Never-smoking Women Research Articles

Phytoestrogens and lung cancer risk: a nested case-control study in never-smoking Chinese women

Since several lines of evidence suggest that estrogens may be involved in lung carcinogenesis, it has been hypothesized that intake of phytoestrogens, similar in molecular structure to mammalian estrogens, may be associated with lung cancer development. The aim was to prospectively evaluate the association between phytoestrogen exposure and lung cancer risk in never-smoking women. We conducted a nested case-control study within a population-based prospective cohort study of women. A total of 478 incident lung cancer cases and their individually matched controls were identified among never-smoking women after a mean follow-up of 15.6 years. Habitual intake of and internal exposure to phytoestrogens were assessed by repeated dietary surveys and urinary biomarkers, respectively. ORs and 95% CIs for lung cancer were estimated in conditional logistic regression models. After adjustment for potential confounders, a moderate intake of dietary isoflavones was inversely associated with lung cancer risk in never-smoking women, with the OR for the second quartile vs. the lowest quartile of intake being 0.52 (95% CI: 0.35, 0.76). Further increasing intake did not convey additional benefits, with ORs (95% CI) for the third and fourth quartiles of 0.53 (0.36, 0.78) and 0.47 (0.31, 0.72), respectively (P-overall<0.001 and P-nonlinearity=0.006). A similar association was seen when exposure to isoflavones was assessed by urinary biomarkers. ORs (95% CI) for the second, third, and fourth quartiles compared with the lowest quartile of urinary isoflavone excretion were 0.57 (0.39, 0.83), 0.64 (0.44, 0.92), and 0.60 (0.41, 0.86), respectively. The inverse association reached a plateau beyond the second quartile, with P-overall=0.04 and P-nonlinearity=0.15. Urinary excretion of gut-microbiota-derived metabolites of lignans was not related to lung cancer risk. This study suggests that moderately increasing intake of isoflavone-rich foods is associated with lower risk of lung cancer in never-smoking women.

Anthropometric Measures and Risk of Rheumatoid Arthritis in the French E3N Cohort Study.

We aimed to assess the relationships between anthropometric measures and risk of rheumatoid arthritis (RA). The E3N cohort included 98,995 women (aged 40–65 years at the recruitment) who completed mailed questionnaires on reproductive factors, lifestyle, and health-related information, including anthropometric measures, every 2–3 years. Cox proportional hazards regression models with age as the time scale and adjusted on known RA risk factors were used to estimate hazard ratios (HRs) and 95% confidence intervals for the risk of incident RA in the overall population (n = 78,452) and after stratification on smoking exposure. Incident RA diagnosis was validated in 698 women. Abdominal obesity (waist circumference >88 cm) was associated with RA (HR = 1.2 (1.0–1.5)), independent of BMI; whereas obesity, defined as BMI ≥ 30 kg/m2, was marginally associated with RA (HR = 1.26 (0.9–1.5), ptrend = 0.0559). Taking lean body shape (BS) as reference, medium BS at puberty (HR = 1.3 (1.0–1.7)) and medium-large BS at perimenopausal period (HR = 1.5 (1.1–1.9)) were associated with the risk of RA among never-smoker women, independent of BMI. Regarding BS trajectory, taking constantly lean BS as reference, constantly large BS from puberty to perimenopause was associated with RA among non-smokers (HR = 2.10 (1.2–3.6)), independent of BMI.

Programmed Death Ligand 2 Gene Polymorphisms Are Associated With Lung Adenocarcinoma Risk in Female Never-Smokers.

