Obstructive sleep apnea in never-smokers with newly diagnosed lung cancer: a prospective study in a predominantly female Korean population

Abstract

Emerging evidence suggests a link between obstructive sleep apnea (OSA) and lung cancer, but tobacco smoking may confound this relationship. This prospective study evaluated the prevalence and clinical features of OSA among never-smokers with lung cancer. Newly diagnosed, never-smoking lung cancer patients underwent respiratory polygraphy before cancer treatment. Of 77 enrolled, 67 patients were analyzed (age, 65 years; women, 83.6%; body mass index, 24 kg/m²). OSA (respiratory event index [REI] ≥ 5/hour) was present in 47.8% of the patients—specifically, in 29.4%, 60.0%, 65.0%, and 44.0% of the patients with stage I, II, III, and IV lung cancer, respectively (P = 0.175). 20.9% of the patients had moderate-to-severe OSA (REI ≥ 15/hour). Adenocarcinoma was the predominant histologic type (97%), and 67.2% had advanced-stage (stage III/IV) lung cancer. REI and the percent night time with oxygen saturation < 90% (T90) did not differ between the patients with advanced- and early-stage lung cancer (REI: 5.3/hour vs. 3.0/hour, P = 0.171; T90: 0.6% vs. 0.2%, P = 0.139). In multivariable logistic regression analyses, neither REI nor T90 was associated with advanced-stage lung cancer. Nearly half of never-smokers with lung cancer had OSA, with many having moderate-to-severe disease, underscoring the need for proper diagnosis and management.

Clinical Trial Registration: NCT05224180

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-45232-7.

Introduction

Obstructive sleep apnea (OSA) is a common disorder characterized by repeated upper airway obstruction during sleep, leading to chronic intermittent hypoxia¹. It is a growing public health concern, as it is frequently comorbid with cardiovascular disease, metabolic disorders, and increased mortality². Recent epidemiological studies have also suggested a link between OSA and cancer, including lung cancer³. A meta-analysis of observational studies reported that patients with OSA had an approximately 30% higher risk of lung cancer than those without OSA⁴. This association is biologically plausible, as the hallmark feature of OSA—chronic intermittent hypoxia—acts as a pro-tumorigenic stimulus by inducing oxidative stress, DNA damage, and systemic inflammation via activation of the hypoxia-inducible factor (HIF) pathway^5–8.

The prevalence of OSA in patients with lung cancer has varied across studies. A German study reported that sleep-disordered breathing had a prevalence of 49% in patients with newly diagnosed lung cancer⁹, while a similar Spanish study reported a prevalence of 80%¹⁰. However, both studies included significant numbers of smokers and patients with chronic obstructive pulmonary disease (COPD), which could have influenced the observed associations between OSA and lung cancer. In the Nurses’ Health Study, a stronger association was observed between OSA and lung cancer in women who had never smoked than in those who had, although this association was not statistically significant¹¹. These findings indicate the need for further investigation of the link between OSA and lung cancer in populations where confounders such as smoking and COPD are adequately controlled.

Furthermore, most prior studies on the relationship between OSA and lung cancer have been conducted in Western countries. Few studies have examined OSA in Asian populations, where lung cancer in never-smokers is more prevalent¹², and where the prevalence of obesity—a major risk factor for OSA—is generally lower than in Western populations^13,14. Thus, in the present study, we aimed to investigate the prevalence of OSA in never-smokers with lung cancer and to examine their clinical characteristics.

Methods

Study design and participants

We prospectively enrolled never-smokers (aged 19–80 years) who were admitted to Seoul National University Hospital for diagnostic work-up and were newly diagnosed with lung cancer between November 2021 and February 2024, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Given the low prevalence of smoking among women in South Korea compared with men¹⁵, the inclusion of only never-smokers was expected to result in a cohort with a predominance of females.

We excluded the following patients: (1) those treated for lung cancer or OSA before enrollment in this study; (2) those with a life expectancy of fewer than 3 months; (3) those with neuromuscular disease, chronic opioid medication use, or severe insomnia not controlled by medication; (4) those receiving supplemental oxygen therapy due to underlying diseases such as heart failure, COPD, interstitial lung disease, hypoventilation syndrome, or stroke, or those with a baseline oxygen saturation (SpO₂) below 90%; and (5) those with unstable medical conditions within 3 months before their enrollment in this study (i.e., hospitalization due to acute exacerbation of underlying lung disease, unstable angina or myocardial infarction, a history of percutaneous coronary intervention or coronary artery bypass surgery, transient ischemic attack, or stroke).

