD was an independent risk factor for the development of lung cancer in the Korean population, regardless of smoking status but other major cancers were not linked with COPD.

Background
Chronic obstructive pulmonary disease (COPD) outpaces other major diseases as a cause of mortality throughout the entire world and is expected to rank third among all causes of death by 2020 [1][2][3].
Interestingly, COPD is a well-known risk factor for the development of lung cancer, independent of smoking behavior [6][7][8]. Therefore, many studies have evaluated the relationship between COPD and lung cancer [6][7][8][9]. The pathologic mechanism contributing to the development of lung cancer in COPD has been explained by telomere shortening, chronic inflammation, the increased expression of growth factors in COPD lungs, and oxidant-induced DNA damage resulting in mutations and carcinogenesis [8,10,11]. However, it is not reported yet whether COPD can be a risk factor for cancers developing outside of the lungs despite the evidence that systemic inflammation is the characteristic feature of COPD [2,5]. In addition to smoking, radiation, exposure to carcinogens, such as asbestos and radon, air pollution, etc., are risk factors for the development of lung cancer [12,13]. Nevertheless, most environmental risk factors for lung cancer, except for smoking exposure, require further validation.
Therefore, the authors hypothesized that the process of tumorigenesis in COPD may not be limited to the lungs but can also affect the body systemically, leading to the development of major cancers outside the lungs. Therefore, this study attempted to prove the hypothesis that COPD is a risk factor for, not only lung cancer but also other major cancers by investigating a cohort in the National Health Insurance Service-National Sample Cohort (NHIS-NSC). The current study also attempted to examine the environmental factors associated with the development of lung cancer in COPD patients.

Study population
This study analyzed data from the NHIS-NSC. The NHIS-NSC is a population-based cohort established by the National Health Insurance Service (NHIS) in South Korea [14]. The NHIS is a single-payer health  [15,16]. Former smokers were defined as those who had not smoked for at least one year [17].
Smoking history and exercise status were evaluated by self-administered questionnaires at baseline in 2002 or 2003. Data on body mass index, blood pressure, fasting serum glucose, total cholesterol, and exercise status were measured at baseline. Body mass index (BMI) was calculated as body weight in kilograms divided by height in meters squared (kg/m 2 ).

Main outcome measures
The primary outcome was the incidence of lung cancer. The secondary outcomes were the incidence of stomach cancer, colorectal cancer, liver cancer, and AML. The outcome measures were ascertained by health insurance claims data in the NHIS from January 1, 2004, to December 31, 2015. The first incident event was only used in the analyses for participants with more than one event. ICD-10 codes were used to identify outcome measures as follows: lung cancer (C33, C34), stomach cancer (C16), colorectal cancer (C18, C19, C20), liver cancer (C22), and AML (C92.0).

Statistical analyses
As shown in Fig. 1, the study participants were stratified into four groups: healthy control group (never smokers without COPD), never smokers with COPD, former smokers with COPD, and current smokers with COPD.
All values were described as mean ± standard deviation. One-way analyses of variance for continuous variables were used for continuous data and chi-square statistics tests were for categorical data. Cox proportional hazards regression analysis was used to identify significant variables predicting the occurrence of an event. Cox proportional hazard models were performed to evaluate the independent effects of COPD on the development of cancer, after adjusting for age, gender, hypertension, diabetes, body mass index, and exercise. Variables selected via univariate test (p < 0.01) were evaluated in a multivariate Cox regression analysis. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated for the risk of lung, stomach, colorectal, and liver cancers, and AML. P-values < 0.01 were deemed statistically significant and all analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

Ethics statement
The present study was approved by the Institutional Review Board of Ajou University Hospital (No. AJIRB-MED-EXP-17-167).