ObjectivesLung cancer in never-smokers is a distinct disease associated with a different genomic landscape, pathogenesis, risk factors, and immune checkpoint inhibitor responses compared to those observed in smokers. This study aimed to identify novel single nucleotide polymorphisms (SNPs) of programmed death-1 (encoded by PDCD1) and its ligands, programmed death ligand 1 (CD274) and 2 (PDCD1LG2), associated with lung cancer risk in never-smoking women.Materials and MethodsDuring September 2002 and July 2012, we enrolled never-smoking female patients with lung adenocarcinoma (LUAD) (n=1153) and healthy women (n=1022) from six tertiary hospitals in Taiwan. SNP data were obtained and analyzed from the genome-wide association study dataset and through an imputation method. The expression quantitative trait loci (eQTL) analysis was performed in both tumor and non-tumor tissues for the correlation between genetic expression and identified SNPs.ResultsA total of 12 PDCD1LG2 SNPs related to LUAD risk were identified in never-smoking women, including rs2381282, rs4742103, rs4237162, rs4742104, rs12237624, rs78096119, rs6476988, rs7857315, rs10975178, rs7854413, rs56001683, and rs7858319. Among them, six tagged PDCD1LG2 SNPs rs2381282, rs4742103, rs4237162, rs4742104, rs78096119, and rs56001683 were significantly associated with LUAD risk. Specifically, two PDCD1LG2 SNPs, rs12237624 and rs78096119, were associated with previous pulmonary tuberculosis infection in relation to LUAD susceptibility. Through an eQTL assay, we found that rs2381282 (p < 0.001), rs12237624 (p = 0.019), and rs78096119 (p = 0.019) were associated with the expression levels of programed death ligand 2.ConclusionsNovel SNPs of programed death ligand 2 associated with lung adenocarcinoma risk were identified. Among them, two SNPs were associated with pulmonary tuberculosis infection in relation to lung adenocarcinoma susceptibility. These SNPs may help to stratify high-risk populations of never-smokers during lung cancer screening.

Never-smokers and the fraction of breast cancer attributable to second-hand smoke from parents during childhood: the Norwegian Women and Cancer Study 1991-2018.

BackgroundSecond-hand smoke (SHS) is not an established risk factor for breast cancer. We examined exposure to SHS from parents during childhood and breast-cancer risk overall and by oestrogen- and progesterone-receptor status in the Norwegian Women and Cancer Study. Furthermore, we utilized our nationally representative prospective cohort study to estimate the fraction of breast cancer attributable to parental SHS during childhood.MethodsWe followed 45 923 never-smoking women, aged 34–70 years, who completed a baseline questionnaire between 1991 and 2007 through linkages to national registries through December 2018. We used Cox proportional-hazards models to estimate age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). We estimated the attributable and the population attributable fraction of breast cancer with 95% CIs.ResultsDuring a mean follow-up of 19.8 (6.8) years, 2185 women developed invasive breast cancer, confirmed by histology. Women exposed to SHS from parents during childhood had an 11% higher (95% CI: 1.02–1.22) risk of breast cancer compared with those who were not. No difference was found for oestrogen (Pheterogeneity = 0.31) and progesterone (Pheterogeneity = 0.95) receptor status. For women exposed, the attributable fraction was 10.3% (95% CI: 1.8–18.0), whereas the population attributable fraction of breast cancer was 7.0% (95% CI: 1.0–13.0).ConclusionsOur results suggest that 1 in 14 breast-cancer cases could have been avoided in the absence of SHS exposure from parents during childhood in a population of never-smoking women. The cancer burden attributable to SHS may be underestimated.

Abstract 2214: The genomic landscape of lung cancer in post-menopausal never-smoker women

Abstract Lung cancer is the deadliest form of cancer worldwide. Cigarette smoking is the primary risk factor for developing lung cancer, fueling global tobacco cessation programs. In the United States, it is projected that by 2065 there will be a 63% reduction in smoking-associated lung cancer burden. However, even with this decline, lung cancer will still account for a significant proportion of cancer-associate mortality, suggesting that factors beyond smoking contribute to lung tumorigenesis. Lung cancer in never smokers is a distinct sub-group that needs specific exploration. It is the 7th highest cause of cancer-deaths worldwide, with an increasing trend in its incidence. Thus far, the majority of tumor genome-wide sequencing efforts in lung cancer have been focused on patient cohorts with a smoking history. We know that LCNS is distinct from lung adenocarcinoma found in smokers at the genetic level, however large gaps in our understanding of this population persist. Through a unique collaboration with the Women's Health Initiative (WHI) we now have access to a large repository of tumor tissue from LCNS patients. We have performed exome-sequencing on this cohort and here we describe novel mutations, structural variants and copy number changes in this cohort. Whole-exome sequencing of 75 tumor-normal pairs was performed. Mutations were identified for the entire cohort using different computational methods. For the identification of single nucleotide variants a consensus dual-caller and filtering methodology was employed. Variants were then analyzed to identify genes with significant mutations using MutSig2CV. Structural variant analysis was performed using SvABA and copy number analysis was performed using TITAN. Finally, we perform correlative analysis of mutations with the metadata curated by the WHI and highlight key features of this cohort. Our mutational analysis reveals showed that there is an enrichment of known oncogenes including KRAS, EGFR and TP53. Additionally, we identified mutations in STK11. Here we describe novel genes and mutations previously unknown to occur in LCNS cohort and describe their potential functional implications. We also report novel structural variants and copy number alterations. Additionally we performed mutational signature analysis and identified novel signatures specific to this cohort. Mutational analysis of our LCNS cohort reveals that this cohort in general has a lower tumor mutational burden compared to their control cohort with a history of smoking. Additionally, we find that this cohort has mutations that have been previously reported in studies in LCNS patients. However, the existence of novel mutations and structural alterations may offer a unique opportunity for future target identification and therapeutic intervention. Citation Format: Sitapriya Moorthi, Amy Paguirigan, Garnet Anderson, Gavin Ha, Alice Berger. The genomic landscape of lung cancer in post-menopausal never-smoker women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2214.