This study was approved by the Institutional Review Board of Seoul National University Hospital (approval no. H-2107–169-1236). All the participants provided written informed consent, and this study was conducted in accordance with the principles outlined in the Declaration of Helsinki.

Evaluation for lung cancer and obstructive sleep apnea

Lung cancer was diagnosed through pathological confirmation obtained via bronchoscopy, including endobronchial ultrasound or computed tomography (CT)-guided transthoracic needle biopsy. Data were collected on demographics, comorbidities, and the results of lung cancer risk factor questionnaires and the Epworth Sleepiness Scale. The final stage of lung cancer was defined as the pathologic tumor, node, metastasis (TNM) stage for surgical cases and the clinical TNM stage for nonsurgical cases, according to the eighth edition of the American Joint Committee on Cancer–Union for International Cancer Control staging guidelines¹⁶. Before lung cancer treatment was initiated, a Type III sleep study was conducted using respiratory polygraphy (Embla-Embletta; Natus, Pleasanton, CA, USA) from 10 p.m. to 7 a.m. during the patient’s hospital stay. Each study underwent an automatic review, followed by a manual review based on the American Academy of Sleep Medicine guidelines¹⁷. Apnea was defined as a ≥ 90% reduction in peak signal amplitude from the pre-event baseline, measured using an oronasal thermal sensor for at least 10 s. If the oronasal thermal sensor was unreliable, the nasal pressure sensor was used as a backup. Hypopnea was defined as a ≥ 30% decrease in peak signal amplitude from the pre-event baseline, measured using a nasal pressure sensor for at least 10 s, accompanied by a ≥ 3% oxygen desaturation from the pre-event baseline. The monitoring time was calculated by subtracting artifact periods and awake time from the total recording time. The awake time was determined based on body position sensor readings, respiratory patterns, or patient-reported notes. The respiratory event index (REI) was calculated as the number of apneas plus hypopneas divided by the monitoring time¹⁸. Patients with an REI of ≥ 5/hour were diagnosed with OSA. An REI of ≥ 15/hour was classified as moderate-to-severe, and an REI of ≥ 30/hour was considered severe. The oxygen desaturation index (ODI) was defined by the number of episodes with ≥ 3% oxygen desaturation per hour during monitoring. The percent night time with SpO₂ < 90% (T90), along with the mean and lowest SpO₂, were also recorded.

Statistical analyses

The target sample size was calculated as 96 patients, assuming an expected OSA prevalence of 50%—a conservative estimate used because the prevalence of OSA specifically in never-smokers with lung cancer has not been previously established—with a 10% margin of error at a 95% confidence interval (CI)^19–21. Categorical variables are presented as counts and percentages, while continuous variables are presented as means with standard deviations or medians with interquartile ranges. Missing values were identified in pulmonary function tests (2 cases), serum tumor markers (7 cases), and maximal standardized uptake values of the main mass in positron emission tomography-CT (2 cases). These missing values were imputed using multivariate imputation by chained equations (MICE, version 3.14.0) in R (R Foundation for Statistical Computing, Vienna, Austria)²². Baseline characteristics of the patients with OSA were compared with those of the patients without OSA using either Student’s t-tests or Mann–Whitney U tests for continuous variables, and χ2 tests or Fisher’s exact tests for categorical variables. The severity of OSA was assessed using the REI, ODI, and T90. Associations between OSA severity indices and advanced-stage lung cancer (stage III/IV) were evaluated using logistic regression analysis, adjusting for confounders—both known confounders, such as age and sex, identified in previous research^23,24, and variables selected via the least absolute shrinkage and selection operator (Lasso) method²⁵. The Lasso method was employed to shrink certain variable coefficients and to set others to zero, aiming to retain the most relevant variables for subset selection. All comparisons were two-sided, with the significance threshold set at P < 0.05. The analyses were conducted using R version 4.3.3.

