Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2020 Mar 17;122(9):1417–1424. doi: 10.1038/s41416-020-0789-7

Female reproductive factors and the risk of lung cancer in postmenopausal women: a nationwide cohort study

Keun Hye Jeon 1, Dong Wook Shin 1,2,✉, Kyungdo Han 3,✉, Dahye Kim 3, Jung Eun Yoo 1,4, Su-Min Jeong 1,5, Jong ho Cho 6
PMCID: PMC7188895  PMID: 32203211

Abstract

Background

Reproductive factors and hormone use in postmenopausal women have been hypothesised to affect the risk of developing lung cancer, but the epidemiological evidence is inconsistent.

Methods

Using the Korean National Health Insurance System database, we identified 4,775,398 postmenopausal women older than 40 years who had undergone both cardiovascular health- and cancer screening between 1 January 2009 and 31 December 2014. Information about reproductive factors was obtained from a self-administered questionnaire. The risk of lung cancer was estimated using Cox proportional hazard regression models.

Results

During a median follow-up of 4.4 years, 16,556 women (15,223 non-smokers) were diagnosed with lung cancer. The risk of lung cancer was not significantly influenced by early menarche age (adjusted hazard ratio [aHR] 1.03 for menarche ≥18 vs. ≤14; 95% confidence interval [CI], 0.98–1.09) or late age at menopause (aHR 1.02 for menopause ≥55 vs. <40; 95% CI, 0.91–1.14). Furthermore, the number of children, duration of breastfeeding and use of hormone replacement therapy were not associated with the risk of lung cancer.

Conclusions

No statistically significant association was found between reproductive factors and the risk of lung cancer in postmenopausal Korean women.

Subject terms: Cancer epidemiology, Lung cancer

Background

Lung cancer is the leading cause of cancer deaths worldwide, and the third most common cancer in women, after breast- and colorectal cancer.1 In most countries, including Korea, the incidence of lung cancer in women is increasing, whereas in men, it has decreased or stabilised.2,3

Lung cancer in women has several characteristics that differ from lung cancer in men. Although smoking is the most important risk factor, a significant portion of lung cancer in women occurs in non-smokers.4 Global statistics estimate that 20% of lung cancer in Western populations develops in non-smokers.1 In Korea, 38% of female non-small-cell lung cancer patients reported themselves to be non-smokers.5 Female lung cancer patients have a higher proportion of adenocarcinoma histology,6 and a higher frequency of mutations in the epidermal growth factor receptor (EGFR)7 than male lung cancer patients. Such sex-related differences suggest that hormonal factors might influence the development of lung cancer.

Hormonal involvement in lung carcinogenesis was first suggested by experimental studies that identified oestrogen and progesterone receptors in human lung cancers.8 Steroid hormone-related receptors, including oestrogen receptors, progesterone receptors and human epidermal growth factor receptor 2, are frequently expressed in tumour lung tissue,8–10 and have been linked to survival in lung cancer patients.11,12 Oestrogen receptor α nuclear expression correlates significantly with adenocarcinoma histology, female sex and a history of never smoking.9 In addition, a recent study revealed a sex-related difference in oestrogen receptor β nuclear expression.8

As a result, it has been hypothesised that reproductive factors and hormone use could affect women’s risk of developing lung cancer. However, the epidemiological evidence is inconsistent and does not fully support that hypothesis. For example, with respect to late age at menopause, studies have variously shown an increase,13,14 a decrease15,16 or no significant change17–19 in lung cancer risk; early age at menarche has been shown to increase15 or have no significant effect16,18–20 on risk; a small number of pregnancies has been shown to increase,19,21,22 decrease20 and have no significant effect15,18 on risk; late age at first birth might decrease20 or have no significant effect15,16,18,22 on risk. Studies on the use of hormones have also produced heterogeneous results: the use of oral contraceptives has been shown to increase16 or have no significant effect18–20,22–26 on risk, and the use of hormone replacement therapy (HRT) might increase,27,28 decrease17,29,30 or have no appreciable influence15,18,19,25,31,32 on risk.

Previous cohort studies have been limited by small sample size (cohort studies published between 2001 and 2015 included 87–3512 lung cancer cases15–22,27,29–34), and case–control designs prone to recall bias. Moreover, the potential association between hormone exposure and lung cancer has not been comprehensively elucidated because several studies focused exclusively on exogenous hormone use.25,27–32,35

Furthermore, even though lung cancer in East Asia shows unique patterns in epidemiology7 and treatment response,36 few studies have been conducted there. East Asian females with lung cancer generally show lower smoking prevalence (9.9% in Korea,5 5.2% in China7 and 17–25.6% in Japan37) than is common in Western countries. Several case–control studies have been carried out in China and Singapore, but only a few cohort studies have been conducted in Asian countries—1 in Japan,18 2 in China22,33 and 2 in Singapore.19,21

In this study, we investigate the association between reproductive factors and the risk of lung cancer among postmenopausal women in a nationwide population cohort in Korea.

Methods

Data source and study setting

The Korean National Health Insurance Service (NHIS) is the single insurer that provides universal insurance for ~97% of the South Korean population. The remaining 3% of the population (in the lowest-income bracket) is covered by the Medical Aid program financed by the government, but it is also administered by the NHIS.

The NHIS provides national health check-up programmes, including a general health examination focused on cardiovascular risk factors, for all citizens aged 40 and above, and all employees regardless of age.38 It records the results of those general health examinations and questionnaires on lifestyle behaviour. In addition, the NHIS provides the National Cancer Screening Program (NCSP),39 which screens all individuals for stomach, liver, colorectal, breast and cervical cancers, as indicated by age.39 During our study period, Korean women were eligible to participate in biennial screening for breast cancer beginning at age 40 and cervical cancer beginning at age 30.39

The NHIS has qualification data on all its enrolees (age, sex, income level and mortality), diagnosis codes from the International Classification of Disease 10th revision (ICD-10), medical treatment information (medical services provided for medical expense claims) and prescription information.40,41 To manage enrolee qualification, the NHIS updates its mortality data through frequent links with mortality data from the Korean National Statistical Office. The NHIS database is widely used in epidemiological studies investigating disease incidence,42–44 and the details of the database profiles are described elsewhere.38,40,45,46 This study was approved by the Institutional Review Board of Samsung Medical Centre (IRB File No. SMC 2018-05-020).

Study population and data collection

From the NHIS database, we collected data for women older than 40 who had undergone both a cardiovascular health screening and an NCSP (breast/cervical cancer) screening between 1 January 2009 and 31 December 2014. Among 4,775,398 postmenopausal women who qualified, those who had previously been diagnosed with cancer (n = 167,910), participants diagnosed with any cancer within 1 year after the date of examination (n = 55,937), individuals who had previously undergone a hysterectomy (n = 17,667), participants who died within 1 year after examination (n = 4565) and those missing data in a key variable (n = 4116) were excluded. We excluded those who had previously undergone a hysterectomy because the questionnaire provided no information about the timing of the hysterectomy, and whether a bilateral oophorectomy had been performed concurrently. After those exclusions, a total of 4,525,203 individuals were included in our analyses (Fig. 1).

Fig. 1.

Fig. 1

Open in a new tab

Flow chart of the cohort study design.