Reproductive Factors and Lung Cancer Risk among Never-Smoking Japanese Women with 21 Years of Follow-Up: A Cohort Study.

Previous studies have reported inconsistent associations between reproductive factors and lung cancer. We used data from the Japan Public Health Center-based Prospective Study, which included 400 incident lung cancer cases (305 adenocarcinoma) among 42,615 never-smoking women followed for a median of 21 years, to examine the associations of reproductive and hormonal factors with lung cancer by histological type using Cox proportional hazards models. Longer fertility span (≥36 years vs. ≤32 years) was associated with increased risk of lung adenocarcinoma (HR, 1.48; 95% CI, 1.07-2.06, P trend = 0.01) but not with all lung cancer or nonadenocarcinoma. Similarly, late age at menopause (≥ 50 years) was associated with increased adenocarcinoma risk (vs. ≤ 47 years, HR, 1.41; 95% CI, 1.01-1.96, P trend 0.04). Compared with premenopausal women, women with natural menopause (HR, 1.99; 95% CI, 1.02-3.88) or surgical menopause (HR, 2.75; 95% CI, 1.33-5.67) were at increased risk of adenocarcinoma. In contrast, breastfeeding was associated with reduced risk of nonadenocarcinoma (HR, 0.51; 95% CI, 0.28-0.92). No significant association with parity, age at first birth, exogenous hormone use, or length of menstrual cycle was detected. Reproductive factors may play a role in lung carcinogenesis. Future studies that include estrogen and progesterone biomarkers may help clarify the role of endogenous hormones in lung carcinogenesis. Fertility span and age at menopause may be useful variables in developing risk prediction models for lung adenocarcinoma among nonsmoking women.

Lung Cancer Characteristics in the World Trade Center Environmental Health Center.

The destruction of the World Trade Center (WTC) towers on 11 September 2001 resulted in acute and chronic dust and fume exposures to community members, including local workers and residents, with well-described aerodigestive adverse health effects. This study aimed to characterize lung cancer in the WTC Environmental Health Center (WTC EHC) focusing on gender and smoking history. WTC EHC patients undergo an initial evaluation that includes WTC exposure information, demographics, and tobacco use. Detailed cancer characteristics are recorded from pathology reports. As of 31 December 2019, 248 WTC EHC patients had a diagnosis of lung cancer. More patients with lung cancer were women (57%) compared to men (43%). Many cases (47% women, 51% men) reported acute dust cloud exposure. Thirty-seven percent of lung cancer cases with available smoking history were never-smokers (≤1 pack-years) and 42% had a ≤5 pack-year history. The median age of cancer diagnosis in never-smoking women was 61 years compared to 66 years in men. Adenocarcinoma was more common in never-smokers compared to ever-smokers (72% vs. 65%) and in women compared to men (70% vs. 65%). We provide an initial description of lung cancers in local community members with documented exposure to the WTC dust and fumes.

P88.03 Asymptomatic COVID-19 in a ROS1 positive Non Small Cell Lung Cancer.

