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Luis M Montuenga

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    MS18 - Role of Biomarkers in Lung Cancer Screening (ID 81)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 6
    • Now Available
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      MS18.01 - Exhaled Breath Biomarkers (Now Available) (ID 3544)

      14:30 - 16:00  |  Presenting Author(s): Nir Peled

      • Abstract
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      Abstract

      The evoloving field of early detection of lung cancer is being implemented around the globe. Low Dose CT scans are standard of care in all guidelines, however real world implementation is stil lacking.

      Biomarker to support early detection is the current UNMET need, as well as non-invasive biomarkers to follow early disease recurrence and monitoring response to therapy.

      The exhaled breath approach is a growing field of interest, where several groups have contributed significant abount of data. There are numerous technologies available while clinical validation is varies between groups.

      This talk will score the current knoledge associated with the exhaled breath analysis associated with lung cancer. Surprizingly, the volatille signature is associated with disesae existance, disesae burden, response to therapy, disease profile and even the related mutatoins.

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      MS18.02 - Circulating Nucleic Acid Biomarkers (Now Available) (ID 3545)

      14:30 - 16:00  |  Presenting Author(s): Gabriella Sozzi  |  Author(s): Mattia Boeri, Ugo Pastorino

      • Abstract
      • Presentation
      • Slides

      Abstract

      Encouraging results in lung cancer (LC) mortality reduction were obtained by the introduction of low dose computed tomography (LDCT) for lung cancer screening. The results of Nelson screening trial showed a 26% reduction in lung cancer mortality in the LDCT arm thus confirming the benefit of LC screening with LDCT already published by the NLST group (1).

      In MILD trial we showed that at 10 years follow up the mortality reduction was even higher (-39%) proving that extended LDCT screening is effective in reducing lung cancer mortality (2).

      Nonetheless, the development of non-invasive complementary biomarkers could be helpful to improve the efficacy of LDCT screening by improving LC risk prediction and defining personalised LDCT screening intervals as well as to decrease false positives identified by LDCT and monitor disease evolution in patients after curative resection.

      The value of circulating tumor DNA (ctDNA) as a biomarker in advanced tumor stages is well established. However, its role in early lung cancer detection is still uncertain. The biggest technical challenge is sensitivity. Current efforts to develop next-generation sequencing (NGS) technologies to study ctDNA in the context of early detection might improve sensitivity in this context.

      The scientific community is awaiting the results of the Circulating Cell-free Genome Atlas (CCGA) Study for early cancer detection, enrolling 15,000 participants in the United States and Canada. Plasma samples collected at baseline and during 5 years of follow-up will be analyzed by whole genome sequencing(WGS) for copy number variation(CNV), targeted DNA sequencing (a 507-gene panel), and whole genome methylome profiling. Preliminary results in an observational case-control setting include 95% specificity, high sensitivity for advanced lung cancer in 54 patients (85% for targeted sequencing, 91% for CNV WGS, and 93% for methylome profiling), and modest sensitivity for 63 patients with stage I to III lung cancer (48% for targeted NGS, 54% for CNV WGS, and 56% for methylome profiling)(3). Therefore, the generalizability of these findings to the screening setting is uncertain.

      In order to implement lung cancer screening programs, we focused on circulating microRNAs which may reflect the contribution not only of the tumor but also of its microenvironment and the host. We developed a plasma miRNA Classifier (MSC) composed of 24 miRNAs which showed high performance in terms of sensitivity (87%) and specificity (81%) in 940 subjects enrolled in the MILD screening trial. The classifier was able to identify, in longitudinal plasma samples of the patients, a risk profile to develop LC up to two years before a significant tumor burden was visible at LDCT(4). These results prompted us to launch in 2013 a prospective screening trial, called bioMILD, to test the efficacy of a combined LDCT-MSC approach as forefront screening tests in a large cohort of 4119 smokers, 50 yrs or older. We succesfully completed the baseline of all the volunteers and executed a LDCT in 11,012 and miRNA test in 9,156 subjects. BioMILD has now reached the 3 yrs follow up for all subjects and 4.2 year median follow up for the all cohort. Analyses of the results are ongoing and will be presented.

      Concerning the origin of the 24 miRNA, since the classifier was able to identify a risk profile to develop lung cancer up to two years before the radiological diagnosis, we hypothesized that that such circulating miRNAs could be released not merely by cancer cells but rather by the damaged lung microenvironment and the host response that may sustain tumor development. Using in vitro models and clinical samples we showed that c-miRNAs originated mostly from blood cells, with activated neutrophils showing modulation of the 24 miRNAs overlapping that observed in plasma of MSC positive subjects(5).

      The role of immunity in modulating the risk of disease development remains to be elucidated, while it could have enormous impact in terms of prevention and early intervention. Therefore we characterized peripheral blood immune cell profiles as possible complementary biomarkers for risk assessment and analyzed their relationship with MSC. In a case control study of 40 lung cancer patients and 20 controls we found immune cell subpopulations differentially expressed between screening detected lung cancer patients and controls. Of interest an MSC high risk profile in patients was associated with specific circulating immune cell subsets including higher numbers of exausted T cells and monocytes/MDSC and lower cytotoxic T and NK cells. These findings suggest that MSC high risk profile might reflect an immunosuppressive status and prompted us to study the possible utility of MSC in lung cancer immunotherapy settings. Using a prospective cohort of 140 consecutive advanced NSCLC patients treated with immune checkpoints inhibitors we found that MSC either alone or in combination with PD-L1 expression in the tumor was associated with patients survival(6). Therefore, plasma MSC, reflecting an impaired tumor immune contexture, could supplement PD-L1 tumor expression to identify a subgroup of patients who do not benefit from immunotherapy.

      References:

      D.R. Aberle, A.M. Adams, C.D. Berg, et al.Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med, 365 (2011), pp. 395-409

      Pastorino U, Silva M, Sestini S. et al. Prolonged Lung Cancer Screening Reduced 10-year Mortality in the MILD Trial. Ann Oncol. 2019 Apr 1.

      GR. Oxnard T. Maddala E. Hubbell et al. Genome-widesequencing for early stage lung cancer detection fromplasma cell-free DNA (cfDNA): the Circulating CancerGenome Atlas (CCGA) study. Paper presented at: 2018 American Society of Clinical Oncology Annual Meeting.June 1–5, 2018; Chicago, IL

      Sozzi G, Boeri M, Rossi M.et al. Clinical Utility of a Plasma-based microRNA Signature Classifier within Computed Tomography Lung Cancer Screening: A Correlative MILD Trial Study. J Clin Oncol. 2014 Mar 10;32(8):768-73.

