Lower Risk Of Lung Cancer Research Articles

Adherence to lifelines diet is associated with lower lung cancer risk in 98,459 participants aged 55 years and above: a large prospective cohort study.

Lifelines Diet Score (LLDS) was developed based on the 2015 Dutch Dietary Guidelines and current international scientific evidence. As a dietary quality assessment tool, the LLDS aims to evaluate the association between the Lifeline diet and the risk of chronic diseases. However, the evidence linking LLDS to lung cancer risk is currently limited. Our objective was to explore whether adherence to the LLDS is associated with reduced incidence and mortality of lung cancer, including its major histological subtypes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Data for this research were sourced from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Trial. The LLDS for each participant was calculated based on responses to the dietary history questionnaire (DHQ), and subsequently analyzed after being categorized into quintiles. The Cox proportional hazards regression model was utilized to compute the hazard ratios (HRs) and 95% confidence intervals (CIs) for both the incidence and mortality of lung cancer, SCLC and NSCLC. Additionally, stratified analyses were conducted to ascertain possible effect modifiers, and several sensitivity analyses were performed to evaluate the robustness of the findings. During the mean follow-up periods of 8.8 years for incidence and 15.1 years for mortality, we identified 1,642 new cases and 1,172 related deaths from lung cancer. Participants in the highest quartiles of LLDS compared to those in the lowest exhibited a reduced incidence (HRQ4:Q1 = 0.80, 95% CI = 0.68-0.94, P for trend = 0.003) and mortality (HRQ4:Q1 = 0.81, 95%CI = 0.67-0.98, P for trend = 0.009) of lung cancer. Furthermore, this negative association remained for SCLC incidence (HRQ4:Q1 = 0.55, 95% CI = 0.35-0.87, P for trend = 0.002) and mortality (HRQ4:Q1 = 0.42, 95% CI = 0.25-0.70, P for trend <0.001). The association between LLDS and the incidence and mortality of lung cancer is not influenced by pre-defined potential effect modifiers (all P interaction > 0.05). The sensitivity analyses substantiated the robustness of the results. In conclusion, our research indicates that among 98,459 U.S. adults aged 55 and older, adherence to the LLDS is linked to a diminished incidence and mortality of lung cancer.

P4.04D.04 Efficiency of the Annual CT Screening Interval for Those at a Lower Risk of Lung Cancer - A CISNET Comparative Modelling Study

P4.04D.04 Efficiency of the Annual CT Screening Interval for Those at a Lower Risk of Lung Cancer - A CISNET Comparative Modelling Study

The association between plasma fatty acids and risk of lung cancer: a prospective cohort study of the UK Biobank.

Fatty acids (FAs) have emerged as significant contributors to tumorigenesis, yet prospective evidence regarding their specific effects on lung cancer risk remains scarce. To investigate the association between plasma FAs and lung cancer incidence, as well as a potential modification effect of genetic susceptibility on lung cancer risk. A cohort study was conducted involving 112,547 cancer-free participants from the UK Biobank, with measurements of plasma FAs, including saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) at baseline (2006-2010). Cox regression models were employed to assess lung cancer risk according to plasma FA quartiles or 1-SD increment. Furthermore, interaction between plasma FAs and polygenic risk score (PRS) was evaluated using an additive model. Over an average 10.9-year follow-up, 1122 lung cancer cases occurred. After multivariable adjustment, MUFAs were positively associated with lung cancer risk (hazard ratio [HR] per 1-SD = 1.32, 95% confidence interval [CI]: 1.13-1.54). In contrast, PUFAs, particularly n-3 PUFAs, n-6 PUFAs, docosahexaenoic acid, and linoleic acid, were associated with a lower risk of lung cancer, with HRs ranging from 0.79 (95% CI: 0.72-0.87) to 0.89 (95% CI: 0.83-0.95). SFAs were not significantly associated with lung cancer risk. Moreover, we observed an additive interaction between plasma PUFAs and genetic risk. Individuals with a high genetic risk and the lowest quartile of plasma PUFAs had the highest risk of lung cancer (HR = 2.20, 95% CI: 1.43-3.38). Our findings suggest that plasma PUFAs may serve as protective factors, while MUFAs represent risk factors for lung cancer, offering novel insights into lung cancer carcinogenesis and prevention.

Re-visiting the association between antidepressant use and the risk of lung cancer.

Observational studies suggest a potential correlation between antidepressants and increased lung cancer risks. However, existing studies are limited to small sample sizes, unadjusted covariates especially smoking status, and unclear exposure duration. We performed a large-scale retrospective cohort study to re-examine the association. We analyzed non-smokers and smokers separately to eliminate the confounding effect of smoking status. We found patients with long-term antidepressant use were at a lower risk of lung cancer in both smokers and non-smokers (odds ratio (OR), 0.61; 95% CI: 0.46-0.80, OR: 0.75; 95% CI: 0.65-0.86). None of the antidepressants was associated with an increased lung cancer risk.

Metformin in Chemoprevention of Lung Cancer: A Retrospective Population-Based Cohort Study in Lithuania.

Background and Objectives: This study aimed to evaluate the potential chemopreventive effect of antidiabetic medications, specifically metformin and pioglitazone, on lung cancer in patients with type 2 diabetes mellitus (T2DM). Additionally, the potential dose-response relationship for metformin use was analyzed. Methods: We conducted a retrospective cohort study utilizing comprehensive national health insurance and cancer registry databases to gather a large cohort of T2DM patients. Cox proportional hazards regression models were used to assess the risk of lung cancer across different antidiabetic medication groups, adjusting for potential confounders such as age and gender. A dose-response analysis was conducted for metformin users. Results: Our results indicated that metformin users had a significantly lower lung cancer risk than the reference group (HR = 0.69, 95% CI [0.55-0.86], p = 0.001). The risk reduction increased with higher cumulative metformin doses: a metformin cumulative dose between 1,370,000 and 2,976,000 had an HR of 0.61 (95% CI [0.49-0.75], p < 0.001) vs. cumulative metformin dose >2,976,000 which had an HR of 0.35 (95% CI [0.21-0.59], p < 0.001). No significant association between pioglitazone use and the risk of lung cancer was found (HR = 1.00, 95% CI [0.25-4.02]). Conclusions: This study shows that metformin may have a dose-dependent chemopreventive effect against lung cancer in T2DM, while the impact of pioglitazone remains unclear and requires further investigation.

Age at first sexual intercourse, age at menarche, and age at menopause: a mendelian randomization study on lung cancer risk.

There is increasing evidence that sex hormones are involved in the development of lung cancer, but the correlation between the reproductive behavior that changes sex hormone levels and lung cancer is not yet clear. Many previous studies have investigated the association between reproductive factors and lung cancer risk, but the results have been inconsistent. Therefore, we conducted a two-sample Mendelian randomization (MR) analysis to explore the potential relationship between age at first sexual intercourse (AFS), age at menarche, and age at menopause, and lung cancer. We performed a MR analysis of the data from the genome-wide association study (GWAS) of European ancestry to evaluate the independent effects of three reproductive behaviors on lung cancer overall (LUCA), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), and small cell lung cancer (SCLC). We mainly used the inverse-variance weighting method for the MR analysis. Sensitivity was determined by a MR-pleiotropy residual sum and outlier analysis, a weighted median analysis, a MR-Egger analysis, and a leave-one-out analysis. The MR analysis results revealed that older AFS had a causal relationship with LUCA [odds ratio (OR) =0.6283, 95% confidence interval (CI): 0.4959-0.7961, P=0.0001), LUAD (OR =0.7042, 95% CI: 0.4967-0.9984, P=0.049), and LUSC (OR =0.6231, 95% CI: 0.4386-0.8853, P=0.0083). Our results revealed a causal relationship between older AFS and a lower risk of lung cancer. Our findings emphasize the importance of providing sex education, as early sexual intercourse may have undesirable effects. In addition, early psychological treatment is also essential.

The associations between dysregulation of human blood metabolites and lung cancer risk: evidence from genetic data

BackgroundMetabolic dysregulation is recognized as a significant hallmark of cancer progression. Although numerous studies have linked specific metabolic pathways to cancer incidence, the causal relationship between blood metabolites and lung cancer risk remains unclear.MethodsGenomic data from 29,266 lung cancer patients and 56,450 control individuals from the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium (TRICL-ILCCO) were utilized, and findings were replicated using additional data from the FinnGen consortium. The analysis focused on the associations between 486 blood metabolites and the susceptibility to overall lung cancer and its three major clinical subtypes. Various Mendelian randomization methods, including inverse-variance weighting, weighted median estimation, and MR-Egger regression, were employed to ensure the robustness of our findings.ResultsA total of 19 blood metabolites were identified with significant associations with lung cancer risk. Specifically, oleate (OR per SD = 2.56, 95% CI: 1.51 to 4.36), 1-arachidonoylglyceropholine (OR = 1.79, 95% CI: 1.22 to 2.65), and arachidonate (OR = 1.67, 95% CI: 1.16 to 2.40) were associated with a higher risk of lung cancer. Conversely, 1-linoleoylglycerophosphoethanolamine (OR = 0.57, 95% CI: 0.40 to 0.82), ADpSGEGDFXAEGGGVR, a fibrinogen cleavage peptide (OR = 0.60, 95% CI: 0.47 to 0.77), and isovalerylcarnitine (OR = 0.62, 95% CI: 0.49 to 0.78) were associated with a lower risk of lung cancer. Notably, isoleucine (OR = 9.64, 95% CI: 2.55 to 36.38) was associated with a significantly higher risk of lung squamous cell cancer, while acetyl phosphate (OR = 0.11, 95% CI: 0.01 to 0.89) was associated with a significantly lower risk of small cell lung cancer.ConclusionThis study reveals the complex relationships between specific blood metabolites and lung cancer risk, highlighting their potential as biomarkers for lung cancer prevention, screening, and treatment. The findings not only deepen our understanding of the metabolic mechanisms of lung cancer but also provide new insights for future treatment strategies.

Association of genetic variants in soy isoflavones metabolism-related genes with decreased lung cancer risk

BackgroundSoy isoflavones have been reported to exhibit anti-tumor effects. We hypothesize that genetic variants in soy isoflavone metabolism-related genes are associated with the risk of lung cancer. MethodsA two-stage case-control study design was conducted in this study. The discovery stage included 300 lung cancer cases and 600 healthy controls to evaluate the association of candidate genetic variants with lung cancer risk. The validation stage involved 1200 cases and 1200 controls to validate the associations found. Furthermore, qPCR was performed to assess the mRNA expression levels of different genotypes of the SNP. ELISA was used to explore the association between genotype and soy isoflavone levels, as well as the association between soy isoflavone levels and lung cancer risk. ResultsA nonlinear association was observed between plasma soy isoflavone levels and lung cancer risk, with higher soy isoflavone levels associated with lower lung cancer risk (P < 0.001). The two-stage case-control study identified that UGT1A1 rs3755319 A > C was associated with decreased lung cancer risk (Recessive model: adjusted OR = 0.69, 95 %CI = 0.57–0.84, P < 0.001). Moreover, eQTL analysis showed that the expression level of UGT1A1 in the rs3755319 CC genotype was lower than in the AA + AC genotype (P < 0.05). The plasma concentration of soy isoflavones in the rs3755319 CC genotype was higher than in the AA + AC genotype (P = 0.008). ConclusionsWe identified a potentially functional SNP, UGT1A1 rs3755319 A > C, as being associated with decreased lung cancer risk. Further experiments will be needed to explore the mechanisms underlying the observed associations.

Serum lipid levels, genetic risk, and lung cancer incidence: A large prospective cohort study.

Previous studies usually focused on the separate association of metabolism or genetic factors with lung cancer risk and have largely ignored their combined effect. We aimed to examine the associations between serum lipid levels, genetic risk, and lung cancer risk. 426,524 participants of the UK Biobank were included. The Cox proportional hazards models and restricted cubic splines were performed to assess the association between serum lipid and lung cancer risk. Polygenic risk score (PRS) was constructed to assess its joint effect and interaction with serum lipid on lung cancer risk. Higher level of apolipoprotein A were significantly correlated with lower lung cancer risk. A inverse-J-shaped relationship between HDL and incident lung cancer was found. Individuals with low total cholesterol, HDL, LDL, apolipoprotein A, and apolipoprotein B, combined with high PRS, showed significantly elevated lung cancer risks. Compared to those with low PRS and low triglycerides, participants with high PRS and elevated triglyceride levels had a notably higher risk. The interaction effect of high PRS and low LDL (RERI:0.25, 95%CI: 0.04-0.46), as well as the interaction effect of high PRS and low apolipoprotein B (RERI:0.28, 95%CI: 0.07-0.48), were both greater than the sum of their individual effects on lung cancer risk. Serum lipids were associated with lung cancer risk. LDL or apolipoprotein B interacting with genetic risk may affect lung cancer risk. Our findings emphasize the need for individuals with heightened genetic risk should pay more attention to their lipid levels to reduce lung cancer risk.

Abstract 844: DNA methylation-derived immune cell profiles and risk of cancers in Black participants in the ARIC Study

Abstract Background: Prior cohort studies assessing cancer risk based on immune cell subtype profiles have predominantly focused on White populations. This limitation can obscure vital insights into how cancer risks vary across races, ethnicities, or exposures. This study was designed with the purpose of examining associations between pre-diagnostic immune cell profiles and cancer risk in Black participants. Methods: In this study, DNA methylation was measured in blood samples collected between 1993 and 1995 from a subset of 2,467 Black participants in the Atherosclerosis Risk in Communities (ARIC) prospective cohort study. Immune cell subtype proportions were estimated using deconvolution based on leukocyte DNA methylation markers. The analysis included 668 incident cancers ascertained between time of blood draw and 2015. Cox proportional hazards regression models were used to analyze the association between immune cell subtype proportions and cancer incidence (all cancers; lung, breast, and prostate cancers). Models controlled for age, sex, BMI, self-reported smoking status, self-reported and methylation-derived smoking pack-years, postmenopausal hormone use, and batch effect, along with other cancer-specific factors. Results: Increased T regulatory cell (Treg) proportions were associated with significantly higher risk of lung cancer (HR: 1.22, 95% CI = 1.06, 1.41 per percent increase; n = 84 cases) and suggestively higher risk of all cancers. Increased B memory cell proportions were associated with significantly higher risk of prostate cancer (HR: 1.17, 95% CI = 1.04, 1.33; n = 173 cases), all cancers (HR: 1.13, 95% CI = 1.05, 1.22), and suggestively higher risk of lung cancer. Increased CD8+ naïve cell proportions were associated with suggestively lower risk of lung cancer and all cancers, and significantly lower risk of all cancers in participants over the median age of 55 years (HR: 0.91, 95% CI = 0.83, 0.98). Cancer risks for other immune cell subtypes were null. Conclusions: These results in Black participants align closely with prior findings in largely White populations. Deconvolution allowed for the extension of work on cancer immunity (which has largely focused on major immune cell types) to immune cell subtypes like B memory cells and CD8+ naïve cells. The results are consistent with Tregs initiating and accelerating cancer development by impeding the usual protective immune response. A large reservoir of CD8+ naïve cells may allow for a more targeted and efficient elimination of malignant clones. Further studies should assess these relationships in other cancer types and better elucidate the interplay of B cells in theorized mechanistic processes. This study provides insight into the role of immune cell subtypes in cancer risk among Black men and women. Funding: NHLBI, NCR, NPCR Citation Format: Christopher S. Semancik, Naisi Zhao, Devin Koestler, Eric Boerwinkle, Jan Bressler, Karl Kelsey, Elizabeth A. Platz, Dominique S. Michaud. DNA methylation-derived immune cell profiles and risk of cancers in Black participants in the ARIC Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 844.

Abstract 3811: Impact of antiviral treatment status on risk of extrahepatic cancers in patients with chronic hepatitis C

Abstract Background: Eradiation of hepatitis C virus (HCV) infection has been shown to reduce risk of liver cancer among HCV patients; however, there has been spare data on the effect of antiviral treatment on the risk of extrahepatic cancers. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we investigated whether antiviral therapy impacts the risk of extrahepatic cancers among patients with HCV. Methods: 17,485 HCV patients were included in the study, and they were followed until incidence of cancer including lung cancer, non-Hodgkin lymphoma (NHL), breast cancer or prostate cancer, death, or last follow-up. An extended landmark modeling approach was considered, which included time-varying covariates and propensity score justification for treatment selection bias and used generalized estimating equations (GEE) with a link function as multinominal distribution for a discrete time-to-event data. Death was considered a competing risk. Results: Compared to untreated patients, patients with HCV treatment had significantly lower risk of lung cancer for direct-acting antiviral (DAA) treatment (hazard ratio (HR) = 0.47, 95% CI, 0.30-0.72) and for interferon-based treatment (IFN) (HR = 0.33, 95% CI, 0.20-0.50). The risk of NHL was only reduced among patients receiving DAA treatment. There were no significant associations between HCV treatment and risks of breast and prostate cancer. Conclusion: Both DAA and IFN antiviral treatment independently reduce the risk of lung cancer, while the protective association with NHL was limited among HCV patients with DAA treatment. Our findings support the importance of timely initiation antiviral therapy in chronic HCV-infected patients. Citation Format: Menghua Tao, Jia Li, Trueman Wu, Stuart C. Gordon, Loralee B. Rupp, Sheri Trudeau, Scott D. Holmberg, Anne C. Moorman, Philip R. Spradling, Eyasu H. Teshale, Mark A. Schmidt, Yihe G. Daida, Mei Lu. Impact of antiviral treatment status on risk of extrahepatic cancers in patients with chronic hepatitis C [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3811.

Abstract 748: Impact of oral supplementation of sulforaphane for 12 months on lung cancer-related gene expression in former smokers at high risk for lung cancer: Results from a randomized placebo-controlled phase II clinical trial

Abstract Introduction: Higher consumption of dietary sulforaphane (SFN), a phytochemical found in many cruciferous vegetables, has been shown to be associated with lower risk of lung cancer (LC). SF activates the NRF2-pathway, which initiates cellular detoxification, antioxidant, and anti-inflammatory responses. To date, no chemoprevention trial for LC has examined the impact of SFN on LC-related gene expression (GE) as an endpoint in nasal and bronchial tissue. The objective of our study was to examine whether oral intake of SF for 12 months impacts the GE of previously identified LC- and premalignant lesions (PML)-related genes in bronchial and nasal brushing samples. Methods: A randomized, placebo-controlled clinical trial (NCT03232138) was conducted in former smokers with ≥ 30 pack-years and quitting smoking for 1-10 years in Western Pennsylvania, USA. Forty-three subjects were randomly assigned to the SFN treatment (n = 21) or placebo group (n = 22) in 2018-2022. Each participant was instructed to take 4 Avmacol® or identical placebo capsules BID for 12 months. Each Avmacol® capsule contained 15 mg of glucoraphanin, which yielded a daily internal dose of 120 μmol SFN. Nasal swabs and bronchial brushings were obtained at baseline and after 12 months. Among the 37 participants who completed the study, RNA was extracted from their nasal swabs and bronchial brushings. We constructed single sample gene signature scores (GSS) using the GSVA algorithm for the following: 1) the NRF2-pathway, 2) genes associated with LC risk in bronchial biopsies, and 3) genes associated with PML. The genes in these sets were stratified by their up- or down-regulation in LC or PML. We evaluated the association between the interaction of SFN supplementation over time (pre-/post-treatment) on GSS using linear mixed models, adjusted for the fixed effects of age at baseline, RNA integrity number (RIN), packyears of smoking, and random effect of participant. Results: GE data was available for 31 participant pairs with bronchial and/or nasal samples. Within nasal tissue, SFN treatment increased both the GSSs of the NRF2-pathway (p=0.0089) and the downregulated LC-risk genes (p=0.0047), and decreased the upregulated LC-risk genes (p=0.012) over time, whereas SFN had no significant impact on GSSs of the NRF2-pathway and LC-risk genes in the bronchial tissue. No association between SFN treatment over time and the PML-related GSS was observed in nasal or bronchial tissue. Conclusion: Our initial analysis indicates that SFN treatment over 12 months impacted LC-associated GE in nasal tissue but not in bronchial tissue from former smokers. The discrepancy results may be due to small sample size and additional studies are warranted to confirm if SFN has direct impact on LC-risk related genes in bronchial tissue (NIH grant No. R01CA213123). Citation Format: Kathryn Demanelis, Avrum Spira, Yohana Kefella, Renwei Wang, Jennifer Adams-Haduch, Thomas W. Kensler, Jennifer E. Beane, David O. Wilson, Jian-Min Yuan. Impact of oral supplementation of sulforaphane for 12 months on lung cancer-related gene expression in former smokers at high risk for lung cancer: Results from a randomized placebo-controlled phase II clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 748.

Abstract 3438: Associations between estimated endotoxin exposure and circulating immunological markers among male farmers

Abstract Occupational exposure to endotoxin has been associated with reduced lung cancer risk. Farmers who perform certain tasks (e.g., raising hogs) can be highly exposed to endotoxin. The mechanisms through which endotoxin could confer a lower risk of lung cancer, while likely to be immune mediated, are not clear. To address this gap, we evaluated associations between estimated endotoxin exposure and circulating immunologic markers among male farmers in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study. Our investigation included 122 non-smoking farmers from Iowa, oversampling those raising hogs (n=61). We evaluated 58 serologic markers, including some linked to lung cancer, that were measured using multiplex bead-based assays. Based on an algorithm linking personal air measurements in BEEA and published data to reported farming tasks, we estimated cumulative endotoxin exposure in the last 30 days and 12 months before sample collection. We used multivariable linear regression to estimate geometric mean ratios of immune markers across exposure quartiles, overall and by season of sample collection. Higher endotoxin exposure in the last 30 days was associated with increased levels of FGF-2, MIP-3A/CCL20, and sIL-4R (Ptrend ≤ 0.02), and with decreased levels of MDC/CCL22 (Ptrend = 0.02). In analyses stratified by season, the positive associations with FGF-2 and MIP-3A/CCL20 were most apparent in the winter (Ptrend = 0.002 and 0.03, respectively); we also observed an inverse association with sCD27 levels in the summer (Ptrend = 0.03). Similar patterns were observed for endotoxin exposure in the last 12 months. This study is the first to use novel algorithm-based endotoxin exposure estimates to evaluate associations with intermediate lung cancer-related markers. Several markers were associated with endotoxin levels in an exposure-response manner. Our findings suggest possible biological mechanisms through which endotoxin may reduce risk of lung cancer. Table 1. Associations between estimated endotoxin exposure in the last 30 days and selected serum im Citation Format: Somayina C. Ezennia, Laura E. Beane-Freeman, Vicky C. Chang, Shuai Xie, Gabriella Andreotti, Melissa C. Friesen, Jonathan N. Hofmann. Associations between estimated endotoxin exposure and circulating immunological markers among male farmers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3438.

Abstract 749: Randomized placebo-controlled phase II clinical trial on oral supplementation of sulforaphane for 12 months that reduced bronchial Ki-67 index in former smokers at high risk for lung cancer

Abstract Background: Epidemiological studies showed higher intake of cruciferous vegetables or their active compounds, isothiocyanates (ITCs), with lower risk of lung cancer. ITCs inhibited tobacco-carcinogen induced lung adenocarcinoma in animal models, along with reduced cellular proliferative marker Ki-67 and increased apoptotic markers Caspase-3 and TUNEL. However, human data lack. The aim of our study was to assess if oral intake of sulforaphane (SFN) for 12 months would stop/reverse the progression of bronchial histopathology, reduce Ki-67 index and/or increase Caspase-3 and TUNEL indices. Methods: A randomized clinical trial (NCT03232138) was conducted in former smokers with ≥ 30 pack-years and quitting smoking for 1-10 years in USA. Forty-three subjects were randomly assigned to the SFN (n = 21) or placebo group (n = 22) in 2018-2022. Each participant was instructed to take 4 Avmacol® or identical placebo capsules BID for 12 months. Each Avmacol® capsule contained 15 mg of glucoraphanin, which yielded a daily internal dose of 120 μmol SFN. Biopsies were collected from 6 predetermined bronchial sites at baseline and the end of treatment, respectively. The primary outcomes were the average changes of histopathology scores, Ki-67, Caspase-3 and TUNEL indices in post- vs. pre-treatment biopsies. Results: Thirty-seven participants completed the study. In the SFN group (n = 17) at baseline, 13 were men, all white, mean age 64.1 (SD 5.3) years, body mass index (BMI) 30.6 (6.1) kg/m2, years of smoking 39.5 (8.2), cigarettes per day (CPD) 23.8 (10.7), and years of quitting smoking 4.3 (2.9). The corresponding figures in the placebo group (n=20) were 9 men, 19 white, age 68.0 (3.2), BMI 28.6 (4.2), years of smoking 42.2 (4.5), CPD 25.5 (8.4), and years of quitting smoking 6.8 (3.2). The baseline medians of total Ki-67 positive nuclei were 22.3 nuclei/mm2 in the SFN group and 22.9/mm2 in the placebo group (p = 0.96). After treatment, the number of positive Ki-67 nuclei decreased by 5.3/mm2 (-24%) in the SFN group and increased by 18.0/mm2 (+79%) in the placebo group (p = 0.014) with adjustment for baseline Ki-67 and other covariates. The post- and pre-treatment difference was even greater in high-density (3+) positive Ki-67, with -46% decrease in the SFN group vs. +99% increase in the placebo group (p = 0.004). There was a dose-response effect of higher compliance with SFN intake on reducing Ki-67 index (ptrend = 0.01). SFN treatment had no impact on Caspase-3, TUNEL, or bronchial histopathology. No severe adverse event was observed in the SFN group. Conclusion: Daily intake of 120 μmol SFN for 12 months significantly reduced Ki-67 index in bronchial tissue. The findings support the potential chemopreventive effect of SFN against lung cancer development in high-risk former smokers (Grant # R01CA213123). Citation Format: Jian-Min Yuan, Thomas W. Kensler, Sanja Dacic, Douglas J. Harman, Renwei Wang, Paula Balogh, Lindsey Seigh, Yen T-H Pham, Jennifer Adams-Haduch, Shivendra Singh, James G. Herman, Avrum Spira, David O. Wilson. Randomized placebo-controlled phase II clinical trial on oral supplementation of sulforaphane for 12 months that reduced bronchial Ki-67 index in former smokers at high risk for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 749.

Abstract 834: Farm animal exposures and the oral microbiome in the Agricultural Health Study

Abstract Raising farm animals involves a variety of exposures, including microbes, antimicrobial agents, bioaerosols, and pesticides that may influence the human microbiome. Exposure to farm animals has also been associated with some cancers including lower risk of lung cancer and elevated risks of certain hematologic malignancies, with heterogeneity by animal species. Increasing epidemiologic evidence suggests that changes in the oral microbiome contribute to cancer development. Few human studies have investigated the potential influence of farm animal exposures on the oral microbiome. We investigated associations between farm animal exposures and the oral microbiome in 1245 Iowa and North Carolina farmers and spouses from the Agricultural Health Study. Participants provided information on types and numbers of farm animals raised in telephone interviews close to the time of oral wash sample collection. DNA was extracted from oral wash specimens and analyzed using 16S rRNA gene (V4 region) sequencing. We evaluated associations between farm animal exposures and alpha diversity metrics [e.g., observed amplicon sequence variants (ASVs)] using linear regression and assessed differences in beta diversity metrics (e.g., weighted Unifrac) using permutational multivariate analysis of variance. In addition, we evaluated associations with the presence and relative abundance of specific genera using zero-inflated negative binomial regression. All analyses adjusted for potential confounders (e.g., sex, age, state of residence, smoking). Overall, 63% of participants reported raising any animals, most commonly cattle (46%) and hogs (20%). Raising sheep/goats was associated with lower alpha diversity [e.g., 18 (95% confidence interval: 3-33) fewer observed ASVs compared to not raising sheep/goats], with an exposure-response trend for increasing number of sheep/goats (13 and 24 fewer observed ASVs for 1-29 and ≥30 sheep/goats vs. none, respectively; Ptrend = 0.048). Increasing numbers of hogs and poultry were associated with higher and lower alpha diversity, respectively. Associations were similar after mutual adjustment for other farm animal types. Based on beta diversity analyses, we did not observe statistically significant differences in microbial compositions between participants with and without farm animals. After adjusting for multiple testing, having any farm animal was associated with an increased relative abundance of Porphyromonas, and several genera were more likely to be absent with specific animal exposures (e.g., Capnocytophaga for cattle and sheep/goats; Corynebacterium and Abiotrophia for sheep/goats). To our knowledge, this was the largest investigation of farm animal exposures and the human microbiome to date. Our preliminary findings suggest that animal farming may alter the oral microbiome and provide new insights into the potential role of animal exposures in cancer etiology. Citation Format: Vicky C. Chang, Vaishnavi Purandare, Rashmi Sinha, Gabriella Andreotti, Shilan Li, Xing Hua, Yukiko Yano, Kathryn R. Dalton, Mikyeong Lee, Christine G. Parks, Stephanie J. London, Dale P. Sandler, Mitchell H. Gail, Jianxin Shi, Jonathan N. Hofmann, Christian C. Abnet, Emily Vogtmann, Laura E. Beane Freeman. Farm animal exposures and the oral microbiome in the Agricultural Health Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 834.

Impact of smoking reduction on lung cancer risk in patients with COPD who smoked fewer than 30 pack-years: a nationwide population-based cohort study

BackgroundThe effects of smoking reduction on the incidence of lung cancer in patients with chronic obstructive pulmonary disease (COPD) are not well known. This study aimed to investigate the effects of changes in smoking habits after COPD diagnosis on lung cancer development in patients who smoked less than 30 pack-years.MethodsThis nationwide retrospective cohort study included 16,832 patients with COPD who smoked less than 30 pack-years at the time of COPD diagnosis. Based on changes in smoking habits in the health screening examination data, smokers were categorized into three groups: quitters, reducers, and sustainers. The primary outcome was the risk of lung cancer development, which was estimated using the Cox proportional hazards model. We also modelled the amount of smoking reduction as a continuous variable.ResultsDuring a median follow-up of 4 years, the cumulative incidence of lung cancer was the highest among sustainers, followed by reducers and quitters. Compared with sustainers, reducers (adjusted HR 0.74, 95% CI:0.56–0.98) and quitters (adjusted HR 0.78, 95% CI:0.64–0.96) had a significantly lower risk of lung cancer. Incidence of lung cancer showed a decreasing trend with a decreasing amount of smoking (P for linearity < 0.01).ConclusionsIn patients with COPD who smoked less than 30 pack-years, smoking reduction and cessation lowered the risk of lung cancer.

The interaction effects of zinc and polygenic risk score with benzo[a]pyrene exposure on lung cancer risk: A prospective case-cohort study among Chinese populations

The relationship of exposure to benzo[a]pyrene (BaP) with lung cancer risk has been firmly established, but whether this association could be modified by other environmental or genetic factors remains to be explored. To investigate whether and how zinc (Zn) and genetic predisposition modify the association between BaP and lung cancer, we performed a case-cohort study with a 5.4-year median follow-up duration, comprising a representative subcohort of 1399 participants and 359 incident lung cancer cases. The baseline concentrations of benzo[a]pyrene diol epoxide-albumin adduct (BPDE-Alb) and Zn were quantified. We also genotyped the participants and computed the polygenic risk score (PRS) for lung cancer. Our findings indicated that elevated BPDE-Alb and PRS were linked to increased lung cancer risk, with the HR (95%CI) of 1.54 (1.36, 1.74) per SD increment in ln-transformed BPDE-Alb and 1.27 (1.14, 1.41) per SD increment in PRS, but high plasma Zn level was linked to a lower lung cancer risk [HR (95%CI)=0.77 (0.66, 0.91) per SD increment in ln-transformed Zn]. There was evidence of effect modification by Zn on BaP-lung cancer association (P for multiplicative interaction = 0.008). As Zn concentrations increased from the lowest to the highest tertile, the lung cancer risk per SD increment in ln-transformed BPDE-Alb decreased from 2.07 (1.48, 2.89) to 1.33 (0.90, 1.95). Additionally, we observed a significant synergistic interaction of BPDE-Alb and PRS [RERI (95%CI) = 0.85 (0.03, 1.67)], with 42% of the incident lung cancer cases among individuals with high BPDE-Alb and high PRS attributable to their additive effect [AP (95%CI) = 0.42 (0.14, 0.69)]. This study provided the first prospective epidemiological evidence that Zn has protective effect against BaP-induced lung tumorigenesis, whereas high genetic risk can enhance the harmful effect of BaP. These findings may provide novel insight into the environment-environment and environment-gene interaction underlying lung cancer development, which may help to develop prevention and intervention strategies to manage BaP-induced lung cancer.

Body mass index and lung cancer risk: Pooled analysis of 10 prospective cohort studies in Japan.

Mounting evidence suggests that body mass index (BMI) is inversely associated with the risk of lung cancer. However, relatively few studies have explored this association in Asian people, who have a much lower prevalence of obesity than Caucasians. We pooled data from 10 prospective cohort studies involving 444,143 Japanese men and women to address the association between BMI and the risk of lung cancer. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in each cohort using the Cox proportional hazards model. A meta-analysis was undertaken by combining the results from each cohort. Heterogeneity across studies was evaluated using Cochran's Q and I2statistics. During 5,730,013 person-years of follow-up, 6454 incident lung cancer cases (4727 men and 1727 women) were identified. Baseline BMI was inversely associated with lung cancer risk in men and women combined. While leanness (BMI <18.5) was associated with a higher risk of lung cancer (HR 1.35; 95% CI, 1.16-1.57), overweight and obesity were associated with a lower risk, with HRs of 0.77 (95% CI, 0.71-0.84) and 0.69 (95% CI, 0.45-1.07), respectively. Every 5 kg/m2 increase in BMI was associated with a 21% lower risk of lung cancer (HR 0.79; 95% CI, 0.75-0.83; p < 0.0001). Our pooled analysis indicated that BMI is inversely associated with the risk of lung cancer in the Japanese population. This inverse association could be partly attributed to residual confounding by smoking, as it was more pronounced among male smokers.

Changes in smoking use and subsequent lung cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.

Reducing cigarettes per day may lower the risk of lung cancer compared with continuing to smoke at the same intensity. Other changes in smoking behaviors, such as increasing cigarette consumption or quitting for a period and relapsing, may also affect lung cancer risk. We examined changes in smoking status and cigarettes per day among 24 613 Finnish male smokers aged 50-69 years who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Longitudinal data on smoking were collected during study follow-up visits 3 times a year (approximately every 4 months) between 1985 and 1993. Incident lung cancer patients through 2012 were identified by the Finnish Cancer Registry. Risk ratios (RRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression. Compared with smoking 20 cigarettes per day continuously across the intervention period, reducing an average of 5 cigarettes per day per year while smoking was associated with a 20% lower risk of lung cancer (95% CI = 0.71 to 0.90). A substantially lower risk of lung cancer was also observed when participants smoked at 50% (RR = 0.72, 95% CI = 0.57 to 0.90) and 10% (RR = 0.55, 95% CI = 0.36 to 0.83) of study visits, relative to smoked at 100% of study visits. Smokers may lower their risk of lung cancer by reducing smoking intensity (cigarettes per day while smoking) and the time they smoke. However, quitting smoking completely is the most effective way for smokers to reduce their risk of lung cancer.

A Statistical Testing Strategy Accounting for Random and Nonrandom (Skewed) X-Chromosome Inactivation Identifies Lung Cancer Susceptibility Loci among Smokers.

Lung cancer is the most common cancer worldwide in mortality and the second in incidence. Epidemiological studies found a higher lung cancer risk for smoking women in comparison to men, but these sex differences, irrespective of smoking habits, remain controversial. One of the hypotheses concerns the genetic contribution of the sex chromosomes. However, while genome-wide association studies identified many lung cancer susceptibility loci, these analyses have excluded X-linked loci. To account for nongenetic factors, we first presented an association test based on an additive-multiplicative hazard model accounting for random/nonrandom X-inactivation process. A simulation study was performed to investigate the properties of the proposed test as compared with the Wald test from a Cox model with random X-inactivation process and the partial likelihood ratio test proposed by Xu et al. accounting for nonrandom X-inactivation process. Then, we performed an X chromosome-wide association study on 9,261 individuals from the population-based cohort CARTaGENE to identify susceptibility loci for lung cancer among current and past smokers. We adjusted for the PLCOm2012 lung cancer risk score used in screening programs. Simulation results show the good behavior of the proposed test in terms of power and type I error probability as compared to the Xu et al. and the Wald test. Using the proposed test statistic and adjusting for the PLCOm2012 score, the X chromosome-wide statistical analysis identified two SNPs in low-linkage disequilibrium located in the IL1RAPL1 (IL-1 R accessory protein-like) gene: rs12558491 (p = 2.75×10-9) and rs12835699 (p = 1.26×10-6). For both SNPs, the minor allele was associated with lower lung cancer risk. Adjusting for multiple testing, no signal was detected using the Wald or the Xu et al. likelihood ratio tests. By taking into account smoking behavior and the X-inactivation process, the investigation of the X chromosome has shed a new light on the association between X-linked loci and lung cancer. We identified two loci associated with lung cancer located in the IL1RAPL1 gene. This finding would have been overlooked by examining only results from other test statistics.