COVID-19 pandemic has led to reconsider the traditional management approach in lung cancer. Oral tyrosine kinase inhibitors (TKIs) are being preferred in oncogene addicted advanced non-Small Cell Lung Cancer. A young never-smoker woman presented with left hilar mass with left pleural effusion in February 2020. There was an incidental detection of thrombus in right main and descending pulmonary artery. She was diagnosed to have ROS1 rearranged advanced NSCLC with pulmonary embolism. She was initiated on conventional chemotherapy with carboplatin and pemetrexed along with anticoagulation. After fourth cycle of chemotherapy, although there was clinical improvement attributed to reduction of amount of effusion and disappearance thrombus, RECIST 1.1 criteria suggested the progression of disease in view of appearance of adrenal metastasis. Meanwhile, she had a history of high risk exposure with a patient of COVID- 19 in July 2020. Although she was asymptomatic, RT- PCR for SARS-COV2 came out to be positive. She remained asymptomatic for next 10 days during hospitalization. Then she was started on Crizotinib and was discharged with advice on further follow up. Although patients on cancer chemotherapy are at high risk of severe COVID-19 diseases, asymptomatic cases can happen. The patients preferably should be shifted to or started on oral TKIs as per available expert recommendations.

Association between sex hormones regulation-related SNP rs12233719 and lung cancer risk among never-smoking Chinese women.

BackgroundThe mechanism of rapidly increased non‐small cell lung cancer (NSCLC) among never‐smoking Chinese women has not been elucidated. Ovarian sex steroid hormones have been suggested to counteract lung cancer development, and sex hormone‐binding globulin (SHBG) is essential in sex hormones regulation. This study aims to exploring single nucleotide polymorphisms (SNPs) in genomic regions associated with SHBG concentrations that contributed to never‐smoking female NSCLC.MethodsCandidate genes were selected by a genome‐wide association (GWAS) meta‐analysis and gene expression profiles of never‐smoking NSCLC of Chinese women. The candidate SNPs limited to common minor allele frequency (MAF), missense variant, ethnic heterogeneous distribution, and SNPs were genotyped using the TaqMan method. A two‐stage case‐control design was adopted for exploration and validation of associations between candidate SNPs and risk of NSCLC. All participants were never‐smoking Chinese women. Chi‐square test and multivariate logistic regression were applied.ResultsBeginning with 12 genomic regions associated with circulating SHBG concentrations and gene expression profiles from never‐smoking NSCLC in Chinese women, candidate SNP rs12233719 and rs7439366 both located in candidate gene UGT2B7, which may be related to circulating SHBG concentrations and cancer risk, were identified. A two‐stage case‐control study was conducted in Shenyang and Tianjin represented as the training stage and validation stage, respectively. Under the dominant model, compared to individuals with the wild G/G genotype, the adjusted OR of those with the T allele was 1.58 (95% CI: 1.15–2.16) in Chinese Shenyang training set, and was 1.49 (95% CI: 1.02–2.18) in Chinese Tianjin validation set, both accompanied with a significant trend relationship consistently. UGT2B7 was upregulated in female NSCLC patients’ tumor tissues and was associated with a poor prognosis in NSCLC.ConclusionOur findings indicated that a sex hormones regulation‐related SNP rs12233719 was associated with never‐smoking female lung cancer risk, which might partially explain NSCLC‐susceptibility in Chinese women.

Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

Characteristics associated with feeding organic foods during complementary feeding: the nationwide Étude Longitudinale Française depuis l'Enfance (ELFE) birth cohort.

Organic food consumption and its effects on health remain understudied in adults and in children. The aim of this study was to describe family characteristics associated with feeding infants organic foods during the complementary feeding period. The analysis included 9764 children from the French Étude Longitudinale Française depuis l'Enfance (ELFE) birth cohort. In addition to telephone interviews conducted at 2, 12 and 24 months, a monthly questionnaire about milk feeding and complementary foods (including organic foods) was completed by parents between 3 and 10 months. Associations between family characteristics and feeding with organic foods during complementary feeding were analysed by multivariable multinomial logistic regression. Overall, 51 % of infants never consumed organic food during the complementary feeding period (up to 10 months), 24 % sometimes, 15 % often and 9 % always or almost always. As compared with infants never fed organic foods, those 'often' or 'always' fed organic foods were born to older mothers, with higher education level or family income, and lower pre-pregnancy BMI. As compared with never-smoking women, women who had stopped smoking before pregnancy were more likely to feed their infant organic foods. Feeding with organic foods was also related to long breast-feeding duration and later introduction to complementary foods. To conclude, associations between feeding with organic foods and family socio-economic position as well as infant feeding practices need to be considered when studying the impact of organic foods on children's health and development.