      Fortunato O, Borzi C, Milione M, et al.Circulating mir-320a promotes immunosuppressive macrophages M2 phenotype associated with lung cancer risk. Int J Cancer. 2019 Jun 1;144(11):2746-2761. doi: 10.1002/ijc.31988. Epub 2019 Jan 6.

      Boeri M, Milione M, Proto C. et al. Circulating miRNAs and PD-L1 Tumor Expression Are Associated with Survival in Advanced NSCLC Patients Treated with Immunotherapy: a Prospective Study. Clin Cancer Res. 2019 Apr 1;25(7):2166-2173. doi: 10.1158/1078-0432.CCR-18-1981. Epub 2019 Jan 7.

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      MS18.03 - Amolecular Diagnostics, Incorporating GWAS and Risk Models: Future Approaches to the Identification of High-Risk Individuals (Now Available) (ID 3546)

      14:30 - 16:00  |  Presenting Author(s): Paul Brennan  |  Author(s): Christopher Ian Amos

      • Abstract
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      Abstract

      Role of Biomarkers in Lung Cancer Screening

      As a part of ongoing research to understand the etiology and early detection of lung cancer, the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) consortium has been genotyping large numbers of lung cancer cases and controls and analyzing biomarkers from case cohort members prior to their diagnosis with lung cancer and matched controls. We are also assembling knowledge about predictors of lung cancer risk to identify biomarkers that will be applied along with radiomic features to select individuals at highest risk for lung cancer to enroll in screening studies and to assist in resolution of cancer risk among those found to have small nodules. To date we have analyzed genetic data from 29,266 patients and 56,450 controls of European descent(1) and curated genotyping information from 20 studies conducted in European descent, 14 from Asian descent and 1 study in African-American Populations(2). Ongoing imputation is allowing us to integrate most of these data for a further analysis that brings together world populations for genetic discovery. Results of these studies have identified 12 strongly replicated loci and an additional 38 loci that are highly significant in some studies but less well replicated. Among the variants that we identified, a variant in BRCA2 (1) is remarkable for conferring over 2 fold increased risk for lung cancer development independent of smoking behavior and thereby indicating a small subset of high risk individuals based on genotype. Further studies to identify rare variants that confer a high risk of lung cancer have identified mutations in ATM and KIAA0930 with odds ratios well over 2. The ATM variant is associated with loss of heterozygosity in tumors but does not cause Ataxia Telangiectasia in homozygotes. We have used genetic information to develop polygenic risk scores and a model that included 221 variants yielded the most improvement in accuracy. Results comparing models to identify individuals at high risk for lung cancer development based on risk scores compared with models based on demographic, clinical and smoking information show a modest increase in prediction accuracy, but identify selected individuals who are at high risk and for whom lung screening would be particularly indicated.

      The genetic information we have developed and curated can also be used with additional approaches to identify predictors of lung cancer risk using shared heritability and Mendelian randomization analyses. Shared heritability analysis identifies strong genetic correlations with all measures of smoking behavior and also with primary biliary cirrhosis and schizophrenia. Mendelian randomization, which removes concerns about change in BMI during cancer development, shows that increased BMI is associated with squamous and small cell lung cancer and not associated with adenocarcinoma(3). Mendelian randomization studies found association of increased lung cancer risk with longer germline telomere length and increased risk associated with higher levels of vitamin B12(4). Further Mendelian randomization studies are underway to evaluate other biochemical factors that may associate with increased lung cancer risk.

      Cohort studies to identify biomarker signatures of risk have identified a reliable panel(5) comprising CEA125, CEA, CYFRA 21-1 and pro-SFTB that along with smoking behavior provide an area under the receiver operator curve of 83%, indicating that a strategy that seeks to identify high risk individuals using data from questionnaires about smoking along with biomarker analysis could substantially improve the yield of low dose spiral CT screening. Further studies of panels of biomarkers including microRNA and circulating cell-free DNA are underway to evaluate the utility of adding additional biomarkers to further identify higher risk individuals.

      1. McKay JD, et al. (2017) Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes. Nature genetics 49(7):1126-1132.

      2. Bosse Y & Amos CI (2018) A Decade of GWAS Results in Lung Cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 27(4):363-379.

      3. Carreras-Torres R, et al. (2017) Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study. PloS one 12(6):e0177875.

      4. Fanidi A, et al. (2018) Is high vitamin B12 status a cause of lung cancer? International journal of cancer. Journal international du cancer.

      5. Integrative Analysis of Lung Cancer E, et al. (2018) Assessment of Lung Cancer Risk on the Basis of a Biomarker Panel of Circulating Proteins. JAMA oncology 4(10):e182078.

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      MS18.04 - Alternative and Promising Biomarkers (Now Available) (ID 3547)

      14:30 - 16:00  |  Presenting Author(s): Ruben Pio

      • Abstract
      • Presentation
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      Abstract

      Randomized controlled trials have demonstrated that lung cancer screening with low-dose computed tomography (LDCT) in subjects at risk is associated with a decrease in mortality (1-3). However, concerns regarding false positive findings, overdiagnosis, or selection criteria may limit their implementation and sustainability. The use of molecular biomarkers that help to overcome some of these limitations offers great potential. Biomarkers should be non-invasive, reproducible and improve the current standard of care for their intended use. Biomarkers could complement image-based screening in two different ways. First, they may allow refinement of screening selection criteria, independent of age and smoking habits, reducing the numbers of individuals exposed to screening and follow-up interventions. Worldwide collaborative efforts have been implemented to gain insights into the association between SNPs and common cancers (4). Lung cancer-associated single nucleotide polymorphisms (SNPs) identified in these studies may be integrated in risk models to limit the costs of lung cancer screening. Secondly, the combination of radiological findings with molecular biomarkers may facilitate the management of indeterminate pulmonary nodules (IPNs). The implementation of LDCT screening programs is rapidly increasing the detection of IPNs, which too often leads to unnecessary follow-up CTs, or even invasive procedures. Molecular markers may help to differentiate patients with malignant IPNs from the larger number of subjects with benign nodules.

