Lung Cancer In Smokers Research Articles

Epidemiology of lung cancer and lung cancer screening programs in China and the United States.

Lung cancer is a heterogeneous disease that is impacted by environmental exposures and by constitutional genetic or epigenetic susceptibilities to disease development and progression. The United States and China have distinct and diverse populations and geographic environmental exposures that contribute to unique patterns of lung cancer incidence and mortality. In this paper, the authors compare trends of incidence and mortality of lung cancer in the US and China, and the impact on lung cancer screening programs in the two countries. It is worth noting that the mortality of lung cancer in the US has decreased gradually while in China it is still increasing over recent years. While decreasing smoking prevalence and the impact of clean air legislation have helped to mitigate the trend in the US relative to China, the increasingly widespread implementation of lung cancer chest CT screening is expected to impact lung cancer incidence and mortality in both countries. Currently there are few studies to compare the environmental and genetic risk factors for US and Chinese populations with regards to lung cancer incidence and mortality. The authors discuss the impact of gender and exposure risks, mainly smoking and environmental pollutants. Of high importance is the incidence of lung cancer in never smokers that is significantly higher in China than in the United States; this is particularly notable in women. These data suggest inclusion of ambient air pollution exposure and gender into lung cancer risk prognostic models to better capture high-risk individuals, especially for non-smoking women.

P2.11-23 Performance of Lung Cancer Risk Prediction Models in I-ELCAP Smokers

To determine the performance of lung cancer risk prediction models in predicting lung cancer in smokers enrolled in the International Early Lung Cancer Program (I-ELCAP). 62,071 asymptomatic ever-smokers enrolled into the international multi-institutions I-ELCAP for low-dose CT screening between 1993-2018. Demographics, smoking history, comorbidities, exposures and family history of lung cancer were collected at time of baseline CT scan. All participants received a baseline screening scan and subsequently annual repeat CT scans, and they were prospectively followed for the diagnosis of lung cancer. Diagnosis and treatment of lung cancer were verified and documented in the ELCAP Management System. To compare the predicted risk of lung cancer, we applied four lung cancer risk models: the Bach Model, the Liverpool Lung Project Incidence (LLPi) Risk model, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model 2012 (PLCOM2012), and the Pittsburgh Predictor Model to the I-ELCAP cohort. Model calibration and discrimination were assessed using expected-to-observed (E/O) ratio and the area under the curve (AUC) statistics. E/O ratio >1 indicates that the model predicts more lung cancer cases than observed. PLCOM2012 model was the most predictive of lung cancer for ever-smokers in I-ELCAP with the AUC 0.61 being the highest, followed by Bach model (AUC 0.58), LLPi model (AUC 0.57) and Pittsburgh Predictor (AUC 0.52). E/O ratios suggested that the PLCOM2012 model, Bach model, LLPi model and Pittsburgh Predictor model tends to overestimate the number of lung cancers. The LLPi model overestimated as many as 4 times more lung cancer cases. Using data from I-ELCAP, the four existing lung cancer risk prediction models have AUCs ranged between 0.52-0.61, PLCOM2012 model was the top performer out of the four models.

1355P - Tumour mutational burden and response to PD-1 inhibitors: An analysis of 89 cases of metastatic melanoma

BackgroundThe era of immunotherapy changed considerably prognosis of melanoma. Nonetheless, only around 40% can get benefit from this treatment, with no biomarkers identified for the therapeutic choice. On the basis of emerging clinical evidence, increased Tumor Mutational Burden (TMB) may be associated with higher sensitivity to immunotherapeutic agents. MethodsThe aim of this study was to analyze in advanced melanoma the relationship between the mutation load and: i) the histologic characteristics, ii) locations according to sun exposure and iii) response to PD-1 inhibitors, in advanced melanoma patients, in a retrospective multicentric analysis by sequencing using FoundationOne®. TMB was characterized as the number of somatic protein-coding base substitution or alterations mutations per megabase (Mb). DNA was extracted from paraffin embedded sections of primary tumor or metastasis. TMB was considered low between 1 and 5 muts/Mb, intermediate between 6 and 19, high if>20 muts/Mb. ResultsIn five centers in France, we included between October 2017 and March 2019 101 patients, aged from 16-year to 92-year-old, with metastatic melanomas. Results were available for 89 cases (12% DNA extraction failure). Acral (n=6, 20%), mucosal (n=5, 17%) and uveal melanoma (n=4, 13%) had a lower TMB compared to sun-exposed melanomas. No melanoma of non-sun-exposed areas had high burden (n=0); intermediate TMB was found in 21% (n=8) and low TMB in 63% of cases (n=19). Conversely, melanoma on chronic exposed areas (face and neck) had high TMB (5/7 cases; 71%). Complete and partial remission after 3 months of anti-PD-1 were more often observed in TMB high patients (n=4;20%) whereas in low and intermediate mutational patients, progression was found in respectively 62% (n=24) and 53% (n=16). ConclusionsTMB is affected by a variety of causes, including ultraviolet light in melanoma and smoking in lung cancer. Desmoplastic melanomas have been reported to have a high prevalence of somatic mutations whereas mucosal and acral have a 5-to 10-fold lower. Our study highlights the importance of TMB with higher response to PD-1 blockade. While it has to be confirmed, sun exposed areas or UV-signature may in be a valuable criterion in helping clinical decision-making. Editorial acknowledgementFoundation One Medicine and Roche Laboratories. Legal entity responsible for the studyFrench hospitals. FundingHas not received any funding. DisclosureC. Allayous: Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Amgen. All other authors have declared no conflicts of interest.