Passive smoking and type2 diabetes among never-smoking women: The Japan Public Health Center-based Prospective Study.

Aims/IntroductionThe aim of the current study was to prospectively evaluate the association between passive smoking from a spouse and the risk of diabetes among never‐smoking Japanese women. Passive smoking at a workplace (or public facilities) was assessed as a secondary measure.Materials and MethodsIn the Japan Public Health Center‐based Prospective Study (baseline 1990 or 1993), we followed 25,391 never‐smoking women aged 40–69 years and without diabetes. Passive smoking was defined as having a husband who was a self‐reported smoker, and the exposure at a workplace (or public facilities) was self‐reported by women. The development of diabetes was identified in questionnaires administered at the 5‐year and 10‐year surveys. A pooled logistic regression model was used to assess the association between passive smoking and the development of diabetes with adjustment for age and possible confounders.ResultsCompared with women whose husbands had never smoked, women whose husband smoked ≥40 cigarettes/day had significantly higher odds of developing diabetes in an age‐adjusted model, but the association was attenuated in a multivariable model (odds ratio 1.34, 95% confidence interval 0.96–1.87). There was a dose–response trend between the number of cigarettes smoked by a husband and the odds of developing diabetes (P = 0.02). Women reporting daily passive smoking at a workplace (or public facilities) had higher odds of developing diabetes than women reporting no such exposure (odds ratio 1.23, 95% confidence interval 0.995–1.53).ConclusionsOur results indicated a higher risk of diabetes among never‐smoking Japanese women with higher exposure to passive smoking from a spouse.

Prise en charge d’un patient par traitement combiné d’une double anomalie EGFR et MET

Lung cancer displays molecular anomalies for which targeted therapies are the standard first line treatment. The EGFR mutation is present in 10% of cases of non-small cell lung cancer in Caucasians. MET amplification associated with an exon 19 EGFR mutation has been identified though it is usually regarded as a mechanism of resistance. We report the case of a 74-year-old never-smoking woman who was diagnosed with stage IV bronchial adenocarcinoma showing both EGFR mutation and MET amplification. Initial treatment with gefitinib did not control the disease. Platinum-based chemotherapy with pemetrexed maintenance allowed a temporary response. Treatment with durvalumab for 27 months was associated with disease stability. Single agent crizotinib was associated with a slight response followed by progression. The concomitant introduction of crizotinib and gefitinib led to a spectacular and durable response with no safety issues. This case highlights the efficacy of concomitant treatment in a patient with two oncogenic drivers.

Prevalence, knowledge and education level associated with secondhand smoke exposure among never-smoking women in Inner Mongolia, Northern China.

INTRODUCTIONCurrently, 40.7% of women in China are exposed daily to secondhand smoke (SHS); however, research on SHS exposure among women in Inner Mongolia is limited. We aimed to investigate the prevalence of SHS exposure, knowledge about the harms of smoking and SHS, and the association between sociodemographic factors and SHS exposure among never-smoking women in Inner Mongolia, Northern China.METHODSThis study was based on a survey of chronic disease and nutrition conducted among Chinese adults in Inner Mongolia during 2015, a cross-sectional study with multi-stage stratified cluster sampling. A total 2293 never-smoking women aged ≥18 years were included in the study. Face-to-face interviews were used to collect data of sociodemographic characteristics, SHS exposure, and related knowledge. Questionnaires were administered by trained investigators, and the reliability and validity of the questionnaires were high. We performed descriptive analysis and logistic regression. All analyses were performed by IBM SPSS Statistics version 19.0.RESULTSOf the total, 69% of young women in Inner Mongolia in 2015 reported that they were exposed to SHS, the highest rate in comparison with older and middle-aged women. A total 49.90% of young women reported being exposed to SHS every day. Respondents had insufficient knowledge regarding smoking and SHS exposure. Compared with older never-smoking women, their young counterparts had a higher risk of SHS exposure, with an odds ratio of 2.143 (95% CI: 1.647–2.787). Education level and ethnicity were also significantly associated with SHS exposure.CONCLUSIONSThis study showed that the highest rates of SHS exposure were among young never-smoking women in Inner Mongolia, and women with high education levels were less likely to be exposed to SHS. Improved public health information is needed that prioritizes SHS exposure among young women in Inner Mongolia. Health education regarding SHS exposure should be widely implemented throughout communities in this region.