      At present, no molecular biomarker of lung cancer is being used in routine clinical practice. The tremendous research efforts regarding the development and use of molecular biomarkers in lung cancer screening have recently been reviewed (5). Biomarkers can derive from cancer cells, the tumor microenvironment, or the immune response to cancer. They can be sampled from many different bodily sources, including whole blood, serum, plasma, airway epithelium, sputum, exhaled breath, or urine. Promising molecular candidates include proteins (e.g. cancer-associated antigens, autoantibodies or other immune-related markers), metabolites, microRNAs, epigenetic markers, DNA mutations or RNA signatures. Markers of this kind are at different phases of development, ranging from their analytical validation to the evaluation of their performance in the intended use population. Ultimately, evaluation of the biomarker in real clinical settings will determine its improvement of current standards and cost. Few biomarkers have reached the clinical testing phase. The application of an RNA-based signature in bronchial epithelial cell samples from the AEGIS-1 and AEGIS-2 prospective multicenter observational trials (NCT01309087 and NCT00746759) improved the diagnostic performance of bronchoscopy for the detection of lung cancer (6). In PANOPTIC (NCT01752114), a prospective multicenter observational study, plasma levels of two proteins, LG3BP and C163A, were used to discriminate benign from malignant nodules (7). The bioMILD study (NCT02247453) is prospectively evaluating the efficacy of a plasma microRNA profiling as a first line-screening test for lung cancer detection. The clinical utility of another microRNA-based signature is been validated in blood samples prospectively collected in the COSMOS-II lung cancer screening trial (8). ECLS (NCT01700257) is a randomized study aimed to assess the clinical and cost effectiveness of a test that measures a panel of seven tumor-associated autoantibodies in blood (9). The study has reached its 12,000-participant target, and initial results are expected soon. The DECAMP consortium is conducting two multicenter prospective observational trials (NCT01785342 and NCT02504697) designed to develop an integrated panel of airway and blood-based molecular markers. DECAMP-1 seeks to improve the discrimination between benign and malignant IPNs, whereas DECAMP-2 will test biomarkers to predict the development of lung cancer in screened asymptomatic high-risk individuals. Novel approaches to overcome sensitivity/specificity limitations are also being tested. Host responses to cancer based on activation of the immune system have proved to provide promising diagnostic and prognostic markers applicable in the context of lung cancer screening (10). A diagnostic signature based on the combined determination of complement-activation fragments and cancer-associated proteins has shown a notable capacity to discriminate those patients with malignant IPNs. Next-generation sequencing technologies are also starting to be applied. The CCGA study (NCT02889978) has recently concluded the enrollment of 15,000 participants (more than 10,000 of them with a diagnosis of cancer) from whom longitudinal plasma samples are being collected and analyzed by DNA sequencing and methylation profiling. This study will provide valuable information about the potential application of deep sequencing technologies in circulating cell-free DNA for the early detection of lung cancer. Finally, deep learning approaches will allow the integration of several levels of information (e.g. radiographic features, clinical characteristics and molecular biomarkers) for the generation of more accurate predictive models.

      In conclusion, molecular biomarkers are potentially useful adjuncts to LDCT screening for lung cancer, either by refining risk prior to LDCT or by assessing malignancy. A remarkable amount of discovery and clinical validation work is ongoing. However, more evidence is still needed to support the implementation of any of the proposed biomarkers in the routine clinical practice. Further development of emerging biomarkers, new technological and integrated approaches, better metrics of clinical utility, and innovative trial designs will be required to speed up the development of lung cancer early detection biomarkers.

      References:

      1. Aberle DR et al. N Engl J Med 2011; 365: 395-409.

      2. De Koning HJ et al. IASLC 19th WCLC 2018; Abstract PL02.05.

      3. Pastorino U et al. Ann Oncol 2019 [Epub ahead of print].

      4. McKay et al. Nat Genet 2017; 49: 1126-1132.

      5. Seijo et al. J Thorac Oncol 2019; 14: 343-357.

      6. Silvestri GA et al. N Engl J Med 2015; 373: 243-251.

      7. Silvestri GA et al. Chest 2018; 154: 491-500.

      8. Marzi M et al. Clin Chem 2016; 62: 743-754.

      9. Sullivan FM et al. BMC Cancer 2017; 17: 187.

      10. Ajona D et al. J Natl Cancer Inst 2013; 105: 1385-1393.

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      MS18.05 - Sputum Biomarkers, Dysplasia and Chemoprevention (Now Available) (ID 3548)

      14:30 - 16:00  |  Presenting Author(s): Robert L. Keith

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      Abstract

      The most dramatic improvements in lung cancer survival will emerge from both early detection and the prevention of disease development. Low dose CT screening trials (NLST and NELSON) have shown significant improvements in survival and advances in lung cancer screening will rely on our ability to better define at risk populations and to more personalize the management of indeterminate pulmonary nodules. This includes identifying and validating biomarkers of risk. The NIH defines biomarkers as ‘characteristics that are objectively measured and evaluated as indicators of normal biologic processes, pathologic processes, or pharmacologic responses to therapeutic interventions’1. The ideal biomarker has excellent sensitivity and specificity and applications to lung cancer screening will mostly focus on two specific areas. The first is improving the selection of at-risk subjects to be screened, and the second is to guide the management of screening detected pulmonary nodules.

      Biomarkers of lung cancer risk can include a variety of potential biospecimens, ranging from sputum and exhaled breath condensates to endobronchial and peripheral lung biopsies. Expectorated sputum has long been viewed as a ‘window to the central airways’ and cytologic changes have been observed in sputum samples to predict the presence of lung cancer2. While sputum cytology can also predict the presence of pre-malignant central airway lesions, sputum collection has largely fallen out of favor due to perceived difficulties in collecting and interpreting specimens, and advances in analyzing other specimens like blood, urine and exhaled breath. Sputum is a readily available resource, and recent methodological advances, most notably automated 3-dimensional morphologic analysis of sputum3, are currently being studied to determine the presence of cancer or pre-malignant lesions. It may also help risk stratify subjects with suspicious LDCT findings. Additional studies have also focused on sputum samples. For example, selected gene promoter methylation in exfoliated cells from sputum has been shown to predict cancer up to 18 months prior to diagnosis4. Other groups have examined sputum miRNA, and their stability make them potentially attractive biomarkers. One study conducted qRT-PCR studies of sputum from subjects with indeterminate pulmonary nodules and found a panel of 3 miRNAs (miRs 21, 31, and 210) with good sensitivity and specificity for identifying malignant nodules5. More recently, a pilot study using metagenetic sequencing of the sputum microbiome suggests there may be bacterial biomarkers indicating the presence of lung cancer6. Exhaled breath condensate is an additional biospecimen that has been studied as an adjunct to screening protocols, and the subject is extensively reviewed in a recent publication7.

      For NSCLC, specific pre-malignant histologic lesions have been used as biomarkers of risk and modifiable endpoints in chemoprevention trials. For adenocarcinoma, atypical adenomatous hyperplasia (AAH, a lesion more commonly found now that more ground glass opacities are noted during LDCT screening) can progress to adenocarcinoma in situ and eventually adenocarcinoma. Multiple studies are currently profiling AAH lesions with a goal of better understanding those that progress to invasive cancer. Lung squamous cell carcinoma (SCC) develops in the central airways where pre-malignant lesions progress through advancing levels of dysplasia (mild, moderate, and severe), followed by carcinoma in situ and ultimately invasive SCC. Change in endobronchial histology has been the primary endpoint in multiple SCC chemoprevention trials8, and longitudinal research has revealed an increased cancer risk in subjects with multiple lesions that persist or progress over time9. Endobronchial dysplasia that regresses (i.e. fails to become invasive cancer) is associated with specific immune responses and ongoing studies are characterizing the lesional immune microenvironment of bronchial dysplasia. This will allow for a better understanding of progressive lesions and advance the field of precision chemoprevention.

