Lung Cancer In Smokers Research Articles

Dietary iron and the risk of lung cancer.

Animal models have suggested the carcinogenic effect of iron due to its oxidative potential. The lung is particularly vulnerable to oxidative stress. However, epidemiological studies investigating the association between dietary iron and the risk of lung cancer have reported inconclusive results. In this systematic review and meta-analysis, we aimed to clarify this association. Methods: We searched PubMed, Web of Science, Scopus and Google scholar for eligible articles published through May 2023 reporting the Relative Risk (RR), Hazard Ratio (HR) or Odds Ratio (OR) with 95% confidence interval (95% CI). Case-control and cohort studies that examined the relationship between dietary iron and lung cancer risk were included and review and meta-analyses articles, experimental studies, abstracts, letters to editor and studies with insufficient data were excluded. Finally, three case-control studies and 6 cohort studies were included. Random effect models were used to calculate the pooled results. Results: Nine studies (cases n=21,943, participants n=1,542,993) were included. There were no significant associations between the highest dietary total iron (heme and non-heme) (RR: 1.09, 95% CI: 0.78 to 1.51) or heme iron (RR: 1.01, 95% CI: 0.73 to 1.38) intake compared to the lowest intake with lung cancer risk. Null-associations were also observed in the subgroup analysis based on smoking status and lung cancer histology. However, in the subgroup of women (cases n=5074), heme iron was associated with a 14% increase in the risk of lung cancer (RR: 1.14, 95% CI: 1.01 to 1.29). Conclusions: The current results demonstrated that there is no significant relationship between dietary iron intake and the risk of lung cancer. However, a positive association was observed between dietary heme iron and the risk of lung cancer in women, which may require further investigation.

Common driver mutations and programmed death-ligand 1 expression in advanced non-small cell lung cancer in smokers and never smokers

BackgroundIn non-small cell lung cancer (NSCLC), there may be a relationship between programmed death-ligand 1 (PD-L1) expression, driver mutations and cigarette smoking.MethodsIn this single-center retrospective study, the relationship between common driver mutations (EGFR mutation and ALK rearrangement) and PD-L1 expression in advanced NSCLC according to the patients’ smoking history was examined. Light, moderate and heavy smokers had smoked < 20, 20–39, and ≥ 40 pack-years, respectively. The level of PD-L1 expression, assessed using Ventana SP263 monoclonal antibody assay, was defined by the tumor proportion score (TPS) as high expression (TPS ≥ 50%), low expression (TPS 1%—49%) and no expression (TPS < 1%).Results101 (52.9%) of 191 advanced NSCLC patients were never smokers. EGFR mutations were more common in never smokers (64.4%) than in smokers (17.8%) with advanced NSCLC (P < 0.0001). A higher proportion of smokers (26.7%) had high PD-L1 expression compared to never smokers (13.9%) (P = 0.042). There was a trend for a higher proportion of male NSCLC patients [28 of 115 (24.3%)] than female patients [10 of 76 (13.2%)] to have high PD-L1 expression (P = 0.087]. High PD-L1 expression was seen in 32 of 110 (29.1%) patients with EGFR wild-type NSCLC but only in 6 of 81 (7.4%) patients with EGFR-mutant tumors (P < 0.0001). Among the 90 smokers with NSCLC, a higher proportion of heavy smokers (35.8%) than non-heavy smokers (13.5%) had high PD-L1 expression (P = 0.034). In patients with adenocarcinoma, high PD-L1 expression was seen in 25 of 77 (32.5%) patients with EGFR wild-type tumors but only in 4 of 70 (5.7%) patients with EGFR-mutant tumors (P < 0.0001). Among patients with adenocarcinoma, a significantly higher proportion of ever smokers (29.3%) than never smokers (13.5%) had high PD-L1 expression (P = 0.032). Among smokers with adenocarcinoma, a significantly higher proportion of heavy smokers (44.1%) than non-heavy smokers (8.3%) had high PD-L1 expression (P = 0.004). On multivariate analysis, after adjusting for gender and smoking status, heavy smoking and EGFR wild-type tumors remained significantly associated with high PD-L1 expression in NSCLCs and also in adenocarcinoma.ConclusionsHeavy smoking and EGFR wild-type tumors were significantly associated with high PD-L1 expression in NSCLCs and also in adenocarcinoma.

Lung Cancer Screening in Asia: An Expert Consensus Report

IntroductionThe incidence and mortality of lung cancer are highest in Asia compared with Europe and USA, with the incidence and mortality rates being 34.4 and 28.1 per 100,000 respectively in East Asia. Diagnosing lung cancer at early stages makes the disease amenable to curative treatment and reduces mortality. In some areas in Asia, limited availability of robust diagnostic tools and treatment modalities, along with variations in specific health care investment and policies, make it necessary to have a more specific approach for screening, early detection, diagnosis, and treatment of patients with lung cancer in Asia compared with the West. MethodA group of 19 advisors across different specialties from 11 Asian countries, met on a virtual Steering Committee meeting, to discuss and recommend the most affordable and accessible lung cancer screening modalities and their implementation, for the Asian population. ResultsSignificant risk factors identified for lung cancer in smokers in Asia include age 50 to 75 years and smoking history of more than or equal to 20 pack-years. Family history is the most common risk factor for nonsmokers. Low-dose computed tomography screening is recommended once a year for patients with screening-detected abnormality and persistent exposure to risk factors. However, for high-risk heavy smokers and nonsmokers with risk factors, reassessment scans are recommended at an initial interval of 6 to 12 months with subsequent lengthening of reassessment intervals, and it should be stopped in patients more than 80 years of age or are unable or unwilling to undergo curative treatment. ConclusionsAsian countries face several challenges in implementing low-dose computed tomography screening, such as economic limitations, lack of efforts for early detection, and lack of specific government programs. Various strategies are suggested to overcome these challenges in Asia.