P2.11-08 CT Screening of Never Smokers

We wanted to update our previous reports of the impact of SHTS on lung cancer and cardiovascular disease in never smokers and the usefulness of low-dose CT (LDCT) screening using the I-ELCAP protocol. Never smokers, defined as having smoked less than 100 cigarettes in their lifetime, were enrolled in our LDCT screening program. All signed IRB-HIPAA compliant consents. Patient demographics, medical history, and validated SHTS-exposure questionnaire were obtained at baseline. The SHTS-exposure score was computed for all participants together with LDCT Ordinal score for coronary artery calcifications (CAC), emphysema, lung cancer diagnosis and treatment were documented. At two of the institutions, we also performed pulmonary function tests, and measured the main pulmonary artery (MPA) and ascending aorta (AA) measurements, determined the automated aortic calcium score and extent of atherosclerotic plaque present in the coronary arteries using CT angiograms. Frequency of abnormal pulmonary function (FEV1/FVC ratio<0.7) and MPA/AA ratio≥1.0 were evaluated. We examined the relationship between SHTS exposure and these disease conditions. Among 14,018 never smokers, 6733 (48.1%) were women, 7276 (51.9%) men. Among them, 5236 (37.4%) had at least one noncalcified nodules (NCNs). Of the 14,018, 855 (6.1%) had at least one NCN 6.0 mm but less than 15.0 mm for which follow-up LDCT is recommended and 113 (0.8%) had NCN 15.0 mm or larger (Table 1). Lung cancer was diagnosed in 55 (0.4%); 53(96.4%) resulting from findings on baseline LDCT and 2(3.6%) from the subsequent annual repeat LDCTs. Of the 55, 47 (85.5%) were clinical stage I; 49 had surgical resection, 4 treated with radiation therapy, and 2 with chemotherapy. Diagnosis was adenocarcinoma in 44, squamous-cell in 7, small-cell in 1 and other in 3. Post-surgically, 45 (81.8%) of the 47 were pathologic Stage IA (T1a-1cN0M0). Of the 14,018 never smokers, the CAC score was 0 for 10,956 (78.2%), 1-3 for 1941 (13.9%), and 4-12 for 1211(8.0%). Emphysema was present in 310 (2.2%) participants. The prevalence of lung cancer (p=0.04) was significantly associated with SHTS exposure, as was CAC (p<0.0001) and emphysema (p=0.03). In the subset of participants where additional measurements are available, abnormal pulmonary function tests (p=0.04), automated aortic calcium score (p=0.009), MPA/AA ratio≥1.0 (p=0.009) and presence and extent of coronary artery plaque (p<0.0001). These results suggest that LDCT screening is of benefit for never smokers exposed to SHTS for identification of early lung cancer, cardiovascular disease and emphysema.

S01.07 The U19 Plans for Integration of Biomarkers Into Future Lung Cancer Screening