      1. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical pharmacology and therapeutics 2001;69:89-95.

      2. Saccomanno G, Archer VE, Auerbach O, Saunders RP, Brennan LM. Development of carcinoma of the lung as reflected in exfoliated cells. Cancer 1974;33:256-70.

      3. Wilbur DC, Meyer MG, Presley C, et al. Automated 3-dimensional morphologic analysis of sputum specimens for lung cancer detection: Performance characteristics support use in lung cancer screening. Cancer cytopathology 2015;123:548-56.

      4. Leng S, Do K, Yingling CM, et al. Defining a gene promoter methylation signature in sputum for lung cancer risk assessment. Clin Cancer Res 2012.

      5. Xing L, Su J, Guarnera MA, et al. Sputum microRNA biomarkers for identifying lung cancer in indeterminate solitary pulmonary nodules. Clinical cancer research : an official journal of the American Association for Cancer Research 2015;21:484-9.

      6. Cameron SJS, Lewis KE, Huws SA, et al. A pilot study using metagenomic sequencing of the sputum microbiome suggests potential bacterial biomarkers for lung cancer. PloS one 2017;12:e0177062.

      7. Marzorati D, Mainardi L, Sedda G, Gasparri R, Spaggiari L, Cerveri P. A review of exhaled breath: a key role in lung cancer diagnosis. Journal of breath research 2019;13:034001.

      8. Keith RL, Miller YE. Lung cancer chemoprevention: current status and future prospects. Nat Rev Clin Oncol 2013;10:334-43.

      9. Merrick DT, Gao D, Miller YE, et al. Persistence of Bronchial Dysplasia Is Associated with Development of Invasive Squamous Cell Carcinoma. Cancer Prev Res (Phila) 2016;9:96-104.

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      MS18.06 - Captive Audience, Teachable Moment - Integrating Tobacco Cessation in Lung Cancer Screening (Now Available) (ID 3549)

      14:30 - 16:00  |  Presenting Author(s): Martin Tammemagi

      • Abstract
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      Abstract

      Cigarette smoking causes more than 480,000 deaths each year in the United States.1Smoking has been causally linked to cancers of the oropharynx, larynx, esophagus, trachea, bronchus, lung, stomach, liver, pancreas, kidney, ureter, cervix, bladder and colorectum and acute myeloid leukemia, as well as to stroke, blindness, cataracts, age-related macular degeneration, periodontitis, aortic aneurysm, early abdominal aortic atherosclerosis, coronary heart disease, pneumonia, atherosclerotic peripheral vascular disease, chronic obstructive pulmonary disease, tuberculosis, asthma, diabetes, reproductive disorders, ectopic pregnancies, erectile dysfunction, hip fractures, rheumatoid arthritis and immune dysfunction.1Lung cancer screening is most effective when applied to individuals at high risk.2Using NLST data, Figure 1 describes how the number of competing-causes deaths, primarily smoking related, increases with lung cancer risk, primarily driven by smoking, and how competing-causes deaths exceeds lung cancer deaths. Successful smoking interventions have the potential to greatly reduce morbidity and mortality in lung cancer screenees. It is likely that smoking cessation interventions in lung cancer screening programs will be cost-effective and may lead to health benefits that exceed those of the lung cancer mortality reduction benefits. Current, U.S. guidelines recommend providing smoking cessation interventions for current smokers in lung cancer screening programs. However, which type of smoking cessation program in the lung cancer screening setting is most effective is unknown.

      Lung cancer screenees generally have longer and more intense smoking histories so they may be more intractable to cessation interventions. On the other hand, screening may provide a teachable moment, which may lead to greater rates of cessation.3The proportion of current smokers selected for screening is greater when selected by risk prediction model, than when selected by NLST-like criteria. The proportion of current smokers in the NLST was 48.2%, in PLCO NLST-eligible participants was 40.4%, and in the Pan-Canadian Early Detection of Lung Cancer Study and Cancer Care Ontario (CCO) pilot, both of which have eligibility criteria of PLCOm2012 6-year risks ≥2%, were 62.8% and 65.4%, respectively.

      Two recent reviews concluded that evidence is lacking to recommend specific tailored smoking cessation approach in the lung cancer screening setting and recommend more research.4,5Currently, in the U.S., 8 trials in the SCALE (Smoking Cessation within the Context of Lung Cancer Screening) collaboration are underway that are investigating different smoking cessation interventions within lung cancer screening programs.6Some of the factor under study in SCALE include the following6:participant eligibility criteria, baseline versus annual screen, participant’s interest in stopping smoking, treatment delivery method and dose, incorporation of positive and negative screening results, perceived risk of lung cancer, and costs of treatments.Results of SCALE are expected after 2021.

      Recently, Cadham and colleagues conducted a meta-analysis of smoking cessation interventions in samples that were similar to those in lung cancer screening programs.7At 6-month follow-up, smoking cessation had the following associations with interventions:

      Electronic/web-based (odds ratio [OR] 1.14, 95% CI 1.03-1.25)

      Telephone counseling (OR 1.21, 95% CI 0.98-1.50)

      In-person counseling (OR 1.46, 95% CI 1.25-1.70)

      Pharmacotherapy (OR 1.53, 95% CI 1.33-1.77).

      CCO’s Lung Cancer Screening Pilot for People at High Riskstarted low dose computed tomography screening in three sites on June 1, 2017. In the first year of screening, 1624 individuals received LDCT scans and current smokers were enrolled in an “opt-out” in-hospital smoking cessation programs. Of scanned participants 88.8% attended in-hospital smoking cessation counselling, and 95.2% were satisfied with their cessation services.

      In conclusion, several intervention approaches appear to be associated with smoking cessation. Multiple approaches appear better than single approaches. Pharmacotherapy and in-person counseling interventions appear to be superior to electronic/web-based or telephone counseling. Successful enrollment into in-person cessation programs is achievable.

      References

      1. United States. Public Health Service. Office of the Surgeon General., National Center for Chronic Disease Prevention and Health Promotion (U.S.). Office on Smoking and Health. The health consequences of smoking--50 years of progress : a report of the Surgeon General.Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014.