Causal relationship between gastro-esophageal reflux disease and risk of lung cancer: insights from multivariable Mendelian randomization and mediation analysis.

A recent study has reported that anti-reflux surgery reduced the risk of lung cancer. However, the exact causal association between gastro-esophageal reflux disease (GORD) and lung cancer remains obscure. Therefore, we conducted a multivariable and network Mendelian randomization (MR) study to explore this potential association and mediation effect. Independent single nucleotide polymorphisms (SNPs) strongly associated with GORD were selected as instrumental variables (IVs) from the corresponding genome-wide association studies (GWAS). The summary statistics were obtained from the largest GORD GWAS meta-analysis of 367 441 (78 707 cases) European individuals, and the summary statistics of lung cancer and pathological subtypes came from International Lung Cancer Consortium (ILCCO) and FinnGen databases. Univariable and multivariable MR analyses were performed to investigate and verify the causal relationship between genetically predicted GORD and lung cancer. Network MR analysis was conducted to reveal the mediating role of GORD between smoking initiation and lung cancer. The univariable MR analysis demonstrated that GORD was associated with an increased risk of total lung cancer in both ILCCO [inverse variance weighted (IVW): odds ratio (OR) = 1.37, 95% confidence interval (CI) 1.16-1.62, P = 1.70E-04] and FinnGen database (IVW: OR = 1.25, 95% confidence interval CI 1.03-1.52, P = 2.27E-02). The consistent results were observed after adjusting the potential confounders [smoking traits, body mass index (BMI) and type 2 diabetes] in multivariable MR analyses. In subtype analyses, GORD was associated with lung adenocarcinoma (IVW: OR = 1.27, 95% CI 1.02-1.59, P = 3.48E-02) and lung squamous cell carcinomas (IVW: OR = 1.50, 95% CI 1.22-1.86, P = 1.52E-04). Moreover, GORD mediated 32.43% (95% CI 14.18-49.82%) and 25.00% (95% CI 3.13-50.00%) of the smoking initiation effects on lung cancer risk in the ILCCO and FinnGen databases, respectively. This study provides credible evidence that genetically predicted GORD was significantly associated with an increased risk of total lung cancer, lung adenocarcinoma and lung squamous cell carcinomas. Furthermore, our results suggest GORD is involved in the mechanism of smoking initiation-induced lung cancer.

Lung Cancer Screening With Low-Dose Computed Tomography.

Approximately 21 900 women and 35 300 men developed lung cancer in Germany in 2018, and 16 514 women and 28 365 men died of it. The outcome mainly depends on the tumor stage. In early stages (stage I or II), treatment can be curative; unfortunately, because early-stage lung cancers are generally asymptomatic, 74% of women and 77% of men already have advanced-stage disease (stage III or IV) at the time of diagnosis. Screening with low-dose computed tomography is an option enabling early diagnosis and curative treatment. This review is based on pertinent articles retrieved by a selective search of the literature on screening for lung cancer. In the studies of lung cancer screening that have been published to date, sensitivity ranged from 68.5% to 93.8%, and specificity from 73.4% to 99.2%. A meta-analysis by the German Federal Office for Radiation Protection revealed a 15% reduction in lung cancer mortality when low-dose computed tomography was used in persons who were judged to be at high risk for lung cancer (risk ratio [RR] 0.85, 95% confidence interval [0.77; 0.95]). 1.9% of subjects died in the screening arm of the metaanalysis, and 2.2% in the control group. The observation periods ranged from 6.6 to 10 years; false-positive rates ranged from 84.9% to 96.4%. Malignant findings were confirmed in 45% to 70% of the biopsies or resective procedures that were performed. Systematic lung cancer screening with low-dose CT lowers mortality from lung cancer in (current or former) heavy smokers. This benefit must be weighed against the high rate of false-positive findings and overdiagnoses.

Dose–response relationship between active smoking and lung cancer mortality/prevalence in the Chinese population: a meta-analysis

BackgroundThe dose‒response relationship-based relative risk (RR) of smoking exposure could better predict the risk of lung cancer than the dichotomous RR. To date, there is a lack of large-scale representative studies illustrating the dose‒response relationship between smoking exposure and lung cancer deaths, and no study has systematically pooled the current evidence in the Chinese population.ObjectivesTo elucidate the dose‒response relationship of smoking and the risk of lung cancer mortality in the Chinese population.MethodsData were derived from studies on dose‒response relationships of smoking exposure and the risk of lung cancer among Chinese adults published before June 30th, 2021. Based on smoking exposure indicators and RR of lung cancer mortality, a series of dose‒response relationship models were developed. For smokers, 10 models were built to fit the dose‒response relationships between pack-years and RR of lung cancer deaths. For quitters, quit-years and corresponding RRs were used, and the pooled dichotomous RR value was used as the starting point to avoid overestimation. Finally, the results were compared with the estimates from 2019 Global Burden of Disease (GBD) study.ResultsA total of 12 studies were included. Among 10 dose‒response relationship models of pack-years with the RR of lung cancer mortality, the integrated-exposure–response (IER) model achieved the best fit. In all models, less than 60 pack-years presented RRs below 10. For former smokers, the RR decreased to 1 when quit-years reached up to 7 years. Both smokers and quitters had much lower RRs than that of the global level estimated by GBD.ConclusionThe risk of lung cancer mortality rose with pack-years and decreased with quit-years among Chinese adults, and both values were far below global level. The results suggested that the dose–response RR of lung cancer deaths associated with smoking in China should be estimated separately.

Cancer prevention with rapamycin

Rapamycin (sirolimus) and other rapalogs (everolimus) are anti-cancer and anti-aging drugs, which delay cancer by directly targeting pre-cancerous cells and, indirectly, by slowing down organism aging. Cancer is an age-related disease and, figuratively, by slowing down time (and aging), rapamycin may delay cancer. In several dozen murine models, rapamycin robustly and reproducibly prevents cancer. Rapamycin slows cell proliferation and tumor progression, thus delaying the onset of cancer in carcinogen-treated, genetically cancer-prone and normal mice. Data on the use of rapamycin and everolimus in organ-transplant patients are consistent with their cancer-preventive effects. Treatment with rapamycin was proposed to prevent lung cancer in smokers and former smokers. Clinical trials in high-risk populations are warranted.

Genotyping, characterization, and imputation of known and novel CYP2A6 structural variants using SNP array data.

CYP2A6 metabolically inactivates nicotine. Faster CYP2A6 activity is associated with heavier smoking and higher lung cancer risk. The CYP2A6 gene is polymorphic, including functional structural variants (SV) such as gene deletions (CYP2A6*4), duplications (CYP2A6*1 × 2), and hybrids with the CYP2A7 pseudogene (CYP2A6*12, CYP2A6*34). SVs are challenging to genotype due to their complex genetic architecture. Our aims were to develop a reliable protocol for SV genotyping, functionally phenotype known and novel SVs, and investigate the feasibility of CYP2A6 SV imputation from SNP array data in two ancestry populations. European- (EUR; n = 935) and African- (AFR; n = 964) ancestry individuals from smoking cessation trials were genotyped for SNPs using an Illumina array and for CYP2A6 SVs using Taqman copy number (CN) assays. SV-specific PCR amplification and Sanger sequencing was used to characterize a novel SV. Individuals with SVs were phenotyped using the nicotine metabolite ratio, a biomarker of CYP2A6 activity. SV diplotype and SNP array data were integrated and phased to generate ancestry-specific SV reference panels. Leave-one-out cross-validation was used to investigate the feasibility of CYP2A6 SV imputation. A minimal protocol requiring three Taqman CN assays for CYP2A6 SV genotyping was developed and known SV associations with activity were replicated. The first domain swap CYP2A6-CYP2A7 hybrid SV, CYP2A6*53, was identified, sequenced, and associated with lower CYP2A6 activity. In both EURs and AFRs, most SV alleles were identified using imputation (>70% and >60%, respectively); importantly, false positive rates were <1%. These results confirm that CYP2A6 SV imputation can identify most SV alleles, including a novel SV.

Abstract 4467: Plasmacytoid dendritic cells, prevalent in the TME of smokers, is associated with a good prognosis and treatment response of LUAD

Abstract Background: Attempts to find therapeutic biomarkers through investigation of subgroup showing good responses to certain drugs in cancer often yielded meaningful results. Smoker’s lung adenocarcinoma has consistently shown a favorable response to immune checkpoint inhibitors (ICIs) than non-smoker’s lung adenocarcinoma. Comparing the macrophages (Mϕ) and dendritic cells (DC) constituting the innate immune tumor microenvironment (TME) in lung cancer of smokers and nonsmokers, we tried to figure out the difference in TME and biomarkers that predict the therapeutic response to ICIs. Methods: The inflammatory TME of current and never smokers’ lung cancer was explored by tumor and adjacent normal appearing lung tissues (Tu and NL hereafter) scRNA sequencing and verified by IF, IHC, and open-source dataset. Results: Compared to lungs of nonsmokers, smokers’ lung have an increased proportion of cell populations involved in innate immunity, and the increased cell population was mostly Mϕ, which were enriched in NL. When the number of Mϕ present in the NL of the corresponding individual were taken as the denominator, Tu of smokers has a lower proportion of Mϕ than that of non-smokers. Further sub-clustering of Mϕ and DCs showed that FCN1-mono and CD163-LGMN Mϕ, which correspond to the initial differentiation into the resident cell population within the tissue, and mo-DC, cDC2, and pDC were significantly enriched in the Tu. Among them, pDC is a functionally differentiated tissue resident cell that showed a different tissue distribution pattern between smokers and non-smokers, so it was estimated as one of the causes of the different treatment response to ICIs between the two patient groups. The difference of pDC’s distribution was further verified through IHC staining using anti-LILRA4 and anti-TLR9 antibody, showing pDC was significantly enriched in the smokers’ TME. A significant increase in TLR9 expression was observed in or around lung cancer immediately after ionizing radiation or cisplatin treatment in LSL-Kras G12D mouse model. The survival analysis of TCGA-LUAD dataset showed that the patients' overexpressing pDC markers such as IRF4 and TLR9 was superior clinical outcomes to the age, gender and smoking matched control group. Comparing the difference in TMB between the top 25% and bottom 25% groups according to the expression of TLR9, it was 5.81/Mb in the upper group and 4.36/Mb in the subgroup, showing a significant difference. Conclusions: pDC is an innate immune cell population that showed a prominent increase in smokers’ TME compared to that of non-smokers, suggesting that its increase may be one the factors that smokers’ lung cancer show favorable responses to ICI than that of non-smokers. These findings suggest that the pDC signature can be developed as a biomarker predicting the response to ICIs and increasing the number of pDCs or its activity may improve treatment outcome of ICIs. Citation Format: Eun Young Kim, Yoon Jin Cha, Yong Jun Choi, Min Kyung Park, Yoon Soo Chang. Plasmacytoid dendritic cells, prevalent in the TME of smokers, is associated with a good prognosis and treatment response of LUAD. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4467.

Abstract 6462: Cigarette smoking reduction and lung cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

Abstract Background. Cigarette smoking is a leading cancer risk factor. In addition to quitting smoking, reducing the number of cigarettes/day may decrease risk of lung cancer compared with continuing to smoke more heavily. However, few cohort studies have longitudinal assessments of cigarette use. Methods. We examined the association of changes in smoking status (trying to quit, not smoking at this time, and still smoking) and changes in cigarettes/day with subsequent incidence of lung cancer in 24,613 Finnish male participants of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a cancer prevention trial of vitamin supplements that collected serial assessments of cigarette use. At baseline (1985-1988), all participants were current smokers 50-69 years old who smoked 5+ cigarettes/day. During the five-to-eight year intervention period, men were asked at 4-month intervals about changes in their smoking use since their last visit. We obtained individual estimates of the proportion of follow-up time (% of time) in each of the three smoking statuses, the transition probabilities between statuses and intercepts and slopes for the number of cigarettes/day. We then examined associations between changes in smoking and in cigarettes/day and subsequent incidence of lung cancer occurring between the end of the trial (April 30, 1993) and December 31, 2012. Using Cox regression, we modeled lung cancer risk ratios (RRs) and 95% confidence intervals (95%CI) associated with changes in smoking (% of time and number of cigarettes/day) relative to individuals who smoked 20 cigarettes/day across all the study visits. Models were additionally adjusted for age at the end of the trial, ATBC intervention group, education, and age at smoking initiation. Results. Overall, 3013 lung cancers were diagnosed during follow-up. The risk of lung cancer was lower among participants who reduced their smoking intensity by 5 or 10 cigarettes/day [RR=0.80(95%CI:0.71,0.89) and RR=0.64(95%CI:0.51,0.81), respectively]. RRs were further decreased among participants who also smoked at only 50% of study visits [-5 cigarettes/day RR=0.71(95%CI:0.57, 0.90) and -10 cigarettes/day RR=0.46(95%CI:0.44, 0.74)]. Individuals with the lowest risk were those who stopped smoking early at follow-up and continued to not smoke over the intervention period. For example, an individual who began the study smoking 15 cigarettes/day, stop smoking at 4 months and remained not smoking had a RR=0.24(95%CI: 0.11, 0.50). Conclusion: Even in the absence of cessation, smokers may meaningfully lower their lung cancer risk by reducing the number of cigarettes they smoke per day and the proportion of time they smoke. Yet, the lowest risk was observed among smokers who quit completely. Citation Format: Daniela S. Gutiérrez-Torres, Sungduk Kim, Paul Albert, Demetrius Albanes, Stephanie J. Weinstein, Maki Inoue-Choi, Neal D. Freedman. Cigarette smoking reduction and lung cancer risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6462.

Abstract 2088: gCNV-Seeker: A comprehensive germline CNV calling pipeline based on whole genome sequencing data

Abstract Germline Copy Number Variation (gCNV) is a type of genomic structural alteration including deletion or duplication of small genomic regions (50bp to 1MB) and can have an important role into cancer etiology. Whole genome sequencing (WGS) has been considered to be the most effective technology for genome-wide identification of gCNVs. However, an easy-to-use gCNV calling pipeline based on WGS data is still lacking. Here, we present the gCNV-Seeker, a user-friendly, rigorous computational pipeline to detect gCNV events based on WGS with standardized quality control and data visualization features. gCNV-Seeker initially adopts GATK probabilistic algorithms to detect a set of raw gCNV events and subsequently applies Binary Segmentation and Pruned Exact Linear Time (PELT) algorithms for re-segmentation and boundary revision of the gCNV candidates, respectively. In addition, gCNV-Seeker is built with several functionalities, including quality control, filtration, annotation and visualization to identify the gCNV regions (gCNVRs) of interest. We applied gCNV-Seeker to the WGS data from 872 lung cancers in never smokers from the Sherlock-Lung study and 3202 WGS data from the 1000 Genomes Project (1KGP) (reference) and identified CNVRs associated with lung cancer risk in never smokers. For example, in comparison to WGS data from 1KGP, we identified several CNVR candidates overlapping with known LC susceptible genes, e.g., the GSTM1/2 homozygous deletion (OR = 1.64, 95% CI=1.43-1.88, P &amp;lt; 0.01) and CYP2A6/7 homozygous or heterozygous deletion (OR = 1.59, 95% CI=1.24-2.03, P &amp;lt; 0.01). To evaluate its performance, we also carried out a comprehensive comparison of gCNV calling results between gCNV-Seeker and the 1KGP structural variant calling pipelines (PMID: 36055201) for common gCNVRs in the 1KGP WGS data. gCNV-Seeker showed a significant improvement on specificity and sensitivity for gCNVR detection compared with the 1KGP pipeline. In terms of specificity, 1315 out of 2692 (HGSV_9692) GSTM1/2 heterozygous deletion events (48.85%) originally identified by 1KGP were detected as homozygous deletions by gCNV-Seeker. These results were further confirmed by manual check. In terms of sensitivity, gCNV-Seeker detected total 299 deletion events in CYP2A6/7 regions, which were also manually confirmed. This corresponds to an increase of 48.02% compared to the 202 deletion events (HGSV_232739 &amp; HGSV_232740) originally identified by the 1KGP pipeline. gCNV-Seeker will be a publicly available cross-platform (Linux and IOS) pipeline accessible in GitHub. Citation Format: Jian Sang, Tongwu Zhang, David Wedge, Maria Teresa Landi. gCNV-Seeker: A comprehensive germline CNV calling pipeline based on whole genome sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2088.

287 Genomic and Immunologic Characterization of Lung Adenocarcinoma in Never Smokers vs. Smokers

OBJECTIVES/GOALS: Smoking is a well-established risk factor for lung cancer, but never smokers account for up to 25% of lung cancer cases. There is mounting evidence that lung cancer in never smokers is biologically distinct. We aim to characterize the genomic and immunologic features of lung adenocarcinoma in never smokers versus smokers. METHODS/STUDY POPULATION: We examined clinical, genomic, and bulk-RNA sequencing data from 499 patients in the TCGA lung adenocarcinoma cohort. Tumor mutation burden was analyzed using maftools (R package). Tumor immune characterization was completed using CIBERSORTx, a digital cytometry tool that uses single cell reference profiles to determine immune cell type frequencies from bulk-RNA sequencing data. Single cell reference profiles for 19 different immune cell types were constructed from sequencing of freshly resected lung tumor tissue from UCSF patients. Partitioning Around Medoids (PAM; R package) was used to identify distinct immune phenotypes based on immune cell composition. Fisher’s exact test was used to evaluate for associations between immune phenotypes and smoking status. RESULTS/ANTICIPATED RESULTS: Of the 499 TCGA lung adenocarcinoma patients, 75 were never smokers, 269 were female, and 246 were over the age of 65. Never smokers had lower tumor mutation burden and lower predicted neoantigen burden compared to smokers (p &lt; 0.001). There was no difference in total tumor immune cell infiltration between never smokers and smokers. PAM yielded 2 distinct clusters/immune phenotypes. The first was enriched in M1 Macrophages, cytotoxic T Cells, helper T Cells, regulatory T Cells, and Plasma Cells. The second was enriched in plasmacytoid Dendritic Cells, M2 Macrophages, and exhausted cytotoxic T Cells. Never smoking status was associated with an increased odds of having the first immune phenotype (OR 1.95, 95% CI: 1.15 - 3.35) and this association was statistically significant (p = 0.0086). DISCUSSION/SIGNIFICANCE: Our findings suggest that never smokers have an immune phenotype that is distinct from that observed in smokers. The distinct immune characteristics we observed could explain clinical trial data suggesting immune checkpoint inhibitors are less effective in never smokers and hold implications for tailoring therapy.

The Tobacco Smoke Component, Acrolein, as a Major Culprit in Lung Diseases and Respiratory Cancers: Molecular Mechanisms of Acrolein Cytotoxic Activity

Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant that seriously threatens human health and life. Due to its high reactivity, cytotoxicity and genotoxicity, acrolein is involved in the development of several diseases, including multiple sclerosis, neurodegenerative diseases such as Alzheimer's disease, cardiovascular and respiratory diseases, diabetes mellitus and even the development of cancer. Traditional tobacco smokers and e-cigarette users are particularly exposed to the harmful effects of acrolein. High concentrations of acrolein have been found in both mainstream and side-stream tobacco smoke. Acrolein is considered one of cigarette smoke's most toxic and harmful components. Chronic exposure to acrolein through cigarette smoke has been linked to the development of asthma, acute lung injury, chronic obstructive pulmonary disease (COPD) and even respiratory cancers. This review addresses the current state of knowledge on the pathological molecular mechanisms of acrolein in the induction, course and development of lung diseases and cancers in smokers.

Abstract P6-08-12: Toward Comprehensive Cancer Prevention for Women Experiencing Homelessness: Demonstrating the Need for Onsite Mammography, Education, Navigation, and Cross Cancer Screenings

Abstract Background: Persons experiencing homelessness (PEH) rarely receive regular preventative health care or consistent cancer screenings. Late stage detection of cancer and barriers to care are prevalent among PEH. Novel programs such as onsite mobile mammography services represents an approach to improve breast cancer disparities among women experiencing homelessness (WEH) and allows for understanding of barriers to cancer screening amongst WEH and to develop best practices. Objectives: During onsite mobile mammography events at shelters for WEH, develop best practices for improving breast cancer screening utilization while developing approaches to increase use of other cancer screenings. Methods: In 2022, the Cleveland Clinic performed onsite mobile mammography screening events at area shelters and day centers. All seven screening events included onsite mammography, breast health education, and patient navigation. After WEH completed the education session, they completed the mammogram. Subsequently, at two events, patients had an opportunity for further consultation with an advanced practice provider (APP) including discussing additional screening tests (ex. colorectal, lung, cervical cancer) beyond mammograms with referrals as needed. Consultations also discussed approaches to reduce cancer risks with further education, referrals for dental care, and assistance securing a primary care provider (PCP). Results: At the events that included consultations, 30 patients received mammograms and 80% (n=24) of patients chose to speak with the APP. Patients seeking consultation were 21-73 years old and identified as Black/African American (n=5), White (n=16), and other (n=3). Topics of discussion included mammograms (n=24, 100%), smoking cessation referral and/or lung cancer screening (n=16, 67%), colorectal cancer screening (n=11, 46%), and cervical cancer/HPV screening (n=11, 46%). Additionally, 46% of patients (n=11) were assisted with securing a PCP and 8% of patients (n=2) were referred for dental services. Discussion: Our preliminary data demonstrate that most WEH undergoing onsite mammography screening are willing to engage in consultation to discuss additional cancer screenings with many patients eligible for additional cancer screenings. Additionally, this approach provided access to PCPs. Three best practices for cross cancer screenings include: 1) Onsite mobile mammography is an appropriate entry point for addressing breast health and also cancer screening broadly. 2) An onsite approach allows for education beyond cancer screening to provide access to primary care and other wrap around services. 3) Clinicians provide credibility and trust when they attend onsite mobile mammography events. Conclusion: Beyond breast cancer screening, WEH benefit from onsite mobile mammography, which can serve as a gateway to cross cancer screenings and access to primary care. Addressing disparities in this population should include wrap around services such as smoking cessation and connection to a PCP. Future research should examine best practices for following up with patients and completing navigation through cross cancer screenings. Citation Format: Pamela Combs, Heather M. Hurwitz, Markayla Mariner, NaSheema Anderson, Kate Mccaffrey, Raymond Jackson, Sarah Kilic, Tiffany Onger, Kimberly Sanders, Tyler Stimpert, Jeremy Suwarna, Jeremy Weleff, Chirag Shah. Toward Comprehensive Cancer Prevention for Women Experiencing Homelessness: Demonstrating the Need for Onsite Mammography, Education, Navigation, and Cross Cancer Screenings [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-12.

Selected Articles from This Issue

Highlights| February 06 2023 Selected Articles from This Issue Author & Article Information Online ISSN: 1538-7755 Print ISSN: 1055-9965 ©2023 American Association for Cancer Research2023American Association for Cancer Research Cancer Epidemiol Biomarkers Prev (2023) 32 (2): 155. https://doi.org/10.1158/1055-9965.EPI-32-2-HI Related Content A commentary has been published: Dietary Factors and Early-Onset Colorectal Cancer in the United States—an Ecologic Analysis A commentary has been published: Longitudinal Changes in Immune Activation Serum Biomarkers Prior to Diagnosis and Risk of B-cell NHL Subtypes A commentary has been published: Race Differences in Patient-Reported Symptoms during Chemotherapy among Women with Early-Stage Hormone Receptor–Positive Breast Cancer View more A commentary has been published: Geographic Patterns in U.S. Lung Cancer Mortality and Cigarette Smoking View less Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record February 6 2023 Citation Selected Articles from This Issue. Cancer Epidemiol Biomarkers Prev 1 February 2023; 32 (2): 155. https://doi.org/10.1158/1055-9965.EPI-32-2-HI Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Symptom burden differences may contribute to racial disparities in breast cancer outcomes. In this retrospective cohort study of 1,273 women with early-stage hormone receptor-positive breast cancer from a large cancer center, Black women more frequently experienced worsening physical and psychological symptoms during chemotherapy compared to White women. Hu and colleagues found that differences in baseline sociodemographic and clinical characteristics contributed to the increasing symptom burden among Black patients. However, most of the differences in the physical symptom changes were not explained by these characteristics, which suggests inadequate symptom management among Black women. More research is needed to ensure equitable symptom management among all patients. Lung cancer remains the leading cause of cancer death in the United States. Shreves and colleagues investigated spatial patterns in smoking prevalence and lung cancer mortality rates by sex. They report the first observation of a significant cluster of counties where the relationship between smoking prevalence... You do not currently have access to this content.

Assessment of the Ecological Association between Tobacco Smoking Exposure and Bladder Cancer Incidence over the Past Half-Century in the United States.

Since tobacco smoking represents the most established risk factor for bladder cancer, we sought to assess the ecological association between tobacco smoking prevalence and bladder cancer incidence and to contrast it with lung cancer. The annual overall tobacco smoking prevalence rates were extracted from the Report of the Surgeon General and the Center for Disease Control between 1953 and 1983. The overall age-adjusted incidence rates for bladder and lung cancers were derived from the Surveillance, Epidemiology, and End Results database between 1983 and 2013 (30-year latency period). Weighted least square regression models were used to assess bladder and lung cancer incidence rate differences (IRD) related to trends in tobacco smoking prevalence. A Wald test was used to compare whether the prevalence of tobacco smoking, as an explanatory variable, differentially predicts bladder versus lung cancer incidence rates. The associations between tobacco smoking prevalence and bladder cancer incidence were not significant in the overall (IRD = +0.04; 95%CI (-0.14; +0.22); p = 0.63), male (IRD = +0.07; 95%CI (-0.09; +0.23); p = 0.37), or female (IRD = +0.12; 95%CI (-0.01; +0.25); p = 0.06) populations. There was an association between tobacco smoking prevalence and lung cancer incidence in the overall (IRD: +3.55; 95%CI ( +3.09; +4.00); p < 0.001), male (IRD: +4.82; 95%CI (+4.44; +5.20); p < 0.001), and female (IRD: +3.55; 95%CI (+3.12; +3.99); p < 0.001) populations. The difference between the observed associations of tobacco smoking prevalence with bladder versus lung cancer incidence was also significant in all examined populations (p < 0.001). Variations in tobacco smoking prevalence only partially explained the trends in the incidence of bladder cancer, indicating that its etiology is complex.

Genetic differences between smokers and never-smokers with lung cancer.

Smoking is a major risk factor for lung cancer, therefore lung cancer epidemiological trends reflect the past trends of cigarette smoking to a great extent. The geographic patterns in mortality closely follow those in incidence. Although lung cancer is strongly associated with cigarette smoking, only about 15% of smokers get lung cancer, and also some never-smokers develop this malignancy. Although less frequent, lung cancer in never smokers is the seventh leading cause of cancer deaths in both sexes worldwide. Lung cancer in smokers and never-smokers differs in many aspects: in histological types, environmental factors representing a risk, and in genes associated with this disease. In this review, we will focus on the genetic differences between lung cancer in smokers versus never-smokers: gene expression, germ-line polymorphisms, gene mutations, as well as ethnic and gender differences. Finally, treatment options for smokers and never-smokers will be briefly reviewed.

Lipid biomarkers that reflect postoperative recurrence risk in lung cancer patients who smoke: a case–control study

BackgroundThe risk of postoperative recurrence is higher in lung cancer patients who smoke than non-smokers. However, objective evaluation of the postoperative recurrence risk is difficult using conventional pathological prognostic factors because of their lack of reproducibility. Consequently, novel objective biomarkers that reflect postoperative risk in lung cancer patients who smoke must be identified. Because cigarette smoking and oncogenesis alter lipid metabolism in lung tissue, we hypothesized that the lipid profiles in lung cancer tissues are influenced by cigarette smoking and can reflect the postoperative recurrence risk in smoking lung cancer patients. This study aimed to identify lipid biomarkers that reflect the smoking status and the postoperative recurrence risk.MethodsPrimary tumor tissues of lung adenocarcinoma (ADC) (n = 26) and squamous cell carcinoma (SQCC) (n = 18) obtained from surgery were assigned to subgroups according to the patient’s smoking status. The ADC cohort was divided into never smoker and smoker groups, while the SQCC cohort was divided into moderate smoker and heavy smoker groups. Extracted lipids from the tumor tissues were subjected to liquid chromatography-tandem mass spectrometry analysis. Lipids that were influenced by smoking status and reflected postoperative recurrence and pathological prognostic factors were screened.ResultsTwo and 12 lipid peaks in the ADC and SQCC cohorts showed a significant positive correlation with the Brinkman index, respectively. Among them, in the ADC cohort, a higher lipid level consisted of three phosphatidylcholine (PC) isomers, PC (14:0_18:2), PC (16:1_16:1), and PC (16:0_16:2), was associated with a shorter recurrence free period (RFP) and a greater likelihoods of progressed T-factor (≥ pT2) and pleural invasion. In the SQCC cohort, a lower m/z 736.5276 level was associated with shorter RFP and greater likelihood of recurrence.ConclusionsFrom our data, we propose three PC isomers, PC (14:0_18:2), PC (16:1_16:1), and PC (16:0_16:2), and a lipid peak of m/z 736.5276 as novel candidate biomarkers for postoperative recurrence risk in lung ADC and SQCC patients who are smokers.

Abstract PR002: A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer

Abstract Background: Smoking is the most common etiology for lung cancer and smoking cessation does not eliminate the risk. An emerging area of interest for risk reduction is immunoprevention. MUC1 glycoprotein is aberrantly expressed in adenocarcinomas, including lung cancer and their premalignant lesions. MUC1 vaccine in the premalignant or high-risk setting may be effective in halting neoplastic development and progression. Trial design: Through the NCI-funded Cancer Prevention Network (CPN), we conducted a two-center pilot trial to evaluate immunogenicity of the MUC1 vaccine (assessed at 12 weeks), and safety (assessed at up to 24 weeks) in current and former heavy smokers. 87 participants were screened in order to have at least 40 evaluable for baseline and 12-week immunogenicity assessments. Smoking history of ≥30 pack-years and either current (still smoking or quit &amp;lt; 1 year prior to pre-registration) or former smoker (quit 1-15 years prior to pre-registration); ages 55-80 years; ECOG performance status ≤1; CT scan of the chest done ≤ 6 months prior to pre-registration showing either negative findings (no nodules) or solid or part-solid nodules &amp;lt; 6 mm in size (consistent with &amp;lt; 1% probability of malignancy, Lung-RADs Version 1.0). Exclusion criteria were standard for lung cancer screening. Methods: MUC1 peptide plus polyICLC adjuvant (Hiltonol) vaccine was given at week 0, 2 and 10. Blood was collected for safety tests and immune assays pre and 2 weeks post each vaccine, and at week 24. Anti-MUC1 IgG titer was evaluated by ELISA. Based on previous studies of this vaccine, 40 evaluable participants would provide 96% power to detect immune response rate of 15% versus 40%, using a 2-sided test of proportions with type I error rate of 0.05. PBMC were assayed for the presence of regulatory T cells (Treg) and myeloid derived suppressor cells (MDSC) (secondary endpoint). Circulating levels of inflammatory cytokines and hsCRP were evaluated using commercially available tests (exploratory endpoint). AEs and toxicities were monitored for up to 24 weeks from the first vaccine. Results: 87 individuals were screened and 50 registered. 45 completed the study, 26 current and 19 former smokers (time since last smoked: average 7.8 years; 11 months -13 years). The vaccine was well-tolerated with injection site reactions being the most common AE. Immune response to the vaccine was lower than expected, with 2 current and 2 former smokers developing anti-MUC1 IgG titers ≥2 fold higher at week 12 over baseline (10%). We found high circulating levels of MDSCs in PBMC of both current and former smokers and very low or no serum cytokines. Conclusions: A preventative vaccine trial was feasible in individuals at high risk for lung cancer. However, we discovered a high level of immune suppression, previously documented only in advanced lung cancer. Mitigating the development of lung cancer in heavy smokers through vaccine administration may be limited by related immunosuppression. Citation Format: Olivera J. Finn, Julie Ward, Tami Krpata, Samantha Fatis, John McKolanis, Jia Xue, Pamela Beatty, Camille Jacqueline, Sharon Kaufman, Colleen Akerley, April Felt, Karrie Fursa, Anne Holland, Liz S. Ambulay, Nathan Foster, Ryan McMurray, Carrie Strand, Andres M. Salazar, Lisa Bengtson, Eva Szabo, Paul Limburg, Malgorzata Wojtowicz, David E. Midthun, Arjun Pennathur. A pilot study of a MUC1 vaccine in current and former smokers at high risk for lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr PR002.

Abstract P025: Tobacco screening practices and perceived barriers in offering tobacco cessation services in the primary prevention of lung cancer among Texas healthcare centers providing behavioral health treatment

Abstract Cigarette smoking is the leading cause of preventable death and illness globally and accounts for over 80% of all lung cancer diagnoses in the U.S. Patients with behavioral health (e.g., mental health and/or substance use) needs have elevated levels of smoking relative to the general population and are thus disparately impacted by tobacco-related cancers. Tobacco screenings, a precursor to providing evidence-based interventions for smoking cessation, play a critical role in the primary prevention of lung cancer. However, their use in behavioral health treatment centers has historically been inconsistent. The aim of this study was to analyze barriers and facilitators to tobacco screening in settings where Texans receive behavioral health care to contextualize current screening trends and, in turn, provide recommendations for improvement. This study assessed the prevalence of mandated tobacco screenings in 80 centers providing healthcare to Texans with behavioral health needs. We examined key factors that could enhance screening conduct (i.e., provision of a tobacco use assessment template, hard stop in the electronic health record [EHR] for patient tobacco use status, and the availability of tobacco screening training), assessed associations between center practices and mandated tobacco screenings, and delineated providers’ perceived barriers to tobacco use intervention provision. Results indicated that 80% of surveyed centers mandated tobacco use screenings; those that did were significantly more likely than those that did not to have a hard stop for tobacco use status in the EHR (p&amp;lt;0.008) and to make training on tobacco screening available to providers (p=0.016). The most widespread barriers to tobacco use disorder care provision, endorsed by at least 50% of all respondents at &amp;gt;1 type of healthcare center (e.g. federally qualified health centers, global local mental health authorities, substance use treatment centers in local mental health authorities, and stand-alone substance use treatment centers), were relative perceived importance of competing diagnoses, lack of community resources for referral, perceived lack of time, lack of provider knowledge or confidence, and belief that patients do not comply with cessation treatment. Overall, there are opportunities for centers providing care to Texans with behavioral health needs to bolster their tobacco screening and intervention capacity to prevent cancer-related disparities in this group. Healthcare centers can support their providers to intervene upon tobacco use by mandating screenings, streamlining clinical workflow with hard stops in patient records, and by educating providers about patient’s interest in quitting along with the importance of treating tobacco with brief evidence-based intervention strategies. Future work should focus on how these healthcare centers can facilitate providers’ ability to link tobacco screenings with smoking cessation services and lung cancer eligibility screening to increase the early detection of lung cancers and prevent tobacco-related cancer disparities. Citation Format: Ammar D. Siddiqi, Maggie Britton, Tzuan A. Chen, Brian J. Carter, Carol Wang, Isabel Martinez Leal, Anastasia Rogova, Bryce Kyburz, Teresa Williams, Mayuri Patel, Lorraine R. Reitzel. Tobacco screening practices and perceived barriers in offering tobacco cessation services in the primary prevention of lung cancer among Texas healthcare centers providing behavioral health treatment. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P025.