Information about health-related behaviours, and the menstrual and reproductive histories of participants, was obtained using a self-administered questionnaire. Participants came to the medical centre on the day of the screening examination, and filled out the questionnaire prior to the exam. According to the NCSP guidelines, women were asked about their age at menarche and age at menopause as continuous variables. For analysis purposes, we categorised age at menarche as ≤14 years, 15–16 years, 17 years and ≥18 years, and age at menopause as <40 years, 40–44 years, 45–49 years, 50–54 years and ≥55 years. The reproductive period was calculated as the interval between the age at menarche and age at menopause. Information on parity number, total lifetime breastfeeding history, HRT history and the use of oral contraceptives was collected categorically: parity number (0, 1 or ≥2 children), total lifetime breastfeeding history (never, <6 months, 6–12 months and ≥12 total months), duration of HRT (never, <2 years, 2–5 years, ≥5 years and unknown) and duration of oral contraceptive use (never, <1 year, ≥1 year and unknown).

Participants’ history of smoking was classified as never smoked, former and <10 pack-years smoker, former and ≥10 pack-years smoker, current and <10 pack-years smoker and current and ≥10 pack-years smoker. Drinking was divided into three levels: none, mild (<30 g of alcohol/day) and heavy (≥30 g/day). Regular exercise was defined as moderate physical activity for more than 30 min, and more than 5 days per week during the past week. Body mass index (BMI) was calculated using weight (kg) divided by height in metres squared (m2), and classified as low (<18.8 kg/m2), normal to overweight (18.5–24.9 kg/m2) and obese (≥25 kg/m2). Hypertension, diabetes and dyslipidaemia were defined using physicians’ diagnoses or the use of medication, based on self-reporting. Household income was categorised into quartiles based on insurance premium levels (in Korea, insurance premiums are determined by income level), with those covered by Medical Aid (poorest 3%) being merged into the lowest-income quartile.

Study outcomes and follow-up

The primary endpoint of this study was newly diagnosed lung cancer, defined as new claims for inpatient or outpatient care with the ICD-10 diagnosis code of C34 (malignant neoplasm of lung and bronchus), and registration in the special co-payment reduction programme for critical illnesses. The NHIS special co-payment reduction programme for cancer and some other intractable diseases relieves the large financial burden of patients with serious and rare diseases. For example, cancer patients pay only 5% of the total medical bill incurred for cancer diagnostic tests or treatment. As enrolment in this programme requires a medical certificate from a physician, the cancer diagnosis variable in our study is considered sufficiently reliable, and has been used in other studies.42,44 The cohort was followed from 1 year after the health check-up date to the date of incident lung cancer, death or the end of the study period (31 December 2016), whichever came first.

Statistical analysis

Continuous variables are presented as the mean ± standard deviation, and categorical variables are presented as the number and percentage. The incidence rates of lung cancer were calculated by dividing the number of incident cases by the total follow-up period. Hazard ratios (HRs) and 95% confidence interval (CI) values for lung cancer were analysed using Cox proportional hazard models for various reproductive factors. A multivariable-adjusted proportional hazard model was applied: (1) model 1 was age-adjusted; (2) model 2 was adjusted for age at menarche and menopause, parity, duration of breastfeeding, duration of HRT, duration of oral contraceptive use, alcohol consumption, smoking, regular exercise, income, BMI, hypertension, diabetes mellitus, dyslipidaemia and cancer; (3) model 3 was adjusted for reproductive period instead of age at menarche and menopause separately, as in model 2. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA), and a P value <0.05 was considered statistically significant.

Results

Baseline characteristics of study participants

During a mean follow-up of 4.4 years (19,910,975 person-years), 16,556 women (15,223 non-smokers) were diagnosed with lung cancer, for an incidence rate of 83.15 cases per 100,000 person-years. Table 1 provides the baseline information and characteristics of the study population. The mean age of the study participants was 61.2 years. Among all participants, only 3.1% were current smokers, 91.9% had breastfed and 14.6% had received HRT.

Table 1.

Selected baseline characteristics of the study population.

Variable Total (N = 4,525,203) Women not diagnosed with lung cancer (N = 4,508,647) Women diagnosed with lung cancer (N = 16,556)
Mean age, y (SD) 61.2 (8.7) 61.3 (8.7) 65.9 (8.7)
Age at menarche, no. (%)
 Mean (SD) 16.3 (1.9) 16.3 (1.9) 16.6 (1.9)
 ≤14 y 712,179 (15.7) 710,254 (15.8) 1925 (11.6)
 15–16 y 1,806,866 (39.9) 1,800,693 (39.9) 6173 (37.3)
 17 y 854,123 (18.9) 850,758 (18.9) 3365 (20.3)
 ≥18 y 1,152,035 (25.5) 1,146,942 (25.4) 5093 (30.8)
Age at menopause, no. (%)
 Mean (SD) 50.2 (4.0) 50.2 (4.0) 50.0 (4.4)
 <40 y 73,474 (1.6) 73,120 (1.6) 354 (2.1)
 40–44 y 237,584 (5.3) 236,500 (5.3) 1084 (6.6)
 45–49 y 1,172,184 (26.0) 1,167,918 (25.9) 4266 (25.8)
 50–54 y 2,510,733 (55.5) 2,501,988 (55.5) 8745 (52.8)
 ≥55 y 531,228 (11.7) 529,121 (11.7) 2107 (12.7)
Reproductive period, no. (%)
 Mean (SD) 33.9 (4.4) 33.9 (4.4) 33.4 (4.7)
 <30 y 562,807 (12.4) 560,192 (12.4) 2615 (15.8)
 30–34 y 1,768,024 (39.1) 1,761,249 (39.1) 6775 (40.9)
 35–39 y 1,844,270 (40.8) 1,838,391 (40.8) 5879 (35.5)
 ≥40 350,102 (7.7) 348,815 (7.7) 1287 (7.8)
Parity, no. (%)
 Nulliparous 99,224 (2.2) 98,847 (2.2) 377 (2.3)
 1 child 347,461 (7.7) 346,491 (7.7) 970 (5.9)
 ≥2 children 4,078,518 (90.1) 4,063,309 (90.1) 15,209 (91.9)
Duration of breastfeeding, no. (%)
 Never 366,238 (8.1) 365,176 (8.1) 1062 (6.4)
 <0.5 y 362,575 (8.0) 361,738 (8.0) 837 (5.1)
 0.5 to < 1 y 804,665 (17.8) 802,226 (17.8) 2439 (14.7)
 ≥1 y 2,991,725 (66.1) 2,979,507 (66.1) 12,218 (73.8)
Hormone therapy, no. (%)
 Never used 3,696,024 (81.7) 3,682,200 (81.7) 13,824 (83.5)
 <2 y 392,482 (8.7) 391,279 (8.7) 1203 (7.3)
 2 to <5 y 150,713 (3.3) 150,263 (3.3) 450 (2.7)
 ≥5 y 119,890 (2.7) 119,457 (2.7) 433 (2.6)
 Missing 166,094 (3.7) 165,448 (3.7) 646 (3.9)
Oral contraceptive use, no. (%)
 Never used 3,646,833 (80.6) 3,633,551 (80.6) 13,282 (80.2)
 <1 y 397,111 (8.8) 395,766 (8.8) 1345 (8.1)
 ≥1 y 261,279 (5.8) 260,236 (5.8) 1043 (6.3)
 Missing 219,980 (4.9) 219,094 (4.9) 886 (5.4)
Smoking history, no. (%)
 Never smoked 4,335,259 (95.8) 4,320,036 (95.8) 15,223 (92.0)
 Former smoker 51,171 (1.1) 50,912 (1.1) 259 (1.6)
 Current smoker 138,773 (3.1) 137,699 (3.1) 1074 (6.5)
Pack years of smoking, no. (%)
 Never smoker 4,335,259 (95.8) 4,320,036 (95.8) 15,223 (92.0)
 Former smoker & <10 40,881 (0.9) 40,729 (0.9) 152 (0.9)
 Former smoker & ≥10 10,290 (0.2) 10,183 (0.2) 107 (0.7)
 Current smoker & <10 91,170 (2.0) 90,685 (2.0) 485 (2.9)
 Current smoker & ≥10 47,603 (1.1) 47,014 (1.0) 589 (3.6)
Drinker
 None 3,908,753 (86.4) 3,894,093 (86.4) 14,660 (88.6)
 Mild 594,527 (13.1) 592,711 (13.2) 1816 (11.0)
 Heavy 21,923 (0.5) 21,843 (0.48) 80 (0.5)
Regular physical activity 1,819,153 (40.2) 1,813,280 (40.2) 5873 (35.5)
Body mass index, no. (%)
 <18.5 kg/m2 102,774 (2.3) 102,319 (2.3) 455 (2.8)
 18.5 to < 23 kg/m2 1,608,543 (35.6) 1,602,747 (35.6) 5796 (35.0)
 23 to < 25 kg/m2 1,182,847 (26.1) 1,178,649 (26.1) 4198 (25.4)
 25 to < 30 kg/m2 1,428,031 (31.6) 1,422,676 (31.6) 5355 (32.3)
 ≥30 kg/m2 203,008 (4.5) 202,256 (4.5) 752 (4.5)
Co-morbid condition
 Hypertension, no. (%) 1,915,482 (42.3) 1,906,972 (42.3) 8510 (51.4)
 DM, no. (%) 622,758 (13.8) 619,999 (13.8) 2759 (16.7)
 Dyslipidaemia, no. (%) 1,657,900 (36.6) 1,651,724 (36.6) 6176 (37.3)
 SBP 125.3 ± 16 125.3 ± 16 127.4 ± 16.2
 DBP 76.7 ± 10.0 76.7 ± 10.0 77.3 ± 10.1
 Glucose 100.4 ± 23.9 100.4 ± 23.9 101.6 ± 24.7
 Cholesterol 207.0 ± 38.8 207.0 ± 38.8 205.0 ± 39.1
Income
 Q1 (lowest) 1,277,758 (28.2) 1,273,270 (28.2) 4488 (27.1)
 Q2 1,007,569 (22.3) 1,004,198 (22.3) 3371 (20.4)
 Q3 1,056,997 (23.4) 1,053,003 (23.4) 3994 (24.1)
 Q4 (highest) 1,182,879 (26.1) 1,178,176 (26.1) 4703 (28.4)
Open in a new tab