The goal of the U19 Integrative analysis of Lung Cancer Etiology and Risk (INTEGRAL) consortium is to develop biomarkers that characterize individual risk for development and progression from lung cancer. We are using a comprehensive strategy, depicted below in Figure 1, for this analysis and we are drawing on world-wide resources and expertise. There are three projects focusing on i) genetics of smoking behavior and lung cancer risk, ii) biomarker discovery and validation for identifying individuals at highest risk for developing lung cancer and iii) evaluation of these biomarkers in screening cohorts along with radiographic analaysis to evaluate risk for lung cancer development and nodule behavior. There are also administrative and biostatistics cores. We will discuss strategies and novel findings from these projects. For Project 1, to assist in genetic analysis, we have reimputed all the available data from lung cancer cases and controls using the haplotype reference consortium to bring together a data lake comprising data from over 100,000 individuals. The consortium provides data to its members and to collaborators who would like to evaluate hypotheses related to lung cancer by providing access for analyses and we currently are supporting 107 projects evaluating lung cancer risk. Additionally, consortium members from the University of Laval have performed transcriptomic analysis of normal lung tissue from over 500 participants undergoing surgery for lung cancer treatment. We are also studying the role that genetic factors have in influencing smoking behavior by collaborating with other large consortia and by studying multiethnic variation using Hawaiian multiethnic populations. Analyses of the genetic data and further extension to the UK Biobank have identified novel genetic loci that contribute to risk. Interaction analysis of the CHRNA3/A5/B4 cluster with all other genomic regions identifies interactions with the 15q25.1 nicotinic receptors that influence lung cancer risk. Results identified genes in the neuroactive ligand receptor interaction pathway as playing a key role in increasing lung cancer risk. A cross-ethnicity analysis identified genetic factors in the major histocompatibility complex (MHC) that affect risk for lung cancer. We imputed sequence variation for 26,044 cases and 20,836 controls in classical HLA genes, fine-mapped MHC associations for lung cancer risk with major histologies and compared results among ethnicities. Independent and novel associations within HLA genes were identified in Europeans primarily affecting risk for squamous cell histology including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets affecting adenocarcinoma risk primarily that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter was better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility. A rare variant analysis yielded a mutation of the ATM gene that is rare in all populations except individuals of Jewish descent that primarily increase risk for adenocarcinoma and has highest risk in nonsmoking women. Analyses of smoking and genetic data have identified gene-smoking interactions that contribute to lung cancer risk, and particularly several genes that protect at-risk smokers from lung cancer development. Mendelian randomization and mediation analyses are underway to evaluate novel biomarkers that can be further studied in project 2. This effort found a surprising result that elevated levels of vitamin B12 increase risk for lung cancer development. Project 2 has been bringing together an approach to analyzing biomarkers using data from existing cohort consortia, which have collected samples prior to the clinical presentation of lung cancers. Results of an initial study showed that analysis of 4 circulating proteins (CEA125, CEA, CYFRA 21-1 and pro-SFTB) yielded an area under the receiver operator curve accuracy of 83%. This level of accuracy is sufficient to consider the panel for recruitment of individuals for screening studies, but we anticipate that adding additional biomarkers will further improve the accuracy of risk prediction. Biomarkers that are being further considered include additional protein markers along with micoRNA species, the inclusion of polygenic risk scores and additional serum-derived biomarkers like vitamins B-6 and B-12 that have been shown in mendelian randomization studies to help in identifying high risk subjects. Project 3 is focused on the establishment and validation of the models in the LDCT screening programs. In collaboration with National Lung Screening Trial, Canadian LDCT screening programs, NELSON and United Kingdom Lung Study (UKLS), we have begun the data harmonization across LDCT studies, including clinic-epidemiological data as well as nodule characteristics. We have established a pipeline of feature extractions for the radiomics analysis and compared the inter-reader variability. The intraclass correlation coefficients are >0.75 for the majority of the radiomics features extracted. We will conduct cross-study validation for the model building to ensure the maximum generalizability of the model. We will start the work on biomarkers and assess their added values in these models. biomarkers, early detection, genetics

Appraising the causal relevance of DNA methylation for risk of lung cancer.

BackgroundDNA methylation changes in peripheral blood have recently been identified in relation to lung cancer risk. Some of these changes have been suggested to mediate part of the effect of smoking on lung cancer. However, limitations with conventional mediation analyses mean that the causal nature of these methylation changes has yet to be fully elucidated.MethodsWe first performed a meta-analysis of four epigenome-wide association studies (EWAS) of lung cancer (918 cases, 918 controls). Next, we conducted a two-sample Mendelian randomization analysis, using genetic instruments for methylation at CpG sites identified in the EWAS meta-analysis, and 29 863 cases and 55 586 controls from the TRICL-ILCCO lung cancer consortium, to appraise the possible causal role of methylation at these sites on lung cancer.ResultsSixteen CpG sites were identified from the EWAS meta-analysis [false discovery rate (FDR) < 0.05], for 14 of which we could identify genetic instruments. Mendelian randomization provided little evidence that DNA methylation in peripheral blood at the 14 CpG sites plays a causal role in lung cancer development (FDR > 0.05), including for cg05575921-AHRR where methylation is strongly associated with both smoke exposure and lung cancer risk.ConclusionsThe results contrast with previous observational and mediation analysis, which have made strong claims regarding the causal role of DNA methylation. Thus, previous suggestions of a mediating role of methylation at sites identified in peripheral blood, such as cg05575921-AHRR, could be unfounded. However, this study does not preclude the possibility that differential DNA methylation at other sites is causally involved in lung cancer development, especially within lung tissue.