Results

Of the 102 patients assessed for eligibility in this study, 77 were deemed eligible. However, six patients refused to undergo respiratory polygraphy, two had invalid test results, and the diagnosis for two others was revised to conditions other than lung cancer (Fig. 1). Thus, 67 patients were included in this study. Their median age was 65 years, 83.6% of them were female, and their median body mass index (BMI) was 24 kg/m². Almost half of the participants (47.8%, 32/67) had OSA, 20.9% (14/67) had moderate-to-severe OSA, and 10.4% (7/67) had severe OSA. None of the participants reported having been previously diagnosed with OSA. Table 1 shows the clinical characteristics of the patients with and without OSA. More than 80% of the patients in each group were female, but the patients with OSA were older than those without OSA (mean age: 67.3 years vs 60.6 years, P = 0.002) and had a higher median BMI (24.9 kg/m² vs. 22.9 kg/m², P = 0.021), median REI (12.4/hour vs. 2.1/hour, P < 0.001), and median T90 (2.4% vs. 0.1%, P < 0.001).

Fig. 1.

Study flowchart.

Table 1.

Clinical characteristics of the patients according to the presence of OSA (REI ≥ 5/hour).

Characteristic	Patients with OSA (n = 32)	Patients without OSA (n = 35)	P
Age, years	67.3 ± 7.2	60.6 ± 9.7	0.002
Female	27 (84.4)	29 (82.9)	> 0.999
BMI, kg/m2	24.9 (22.4–27.1)	22.9 (21.9–24.8)	0.021
Neck circumference, cm	35.7 (33.8–37.7)	33.4 (32.0–36.8)	0.023
Friedman tongue position			0.672
Grade I	8 (25.0)	11 (31.4)
Grade II	3 (9.4)	5 (14.3)
Grade III	8 (25.0)	5 (14.3)
Grade IV	13 (40.6)	14 (40.0)
Friedman tonsil size			0.342
1	29 (90.6)	34 (97.1)
2	3 (9.4)	1 (2.9)
Symptoms of OSA
Habitual snoring	22 (68.8)	18 (51.4)	0.232
Witnessed apnea	4 (12.5)	3 (8.6)	0.701
Gasping or choking	5 (15.6)	6 (17.1)	> 0.999
Daytime sleepiness	14 (43.8)	13 (37.1)	0.763
Non-restorative sleep	15 (46.9)	14 (40.0)	0.749
Fatigue	13 (40.6)	18 (51.4)	0.522
Insomnia symptoms	14 (43.8)	14 (40.0)	0.950
Epworth Sleepiness Scale	3 (1–4)	3 (1–4)	0.934
Diagnostic routes of lung cancer			0.063
Medical checkups or incidental findings	19 (59.4)	29 (82.9)
Symptoms related to lung cancer*	13 (40.6)	6 (17.1)
ECOG performance status			0.096
0	27 (84.4)	34 (97.1)
1	5 (15.6)	1 (2.9)
History of lung cancer in first-degree relative	7 (21.9)	3 (8.6)	0.175
Exposure to secondhand tobacco smoke			0.939
Almost none	15 (46.9)	18 (51.4)
< 2 years or < 1 h/day	4 (12.5)	3 (8.6)
≥ 2 years and ≥ 1 h/day	13 (40.6)	14 (40.0)
Alcohol intake in the past year			0.017
Never	27 (84.4)	21 (60.0)
< 2 times/week	3 (9.4)	13 (37.1)
≥ 2 times/week	2 (6.2)	1 (2.9)
Cooking oil exposure			0.641
Almost none	15 (46.9)	21 (60.0)
1–2 days/week	13 (40.6)	12 (34.3)
3–4 days/week	1 (3.1)	1 (2.9)
≥ 5 days/week	3 (9.4)	1 (2.9)
Living in a rural area	6 (18.8)	4 (11.4)	0.501
Occupational exposure to carcinogenic agents	0 (0.0)	0 (0.0)	> 0.999
Menopause (n = 56)	26 (96.3)	24 (82.8)	0.195
Comorbidities
Hypertension	18 (56.2)	12 (34.3)	0.119
Diabetes mellitus	8 (25.0)	2 (5.7)	0.039
Asthma	2 (6.2)	1 (2.9)	0.603
Bronchiectasis	3 (9.4)	3 (8.6)	> 0.999
COPD	1 (3.1)	0 (0.0)	0.478
History of pulmonary tuberculosis	4 (12.5)	3 (8.6)	0.701
History of malignancy other than lung cancer	1 (3.1)	7 (20.0)	0.056
Pulmonary function test
FVC, % predicted	101.3 ± 14.2	103.1 ± 16.5	0.640
FEV1, % predicted	102.0 (90.0–113.0)	106.0 (96.5–121.0)	0.340
DLCO, %	93.0 ± 20.3	92.9 ± 16.5	0.980
Polysomnographic indices
REI, /hour	12.4 (6.8–24.4)	2.1 (1.4–3.0)	< 0.001
ODI, /hour	17.4 (9.1–28.0)	3.9 (2.4–4.8)	< 0.001
T90, %	2.4 (0.6–7.3)	0.1 (0.0–0.3)	< 0.001
Mean SpO2, %	93.4 ± 1.7	94.7 ± 1.7	0.002
Lowest SpO2, %	82.7 ± 5.0	88.3 ± 3.6	< 0.001
CEA, ng/mL	3.0 (1.2–9.2)	2.8 (1.2–9.2)	0.846
CYFRA 21–1, ng/mL	2.8 (1.7–5.4)	2.2 (1.5–3.9)	0.390
Maximal diameter of main mass, mm	29.5 (25.0–42.5)	29.0 (25.5–39.0)	0.656
Maximal SUVs of main mass on PET-CT	10.4 ± 4.2	10.9 ± 5.3	0.682
Part-solid nodule	2 (6.2)	4 (11.4)	0.675
Location			0.744
RUL	9 (28.1)	9 (25.7)
RML	1 (3.1)	1 (2.9)
RLL	10 (31.2)	10 (28.6)
LUL	8 (25.0)	6 (17.1)
LLL	4 (12.5)	9 (25.7)
Histologic type			0.224
Adenocarcinoma	30 (93.8)	35 (100.0)
Squamous cell carcinoma	1 (3.1)	0 (0.0)
Small cell lung cancer	1 (3.1)	0 (0.0)
EGFR mutation	19 (59.4)	25 (71.4)	0.435
ALK translocation	4 (12.5)	2 (5.7)	0.414
Clinical stage			0.507
I	10 (31.2)	14 (40.0)
II	4 (12.5)	5 (14.3)
III	7 (21.9)	3 (8.6)
IV	11 (34.4)	13 (37.1)
Pathologic stage (n = 33)			0.172
I	4 (28.6)	12 (63.2)
II	3 (21.4)	2 (10.5)
III	7 (50.0)	5 (26.3)
Final stage†			0.175
I	5 (15.6)	12 (34.3)
II	3 (9.4)	2 (5.7)
III	13 (40.6)	7 (20.0)
IV	11 (34.4)	14 (40.0)