SD standard deviation.

Compared with the women not diagnosed with lung cancer, lung cancer cases had a higher mean age at study entry (65.9 vs. 61.3 years), a higher proportion of current and past smokers (6.5 and 1.6 vs. 3.1 and 1.1%), a tendency to exercise less (35.5 vs. 40.2%), more hypertension (51.4 vs. 42.3%) and more diabetes (16.7 vs. 13.8%). With respect to reproductive factors, only the duration of breastfeeding differed; the proportion of women breastfeeding for ≥1 year in lung cancer patients was 73.8%, which was higher than that among women not diagnosed with lung cancer (66.1%). The mean ages of menarche and menopause for lung cancer patients and the non-case group were 16.6 vs. 16.3 and 50.0 vs. 50.2 years, respectively, and the mean reproductive period was 33.4 vs. 33.9 years. Supplementary Table 1 provides a baseline characteristic analysis according to smoking status.

Associations between reproductive factors and the risk of lung cancer

None of the menstrual or reproductive variables analysed showed a statistically significant association with lung cancer (Table 2). In multivariate-adjusted model 2, the HRs for lung cancer were 1.03 (95% CI, 0.98–1.09) for those whose age at menarche was ≥18 years compared with those aged ≤14 years, 1.02 (95% CI, 0.91–1.14) for those whose age at menopause was ≥55 years compared with those <40 years old, 0.95 (95% CI, 0.84–1.06) for the group having ≥2 parity compared with those with nulliparity, 0.95 (95% CI, 0.88–1.02) for the group breastfeeding for ≥1 year compared with those with no breastfeeding history, 1.04 (95% CI, 0.95–1.15) for the group on HRT for ≥5 years compared with the never-HRT group and 1.06 (95% CI, 0.99–1.13) for the patients who had used oral contraception for ≥1 year compared with never-users. Furthermore, when model 3 was adjusted for reproductive period instead of age at menarche and menopause as in model 2, similar trends were observed. The reproductive period was calculated as the interval between the age at menarche and the age at menopause, indicating a strong correlation among those variables. Therefore, we analysed them separately. Moreover, a sensitivity analysis restricted to non-smokers showed no statistically significant association between reproductive factors and the risk of lung cancer (Supplementary Table 2).

Table 2.

Hazard ratios (HR) and 95% confidence intervals (CI) for the association between reproductive factors and the risk of lung cancer among postmenopausal women.