Risk factors for primary lung cancer among never-smoking women in South Korea: a retrospective nationwide population-based cohort study.

Background/AimsWe performed a large-scale, retrospective, nationwide, cohort study to investigate the risk factors for lung cancer among never-smoking Korean females.MethodsThe study data were collected from a general health examination and questionnaire survey of eligible populations conducted between January 1, 2003 and December 31, 2004; the data were acquired from the tailored big data distribution service of the National Health Insurance Service. After a 1-year clearance period, 5,860,922 of 6,318,878 never-smoking female participants with no previous history of lung cancer were investigated. After a median follow-up of 11.4 years, 43,473 (0.74%) participants were defined as “newly diagnosed lung cancer”.ResultsAfter adjusting for all variables at baseline, the variables older age, lower body mass index (BMI), less exercise, frequent alcohol drinking, meat-based diet, rural residence, and previous history of cancer were associated with a higher incidence of lung cancer. Low BMI (< 18.5 kg/m2: hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.27 to 1.40) was a significant independent risk factor; as BMI decreased, HR increased. Negative associations between BMI and lung-cancer development were also observed after controlling for age (p for trend < 0.001). Drinking alcohol one to two times a week (HR, 1.25; 95% CI, 1.21 to 1.28) and eating a meat-based diet (HR, 1.08; 95% CI, 1.01 to 1.15) were associated with lung-cancer incidence.ConclusionsModifiable baseline characteristics, such as BMI, exercise, alcohol consumption, and diet, are risk factors for lung-cancer development among never- smoking females. Thus, lifestyle modifications may help prevent lung cancer.

Is second hand smoking associated with atrial fibrillation risk among women in Israel? A case-control study.

The first complete ban on indoor smoking in all public spaces (including bars and restaurants) occurred in 1994 in Israel, because of clear scientific evidence that SHS (Second Hand Smoking) is dangerous to non-smokers. Despite the smoking-ban law warning about the dangers of smoking, SHS remains in houses. The role of cigarette smoking on cardiac arrhythmia is less clearly defined and secondhand smoke (SHS) impact on the risk of atrial fibrillation (AF) remains unknown. The aim of this study was to evaluate the relationship between SHS and AF risk in Israeli women. This was a population-based case-control study consisting of never-smoking women aged 30-80 from Israel: 102 cases (diagnosed) of AF and 109 population- based controls. All participants were interviewed using a socio-demographic questionnaire that also related to past and current exposure to SHS. SHS was associated with AF risk with adjusted odds ratio (OR) of 3.81 (95% confidence interval, CI 2.02-7.18). Higher exposure to SHS was associated with higher risk of AF compared to never-exposed women. Those exposed to SHS during one, two, or three life-periods (childhood, adolescence or adulthood) had an OR of 1.71 (95% CI 0.76-3.86), 2.87 (95% CI 1.25-6.56), and 9.14 (95% CI 4.09-20.44), respectively. Moreover, exposure to one pack/day increased the risk of AF by 2.89 times compared to 'never exposed' (95% CI 2.05-4.09). SHS exposure in women who never smoked is associated with increased risk for AF.

A20 Estrogen Metabolism in Patients with EGFR-Mutated and ALK-Mutated Non-Small Cell Lung Cancer (NSCLC)