Data are presented as means ± SDs, medians (interquartile ranges), or numbers (percentages).

*Symptoms related to lung cancer include cough, hemoptysis, dyspnea, chest pain, weight loss, fever, bone pain, etc.

^†The final stage of lung cancer was defined as the pathologic tumor, node, metastasis (TNM) stage for surgical cases and the clinical TNM stage for nonsurgical cases, according to the eighth edition of the American Joint Committee on Cancer–Union for International Cancer Control staging guidelines.

BMI = body mass index, CEA = carcinoembryonic antigen, COPD = chronic obstructive pulmonary disease, CYFRA = cytokeratin 19 fragment antigen, DLCO = diffusing capacity of the lung for carbon monoxide, ECOG = Eastern Cooperative Oncology Group, FEV₁ = forced expiratory volume in one second, FVC = forced vital capacity, LLL = left lower lobe, LUL = left upper lobe, ODI = oxygen desaturation index, OSA = obstructive sleep apnea, PET-CT = positron emission tomography-computed tomography, REI = respiratory event index, RLL = right lower lobe, RML = right middle lobe, RUL = right upper lobe, SpO₂ = oxygen saturation, SUV = standardized uptake value, T90 = percent night time with oxygen saturation < 90%

Additionally, the patients with OSA were less likely than those without OSA to be diagnosed with lung cancer via medical checkups or incidental findings (59.4% vs. 82.9%, P = 0.063), and more likely to be diagnosed with lung cancer due to related symptoms. There were no significant differences between the two groups in history of lung cancer in first-degree relatives and in exposure to secondhand tobacco smoke or cooking oil. No patient reported occupational exposure to carcinogenic agents. Diabetes mellitus was more prevalent in the patients with OSA (25.0% vs. 5.7%, P = 0.039). One patient was diagnosed with COPD. Eight patients had a history of cancer other than lung cancer, but all had been declared cured more than five years after their diagnosis. Adenocarcinoma was the most common histologic type (97%). One patient had squamous cell carcinoma, one had small cell lung cancer, and both had experienced significant exposure to secondhand tobacco smoke. The proportions of EGFR mutation and ALK translocation were not significantly different between patients with OSA and those without OSA (EGFR mutation: 59.4% vs. 71.4%, P = 0.435; ALK translocation: 12.5% vs. 5.7%, P = 0.414).