Case no. Duration (person-years) IR per 100 000 person-years HR (95% CI)
Model 1 (age-adjusted) Model 2 (multivariablea) Model 2 (multivariableb)
Age at menarche
 ≤14 y 1925 2,958,968.8 65.1 1 (ref.) 1 (ref.)
 15–16 y 6173 2,718,665.8 78.7 1.02 (0.97–1.07) 1.02 (0.97–1.08)
 17 y 3365 7,840,631.0 87.4 0.98 (0.93–1.04) 0.99 (0.93–1.05)
 ≥18 y 5093 9,111,375.6 96.8 1.03 (0.97–1.08) 1.03 (0.98–1.09)
Age at menopause
 <40 y 354 332,191.7 106.6 1 (ref.) 1 (ref.)
 40–44 y 1084 1,077,353.8 100.6 0.98 (0.87–1.11) 0.99 (0.88–1.12)
 45–49 y 4266 5,248,111.7 81.3 0.93 (0.83–1.03) 0.95 (0.85–1.06)
 50–54 y 8745 10,955,113.3 79.8 0.93 (0.84–1.04) 0.96 (0.87–1.07)
 ≥55 y 2107 2,298,204.9 91.7 0.98 (0.88–1.10) 1.02 (0.91–1.14)
Reproductive period
 <30 y 2615 2,578,602.2 101.4 1 (ref.) 1 (ref.)
 30–34 y 6775 7,951,785.0 85.2 0.97 (0.93–1.02) 0.98 (0.94–1.03)
 35–39 y 5879 7,911,853.1 74.3 0.97 (0.93–1.02) 0.99 (0.95–1.04)
 ≥40 y 1287 1,468,735.2 87.6 1.02 (0.96–1.10) 1.05 (0.98–1.12)
Parity
 Nulliparous 377 466,390.6 80.8 1 (ref.) 1 (ref.) 1 (ref.)
 1 child 970 1,410,842.3 68.8 0.95 (0.85–1.07) 1.00 (0.88–1.14) 1.00 (0.88–1.14)
 ≥2 children 15,209 18,033,742.6 84.3 0.84 (0.75–0.93) 0.95 (0.84–1.06) 0.95 (0.84–1.06)
Duration of breastfeeding
 Never 1062 1,520,411.3 69.9 1 (ref.) 1 (ref.) 1 (ref.)
 <0.5 y 837 1,458,435.9 57.4 0.86 (0.79–0.94) 0.91 (0.82–1.00) 0.91 (0.82–1.00)
 0.5 to <1 y 2439 3,478,988.5 70.1 0.88 (0.82–0.94) 0.95 (0.87–1.03) 0.95 (0.88–1.03)
 ≥1 y 12,218 13,453,139.8 90.8 0.87 (0.82–0.93) 0.95 (0.88–1.02) 0.95 (0.88–1.02)
Hormone therapy
 Never used 13,824 16,255,096.0 85.0 1 (ref.) 1 (ref.) 1 (ref.)
 <2 y 1203 1,744,475.1 69.0 1.05 (0.99–1.12) 1.05 (0.99–1.11) 1.05 (0.99–1.11)
 2 to <5 y 450 675,304.8 66.6 0.98 (0.89–1.07) 0.96 (0.88–1.06) 0.96 (0.88–1.06)
 ≥5 y 433 535,470.9 80.9 1.05 (0.96–1.16) 1.04 (0.95–1.15) 1.04 (0.95–1.15)
 Missing 646 700,628.7 92.2 1.09 (1.01–1.18) 1.07 (0.98–1.16) 1.07 (0.98–1.16)
Oral contraceptive use
 Never used 13,282 16,005,619.4 83.0 1 (ref.) 1 (ref.) 1 (ref.)
 <1 y 1345 176,6051.5 76.2 0.99 (0.94–1.05) 0.99 (0.94–1.05) 0.99 (0.94–1.05)
 ≥1 y 1043 1,171,489.9 89.0 1.07 (1.01–1.14) 1.06 (0.99–1.13) 1.06 (0.99–1.13)
 Missing 886 967,814.6 91.6 1.07 (1.00–1.15) 1.05 (0.97–1.13) 1.05 (0.97–1.13)
Pack years of smoking
 Never smoker 15,223 19,118,652.5 79.6 1 (ref.) 1 (ref.) 1 (ref.)
 Former smoker & <10 152 168,394.2 90.3 1.30 (1.11–1.52) 1.27 (1.08–1.49) 1.27 (1.08–1.49)
 Former smoker & ≥10 107 44,052.2 242.9 2.65 (2.19–3.20) 2.59 (2.14–3.14) 2.59 (2.14–3.14)
 Current smoker & <10 485 376,445.3 128.8 2.03 (1.85–2.22) 1.98 (1.80–2.17) 1.98 (1.80–2.17)
 Current smoker & ≥10 589 203,431.2 289.5 3.48 (3.20–3.77) 3.40 (3.12–3.69) 3.40 (3.12–3.69)
Alcohol consumption
 None 14,660 17,293,429.6 84.8 1 (ref.) 1 (ref.) 1 (ref.)
 Mild (<30 g/d) 1816 2,525,463.6 71.9 1.13 (1.08–1.19) 1.03 (0.98–1.09) 1.03 (0.98–1.09)
 Heavy (≥30 g/d) 80 92,082.2 86.9 1.53 (1.23–1.91) 1.05 (0.84–1.31) 1.05 (0.84–1.31)
Regular physical activity
 No 10,683 11967393.3 89.3 1 (ref.) 1 (ref.) 1 (ref.)
 Yes 5873 7943582.1 73.9 0.96 (0.93–0.99) 0.97 (0.94–1.00) 0.97 (0.94–1.00)
Body mass index (kg/m2)
 <18.5 455 427,226.4 106.5 1.07 (0.97–1.17) 1.02 (0.93–1.12) 1.02 (0.93–1.12)
 18.5 to <23 kg/m2 5796 6,953,966.4 83.4 1 (ref.) 1 (ref.) 1 (ref.)
 23 to <25 kg/m2 4198 5,253,687.4 79.9 0.94 (0.90–0.98) 0.95 (0.91–0.99) 0.95 (0.91–0.99)
 25 to <30 kg/m2 5355 6,390,031.5 83.8 0.94 (0.90–0.97) 0.94 (0.91–0.98) 0.94 (0.91–0.98)
 ≥30 752 886,063.8 84.9 0.97 (0.90–1.04) 0.96 (0.88–1.03) 0.96 (0.88–1.03)
Co-morbidity
Hypertension
 No 8046 11,397,844.2 70.6 1 (ref.) 1 (ref.) 1 (ref.)
 Yes 8510 8,513,131.2 100.0 1.03 (1.00–1.07) 1.05 (1.01–1.08) 1.05 (1.01–1.08)
Diabetes mellitus
 No 13,797 17,214,825.2 80.2 1 (ref.) 1 (ref.) 1 (ref.)
 Yes 2759 2,696,150.2 102.3 1.04 (1.00–1.09) 1.04 (0.99–1.08) 1.04 (0.99–1.08)
Dyslipidaemia
 No 10,380 12,762,248.2 81.3 1 (ref.) 1 (ref.) 1 (ref.)
 Yes 6176 7,148,727.3 86.4 1.00 (0.97–1.03) 0.98 (0.95–1.02) 0.98 (0.95–1.02)
Income
 Q1 (lowest) 4488 5,481,769.8 81.9 1.04 (1.00–1.09) 1.00 (0.96–1.04) 1.00 (0.96–1.04)
 Q2 3371 4,452,819.7 75.7 0.98 (0.94–1.03) 0.96 (0.92–1.00) 0.96 (0.92–1.00)
 Q3 3994 4,749,847.9 84.1 0.98 (0.94–1.03) 0.97 (0.93–1.01) 0.97 (0.93–1.02)
 Q4 (highest) 4703 5,226,537.9 90.0 1 (ref.) 1 (ref.) 1 (ref.)
Open in a new tab

IR incidence rate, HR hazard ratio, CI confidence interval.

aAdjusted for age, age at menarche and menopause, parity, duration of breastfeeding, duration of HRT, duration of oral contraceptive use, alcohol consumption, smoking, regular exercise, income, BMI, hypertension, diabetes mellitus, dyslipidaemia and cancer.

bAdjusted for age, reproductive period, parity, duration of breastfeeding, duration of HRT, duration of oral contraceptive use, alcohol consumption, smoking, regular exercise, income, BMI, hypertension, diabetes mellitus, dyslipidaemia and cancer.

Other factors associated with lung cancer

Compared with never-smokers, current smokers were at a significantly increased risk for lung cancer (aHR 1.98; 95% CI, 1.80–2.17 for <10 pack years and aHR 3.40; 95% CI, 3.12–3.69 for ≥10 pack years). The risk of lung cancer in women who were former smokers also remained elevated compared with never-smokers (aHR 1.27; 95% CI, 1.08–1.49 for <10 pack years and aHR 2.59; 95% CI, 2.14–3.14 for ≥10 pack years). Hypertension was associated with a slightly elevated risk of lung cancer (aHR 1.05; 95% CI, 1.01–1.08). Alcohol consumption, physical activity, BMI, diabetes mellitus, dyslipidaemia and income level were not statistically significant in the multivariable analyses.

Discussion

In the largest cohort study to date, we found that a wide range of reproductive history measures made no consistent contributions to lung cancer risk. The strengths of our study include an unprecedentedly large representative sample size and outcome incidence (more than 4.5 million women with 16,556 incident lung cancer cases), a comprehensive evaluation of the reproductive variables of interest and minimal follow-up losses (1.3%).