Prior studies have shown that the human lung can extensively metabolize estrogen to reactive catechols. Of greatest concern is 4-hydroxyestrogen (4-OHE), a putative carcinogen, produced by cytochrome P450 1B1 (CYP1B1). In contrast, CYP1A1 metabolizes parent estrogens to 2-hydroxyestrogen (2-OHE), which are less reactive and converted to derivatives that may be antiproliferative. Data from this group strongly suggest that 4-OHE contributes to lung tumorigenesis, though its role in driver-mutated NSCLC has not been investigated. This study assessed estrogen metabolite profiles in EGFR-mutated and ALK-mutated NSCLC patients as compared to cancer-free subjects. Advanced-stage NSCLC patients with tumors that possessed either an EGFR (n = 14) or ALK (n = 8) mutation and cancer-free subjects (n = 17) were recruited from Fox Chase Cancer Center. Tumor mutation status of NSCLC patients was determined by tissue biopsy. All study participants were 50 years of age or older to circumvent any confounding influence of young age or premenopausal status on estrogen levels. NSCLC patients included 14 females and 8 males. Cancer-free subjects serving as controls were never-smoking women. Urine specimens were collected from study participants and urinary estrogen species (E1, E2, E3, 4-OHEs, 2-OHEs, 2-OMEs) were quantified using UPLC-MS/MS. Medians were calculated and the Wilcoxon rank-sum test was used to compare estrogen metabolite measures (4-OHEs/total estrogen, 2-OHE/total estrogen, and the ratio of 4-OHEs/2-OHEs) between NSCLC patients and control subjects. EGFR-mutated NSCLC patients had a significantly higher proportion of 4-OHEs/total estrogen (0.18 vs. 0.05, p-value = 0.048) and a trend towards lower 2-OHEs/total estrogen (0.18 vs. 0.26, p-value = 0.084) as compared to cancer-free control subjects. The ratio of 4-OHEs/2-OHEs was higher in EGFR-mutated NSCLC patients as compared to cancer-free controls (0.90 vs. 0.16, p = 0.053). Differences were not seen between ALK-mutated NSCLC patients and cancer-free subjects for the measures of 4-OHE/total estrogen (0.09 vs. 0.05, p-value = 0.842), 2-OHE/total estrogen (0.20 vs. 0.26, p-value = 0.238), and the ratio of 4-OHEs/2-OHEs (0.34 vs. 0.16, p-value = 0.669). The greater relative level of 4-OHE to 2-OHE in EGFR-mutated NSCLC patients suggests that enhanced production of 4-OHE may contribute to the development of EGFR-mutated lung tumors. Targeting CYP1B1, the enzyme responsible for 4-OHE production, may be of therapeutic interest. Research is ongoing to validate these findings in a larger cohort of EGFR-mutated NSCLC patients.

White Blood Cell Count and Risk of Incident Lung Cancer in the UK Biobank.

The contribution of measurable immunological and inflammatory parameters to lung cancer development remains unclear, particularly among never smokers. We investigated the relationship between total and differential white blood cell (WBC) counts and incident lung cancer risk overall and among subgroups defined by smoking status and sex in the United Kingdom (UK). We evaluated 424 407 adults aged 37-73 years from the UK Biobank. Questionnaires, physical measurements, and blood were administered and collected at baseline in 2006-2010. Complete blood cell counts were measured using standard methods. Lung cancer diagnoses and histological classifications were obtained from cancer registries. Multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals of incident lung cancer in relation to quartiles (Q) of total WBC and subtype-specific counts, with Q1 as the reference. There were 1493 incident cases diagnosed over an average 7-year follow-up. Overall, the highest quartile of total WBC count was statistically significantly associated with elevated lung cancer risk (HRQ4 = 1.67, 95% CI = 1.41 to 1.98). Among women, increased risks were found in current smokers (n cases / n = 244 / 19 464, HRQ4 = 2.15, 95% CI = 1.46 to 3.16), former smokers (n cases / n = 280 / 69 198, HRQ4 = 1.75, 95% CI = 1.24 to 2.47), and never smokers without environmental tobacco smoke exposure (ncases / n = 108 / 111 294, HRQ4 = 1.93, 95% CI = 1.11 to 3.35). Among men, stronger associations were identified in current smokers (ncase s / n = 329 / 22 934, HRQ4 = 2.95, 95% CI = 2.04 to 4.26) and former smokers (nc ases / n = 358/71 616, HRQ4 = 2.38, 95% CI = 1.74 to 3.27) but not in never smokers. Findings were similar for lung adenocarcinoma and squamous cell carcinoma and were driven primarily by elevated neutrophil fractions. Elevated WBCs could potentially be one of many important markers for increased lung cancer risk, especially among never-smoking women and ever-smoking men.