Nitric Oxide Metabolites and Lung Cancer Incidence: A Matched Case-Control Study Nested in the ESTHER Cohort.

Studies suggest that nitric oxide (NO) may have a possible role in lung carcinogenesis. This study is aimed to evaluate the association of the NO metabolites, namely, nitrite and nitrate, with lung cancer incidence. We conducted a matched case-control study (n = 245 incident lung cancer cases and n = 735 controls) based on the German ESTHER cohort (n = 9,940). Controls were matched to cases on age, sex, smoking status (never/former/current smoking), and pack-years of smoking. The sum of nitrite and nitrate was measured in urine samples using a colorimetric assay and was standardized for renal function by urinary creatinine. Conditional logistic regression models, adjusted for lifestyle factors, asthma prevalence, and family history of lung cancer, were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). Among incident lung cancer cases, high nitrite/nitrate levels were statistically significantly associated with current smoking, a low BMI, and the oxidative stress biomarker 8-isoprostane levels. Nitrite/nitrate levels in the top quintile were statistically significantly associated with lung cancer incidence: the OR (95% CI) was 1.37 (1.04-1.82) for comparison with the bottom quintile. This association was unaltered after additional adjustment for 8-isoprostane levels and C-reactive protein (CRP). In conclusion, this large cohort study suggested that subjects with high urinary nitrite/nitrate concentrations had an increased risk of lung cancer and this association was independent of smoking, CRP, 8-isoprostane levels, and other established lung cancer risk factors. Further studies are needed to validate these findings and to confirm the hypothesis that pathologically high levels of NO are involved in lung cancer development.

Angiotensin II-induced micro RNA-21 culprit for non-small-cell lung adenocarcinoma.

Lung cancer is among the most complicated cancers, with an estimated 1.6 million deaths each year for both men and women. However, the proportion of lung cancer patients in developing nations has increased from 31% to 49.9% in the last two decades. There are two main subtypes of lung cancer, small-cell lung carcinoma and non-small-cell lung carcinoma (NSCLC), accounting for 15% and 85% of all lung cancer, respectively. Adenocarcinoma is the most common type of lung cancer in smokers and nonsmokers in men and women regardless of their age. Chemicals in cigarette smoke and nicotine enter our bloodstream and can then affect the entire body and finally lead to the activation of several important, pro-survival signaling pathways. The biologically active peptide of RAAS on overstimulation enhance Ang II mediates cell proliferation, fibrosis and inflammatory effects via AT1 receptor. Very few studies highlight the diagnostic and therapeutic potential of miRNAs with the EGFR-regulated miRNA-21.

Smoking alters the evolutionary trajectory of non-small cell lung cancer.

Smoking is the biggest risk factor for lung cancer. Smokers have a much higher chance of developing lung tumors with a worse survival rate; however, non-smokers also develop lung tumors. A number of questions remain including the underlying difference between smoker and non-smoker lung cancer patients and the involvement of genetic and epigenetic processes in tumor development. The present study analyzed the mutation data of 100 non-small cell lung cancer (NSCLC) patients, 12 non-smokers, 48 ex-smokers and 40 smokers, from Tracking Non-Small Cell Lung Cancer Evolution through Therapy Consortium. A total of 68 genes exhibited different mutation patterns across non-smokers, ex-smokers and smokers. A number of these 68 genes encode membrane proteins with biological regulation, metabolic process, and response to stimulus functions. For each group of patients, the top 10 most frequently mutated genes were selected and their oncogenetic tree inferred, which reflected how the genes evolve during tumor genesis. By comparing the oncogenetic trees of non-smokers and smokers, it was identified that in non-smokers, the mutation of epidermal growth factor receptor (EGFR) was an early genetic alteration event and EGFR was the key driver, but in smokers, the mutation of titin (TTN) was more important. Based on network analysis, TTN can interact with spectrin α erythrocytic 1 through calmodulin 2 and troponin C1. These genetic differences during tumorigenesis of non-smoker and smoker lung cancer patients provided novel insights into the effects of smoking on the evolutionary trajectory of non-small cell lung cancer and may prove helpful for targeted therapy of different lung cancer subtypes.

The Associations of Fruit and Vegetable Intake with Lung Cancer Risk in Participants with Different Smoking Status: A Meta-Analysis of Prospective Cohort Studies.