None of the menstrual variables analysed in our study showed a statistically significant association with lung cancer. Decades ago, a case–control study reported that a later age at menopause was associated with an increased lung cancer risk,13,14 whereas more recent studies found that a later age at menopause was associated with a reduced risk of lung cancer.15,47 With respect to menarche, Brinton et al.15 reported that early menarche was associated with an increased risk of adenocarcinoma, and a few other studies reported an increased risk for lung cancer with a later age at menarche, but the risk estimates were not statistically significant.19,22 Most other studies reported null associations.16,20,22,23,26,48–54 Weiss et al. reported that a longer reproductive period was associated with a decrease in the risk of lung cancer (HR 0.60 for 36 vs. <31 years; 95% CI, 0.39–0.93),22 but other studies reported null associations.18,21,33 Overall, previous studies showed that menstrual variables were not consistently associated with lung cancer risk, and our results support that finding.

Concerning parity, Kabat et al. reported an increased risk with increasing parity in Canada,20 but most other cohort studies reported an inverse association19,21–23,55 or null effect.15,17,18,26,48,50,51,53,56,57 A recent meta-analysis of 11 case–control and 5 cohort studies also found no overall relationship with parity.58 Our result of no association with parity concurs with that meta-analysis.

Only a few epidemiologic studies have examined the association between duration of breastfeeding and lung cancer, and their results showed null effects.18,21,33 Those studies were all conducted in East Asia, and our null result is consistent with theirs.

Previous findings about the association between HRT and lung cancer are conflicting, with studies reporting a reduced risk,17,29,30 an increased risk27,28 and a null effect.15,16,19,23,25,31,32,49 A systemic review that analysed 6 case–control studies showed a protective association between HRT and lung cancer,59 but a recent meta-analysis of 14 cohort studies found no statistically significant association between HRT and lung cancer.60 Our largest-ever cohort study confirms the null association.

The epidemiologic literature is also inconsistent with regard to the role of oral contraceptives in lung cancer risk. Some case–control studies14,53,59 noted that women who had used an oral contraceptive had a decreased risk relative to women who had not used one. But most other studies reported a null association.18–20,22–26,51 A systemic review61 that analysed nine case–control and five cohort studies showed no statistically significant association between oral contraceptive use and lung cancer, which is consistent with our findings.

While not the focus of our study, our data show that smoking is a definite risk factor for the development of lung cancer, producing a clear dose–response relationship. In East Asia, smoking prevalence in females has been relatively low due to a social atmosphere that deters women from smoking.62 Indeed, in our study, only 3.1 and 1.1% women identified themselves as current or past smokers. The other 95.8% were never-smokers at cohort entry, and 92.0% of lung cancer patients were never-smokers. However, the female smoking rate is increasing, especially in younger populations,63 and there are many hidden smokers.62 Some studies suggest that women are more susceptible to tobacco carcinogenesis than men.64–66 In the absence of other potent risk factors for women, our study’s results emphasise the importance of abstinence from smoking to prevent lung cancer in women.

In our study, having hypertension was slightly associated with an increase in lung cancer risk (aHR 1.05; 95% CI, 1.01–1.08) in women. Lindgren et al. reported that elevated blood pressure was associated with increased risk of lung cancer in smoking, hypertensive men,67 but most other cohort studies reported a null effect.68–72 The biological mechanism of such an association has rarely been investigated, but one recent study suggested that angiotensin-converting enzyme inhibitors are linked to a small increase in the risk of lung cancer and could be a potential confounder.73 Further studies are required to clarify this issue.

This study has several limitations. First, all the primary variables of interest were based on self-reported reproductive histories, and we therefore cannot exclude the possibility of bias caused by inaccurate recall. However, our data showed a null association, and it seems unlikely that recall bias could noticeably change that conclusion. Second, information on the components of HRT and oral contraceptives (e.g. oestrogen alone or oestrogen–progesterone) was unavailable. However, many studies, including the Women’s Health Initiative trials, reported that neither the use of oestrogen plus progestin nor oestrogen alone was associated with lung cancer incidence,28,74,75 and the HRT formula is unlikely to affect our conclusion of no association. Third, information about other possible risk factors for lung cancer (second-hand smoke exposure,76–78 indoor pollutants79,80 and a family history of lung cancers14,81) was also unavailable. Fourth, our study participants were limited to health-screening participants and might be healthier and more engaged in having a healthy lifestyle than the general population. Fifth, the follow-up period was relatively short at 4.4 years. Sixth, we could not include the pathological type of lung cancer because our data could not be linked to cancer registry data.

Conclusions

Overall, this study found no statistically significant association between reproductive factors or hormone use, and the risk of lung cancer in postmenopausal Korean women, among whom smoking prevalence is very low. Further studies are warranted to discover additional risk factors for lung cancer in the female population.

Supplementary information

Supplementary Table 1 (20.9KB, docx)
Supplementary Table 2 (23.9KB, docx)

Acknowledgements

We thank the staff at the National Health Insurance Services for their provision of data and administrative support.

Author contributions

Study design: K.H.J., D.W.S., J.E.Y., S.-M.J. and J.H.C. Data assembly and analysis: K.-D.H. and D.K. Initial draft of the paper: K.H.J. All authors approved the paper.

Ethics approval and consent to participate

This study has been approved by the Institutional Review Board of Samsung Medical Center (IRB File No. SMC 2018-05-020). The IRB has approved a waiver of the requirement to obtain informed consent from research participants. This study was performed in accordance with the Declaration of Helsinki.

Consent to publish

None.

Data availability

The data that support the findings of this study are available from NHIS. Restrictions apply to the availability of these data, which were used under license for this study. Data are available at https://nhiss.nhis.or.kr with the permission of NIHS.

Competing interests

The authors declare no competing interests.

Funding information

None.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Dong Wook Shin, Email: dwshin.md@gmail.com.

Kyungdo Han, Email: hkd917@naver.com.

Supplementary information

Supplementary information is available for this paper at 10.1038/s41416-020-0789-7.