Association of Untargeted Urinary Metabolomics and Lung Cancer Risk Among Never-Smoking Women in China

Chinese women have the highest rate of lung cancer among female never-smokers in the world, and the etiology is poorly understood. To assess the association between metabolomics and lung cancer risk among never-smoking women. This nested case-control study included 275 never-smoking female patients with lung cancer and 289 never-smoking cancer-free control participants from the prospective Shanghai Women's Health Study recruited from December 28, 1996, to May 23, 2000. Validated food frequency questionnaires were used for the collection of dietary information. Metabolomic analysis was conducted from November 13, 2015, to January 6, 2016. Data analysis was conducted from January 6, 2016, to November 29, 2018. Untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry and nuclear magnetic resonance metabolomic profiles were characterized using prediagnosis urine samples. A total of 39 416 metabolites were measured. Incident lung cancer. Among the 564 women, those who developed lung cancer (275 participants; median [interquartile range] age, 61.0 [52-65] years) and those who did not develop lung cancer (289 participants; median [interquartile range] age, 62.0 [53-66] years) at follow-up (median [interquartile range] follow-up, 10.9 [9.0-11.7] years) were similar in terms of their secondhand smoke exposure, history of respiratory diseases, and body mass index. A peak metabolite, identified as 5-methyl-2-furoic acid, was significantly associated with lower lung cancer risk (odds ratio, 0.57 [95% CI, 0.46-0.72]; P < .001; false discovery rate = 0.039). Furthermore, this peak was weakly correlated with self-reported dietary soy intake (ρ = 0.21; P < .001). Increasing tertiles of this metabolite were associated with lower lung cancer risk (in comparison with first tertile, odds ratio for second tertile, 0.52 [95% CI, 0.34-0.80]; and odds ratio for third tertile, 0.46 [95% CI, 0.30-0.70]), and the association was consistent across different histological subtypes and follow-up times. Additionally, metabolic pathway analysis found several systemic biological alterations that were associated with lung cancer risk, including 1-carbon metabolism, nucleotide metabolism, oxidative stress, and inflammation. This prospective study of the untargeted urinary metabolome and lung cancer among never-smoking women in China provides support for the hypothesis that soy-based metabolites are associated with lower lung cancer risk in never-smoking women and suggests that biological processes linked to air pollution may be associated with higher lung cancer risk in this population.

Constituents of Household Air Pollution and Risk of Lung Cancer among Never-Smoking Women in Xuanwei and Fuyuan, China.

Background:Lung cancer rates among never-smoking women in Xuanwei and Fuyuan in China are among the highest in the world and have been attributed to the domestic use of smoky (bituminous) coal for heating and cooking. However, the key components of coal that drive lung cancer risk have not been identified.Objectives:We aimed to investigate the relationship between lifelong exposure to the constituents of smoky coal (and other fuel types) and lung cancer.Methods:Using a population-based case–control study of lung cancer among 1,015 never-smoking female cases and 485 controls, we examined the association between exposure to 43 household air pollutants and lung cancer. Pollutant predictions were derived from a comprehensive exposure assessment study, which included methylated polycyclic aromatic hydrocarbons (PAHs), which have never been directly evaluated in an epidemiological study of any cancer. Hierarchical clustering and penalized regression were applied in order to address high colinearity in exposure variables.Results:The strongest association with lung cancer was for a cluster of 25 PAHs [odds ratio (OR): 2.21; 95% confidence interval (CI): 1.67, 2.87 per 1 standard deviation (SD) change], within which 5-methylchrysene (5-MC), a mutagenic and carcinogenic PAH, had the highest individual observed OR (5.42; 95% CI: 0.94, 27.5). A positive association with nitrogen dioxide () was also observed (OR: 2.06; 95% CI: 1.19, 3.49). By contrast, neither benzo(a)pyrene (BaP) nor fine particulate matter with aerodynamic diameter () were associated with lung cancer in the multipollutant models.Conclusions:To our knowledge, this is the first study to comprehensively evaluate the association between lung cancer and household air pollution (HAP) constituents estimated over the entire life course. Given the global ubiquity of coal use domestically for indoor cooking and heating and commercially for electric power generation, our study suggests that more extensive monitoring of coal combustion products, including methylated PAHs, may be warranted to more accurately assess health risks and develop prevention strategies from this exposure. https://doi.org/10.1289/EHP4913