Baseline characteristics of this cohort
The baseline characteristics of the NHIS-NSC participants are shown in Table 1.   (Table 3). However, COPD with any smoking status did not contribute to the other major cancers analyzed, which included stomach cancer, colorectal cancer, and liver cancer (Table 3). Our study provides a comprehensive analysis of COPD as a risk factor for major cancers in the Korean population. Our data revealed that COPD in the Korean population was an independent risk factor contributing to the development of lung cancer but was not linked to the development of other major cancers, irrespective of smoking status. In this analysis of a national cohort representative of the Korean population with up to 12 years of follow-up, multivariate analysis demonstrated that male gender, lower BMI, and exercise status, along with smoking and COPD diagnosis, were independent risk factors for the development of lung cancer.
Our study presents several interesting findings.
First, our data showed that COPD diagnosis was independently associated with the occurrence of lung cancer by all models analyzed by Cox regression analyses, suggesting that COPD per se contributes to the development of lung cancer, irrespective of smoking behavior. Subsequently, the prevalence of lung cancer in our cohort (1.27% of never-smokers with COPD, 2.97% of former smokers of COPD, and 4.79% of smokers with COPD over 12 years, and 0.63% in the healthy control group) was higher according to smoking status and COPD diagnosis.
The association between COPD and lung cancer has been explained by several mechanisms [18][19][20].
Repeated injury and repair by chronic inflammation and frequent exacerbations in COPD may result in tissue injury and DNA damage, leading to malignant cell transformation and the development of lung cancer [18]. Multiple genetic factors may explain the link between the development of COPD and lung carcinogenesis [19,20]. However, there is an opposing perspective that the pathologic processes of COPD and lung cancer appear to be different, since features of COPD include destruction and apoptosis, whereas lung cancer is characterized by unrestrained proliferation and lack of apoptosis [9,21].
Recent bodies of clinical evidence have suggested that emphysema and severe airflow obstruction increased the risk of lung cancer beyond the effect of smoking [22,23]. Several pathological mechanisms, including premature aging, genetic predisposition, and epigenetic changes, have been proposed to explain the carcinogenesis in emphysematous lungs [10,24]. Inflammation is increased in COPD and experiments with anti-inflammatory treatments, such as Nrf2 activators and statins, showed the potential to inhibit the proliferation of cancer cells by reducing inflammation [25]. In a clinical trial in a large Veterans Affairs patient cohort, statins were shown to be protective against the development of lung cancer, reducing the incidence of lung cancer over 50% [26].
Second, our data found that the prevalence of stomach cancer, colorectal cancer, and liver cancer was higher in patients with smoking status and COPD diagnoses. However, multivariate analyses failed to prove an independent association between COPD and other major cancers. Liver cancer appeared to be independently associated with smokers with COPD, but this finding was insignificant by this study's rigorous adoption of significant p-values less than 0.01. Theoretically, the spillover of aberrant inflammation in COPD can lead to systemic consequences, such as carcinogenesis in other organs. Nonetheless, our study should reject our original hypothesis that COPD is an independent risk factor for the development of major cancers occurring outside the lungs. To our knowledge, no study has ever reported any link between COPD and major cancers occurring outside the lung.
Third, this cohort study identified environmental factors including low exercise level and lower BMI, as independent risk factors contributing to the development of lung cancer, indicating that multidisciplinary approaches are required for the prevention of lung cancer in COPD.
Our finding that a reduced BMI was independently linked to the development of lung cancer contradicts the conventional notion that obesity is pathogenically linked to carcinogenesis [27,28].
Several studies highlighted an obesity paradox suggesting that obesity may be protective and associated with reduced lung cancer mortality after surgery or chemotherapy [27,29,30]. Although the mechanisms behind this paradoxical relationship are not fully understood, anti-tumor adipokines, anti-tumor energy reserve, metabolic fitness, relative lack of sarcopenia, etc., have been suggested as potential biological mechanisms to explain this obesity paradox [29]. Most studies, however, have focused on the mortality of patients with lung cancer after surgery or chemotherapy [27,29,30]. Our study is different from previous studies of patient prognosis after a lung cancer diagnosis because we investigated the development of cancers in a cancer-free cohort by a longitudinal design [27,29,30].
Our findings are supported by previous reports that emphysema characterized by lower BMI was a risk factor for lung cancer, although this study did not examine the phenotype of COPD in our cohort [31,32].
However, a recent cohort study comparing 433 COPD patients with 279 healthy controls reported that obesity in COPD patients predicted higher lung cancer risk [31]. Therefore, further studies are needed to investigate the controversial relationship between obesity and lung cancer.
Our finding that lower exercise levels were an independent risk factor for the development of lung cancer is supported by previous studies [33][34][35]. Some studies reported an approximate 25% reduction in lung cancer risk by higher levels of physical activities [33,35]. Good adherence to established nutrition and physical activity through cancer prevention guidelines is recommended since significant reductions in overall cancer incidence and mortality were reported by these methods

Conclusion
Our data demonstrated that a COPD diagnosis was an independent risk factor contributing to the development of lung cancer but was not linked with other major cancers in the Korean population.
This study also revealed that age, male gender, lower BMI, and low exercise level, along with smoking and COPD were independent factors contributing to the development of lung cancer, suggesting that multidisciplinary approaches are required for the prevention of lung cancer in COPD patients.

Ethics approval
The present study was approved by the Institutional Review Board of Ajou University Hospital (No. AJIRB-MED-EXP-17-167).

Consent for publication
Not applicable

Availability of data and material
NHIS-NSC is an open and public data to which any researcher can get access through the website (https://rdata.nhis.or.kr).

Conflict of interest statement
All the authors have nothing to declare.

Authors' contributions
Song Vogue Ahn and Bumhee Park helped the preparation of this manuscript and equally contributed to this paper as a first author.
Joo Hun Park coordinated and designed this study, helped the preparation of this manuscript, and is responsible for the integrity of this paper as a corresponding author.  Figure 1 The study participants were stratified into four groups: healthy control group (never smokers without COPD), never smokers with COPD, former smokers with COPD, and current smokers with COPD.