References

  • 1.Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
  • 2.Jung KW, Won YJ, Kong HJ, Lee ES. Cancer statistics in Korea: Incidence, mortality, survival, and prevalence in 2016. Cancer Res. Treat. 2019;51:417–430. doi: 10.4143/crt.2019.138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Lewis DR, Check DP, Caporaso NE, Travis WD, Devesa SS. US lung cancer trends by histologic type. Cancer. 2014;120:2883–2892. doi: 10.1002/cncr.28749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Wakelee HA, Chang ET, Gomez SL, Keegan TH, Feskanich D, Clarke CA, et al. Lung cancer incidence in never smokers. J. Clin. Oncol. 2007;25:472–478. doi: 10.1200/JCO.2006.07.2983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Cho J, Choi SM, Lee J, Lee CH, Lee SM, Kim DW, et al. Proportion and clinical features of never-smokers with non-small cell lung cancer. Chin. J. Cancer. 2017;36:20. doi: 10.1186/s40880-017-0187-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Cheng TY, Cramb SM, Baade PD, Youlden DR, Nwogu C, Reid ME. The international epidemiology of lung cancer: latest trends, disparities, and tumor characteristics. J. Thorac. Oncol. 2016;11:1653–1671. doi: 10.1016/j.jtho.2016.05.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Zhou F, Zhou C. Lung cancer in never smokers-the East Asian experience. Transl. Lung Cancer Res. 2018;7:450–463. doi: 10.21037/tlcr.2018.05.14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Cheng TD, Darke AK, Redman MW, Zirpoli GR, Davis W, Payne Ondracek R, et al. Smoking, sex, and non-small cell lung cancer: steroid hormone receptors in tumor tissue (S0424) J. Natl. Cancer Inst. 2018;110:734–742. doi: 10.1093/jnci/djx260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Raso MG, Behrens C, Herynk MH, Liu S, Prudkin L, Ozburn NC, et al. Immunohistochemical expression of estrogen and progesterone receptors identifies a subset of NSCLCs and correlates with EGFR mutation. Clin. Cancer Res. 2009;15:5359–5368. doi: 10.1158/1078-0432.CCR-09-0033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Stabile LP, Davis AL, Gubish CT, Hopkins TM, Luketich JD, Christie N, et al. Human non-small cell lung tumors and cells derived from normal lung express both estrogen receptor alpha and beta and show biological responses to estrogen. Cancer Res. 2002;62:2141–2150. [PubMed] [Google Scholar]
  • 11.Stabile LP, Dacic S, Land SR, Lenzner DE, Dhir R, Acquafondata M, et al. Combined analysis of estrogen receptor beta-1 and progesterone receptor expression identifies lung cancer patients with poor outcome. Clin. Cancer Res. 2011;17:154–164. doi: 10.1158/1078-0432.CCR-10-0992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Meert AP, Martin B, Paesmans M, Berghmans T, Mascaux C, Verdebout JM, et al. The role of HER-2/neu expression on the survival of patients with lung cancer: a systematic review of the literature. Br. J. Cancer. 2003;89:959–965. doi: 10.1038/sj.bjc.6601252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Taioli E, Wynder EL. Re: endocrine factors and adenocarcinoma of the lung in women. J. Natl. Cancer Inst. 1994;86:869–870. doi: 10.1093/jnci/86.11.869. [DOI] [PubMed] [Google Scholar]
  • 14.Wu AH, Yu MC, Thomas DC, Pike MC, Henderson BE. Personal and family history of lung disease as risk factors for adenocarcinoma of the lung. Cancer Res. 1988;48:7279–7284. [PubMed] [Google Scholar]
  • 15.Brinton LA, Gierach GL, Andaya A, Park Y, Schatzkin A, Hollenbeck AR, et al. Reproductive and hormonal factors and lung cancer risk in the NIH-AARP Diet and Health Study cohort. Cancer Epidemiol. Biomark. Prev. 2011;20:900–911. doi: 10.1158/1055-9965.EPI-10-1325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Baik CS, Strauss GM, Speizer FE, Feskanich D. Reproductive factors, hormone use, and risk for lung cancer in postmenopausal women, the Nurses’ Health Study. Cancer Epidemiol. Biomark. Prev. 2010;19:2525–2533. doi: 10.1158/1055-9965.EPI-10-0450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Schwartz AG, Ray RM, Cote ML, Abrams J, Sokol RJ, Hendrix SL, et al. Hormone use, reproductive history, and risk of lung cancer: the women’s health initiative studies. J. Thorac. Oncol. 2015;10:1004–1013. doi: 10.1097/JTO.0000000000000558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Liu Y, Inoue M, Sobue T, Tsugane S. Reproductive factors, hormone use and the risk of lung cancer among middle-aged never-smoking Japanese women: a large-scale population-based cohort study. Int. J. Cancer. 2005;117:662–666. doi: 10.1002/ijc.21229. [DOI] [PubMed] [Google Scholar]
  • 19.Seow A, Koh WP, Wang R, Lee HP, Yu MC. Reproductive variables, soy intake, and lung cancer risk among nonsmoking women in the Singapore Chinese Health Study. Cancer Epidemiol. Biomark. Prev. 2009;18:821–827. doi: 10.1158/1055-9965.EPI-08-0892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Kabat GC, Miller AB, Rohan TE. Reproductive and hormonal factors and risk of lung cancer in women: a prospective cohort study. Int. J. Cancer. 2007;120:2214–2220. doi: 10.1002/ijc.22543. [DOI] [PubMed] [Google Scholar]
  • 21.Tan HS, Tan MH, Chow KY, Chay WY, Lim WY. Reproductive factors and lung cancer risk among women in the Singapore Breast Cancer Screening Project. Lung Cancer. 2015;90:499–508. doi: 10.1016/j.lungcan.2015.10.003. [DOI] [PubMed] [Google Scholar]
  • 22.Weiss JM, Lacey JV, Jr., Shu XO, Ji BT, Hou L, Yang G, et al. Menstrual and reproductive factors in association with lung cancer in female lifetime nonsmokers. Am. J. Epidemiol. 2008;168:1319–1325. doi: 10.1093/aje/kwn257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Meinhold CL, Berrington de Gonzalez A, Bowman ED, Brenner AV, Jones RT, Lacey JV, Jr., et al. Reproductive and hormonal factors and the risk of nonsmall cell lung cancer. Int. J. Cancer. 2011;128:1404–1413. doi: 10.1002/ijc.25434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Gorlova OY, Zhang Y, Schabath MB, Lei L, Zhang Q, Amos CI, et al. Never smokers and lung cancer risk: a case-control study of epidemiological factors. Int. J. Cancer. 2006;118:1798–1804. doi: 10.1002/ijc.21561. [DOI] [PubMed] [Google Scholar]
  • 25.Elliott AM, Hannaford PC. Use of exogenous hormones by women and lung cancer: evidence from the Royal College of General Practitioners’ Oral Contraception Study. Contraception. 2006;73:331–335. doi: 10.1016/j.contraception.2005.10.003. [DOI] [PubMed] [Google Scholar]
  • 26.Wu-Williams AH, Dai XD, Blot W, Xu ZY, Sun XW, Xiao HP, et al. Lung cancer among women in north-east China. Br. J. Cancer. 1990;62:982–987. doi: 10.1038/bjc.1990.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Slatore CG, Chien JW, Au DH, Satia JA, White E. Lung cancer and hormone replacement therapy: association in the vitamins and lifestyle study. J. Clin. Oncol. 2010;28:1540–1546. doi: 10.1200/JCO.2009.25.9739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Chlebowski RT, Schwartz AG, Wakelee H, Anderson GL, Stefanick ML, Manson JE, et al. Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet. 2009;374:1243–1251. doi: 10.1016/S0140-6736(09)61526-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Rodriguez C, Spencer Feigelson H, Deka A, Patel AV, Jacobs EJ, Thun MJ, et al. Postmenopausal hormone therapy and lung cancer risk in the cancer prevention study II nutrition cohort. Cancer Epidemiol. Biomark. Prev. 2008;17:655–660. doi: 10.1158/1055-9965.EPI-07-2683. [DOI] [PubMed] [Google Scholar]