Figure 2 shows the presence and severity of OSA according to the final stage of lung cancer. OSA was present in 29.4%, 60.0%, 65.0%, and 44.0% of patients with stage I, II, III, and IV lung cancer, respectively (P = 0.175). Moderate-to-severe OSA was present in 5.9%, 20.0%, 30.0%, and 24.0% of patients with stage I, II, III, and IV lung cancer, respectively (P = 0.256). Severe OSA was not observed in patients with early-stage (stage I/II) lung cancer but was present in 15.6% of those with advanced-stage (stage III/IV) lung cancer (P = 0.086). Table S1 presents the clinical characteristics of the patients with early-stage and advanced-stage lung cancer (see Supplemental Material). The polysomnographic indices, including REI and T90, did not differ between the patients with advanced-stage and early-stage lung cancer (median REI: 5.3/hour vs. 3.0/hour, P = 0.171; median T90: 0.6% vs. 0.2%, P = 0.139; Fig. 3). The median ODI was slightly higher in patients with advanced-stage lung cancer than in those with early-stage lung cancer (8.8/hour vs. 4.5/hour, P = 0.037). In univariable logistic regression analysis, both REI and ODI showed a trend of association with advanced-stage lung cancer (odds ratio [OR] = 1.06, 95% CI 1.00–1.14, P = 0.095; and OR = 1.06, 95% CI 1.01–1.15, P = 0.059, respectively; Table 2). However, these associations lost statistical significance after the results were adjusted for age, sex, and diagnostic routes of lung cancer (i.e., medical checkups or incidental findings vs lung cancer-related symptoms) in the multivariable logistic regression. The adjusted OR for REI was 1.04 (95% CI 0.97–1.14, P = 0.308); and for ODI, 1.05 (95% CI 0.98–1.15, P = 0.211). T90 did not show associations with advanced-stage lung cancer in either the univariable logistic regression (OR = 1.02, 95% CI 0.97–1.12, P = 0.489) or the multivariable logistic regression (adjusted OR = 1.00, 95% CI 0.94–1.10, P = 0.938).

Fig. 2.

Presence and severity of OSA according to the lung cancer stage. OSA = obstructive sleep apnea.

Fig. 3.

Severity indices of OSA according to the lung cancer stage (I/II vs. III/IV). ODI = oxygen desaturation index, OSA = obstructive sleep apnea, REI = respiratory event index, T90 = percent night time with oxygen saturation < 90%.

Table 2.

Logistic regression analysis of OSA severity indices associated with advanced-stage (stage III/IV) lung cancer.

	Univariable		Multivariable
	OR (95% CI)	P	Adjusted OR (95% CI)*	P
REI, /hour	1.06 (1.00–1.14)	0.095	1.04 (0.97–1.14)	0.308
ODI, /hour	1.06 (1.01–1.15)	0.059	1.05 (0.98–1.15)	0.211
T90, %	1.02 (0.97–1.12)	0.489	1.00 (0.94–1.10)	0.938
Age, year	0.99 (0.94–1.05)	0.501
Female sex	0.73 (0.15–2.86)	0.668
Symptoms related to lung cancer	14.00 (2.56–261.98)	0.014

*Adjusted for age, sex, and diagnostic routes of lung cancer (medical checkups or incidental findings vs. symptoms related to lung cancer).

CI = confidence interval, ODI = oxygen desaturation index, OR = odds ratio, OSA = obstructive sleep apnea, REI = respiratory event index, T90 = percent night time with oxygen saturation < 90%

Discussion

In this study, we found that OSA was present in 47.8% of never-smoking patients with lung cancer, with 20.9% of patients having moderate-to-severe OSA. Several studies have suggested an association between OSA and cancer, and more recently, this link has been further explored specifically in lung cancer^3,4. Large epidemiologic studies have reported a higher incidence of lung cancer among patients with OSA. In a nationally representative health insurance database spanning the years 2003–2012 in the U.S., the incidence of lung cancer was higher among patients with OSA than in a demographically matched cohort without OSA, with adjustments made for age and gender (hazard ratio [HR] = 1.09, 95% CI 1.05–1.13)³. However, after adjustments for comorbidities, this association lost statistical significance. Recently, a meta-analysis of approximately 4.9 million patients from four observational studies showed that OSA was associated with a higher incidence of lung cancer (HR = 1.25, 95% CI 1.02–1.53)⁴. Similarly, a study of 181,070 patients with OSA (2011–2018) and age- and sex-matched controls from the Korean National Health Information Database found a higher incidence of lung cancer in those with OSA, even after adjusting for comorbidities (HR = 1.95, 95% CI 1.74–2.18)²⁶. The adjusted HR for lung cancer was 2.14 (95% CI 1.69–2.70) in female patients and 1.90 (95% CI 1.67–2.16) in male patients.

Several prospective observational studies have reported the prevalence of OSA in patients with newly diagnosed lung cancer, although the rates vary (Table 3). In a study conducted in Germany involving 100 patients, the prevalence of sleep-disordered breathing (SDB) was 49%, with SDB assessed by a Type IV sleep study that used a nasal pressure sensor and pulse oximetry⁹. Moderate-to-severe SDB was found in 17% of the patients. However, 84% of the patients were smokers, and 29% had COPD. In a study from Spain that included 60 patients, the prevalence of OSA was 80%¹⁰. In that cohort, 90% were smokers with a median tobacco consumption of 51 pack-years, and half had COPD. Similarly, a study conducted in Egypt with 153 patients reported an OSA prevalence of 87.6%, with 77.1% smokers²⁷. In a study from India that involved 30 patients, 56.7% were found to have OSA, with 86.6% smokers and 3.3% having self-reported COPD²⁸.

Table 3.

Recent prospective observational studies that reported the prevalence of OSA in patients with newly diagnosed lung cancer.

	Dreher et al.9	Cabezas et al.10	Bhaisare et al.28	Zidan et al.27	Present study
Country	Germany	Spain	India	Egypt	South Korea
N	100	60	30	153	67
Age, years	68.1 ± 8.6	67.8 ± 11	55 (IQR, 12)	59.98 ± 11.11	65 (IQR, 13)
Male sex (%)	67	58	87	78.4	16.4
BMI, kg/m2	26.0 ± 4.6	28.1 ± 5.4	19.4 ± 3.9	25.63 ± 5.27	24 (IQR, 3.65)
Smoker (%)	84	90	86.6	77.1	0
COPD (%)	29	50	3.3a	NR	1.5
Adenocarcinoma (%)	45	46.7	56.7	42.5	97
Advanced-stage (stage III/IV) lung cancer (%)	78	65	100	92.8	67.2
Diagnosis of OSA	Type IV sleep study	Type III sleep study	Type I polysom-nography	Type IV sleep study	Type III sleep study
Prevalence of OSA (%)	49	80	56.7	87.6	47.8
Prevalence of moderate-to-severe OSA (%)	17	50	30	32	20.9

^aPrevalence of self-reported COPD.

BMI = body mass index, COPD = chronic obstructive pulmonary disease, IQR = interquartile range, NR = not reported, OSA = obstructive sleep apnea.

As summarized in Table 3, recent prospective observational studies that evaluated the prevalence of OSA in patients with newly diagnosed lung cancer included a high proportion of smokers and patients with COPD. Smoking and COPD are potential confounders in the relationship between OSA and lung cancer because both factors are associated with the development of lung cancer and the presence of OSA. Tobacco smoking is the most common risk factor for COPD and lung cancer²⁹. Smoking can also contribute to upper airway inflammation and collapsibility, thereby increasing the risk of OSA ^30,31. The predominant chronic bronchitis phenotype of COPD may predispose patients to a higher risk of OSA due to associated features, such as increased BMI, cor pulmonale, and peripheral fluid retention³⁰. While sleeping in the supine position, rostral fluid shift can promote upper airway narrowing. COPD itself is a strong risk factor for lung cancer due to their shared mechanisms, such as chronic airway inflammation, epigenetic changes in DNA methylation, and abnormal lung repair mechanisms²⁹. Moreover, OSA and COPD involve intermittent or sustained hypoxemia, respectively³⁰, which may further confound the understanding of hypoxia-related mechanisms linking OSA to tumorigenesis. Therefore, the high prevalence of smoking and COPD in previous studies could have introduced bias, complicating the interpretation of the association between OSA and lung cancer. Indeed, recent findings from women in the Nurses’ Health Study showed that the association between self-reported OSA and lung cancer appeared stronger in never-smokers than in smokers, although this finding was not statistically significant (HR = 2.96, 95% CI 1.42–6.18 vs HR = 1.37, 95% CI 0.91–2.06; P for interaction = 0.09)¹¹. In the present study, which included only never-smokers with newly diagnosed lung cancer and a 1.5% prevalence of COPD, OSA was still prevalent; half of the participants had OSA, and one-fifth had moderate-to-severe OSA.

Although the precise mechanisms connecting OSA to lung cancer have yet to be fully clarified, current evidence indicates that intermittent hypoxia—a hallmark feature of OSA—may significantly contribute to tumorigenesis^5,6. Intermittent hypoxia leads to oxidative stress, induces DNA damage, and triggers systemic inflammation, thereby creating a biological environment favorable for cancer development and progression through the HIF^7,8. In addition, sleep fragmentation associated with OSA may promote tumorigenesis by enhancing sympathetic activation, systemic inflammation, and immune dysregulation^4,32.

In the present study, OSA severity indices, including REI and T90, did not vary with the lung cancer stage, consistent with previous studies^9,10,27,28. Patients with OSA were more likely to present with cancer-related symptoms than those without OSA. After adjusting for this factor in the multivariable logistic regression model, any observed link between advanced-stage lung cancer and OSA severity indices lost statistical significance.

Our study has several limitations. First, the predominance of female participants is a major limitation, with only 16.4% being male. In contrast, previous studies reported a higher proportion of male participants (58%–87%)^9,10,27,28. This discrepancy is likely due to our inclusion criteria of never-smokers, the majority of whom are women in South Korea. According to national data from 2023, the prevalence of current smoking among South Korean adults was 32.4% in men and 6.3% in women¹⁵. As a result, the findings of this study may not be fully generalizable to populations with a higher proportion of men. Second, another major limitation is the absence of a non-cancer comparison group. However, in a large, population-based study of Korean women aged 40–69 years using gold-standard polysomnography, the prevalence of sleep-disordered breathing (apnea–hypopnea index ≥ 5/hour) was found to be 16.8% overall, rising to 28.6% in women aged 60–69 years³³. Since our cohort consists of never-smoking women with a median age of 65 years, the observed OSA prevalence of 47.8% is substantially higher than that expected in the general population. Third, adenocarcinoma was the predominant histologic subtype, which is consistent with previous observations that lung cancer in never-smokers—particularly among East Asian populations—is largely of this subtype³⁴. However, this histologic predominance may limit the generalizability of the study findings to other populations. Fourth, as this study was cross-sectional in nature, the temporal and causal relationship between OSA and lung cancer cannot be established, and the possibility that lung cancer itself may influence sleep-disordered breathing—through factors such as airway obstruction, diaphragmatic dysfunction, or systemic inflammation—cannot be excluded. Fifth, the final sample size did not reach the initial target of 96 patients, which was calculated based on a 10% margin of error. Although we aimed to enroll all eligible patients consecutively, some refused to participate or were unable to comply with the respiratory polygraphy within the narrow time window prior to initiating cancer therapy. Consequently, the actual margin of error for our observed OSA prevalence (47.8%) increased to approximately 12.0%. This relatively small sample size may limit the generalizability of the findings and the feasibility of subgroup analyses. Larger multicenter studies are needed to confirm the results and further elucidate the relationship between OSA and lung cancer in never-smokers.

Conclusions

Lung cancer survival rates have been steadily increasing³⁵. Accordingly, comprehensive management strategies, encompassing not only the treatment of the primary malignancy but also the identification and management of comorbid conditions, are of growing importance. In the present study, nearly half of the never-smokers with lung cancer were found to have OSA, with a substantial proportion exhibiting moderate-to-severe OSA. These findings highlight the need for the diagnosis and management of OSA in this population.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

J.C.: Conceptualization; investigation; methodology; validation; visualization; formal analysis; funding acquisition; project administration; data curation; supervision; writing—original draft; writing—review and editing J.P.: Investigation; data curation; writing—original draft; writing—review and editing S.Y.K.: Investigation; data curation; writing—review and editing S.J.: Investigation; data curation; writing—review and editing Y.S.P: Investigation; supervision; writing—review and editing.

Funding

This research was supported by grant no. 03–2021-0440 from the Seoul National University Hospital Research Fund.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.