      2. Tammemagi MC, Katki HA, Hocking WG, et al. Selection criteria for lung-cancer screening. The New England journal of medicine. 2013;368(8):728-736.

      3. Taylor KL, Cox LS, Zincke N, Mehta L, McGuire C, Gelmann E. Lung cancer screening as a teachable moment for smoking cessation. Lung cancer (Amsterdam, Netherlands). 2007;56(1):125-134.

      4. Iaccarino JM, Duran C, Slatore CG, Wiener RS, Kathuria H. Combining smoking cessation interventions with LDCT lung cancer screening: A systematic review. Preventive medicine. 2019;121:24-32.

      5. Pineiro B, Simmons VN, Palmer AM, Correa JB, Brandon TH. Smoking cessation interventions within the context of Low-Dose Computed Tomography lung cancer screening: A systematic review. Lung cancer (Amsterdam, Netherlands). 2016;98:91-98.

      6. Joseph AM, Rothman AJ, Almirall D, et al. Lung Cancer Screening and Smoking Cessation Clinical Trials. SCALE (Smoking Cessation within the Context of Lung Cancer Screening) Collaboration. American journal of respiratory and critical care medicine. 2018;197(2):172-182.

      7. Cadham C. Systematic Review and Meta-Analysis of Smoking Cessation Interventions for Potential Use in Lung Cancer Screening Settings: 6- and 12-Month Outcomes. . American Society of Preventive Oncology Annual Meeting ASPO 2019; Monday, March 11, 2019, 2019; Tampa, Florida.

      8. Tammemagi MC, Church TR, Hocking WG, et al. Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts. PLoS medicine. 2014;11(12):e1001764.

      Figure 1. Lung cancer and competing causes deaths in the National Lung Screening Trial by PLCOm2012 model risk level (taken from 8)

      nlstdeathsbyintervention.png

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    OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Biology
    • Presentations: 9
    • Now Available
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      OA08.01 - Organoid Cultures as Novel Preclinical Models of Non-Small Cell Lung Cancer (Now Available) (ID 2115)

      11:00 - 12:30  |  Presenting Author(s): Ming Sound Tsao  |  Author(s): Roushi Shi, Nikolina Radulovich, Christine Ng, Hirotsugu Notsuda, Michael Cabanero, Sebastiao N Martins-Filho, Vibha Raghavan, Quan Li, Arvind Singh Mer, Ni Liu, Nhu-An Pham, Benjamin Haibe-Kains, Geoffrey Liu, Nadeem Moghal

      • Abstract
      • Presentation
      • Slides

      Background

      There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease. Organoids, which are cells grown in three-dimensional environments in Matrigel, have emerged as novel preclinical models of cancer. Recently protocols for generating NSCLC organoids have been reported, but the growth, and molecular features of organoids as compared to their matching primary patient tumor or patient-derived xenografts (PDX) remain vague.

      Method

      Thirty surgically resected NSCLC patient tumor and 35 PDX tissue of lung adenocarcinoma and squamous cell carcinoma subtypes were processed for organoid establishment. Organoids and matching tumor tissues were characterized by histology and immunohistochemistry, and molecularly profiled by whole exome and RNA-sequencing. Subcutaneous injection of organoids in vivo was performed to confirm tumorgenicity. Organoids were subjected to drug testing and drug response was verified in the matched PDX.

      Result

      Using a novel culture condition that our laboratory developed, we have collected tumor samples from 16 primary and 13 PDX samples of adenocarcinoma (n=29) and 14 primary and 22 PDX samples of squamous cell carcinoma (n=36). Over 85% (57/65) of our patient and PDX tumor tissues formed organoids that exhibited a wide range of short-term (<3 months) and long-term (>3 months) growth. Specifically, the success rate of establishing short-term and long-term models are 74% (48/65) and 14% (9/65), respectively. The long-term propagable organoids recapitulated the histology of the patient and PDX tumor. They also retained the ability to form xenograft in NOD-SCID mice. The organoids preserved mutation, copy number aberrations and global gene expression profile of the parental tumors. We additionally showed the utility of short-term and long-term organoids for identifying biomarkers of sensitivity to drugs and combinational targeted therapies.

      Conclusion

      NSCLC organoids are novel patient-derived ex-vivo tumor models for anti-cancer drug screening and biomarker discovery, thus could be incorporated into novel drug discovery pipelines. Further efforts are ongoing to increase the success rate of establishing long-term organoid lines.

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      OA08.02 - A Multidisciplinary Multi-Omics Study of Spatial and Temporal Tumor Evolution in Thoracic Cancers with Clinical Implications (Now Available) (ID 2365)

      11:00 - 12:30  |  Presenting Author(s): Matthieu Foll  |  Author(s): Nicolas Alcala, Lise Mangiante, Arnaud Poret, Aurélie Gabriel, Jules L Derks, Laura Moonen, Sandrine Boyault, Nolwenn Le Stang, Akram Ghantous, Séverine Tabone-Eglinger, Francesca Damiola, Jean-Yves Blay, James McKay, Anne Marie Clasina Dingemans, Ernst-Jan M Speel, Christophe Caux, Nicolas Girard, Sylvie Lantuejoul, Talya Dayton, Francoise Galateau Sallé, Lynnette Fernandez-Cuesta

      • Abstract
      • Presentation
      • Slides

      Background

      In the context of the MESOMICS and lungNENomics projects1, we generated comprehensive molecular profiles of Malignant Pleural Mesothelioma (MPM)2 and pulmonary carcinoids (PCa)3. We showed that a continuous molecular model can better explain the prognosis of MPM than the three histologies, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples. We also identified a new entity of PCa (supra-carcinoids) with carcinoid-like morphology yet the molecular and clinical features of LCNEC, which challenges the general believe that PCa have no relationship or genetic, epidemiologic, and clinical traits in common with LCNEC and SCLC. These two studies suggest an important role of heterogeneity in the biology of these tumors.

      Method

      Much progress has been made in revealing the evolutionary history of individual cancers, in particular using multi-region sequencing. However, most studies focused on a single ‘omic technique, and lacked temporal samples. Here we present the results of an innovative approach to study spatial and temporal tumor evolution based on (i) integration of whole-genome and transcriptome sequencing and EPIC 850K methylation arrays on multiple regions from 12 MPM, and (ii) a novel tumor-derived organoid-based strategy for studying the evolution of PCa.

      mesomics_example.png

      Figure 1. Multi-omic multi-regional profiling of a MPM patient. A) Somatic Copy Number Variants (CNV), somatic Structural Variants (SV), kernel density plots of (top) somatic single nucleotide variants (SNVs) allelic fractions, (middle) expression normalized read counts, and (bottom) methylation array M-values. B) Projection of the transcriptomic profile of two tumoral regions into the Principal Component Analysis (PCA) space computed from 284 malignant pleural mesotheliomas2C) Expression (z-score of normalized read counts) for two clinically relevant genes with substantial inter-regional differences.

      Biorepositories: French MESOBANK; LungNEN Network

      Result

      In the data analyses of the 12 MPM we detected significant intra-tumor heterogeneity (ITH) in the expression of immune checkpoints and pro-angiogenic genes (see example in Fig. 1). This might explain the modest and variable response to treatment in clinical trials assessing immunotherapies and antiangiogenic drugs. In the case of PCa, we are currently analysing the organoids genomic data and we will present the preliminary data for the temporal evolution of these diseases.

      Conclusion

      We found that our approach can detect clinically and biologically meaningful ITH. All the computational methods we developed for these evolutionary studies are available to the scientific community4.

      1RareCancersGenomics.com
      2Alcala et al., under review in Cancer Res
      3Alcala et al., under review in Nat Commun
      4https://github.com/IARCbioinfo

      LFC and MF co-supervised this work

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      OA08.03 - A Single-Cell Resolution Map of EMT and Drug Resistance States for Evaluating NSCLC Clinical Specimens (Now Available) (ID 2771)

      11:00 - 12:30  |  Presenting Author(s): Loukia Georgiou Karacosta  |  Author(s): Benedict Anchang, Nikolaos Ignatiadis, Samuel C Kimmey, Jalen A Benson, Joseph B Shrager, Arthur Wai Sung, Joel W Neal, Heather A Wakelee, Robert Tibshirani, Sean C Bendall, Sylvia K Plevritis

      • Abstract
      • Presentation
      • Slides

      Background

      The role of epithelial-mesenchymal transition (EMT) in NSCLC is well reported and has been shown to prime cells for metastasis. EMT can be adopted or reversed (i.e. mesenchymal-epithelial transition, MET) by cells, revealing plasticity that can also lead to drug resistance. Although it is appreciated that EMT is not a binary process of two extremes but instead a spectrum of intermediate states of EMT phenotypes, these are poorly defined at the single-cell proteomic level in NSCLC clinical specimens. Our overall goal was to dynamically capture and characterize EMT-related drug resistance states in lung cancer cells to construct a single-cell resolution state map of clinical applicability.

      Method

      We used mass cytometry (CyTOF) time-course experimentation and novel computational tools to analyze TGFβ and drug treated NSCLC cell lines, as well as NSCLC clinical samples to identify clinically relevant drug resistant EMT and MET states and construct a single-cell resolution proteomic map of phenotypic states.

      Result

      Through TGFβ treatment and withdrawal we resolved previously unrealized EMT and MET states in NSCLC cell lines by analyzing the expression of up to 30 surface and intracellular markers. Using a novel computational tool (TRACER) we also provide evidence that EMT and MET trajectories differ and exert differential drug sensitivity profiles. We used the identified EMT and MET states to construct a NSCLC reference EMT-MET state map, on which we projected NSCLC clinical samples to characterize their phenotypic profile in terms of our in vitro EMT-MET analysis. Finally, we extended our mass cytometry time-course analysis to NSCLC cells that underwent various drug treatments (e.g. Erlotinib, Docetaxel) and subsequent withdrawal to augment our EMT-MET state map with drug resistance phenotypic traits. We found that NSCLC resistant cells displayed through time overlapping morphological and cell signaling features with EMT and MET and were able to rebound from short-term drug-induced effects. These data are currently being used to evaluate EMT-related drug resistant cell states detected in pleural effusions during and after the course of treatment in different NSCLC patient therapy time-points.

      Conclusion

      In summary, we provide a framework that can be extended to phenotypically characterize clinical samples with single-cell resolution in the context of in vitro studies showing differential EMT-MET traits related to drug sensitivity. This sets the foundation for developing tools towards evaluating - at a personalized level – disease status and response to treatment in NSCLC patients.

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      OA08.04 - Discussant - OA08.01, OA08.02, OA08.03 (Now Available) (ID 3760)

      11:00 - 12:30  |  Presenting Author(s): Luca Roz

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA08.05 - Notch Inhibition Overcomes Resistance to Tyrosine Kinase Inhibitors Promoted by Gate-Keeper Mutations in EGFR-Driven Lung Adenocarcinoma  (Now Available) (ID 639)

      11:00 - 12:30  |  Presenting Author(s): Antonio Maraver  |  Author(s): Emilie Bousquet, Xavier Quantin, Jean Louis Pujol, Kwok-Kin Wong, Jean-Charles Soria, Julien Mazieres, Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR mutated lung adenocarcinoma patients treated with gefitinib and osimertinib showed a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It has been generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, indicating that the use of single drug to treat efficiently EGFR-driven lung adenocarcinoma might have limited value while a strategy based on combinational drug therapy could be more effective at mitigating the effects of gatekeeper mutations.

      Method

      We have combined the use of EGFR-driven genetic engineered mouse models and patient-derived xenografts, adenocarcinoma cell lines and primary samples from EGFR mutated patients.

      Result

      We uncover here that gefitinib and osimertinib increase STAT3 phosphorylation (pSTAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induces a pSTAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we show that tyrosine kinase inhibitor resistant tumors, with EGFRT790M and EGFRC797S mutations, are highly responsive to the combined treatment of Notch inhibitors with gefitinib and osimertinib respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increase during relapse and correlate with shorter progression-free survival.

      Conclusion

      Our results show that the Notch pathway plays a major role in the relapse of lung adenocarcinoma patients treated with EGFR TKIs, providing a rationale to treat patients that become resistant to EGFR TKI with a combination of the same TKI and Notch inhibitors.

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      OA08.06 - Reciprocal Change in Glucose Metabolism of Cancer and Immune Cells Mediated by Different GLUT Predicts Immunotherapy Response (Now Available) (ID 642)

      11:00 - 12:30  |  Presenting Author(s): Hongyoon Choi  |  Author(s): Kwon Joong Na, Young Tae Kim

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor metabolism represented by aerobic glycolysis is dynamically changed in tumor microenvironment (TME) to achieve immune escape. However, in vivo properties of glucose metabolism in cancer and immune cells are poorly understood and their clinical implications are still lacking. We scrutinized the association of tumor metabolism and immune properties of TME by comprehensive analyses using tissue RNA-seq, positron emission tomography (PET), and single cell RNA-seq data.

      Method

      Lung squamous cell carcinoma (LUSC) samples with both RNA-seq and 18F-deoxyglucose (FDG) PET (n = 63) were collected to examine the association of in vivo glucose metabolism, gene expression levels related to glucose metabolism, and immune cell enrichment. An overall enrichment score of TME (ImmuneScore) was estimated from tissue RNA-seq data. The gene expression levels of each cell component of TME were analyzed by single cell RNA-seq from lung cancer patients. The expression patterns of glucose transporters (GLUTs) were evaluated in patients who underwent immunotherapy to investigate whether it can predict immunotherapy response.

      Result

      Single cell RNA-seq showed that GLUT1 was mostly expressed in cancer cells while GLUT3 was mostly found in myeloid cells in TME. ImmuneScore showed a negative correlation with GLUT1 (r=-0.70, p<0.01) and a positive correlation with GLUT3 (r=0.39, p<0.01) in LUSC samples, and it was validated in TCGA cohort (r=-0.44, p<0.01 for GLUT1; r=0.26, p<0.01 for GLUT3). LUSC samples were divided into two distinct groups (immure-rich and immune-poor) by ImmuneScore. In immune-poor cluster, FDG uptake was positively correlated with GLUT1 (r=0.27, p=0.04), while not correlated with GLUT3. In immune-rich cluster, FDG uptake was positively correlated with GLUT3 (r=0.78, p=0.01), while not correlated with GLUT1. ImmuneScore was negatively correlated with FDG uptake in immune-poor cluster, while there was positive correlation in immune-rich cluster. We defined GLUT3-GLUT1 ratio (GLUTratio) as a metabolic biomarker representing immune status in TME. High GLUTratio indicates increased metabolic activity in immune cells and decreased metabolic activity in cancer cells in TME. For melanoma patients who underwent anti-PD-1 therapy, GLUTratio was significantly higher in responders than nonresponders (p=0.03).

      abtract_figure.jpg

      Conclusion

      Our findings support a reciprocal change of glucose metabolism between cancer and immune cells within TME mediated by different GLUTs. A new glucose metabolism-based biomarker, GLUTratio, can reflect reciprocal metabolic activity of immune and cancer cells in TME, and be a feasible predictive biomarker for immunotherapy.

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      OA08.07 - Aberrant Epigenetic SMAD3 Signaling in Tumor-Associated Fibroblasts Modulates Fibrosis and Response to Nintedanib in NSCLC (Now Available) (ID 1972)

      11:00 - 12:30  |  Presenting Author(s): Rafael Yamashita Ikemori  |  Author(s): Marta Gabasa, Miguel Vizoso, Paula Duch, Sebastian Moran, Sabrina Gea-Sorli, Paloma Bragado, Toni Jauset, Manel Esteller, Laura Soucek, Eduard Monsó, Victor Peinado, Cristina Fillat, Frank Hilberg, Noemi Reguart, Jordi Alcaraz

      • Abstract
      • Presentation
      • Slides

      Background

      Tumor-associated fibroblasts (TAFs) exhibit a fibrotic phenotype in non-small cell lung cancer (NSCLC) that has beeen associated with critical steps of cancer progression. Paradoxically, we reported that the profibrotic TGF-β transcription factor SMAD3 was epigenetically downregulated through promoter hypermethylation in TAFs from NSCLC patients compared to patient-matched control fibroblasts. In addition, we reported that the antifibrotic drug nintedanib elicited a stronger inhibition of the fibrotic phenotype and its tumor-promoting effects in TAFs from adenocarcinoma (ADC) patients compared to squamous cell carcinoma (SCC) patients upon TGF-β1 stimulation in vitro, which was consistent with the selective therapeutic response to nintedanib observed in a clinical trial in ADC (but not SCC) patients. These previous results support the hypothesis that TGF-β1 signaling may be altered in lung TAFs according to their histologic subtype.

      Method

      In this study we tested our working hypothesis by determining the expression and activity of SMAD3 and its closely related homologue SMAD2 in patient-derived TAFs and paired control fibroblasts, and by dissecting their potential contribution to the differential therapeutic responses to nintedanib observed in ADC and SCC using in vitro and in vivo preclinical models.

      Result

      In vitro studies revealed a marked SMAD3 epigenetic repression through promoter hypermethylation, a low pSMAD3/pSMAD2 ratio and a limited fibrotic phenotype selectively in SCC-TAFs. In contrast, ADC-TAFs overexpressed a panel of fibrotic markers upon TGF-β1 stimulation concomitantly with a high pSMAD3/pSMAD2 ratio and a limited SMAD3 promoter methylation. Histologic analysis of a large patient cohort (112 ADC, 96 SCC) confirmed that the extent of fibrosis is larger in ADC than SCC patients. In addition, knocking-down SMAD3 in ADC-TAFs was sufficient to reduce the antifibrotic and antigrowth effects of nintedanib in vitro and in tumor xenografts in vivo. On the other hand, long-term exposure of pulmonary fibroblasts to cigarette smoke condensate was sufficient to hypermethylate the SMAD3 promoter. Since SCC and ADC tumors typically arise in the upper airways and distal pulmonary sites, respectively, it is conceivable that fibroblasts might be more exposed to the smoking epigenetic effects on SMAD3 in SCC.

      Conclusion

      We report for the first time that tumor fibrosis is higher in ADC than SCC patients, in association with a selective therapeutic response to the antifibrotic drug nintedanib in the former, and identify the subtype-specific extent of SMAD3 epigenetic repression in TAFs and the subsequent aberrant SMAD3/SMAD2 imbalance as major regulatory mechanisms of tumor fibrosis and response to nintedanib in NSCLC.

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      OA08.08 - Discussant - OA08.05, OA08.06, OA08.07 (Now Available) (ID 3761)

      11:00 - 12:30  |  Presenting Author(s): Luis M Montuenga

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA08.09 - Adi F. Gazdar Lectureship Award for Translational Science (Now Available) (ID 3898)

      11:00 - 12:30  |  Presenting Author(s): Roman Thomas

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      OA08.08 - Discussant - OA08.05, OA08.06, OA08.07 (Now Available) (ID 3761)

      11:00 - 12:30  |  Presenting Author(s): Luis M Montuenga

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-26 - Genetic and Molecular Profiling of Non-Smoking Related Lung Adenocarcinomas (ID 1701)

      09:45 - 18:00  |  Author(s): Luis M Montuenga

      • Abstract
      • Slides

      Background

      The etiology and many details of the genomic profile and molecular basis of lung adenocarcinomas (LuADs) in nonsmoker patients remain elusive. Further, the scarcity of primary cultures available from non-smoking related lung adenocarcinomas (NSK-LuADs) contributes to hamper our biological understanding of these tumors.

      Method

      We established patient-derived cancer cell (PDCs) cultures from NSK-LuADs, and performed whole exome sequencing (WES) and RNA sequencing (RNA-seq) analysis to delineate their genomic architecture. For validations, we analyzed independent cohorts of LuADs.