  • 30.Olsson H, Bladstrom A, Ingvar C. Are smoking-associated cancers prevented or postponed in women using hormone replacement therapy? Obstet. Gynecol. 2003;102:565–570. doi: 10.1016/s0029-7844(03)00564-7. [DOI] [PubMed] [Google Scholar]
  • 31.Clague J, Reynolds P, Sullivan-Halley J, Ma H, Lacey JV, Jr., Henderson KD, et al. Menopausal hormone therapy does not influence lung cancer risk: results from the California Teachers Study. Cancer Epidemiol. Biomark. Prev. 2011;20:560–564. doi: 10.1158/1055-9965.EPI-10-1182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Smith JR, Barrett-Connor E, Kritz-Silverstein D, Wingard DL, Al-Delaimy WK. Hormone use and lung cancer incidence: the Rancho Bernardo cohort study. Menopause. 2009;16:1044–1048. doi: 10.1097/gme.0b013e3181a1ba04. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Gallagher LG, Rosenblatt KA, Ray RM, Li W, Gao DL, Applebaum KM, et al. Reproductive factors and risk of lung cancer in female textile workers in Shanghai, China. Cancer Causes Control. 2013;24:1305–1314. doi: 10.1007/s10552-013-0208-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Pukkala E, Tulenheimo-Silfvast A, Leminen A. Incidence of cancer among women using long versus monthly cycle hormonal replacement therapy, Finland 1994-1997. Cancer Causes Control. 2001;12:111–115. doi: 10.1023/a:1008934919159. [DOI] [PubMed] [Google Scholar]
  • 35.Schabath MB, Wu X, Vassilopoulou-Sellin R, Vaporciyan AA, Spitz MR. Hormone replacement therapy and lung cancer risk: a case-control analysis. Clin. Cancer Res. 2004;10:113–123. doi: 10.1158/1078-0432.ccr-0911-3. [DOI] [PubMed] [Google Scholar]
  • 36.Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500. doi: 10.1126/science.1099314. [DOI] [PubMed] [Google Scholar]
  • 37.Yano T, Miura N, Takenaka T, Haro A, Okazaki H, Ohba T, et al. Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival. Cancer. 2008;113:1012–1018. doi: 10.1002/cncr.23679. [DOI] [PubMed] [Google Scholar]
  • 38.Lee H, Cho J, Shin DW, Lee SP, Hwang SS, Oh J, et al. Association of cardiovascular health screening with mortality, clinical outcomes, and health care cost: a nationwide cohort study. Prev. Med. 2015;70:19–25. doi: 10.1016/j.ypmed.2014.11.007. [DOI] [PubMed] [Google Scholar]
  • 39.Yoo KY. Cancer control activities in the Republic of Korea. Jpn. J. Clin. Oncol. 2008;38:327–333. doi: 10.1093/jjco/hyn026. [DOI] [PubMed] [Google Scholar]
  • 40.Lee J, Lee JS, Park SH, Shin SA, Kim K. Cohort profile: The National Health Insurance Service-National Sample Cohort (NHIS-NSC), South Korea. Int. J. Epidemiol. 2017;46:e15. doi: 10.1093/ije/dyv319. [DOI] [PubMed] [Google Scholar]
  • 41.Lee YH, Han K, Ko SH, Ko KS, Lee KU, Taskforce Team of Diabetes Fact Sheet of the Korean Diabetes Association. Data analytic process of a nationwide population-based study using National Health Information Database Established by National Health Insurance Service. Diabetes Metab. J. 2016;40:79–82. doi: 10.4093/dmj.2016.40.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Lee KR, Hwang IC, Han KD, Jung J, Seo MH. Waist circumference and risk of breast cancer in Korean women: a nationwide cohort study. Int. J. Cancer. 2018;142:1554–1559. doi: 10.1002/ijc.31180. [DOI] [PubMed] [Google Scholar]
  • 43.Choi YJ, Lee DH, Han KD, Kim HS, Yoon H, Shin CM, et al. The relationship between drinking alcohol and esophageal, gastric or colorectal cancer: a nationwide population-based cohort study of South Korea. PLoS ONE. 2017;12:e0185778. doi: 10.1371/journal.pone.0185778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Lee JH, Kim HJ, Han KD, Kim HN, Park YM, Lee JY, et al. Cancer risk in 892 089 patients with psoriasis in Korea: a nationwide population-based cohort study. J. Dermatol. 2019;46:95–102. doi: 10.1111/1346-8138.14698. [DOI] [PubMed] [Google Scholar]
  • 45.Shin DW, Cho B, Guallar E. Korean national health insurance database. JAMA Intern. Med. 2016;176:138. doi: 10.1001/jamainternmed.2015.7110. [DOI] [PubMed] [Google Scholar]
  • 46.Cheol Seong S, Kim YY, Khang YH, Heon Park J, Kang HJ, Lee H, et al. Data resource profile: The National Health Information Database of the National Health Insurance Service in South Korea. Int. J. Epidemiol. 2017;46:799–800. doi: 10.1093/ije/dyw253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Brenner AV, Wang Z, Kleinerman RA, Lei S, Metayer C, Wang W, et al. Menstrual and reproductive factors and risk of lung cancer among Chinese women, Eastern Gansu Province, 1994-1998. J. Epidemiol. 2003;13:22–28. doi: 10.2188/jea.13.22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Pesatori AC, Carugno M, Consonni D, Caporaso NE, Wacholder S, Tucker M, et al. Reproductive and hormonal factors and the risk of lung cancer: the EAGLE study. Int. J. Cancer. 2013;132:2630–2639. doi: 10.1002/ijc.27926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Lim WY, Chen Y, Chuah KL, Eng P, Leong SS, Lim E, et al. Female reproductive factors, gene polymorphisms in the estrogen metabolism pathway, and risk of lung cancer in Chinese women. Am. J. Epidemiol. 2012;175:492–503. doi: 10.1093/aje/kwr332. [DOI] [PubMed] [Google Scholar]
  • 50.Koushik A, Parent ME, Siemiatycki J. Characteristics of menstruation and pregnancy and the risk of lung cancer in women. Int. J. Cancer. 2009;125:2428–2433. doi: 10.1002/ijc.24560. [DOI] [PubMed] [Google Scholar]
  • 51.Schwartz AG, Wenzlaff AS, Prysak GM, Murphy V, Cote ML, Brooks SC, et al. Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in women. J. Clin. Oncol. 2007;25:5785–5792. doi: 10.1200/JCO.2007.13.3975. [DOI] [PubMed] [Google Scholar]
  • 52.Zatloukal P, Kubik A, Pauk N, Tomasek L, Petruzelka L. Adenocarcinoma of the lung among women: risk associated with smoking, prior lung disease, diet and menstrual and pregnancy history. Lung Cancer. 2003;41:283–293. doi: 10.1016/s0169-5002(03)00234-4. [DOI] [PubMed] [Google Scholar]
  • 53.Kreuzer M, Gerken M, Heinrich J, Kreienbrock L, Wichmann HE. Hormonal factors and risk of lung cancer among women? Int. J. Epidemiol. 2003;32:263–271. doi: 10.1093/ije/dyg064. [DOI] [PubMed] [Google Scholar]
  • 54.Seow A, Poh WT, Teh M, Eng P, Wang YT, Tan WC, et al. Diet, reproductive factors and lung cancer risk among Chinese women in Singapore: evidence for a protective effect of soy in nonsmokers. Int. J. Cancer. 2002;97:365–371. doi: 10.1002/ijc.1615. [DOI] [PubMed] [Google Scholar]