The results of epidemiological studies on the relationship between fruit and vegetable intake and lung cancer risk were inconsistent among participants with different smoking status. The purpose of this study was to investigate these relationships in participants with different smoking status with prospective cohort studies. A systematic literature retrieval was conducted using PubMed and Scopus databases up to June 2019. The summary relative risks (RRs) and the corresponding 95% confidence intervals (CIs) were calculated by random-effects model. The nonlinear dose-response analysis was carried out with restricted cubic spline regression model. Publication bias was estimated using Begg’s test. Nine independent prospective studies were included for data synthesis. Dietary consumption of fruit was negatively correlated with lung cancer risk among current smokers and former smokers, and the summery RRs were 0.86 (95% CI: 0.78, 0.94) and 0.91 (95% CI: 0.84, 0.99), respectively. Consumption of vegetable was significantly associated with reduced risk of lung cancer for current smokers (summary RR = 87%; 95% CI: 0.78, 0.94), but not for former smokers and never for smokers. Dose-response analysis suggested that risk of lung cancer was reduced by 5% (95% CI: 0.93, 0.97) in current smokers, and reduced by 4% (95% CI: 0.93, 0.98) in former smokers with an increase of 100 grams of fruit intake per day, respectively. Besides, dose-response analysis indicated a 3% reduction in lung cancer risk in current smokers for 100 gram per day increase of vegetable intake (95% CI: 0.96, 1.00). The findings of this study provide strong evidence that higher fruit consumption is negatively associated with the risk of lung cancer among current smokers and former smokers, while vegetable intake is significantly correlated with reducing the risk of lung cancer in current smokers. These findings might have considerable public health significance for the prevention of lung cancer through dietary interventions.

Lycopene Inhibits Smoke-Induced Chronic Obstructive Pulmonary Disease and Lung Carcinogenesis by Modulating Reverse Cholesterol Transport in Ferrets

Chronic obstructive pulmonary disease (COPD) and lung cancer share the same etiologic factor, cigarette smoking. Higher consumption of dietary lycopene has been associated with lower risks of COPD and lung cancer in smokers. We investigated whether lycopene feeding protects against COPD and lung cancer in ferrets, a nonrodent model that closely mimics cigarette smoke (CS)-induced chronic bronchitis, emphysema, and lung tumorigenesis in human. We also explored whether the protective effect of lycopene is associated with restoring reverse cholesterol transport (RCT), a key driver in persistent inflammation with CS exposure. Ferrets (4 groups, n = 12-16/group) were exposed to a combination of tobacco carcinogen (NNK) and CS with or without consuming lycopene at low and high doses (equivalent to ∼30 and ∼90 mg lycopene/day in human, respectively) for 22 weeks. Results showed that dietary lycopene at a high dose significantly inhibited NNK/CS-induced chronic bronchitis, emphysema, and preneoplastic lesions, including squamous metaplasia and atypical adenomatous hyperplasia, as compared with the NNK/CS alone (P < 0.05). Lycopene feeding also tended to decrease the lung neoplastic lesions. Furthermore, lycopene feeding significantly inhibited NNK/CS-induced accumulation of total cholesterol, and increased mRNA expression of critical genes related to the RCT (PPARα, LXRα, and ATP-binding cassette transporters ABCA1 and ABCG1) in the lungs, which were downregulated by the NNK/CS exposure. The present study has provided the first evidence linking a protective role of dietary lycopene against COPD and preneoplastic lesions to RCT-mediated cholesterol accumulation in lungs.

Abstract SY26-02: Sherlock-Lung: Tracing lung cancer mutational processes in never smokers

Abstract Globally, about 2 million people are diagnosed with lung cancer annually, making it the most common type of cancer in the world. In addition, lung cancer is the leading cause of cancer death among both men and women, accounting for ~25% of all cancer deaths in the United States and ~19% of cancer deaths worldwide. Although tobacco smoking is the most common cause of lung cancer, it is estimated that 10-25% of all patients diagnosed with lung cancer worldwide are never smokers, with higher proportions in Asians and women. Compared to former and current smokers with lung cancer, lung cancers in never smokers tend to present at an earlier age and more frequently have adenocarcinoma histology. Although a few risk factors are known to contribute to the etiology of lung cancer in never smokers, a large fraction of cancer cases cannot be explained by established environmental and genetic risk factors, highlighting the need for research in this area. One promising approach to identify the etiological factors involved in lung tumorigenesis in never smokers is based on the study of the “mutational signatures” that the exogenous and endogenous processes leave on the tumor tissue and surrounding areas. Somatic mutations accumulate throughout individuals’ lifetime, as a result of the balance between DNA damage and DNA repair. Mutational sources can change over time and mutational signatures can provide information on the tumor evolutionary trajectory, tracking activities of mutational processes. We designed “Sherlock-Lung” to identify mutational signatures in lung cancers from never smokers and order them based on their clonal and subclonal localization to have an insight on the factors involved in the initiation of the tumors. Prevention and treatment strategies are likely to be more effective when targeting the tumor initiating factors rather than those responsible for the tumor progression. Here, we present the Sherlock-Lung study design, which includes a combination of lung cancer cases from populations highly exposed to lung cancer risk factors and populations with unknown exposures. We also present preliminary data from this study and what we have learned from whole genome sequencing analysis of the mutational landscape of lung cancers from smokers and nonsmokers and from different histological subtypes. For example, although the mutational signature associated with tobacco smoking is largely clonal in all lung cancers from smokers, consistent with an initiating role of tobacco smoking in lung tumorigenesis, the mutational signatures distribution varies across histological subtypes. Moreover, the frequency of mutations in major cancer driver genes varies dramatically between smokers and never smokers, and mutational signatures distribution appears to differ between tumors with and without specific driver genes. In never smokers, without the dominant mutational source of tobacco smoking, other signatures emerged, e.g., that associated with reactive oxygen species. Although this approach has already revealed important information on the etiological processes involved in tumorigenesis of lung cancer and other cancer types, there is a growing list of open questions and challenges that need to be addressed. In population studies, careful exposure assessment to identify and validate new mutational signatures and the inclusion of study subjects from different geographical locations and ethnicities are critical. Citation Format: Maria Teresa Landi, Tongwu Zhang, Montserrat Garcia-Closas, Yohan Bossé, Jianxin Shi, Bin Zhu, Qing Lan, Nathaniel Rothman, Jiyeon Choi, Neil E. Caporaso, Wei Zhao, Chongyi Chen, Eytan Ruppin, Jennifer Rosenbaum, Dmitry Gordenin, Sai Yendamuri, Chris Amos, Paul Brennan, David C. Christiani, Geoff Liu, Bonnie Gould Rothberg, Matthew Schabath, Han Liang, Ludmil Alexandrov, David Wedge, Stephen Chanock. Sherlock-Lung: Tracing lung cancer mutational processes in never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY26-02.

Integration of biological factors in the treatment plan evaluation in breast cancer radiotherapy.

Tumor biology and patient smoking status have clear effects on the benefit of breast radiotherapy. This study developed treatment evaluation strategies that integrated dosimetry, tumor aggressiveness and smoking status for patients undergoing hypo-fractionated whole breast irradiation with simultaneous integrated boost. The evaluation method Plan Quality Metrics (PQM) was adapted for breast cancer. Radiotherapy (RT) benefit was assessed for three levels of tumor aggressiveness; RT risk was estimated using mean dose to organs at risk and published Excess Relative Risk per Gy data for lung cancer and cardiac mortality for smokers and non-smokers. Risk for contralateral breast cancer was also evaluated. PQM and benefit/risk was applied to four patient groups (n = 10 each). Plans using 3D conformal radiotherapy (3DCRT), 3DCRT plus intensity-modulated radiation therapy (IMRT), 3DCRT plus volumetric modulated arc therapy (VMAT) and VMAT were evaluated for each patient. 3DCRT-IMRT hybrid planning resulted in higher PQM score (median 87.0 vs. 3DCRT 82.4, p < 0.01), better dose conformity, lower doses to the heart, lungs and contralateral breast. Survival benefit was most predominant for patients with high-risk breast cancer (>7% and >4.5% gain for non-smokers and smokers). For smokers with intermediate- or low-risk breast cancer, RT induced mortality risk dominated for all techniques. When considering the risk of local recurrence, RT benefitted also smokers (>5% and >2% for intermediate- and low-risk cancer). PQM methodology was suggested for breast cancer radiotherapy evaluation. Further validation is needed. RT was beneficial for all patients with high risk of recurrence. A survival benefit for smokers with low or intermediate risk of recurrence could not be confirmed.

Abstract 595: Circulating levels of coenzyme Q10 and lung cancer risk

Abstract Background: Coenzyme Q10 (CoQ10) is an ubiquitous molecule in living organisms that serves as a cofactor in energy production via the electron-transport chain (ETC). Research has previously shown that deficiencies in CoQ10 can result in a variety of detrimental outcomes including cardiovascular disease and neurological disorders. More recently, epidemiological studies have reported low CoQ10 levels being associated with increased risk of breast, ovarian, and skin cancers. However, studies exploring the link between CoQ10 and lung cancer risk are largely lacking. Methods: A nested case-control study including 201 lung cancer cases and 395 matched controls from the Southern Community Cohort Study (SCCS) was conducted. Plasma CoQ10 levels were measured using high-performance liquid chromatography (HPLC). A conditional logistic regression model was applied to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between plasma CoQ10 concentrations and lung cancer risk. CoQ10 level was categorized by tertile distribution among controls. Results: Plasma CoQ10 concentration was inversely associated with risk of lung cancer. Compared to the first tertile, the ORs (95% CI) were 0.82 (0.52-1.31) and 0.57 (0.34-0.96) for the second and third tertile, respectively, (P for trend=0.038), after adjusting for age, smoking status and pack-years of smoking. Additional adjustment for alcohol consumption, education, income, history of COPD and BMI slightly attenuated the association (OR=0.60, 95% CI=0.34-1.08, comparing third to first tertile). No notable difference was found between African Americans and European Americans. Stratified analysis identified a significant association between CoQ10 and lung cancer in current smokers (OR=0.47, 95% CI=0.26-0.87, third vs. first tertile), but not in former/never smokers (OR=0.84, 95% CI=0.35-2.03). The significant associations between CoQ10 and lung cancer risk were more evident in cases who were diagnosed within one year of blood draw (OR=0.17, 95% CI=0.04-0.73, third vs. first tertile, P for trend=0.023) than in cases diagnosed after one year following blood draw (OR=0.72, 95% CI=0.36-1.41). Conclusions: Findings from this study suggest that Coenzyme Q10 may be a potential marker for lung cancer, although the stronger effect shortly after diagnosis indicates the association may be related to dietary or other changes associated with the cancer diagnosis rather than CoQ10 being a causal risk biomarker. Further studies exploring the link between CoQ10 and lung cancer risk are necessary to better understand the role of CoQ10 in lung carcinogenesis. Citation Format: Chris Shidal, Hyung-Suk Yoon, Wei Zheng, Jie Wu, Adrian A. Franke, William J. Blot, Xiao-Ou Shu, Qiuyin Cai. Circulating levels of coenzyme Q10 and lung cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 595.

Abstract 3332: Clonal nuclear and mitochondrial genetic alterations in smoker lung cancer patients and their histologically normal appearing follow-up biopsies

Abstract Understanding the cascade of molecular events leading to metastatic progression of lung squamous cell carcinomas (LSCC) is critical to intervene with appropriate treatment options. In this era of precision medicine, identification of key genetic alterations through cutting edge technologies such as high-resolution single nucleotide polymorphism arrays and next generation sequencing have revolutionized cancer therapeutics and surveillance impacting overall survival. The present study investigated resected primary cancer tissues and matched bronchoscopically abnormal follow up mucosal biopsies from 4 LSCC patients with an aim to characterize clonal molecular genetic changes therein. A total of 25 samples including matched normal lymph node as control from these subjects were analyzed on Affymetrix high-resolution 250K SNP array (NspI) platform. Copy number loss and copy neutral loss (LOH) and genomic amplifications were measured in these samples and clonal molecular alterations were also assessed. We observed clonal copy number and copy neutral loss in various potential tumor suppressor genes (TSGs) including GPC5, LTBP1, SOX6, IRF2, LRP8, GSTT1, DAPK1, CACNA1C, DNAH8, CDKAL1, PPP2R2B, CDH4, MAL1D1, PTPRT, NRG2 and FMNL2. Notably, homozygous deletion was observed in one patient in 10q11.1-10q11.22 chromosomal region. The genes effected due to homozygous deletion includes: MARCH8, ANUBL1, FAM21C, CTGLF1, PTPN20A, PTPN20A, PTPN20B, FRMPD2L1, FRMPD2L2, SYP15, GPRIN2, PPYR1 and ANXA8. Clonal amplification (3-10 fold) of molecules that primarily function in mitochondria was also noted in primary cancer and corresponding mucosal biopsies of the majority of these subjects. This includes SUPV3L1, PDK2, MDH1, VDAC2, LONP1, NDUFA11, and OGG1, key molecules, which regulate normal mitochondrial function and homeostasis. Thus, molecular profiling of histologically normal appearing biopsies utilizing high-resolution SNP arrays identified primary cancer associated novel nuclear and mitochondrial genetic alterations in resected lung cancer patients who were heavy smokers. Presence of LSCC associated clonal genetic alterations in the histologically normal appearing mucosal biopsies suggests for possible treatment refractory secondary tumor evolution from the respiratory epithelium harboring the necessary molecular aberrations. Periodic navigation through molecular profiling of the resected LSCC patients and further functional characterization of the identified molecules could lead to the development of new monitoring and treatment strategies. Acknowledgement: Supported by UTHSCT, Willett Foundation and ECSU-NIH-MARC award. Note: This abstract was not presented at the meeting. Citation Format: Julie V. Philley, Kayla Johnston, Hirendra N. Banerjee, David E. Griffith, Santanu Dasgupta. Clonal nuclear and mitochondrial genetic alterations in smoker lung cancer patients and their histologically normal appearing follow-up biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3332.

Mortalité par cancer du poumon chez les hommes salariés selon l’activité professionnelle

The objective of this article is to describe the changes in lung cancer mortality among employed men over the period 1976-2005, according to their activity sector and socio-professional categories. This work was done as part of the Cosmop monitoring program. The socio-professional data come from the DADS panel constituted by INSEE. For each person of the panel, the vital status was searched until 2005 by matching the national file of medical causes of death managed by Inserm's CépiDC (Epidemiological Center for Mortality by Medical Causes). The results show large disparities in mortality among male employees by activity sector. Over the period 1976-2005, the rates vary twofold between the sector with the highest rate (Construction, 98 p.100,000 person-years) and the sector with the lowest rate (Education, 43 p.100,000 person-years). For most of the activity sectors, mortality rates increased between the periods 1976-1985 and 1986-1995 before decreasing over the period 1996-2005. Some activity sectors stand out by an increase in mortality over the study period. This is the case for construction, education and public administration. It is essential to continue the surveillance of cancers by social category and activity sector. This will permit us to identify sectors in which specific preventive actions should be carried out, particularly on smoking for lung cancer.

Cardiorespiratory Fitness Incidence and Mortality from Lung Cancer in Male Smokers

Cardiorespiratory Fitness Incidence and Mortality from Lung Cancer in Male Smokers

Association of inflammatory biomarkers with lung cancer in North Indian population.

Lung cancer is characterized by uncontrolled cell growth of the lung tissues. It is the leading cause of cancer-related deaths worldwide. The study aimed to determine the circulating CRP, TNF-α, IL-6 and IL-8 levels in lung cancer and healthy control and also established association between these biomarkers with the smoking status as well as the stages of the disease. 51 lung cancer patients and 51 healthy controls were enrolled in this case-control study. The serum levels of CRP, TNF-α, IL-6 and IL-8 were measured in lung cancer patients and healthy control groups. The levels of serum CRP, TNF-α, IL-6 and IL-8 were significantly higher in lung cancer patients when compared with controls(P<0.0001). The levels of these biomarkers were also significantly higher in stage iii/iv as compared to stage i/ii(P<0.001). Significant difference in the levels of these biomarkers were also found in smoker and non-smoker lung cancer patients as compared to controls(P<0.001). CRP, TNF-α, IL-6 and IL-8 are the promising biomarkers in the identification of lung cancer patients. The study also supports the association of inflammatory markers to lung cancer risk. Hence these findings suggest the levels of these biomarkers could be a useful tool for guiding the diagnosis of lung cancer.

Impact of smoke-free ordinance strength on smoking prevalence and lung cancer incidence.

6578 Background: Smoke-free ordinances (SFO) have been shown to decrease the prevalence of cardiovascular and pulmonary disease, but there is limited data on the impact of such policies on lung cancer incidence. We investigated the relationship between strength of county-level SFO with smoking prevalence and lung cancer incidence in Indiana. Methods: Following IRB approval, we queried the Indiana State Cancer Registry and Indiana Tobacco Prevention and Cessation Commission’s policy database between 1995 and 2016. County-level characteristics included population, income, poverty, education, race/ethnicity, sex, and rurality. Lung cancer diagnosis and stage were also collected. Using generalized estimating equations (GEE) with robust standard errors and accounting for the clustering effect at county level, we performed multivariable analyses of smoking prevalence and age-adjusted lung cancer rates with respect to the strength of smoke-free ordinances at the county level over time. Results: Indiana consists of 92 counties, 24 of which had SFO by 2011. In 2012, Indiana enacted a law mandating at least a moderate state-wide SFO. From 1995 to 2016, 110,935 Indiana residents were diagnosed with lung cancer. Indiana also had an average age-adjusted yearly lung cancer incidence of 76.8 per 100,000 population and average yearly smoking prevalence of 25% during this time. Smoking prevalence was 1.2% (95% CI [-1.88, -0.52]) lower in counties with comprehensive or moderate SFO compared with those with weak or no SFO. Counties that had comprehensive or moderate SFO had an 8.36 (95% CI [-11.45, -5.27]) decrease in new lung cancer diagnosis per 100,000 population per year compared with counties that had weak or no SFO. Conclusions: Stronger municipal smoke-free air ordinances are associated with decreased smoking prevalence and fewer new lung cancer cases. Strengthening smoke-free ordinances is paramount to decreasing lung cancer incidence.

A Study on Lung Cancer in non Smokers and Smokers in a Tertiary Care Hospital of Eastern India

A Study on Lung Cancer in non Smokers and Smokers in a Tertiary Care Hospital of Eastern India