      Result

      The analysis revealed non-smoker related alterations such as those at the growth factor receptors RET, ALK, EGFR and ERBB2. There were also mutations affecting signal transduction molecules such as AKT1, BRAF and KRAS, and mutations in tumor suppressor genes, including TP53, CDKN2A, RB1, ARID1A, ATM and STK11. We also identified new fusions and recurrent mutations in some genes, one of them, a possible regulator of gene expression, affecting ten percent of the LuADs, thus constituting a potentially relevant tumor suppressor gene. We also report a predominance of RB1-inactivation, mostly complex intragenic rearrangements (homozygous deletions or duplications) in EGFR-mutant tumors. Three EGFR-/RB1-mutant tumors, treated with EGFR-TKIs, and one EGFR-wild type tumor, treated with standard chemotherapy, developed small cell lung cancer and/or squamous cell carcinoma transformation, evident in the re-biopsies and/or PDCs. Finally, we found pathogenic germ-line mutations at genes associated to familiar-cancer syndromes, especially the TP53-associated Li Fraumeni syndrome, affecting ten percent of EGFR-mutant LuADs patients, underscoring a genetic predisposition origin for a subset of NSK-LuADs.

      Conclusion

      The recurrent gene inactivation found in candidate gene in LuADs heralds a tumor suppressor role which deserves further exploration. The pre-existent inactivation of RB1 predominates in EGFR-mutant tumors and may underlie an extremely ductile nature, albeit additional gene alterations are required to overcome sensitivity to the TKIs. Given their potential clinical and therapeutic implications, testing for RB1-alterations and for the Li-Fraumeni syndrome in EGFR-mutant LuADs patients may need to be incorporated in the clinical settings.

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    P1.09 - Pathology (ID 173)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Pathology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.09-13 - Prognostic Value of TMPRSS4 Expression and Its Role as Diagnostic Biomarker by Liquid Biopsy in Early Stage NSCLC (ID 2499)

      09:45 - 18:00  |  Author(s): Luis M Montuenga

      • Abstract
      • Slides

      Background

      Relapse rates in surgically-resected non-small cell lung cancer (NSCLC) patients are between 30-45% within 5 years of diagnosis, which reflects the clinical need to identify those patients at high risk of recurrence and death. TMPRSS4 is a serine protease that plays a role in lung cancer growth, development of metastasis and resistance to chemotherapy in NSCLC models. TMPRSS4 is overexpressed through promoter hypomethylation in NSCLC tumors.

      Method

      Two cohorts of NSCLC patients (MD Anderson (MDA), n=489; and Clinica Universidad de Navarra (CUN), n=95) were used to investigate the prognostic value of TMPRSS4. The WHO 2004 classification and 8th TNM edition was used for tumor stratification. We have also developed a method to quantify he degree of TMPRSS4 and SHOX2 methylation status in liquid biopsy (plasma and bronchoalveolar lavages (BALS)) by digital droplet PCR (ddPCR), in tumor-free individuals and patients with NSCLC.

      Result

      High levels of TMPRSS4 were significantly associated with reduced relapse-free survival (RFS, p<0.001) and overall survival (OS, p<0.001) in the MDA cohort, and with OS in the CUN cohort (p<0.049). In univariate Cox regression analysis using the MDA cohort, high TMPRSS4 levels were RFS (HR=2.09; 95% IC [1.53-2.87], p<0.001) and OS (HR=1.82; 95% IC [1.38-2.41], p<0.001). In multivariate analyses, TMPRSS4 was found as an independent prognostic factor for both RFS (HR=1.82, IC [1.28-2.60], p<0.001) and OS (HR=1.44, IC [1.07-1.94], p<0.014).
      In our MDA cohort, stage IA and stage IB showed no statistical differences for RFS (p=0.27) or OS (p<0.001). However, when considering the protein expression of TMPRSS4 we were able to substratify stage IA patients in low and high risk patients, since those with high TMPRSS4 levels showed a significantly reduced RFS (p=0.002) and OS (p<0.001). Similar tendency was observed for stage IB, although statistical differences were not found.

      After successful establishment of the ddPCR conditions for TMPRSS4 and SHOX2 methylation status, we analyzed plasmas and BALS in case-control studies. In BALS (79 NSCLC patients and 26 controls), significant hypomethylation (p<0.01) was found for TMPRSS4 in the case of patients with early stage NSCLC in comparison with controls, with an AUROC of 0.72 (95% IC, 0.57-0.87) (p=0.008). SHOX2 was significantly hypermethylated in BALS from early stage NSCLC compared to controls (p<0.01), with an AUROC of 0.71 (95% IC, 0.56- 0.86) (p=0.01). In the case of plasmas (89 NSCLC patients and 25 controls): in early stages, a significant hypomethylation was found for TMPRSS4 (p<0.05), with an AUROC of 0.73 (95% IC, 0.54-0.90) (p=0.015). For SHOX2, only late stages NSCLC showed significant hypermethylation with respect to controls (p<0.05), with an AUROC of 0.68 (95% IC, 0.54-0.80) (p=0.025).

      Conclusion

      High TMPRSS4 levels are associated with worse prognosis in NSCLC patients. TMPRSS4 expression significantly discriminates patients with higher risk of disease progression and poor survival outcome in early stage NSCLC. Methylation status of TMPRSS4 can be used in both plasma and BALS to identify patients with NSCLC.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-38 - Identification of a Novel Synthetic Lethal Vulnerability in Non-Small Cell Lung Cancer by Co-Targeting TMPRSS4 and DDR1 (ID 2191)

      10:15 - 18:15  |  Author(s): Luis M Montuenga

      • Abstract
      • Slides

      Background

      Synthetic lethality has been defined as the inability of cells to proliferate when co-targeting two genes, with a synergistically superior inhibition than that found for each individual gene. Consistent co-expression of two genes involved in a similar function is a predictor of synthetic lethality, a strategy that is being applied to find out novel cancer vulnerabilities.

      Method

      Large-scale bioinformatics analyses across 5 public databases were used to identify genes consistently co-expressed with TMPRSS4, a novel therapeutic target that we have previously identified in NSCLC. Pyrosequencing was used to evaluate methylation levels in patients and cell lines. Functional in vitro experiments and animal models were used to assess synthetic lethality of TMPRSS4 and DDR1 in NSCLC.

      Result

      Consistent co-expression between TMPRSS4 and DDR1 was found in all NSCLC databases evaluated. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down cells, but not single knock-out cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and apoptosis. Moreover, double knock-down cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in mice injected with double knock-down-injected cells and lack of 18FDG-uptake by microPET analysis.

      Conclusion

      We have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4. This may help designing therapeutic strategies to impair NSCLC growth by co-targeting both genes.

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