  • 55.Paulus JK, Asomaning K, Kraft P, Johnson BE, Lin X, Christiani DC. Parity and risk of lung cancer in women. Am. J. Epidemiol. 2010;171:557–563. doi: 10.1093/aje/kwp441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Matsuo K, Ito H, Yatabe Y, Hiraki A, Hirose K, Wakai K, et al. Risk factors differ for non-small-cell lung cancers with and without EGFR mutation: assessment of smoking and sex by a case-control study in Japanese. Cancer Sci. 2007;98:96–101. doi: 10.1111/j.1349-7006.2006.00347.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Gao YT, Blot WJ, Zheng W, Ershow AG, Hsu CW, Levin LI, et al. Lung cancer among Chinese women. Int. J. Cancer. 1987;40:604–609. doi: 10.1002/ijc.2910400505. [DOI] [PubMed] [Google Scholar]
  • 58.Dahabreh IJ, Trikalinos TA, Paulus JK. Parity and risk of lung cancer in women: systematic review and meta-analysis of epidemiological studies. Lung Cancer. 2012;76:150–158. doi: 10.1016/j.lungcan.2011.10.014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Pesatori AC, Carugno M, Consonni D, Hung RJ, Papadoupolos A, Landi MT, et al. Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO) Br. J. Cancer. 2013;109:1954–1964. doi: 10.1038/bjc.2013.506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Bae JM, Kim EH. Hormonal replacement therapy and the risk of lung cancer in women: an adaptive meta-analysis of cohort studies. J. Prev. Med. Public Health. 2015;48:280–286. doi: 10.3961/jpmph.15.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Wu W, Yin ZH, Guan P, Ren YW, Zhou BS. Association of oral contraceptives use and lung cancer risk among women: an updated meta-analysis based on cohort and case-control studies. Asian Pac. J. Cancer Prev. 2014;15:1205–1210. doi: 10.7314/apjcp.2014.15.3.1205. [DOI] [PubMed] [Google Scholar]
  • 62.Jung-Choi KH, Khang YH, Cho HJ. Hidden female smokers in Asia: a comparison of self-reported with cotinine-verified smoking prevalence rates in representative national data from an Asian population. Tob. Control. 2012;21:536–542. doi: 10.1136/tobaccocontrol-2011-050012. [DOI] [PubMed] [Google Scholar]
  • 63.Hitchman SC, Fong GT. Gender empowerment and female-to-male smoking prevalence ratios. Bull. World Health Organ. 2011;89:195–202. doi: 10.2471/BLT.10.079905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Ryberg D, Hewer A, Phillips DH, Haugen A. Different susceptibility to smoking-induced DNA damage among male and female lung cancer patients. Cancer Res. 1994;54:5801–5803. [PubMed] [Google Scholar]
  • 65.Thomas L, Doyle LA, Edelman MJ. Lung cancer in women: emerging differences in epidemiology, biology, and therapy. Chest. 2005;128:370–381. doi: 10.1378/chest.128.1.370. [DOI] [PubMed] [Google Scholar]
  • 66.Dogan S, Shen R, Ang DC, Johnson ML, D’Angelo SP, Paik PK, et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin. Cancer Res. 2012;18:6169–6177. doi: 10.1158/1078-0432.CCR-11-3265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Lindgren A, Pukkala E, Nissinen A, Tuomilehto J. Blood pressure, smoking, and the incidence of lung cancer in hypertensive men in North Karelia, Finland. Am. J. Epidemiol. 2003;158:442–447. doi: 10.1093/aje/kwg179. [DOI] [PubMed] [Google Scholar]
  • 68.Stocks T, Van Hemelrijck M, Manjer J, Bjorge T, Ulmer H, Hallmans G, et al. Blood pressure and risk of cancer incidence and mortality in the Metabolic Syndrome and Cancer Project. Hypertension. 2012;59:802–810. doi: 10.1161/HYPERTENSIONAHA.111.189258. [DOI] [PubMed] [Google Scholar]
  • 69.Inoue M, Noda M, Kurahashi N, Iwasaki M, Sasazuki S, Iso H, et al. Impact of metabolic factors on subsequent cancer risk: results from a large-scale population-based cohort study in Japan. Eur. J. Cancer Prev. 2009;18:240–247. doi: 10.1097/CEJ.0b013e3283240460. [DOI] [PubMed] [Google Scholar]
  • 70.Rosengren A, Himmelmann A, Wilhelmsen L, Branehog I, Wedel H. Hypertension and long-term cancer incidence and mortality among Swedish men. J. Hypertens. 1998;16:933–940. doi: 10.1097/00004872-199816070-00006. [DOI] [PubMed] [Google Scholar]
  • 71.Tulinius H, Sigfusson N, Sigvaldason H, Bjarnadottir K, Tryggvadottir L. Risk factors for malignant diseases: a cohort study on a population of 22,946 Icelanders. Cancer Epidemiol. Biomark. Prev. 1997;6:863–873. [PubMed] [Google Scholar]
  • 72.Grove JS, Nomura A, Severson RK, Stemmermann GN. The association of blood pressure with cancer incidence in a prospective study. Am. J. Epidemiol. 1991;134:942–947. doi: 10.1093/oxfordjournals.aje.a116178. [DOI] [PubMed] [Google Scholar]
  • 73.Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ. 2018;363:k4209. doi: 10.1136/bmj.k4209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women’s Health Initiative randomized trials. JAMA. 2013;310:1353–1368. doi: 10.1001/jama.2013.278040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Chlebowski RT, Anderson GL, Manson JE, Schwartz AG, Wakelee H, Gass M, et al. Lung cancer among postmenopausal women treated with estrogen alone in the women’s health initiative randomized trial. J. Natl. Cancer Inst. 2010;102:1413–1421. doi: 10.1093/jnci/djq285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 76.Wang A, Kubo J, Luo J, Desai M, Hedlin H, Henderson M, et al. Active and passive smoking in relation to lung cancer incidence in the Women’s Health Initiative Observational Study prospective cohort. Ann. Oncol. 2015;26:221–230. doi: 10.1093/annonc/mdu470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Kurahashi N, Inoue M, Liu Y, Iwasaki M, Sasazuki S, Sobue T, et al. Passive smoking and lung cancer in Japanese non-smoking women: a prospective study. Int. J. Cancer. 2008;122:653–657. doi: 10.1002/ijc.23116. [DOI] [PubMed] [Google Scholar]
  • 78.Trichopoulos D, Kalandidi A, Sparros L, MacMahon B. Lung cancer and passive smoking. Int. J. Cancer. 1981;27:1–4. doi: 10.1002/ijc.2910270102. [DOI] [PubMed] [Google Scholar]
  • 79.Xue Y, Jiang Y, Jin S, Li Y. Association between cooking oil fume exposure and lung cancer among Chinese nonsmoking women: a meta-analysis. Onco Targets Ther. 2016;9:2987–2992. doi: 10.2147/OTT.S100949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Janerich DT, Thompson WD, Varela LR, Greenwald P, Chorost S, Tucci C, et al. Lung cancer and exposure to tobacco smoke in the household. N. Engl. J. Med. 1990;323:632–636. doi: 10.1056/NEJM199009063231003. [DOI] [PubMed] [Google Scholar]
  • 81.Osann KE. Lung cancer in women: the importance of smoking, family history of cancer, and medical history of respiratory disease. Cancer Res. 1991;51:4893–4897. [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Table 1 (20.9KB, docx)
Supplementary Table 2 (23.9KB, docx)

Data Availability Statement

The data that support the findings of this study are available from NHIS. Restrictions apply to the availability of these data, which were used under license for this study. Data are available at https://nhiss.nhis.or.kr with the permission of NIHS.

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES