Virtual Library

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    ES07 - Beyond the Diagnosis - Collaborative Care for Change (ID 775)

    • Event: WCLC 2018
    • Type: Educational Session
    • Track: Nursing and Allied Professionals
    • Presentations: 5
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 205 BD
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      ES07.01 - A Moment in Time for the Unplanned Conversations (ID 11378)

      13:30 - 13:50  |  Presenting Author(s): Kelly McGuigan

      • Abstract

      Abstract not provided

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      ES07.02 - Special Needs and Wellness in Lung Cancer Patients - Australian Perspective (ID 11379)

      13:50 - 14:00  |  Presenting Author(s): Maria Ftanou

      • Abstract

      Abstract not provided

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      ES07.03 - Special Needs and Wellness in Lung Cancer Patients - European Perspective (ID 11380)

      14:00 - 14:10  |  Presenting Author(s): Rossie Navon

      • Abstract

      Abstract not provided

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      ES07.04 - Leveraging Social Media to Change the Public Conversation on Lung Cancer Stigma (ID 11381)

      14:10 - 14:30  |  Presenting Author(s): Lisa Carter-Harris

      • Abstract

      Abstract not provided

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      ES07.05 - Research Update: Patient’s Perspective on Living with Malignant Pleural Mesothelioma (ID 11382)

      14:30 - 14:50  |  Presenting Author(s): Angela Mary Tod

      • Abstract

      Abstract not provided

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    MA14 - Survivorship, Socioeconomic and End-of-Life Considerations (ID 915)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/25/2018, 10:30 - 12:00, Room 205 BD
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      MA14.01 - Life Sustaining Procedures, Palliative Care and Hospital Cost Trends in Dying Lung Cancer Patients in U.S. Hospitals: 2005-2014 (ID 14134)

      10:30 - 10:35  |  Presenting Author(s): Jinwook Hwang  |  Author(s): Ji won Yoo, Jay Shen, Sun Jung Kim, Sung Youn Chun

      • Abstract
      • Presentation
      • Slides

      Background

      Little is known about the extent to which dying patients with lung cancer receive life-sustaining treatments and palliative care services at the end-of-life in U.S. hospitals. We examine hospital cost trends and the impact of palliative care utilization on the use of life-sustaining procedures in this population.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Retrospective nationwide cohort analysiswas performed using National Inpatient Sample (NIS) data from 2005 and 2014. We examined the receipt of both palliative care and life-sustaining procedures, defined as systemic procedures, local procedures, or surgeries using the International Classification of Diseases, 9th revision (ICD-9-CM).

      4c3880bb027f159e801041b1021e88e8 Result

      Figure 1.

      스크린샷 2018-05-05 05.44.27.png

      We used compound annual growth rates (CAGR) to determine temporal trends and multilevel multivariate regressions to identify factors associated with hospital cost. Among 77,394,755 hospitalizations, 120,144 patients were examined. During 10 years, the CAGR of hospital cost was 7.05% (p<.0001). In contrast, the CAGR of hospital lengths of stay was -3.77% (p<.0001). The CAGRs of palliative care was over ten percentage (13.30 %, p<.0001). However, the CAGRs of systemic procedures, local procedures, and surgeries were less than around one percentage (-1.13%, -1.07% and 1.42%, each p<.0001). Systemic procedures, local procedures and surgeries were associated with increased hospital cost and lengths of stay by 50.6%, 74.4%, 68.5%, and 7.4%, 50.6%, 4.6% respectively (each p<.001). Palliative care was associated with decreased hospital cost and length of stay by 28.6% and 4.6% (each, p<.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      The volume of life-sustaining treatments is the biggest driver of cost increase although there is a cost-saving effect from greater palliative care utilization at the end-of-life in dying lung cancer patients.

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      MA14.02 - Use and Impact of A Systematic Advanced Care Planning in Hospitalized Lung Cancer Patients: A Prospective Study. (ID 13997)

      10:35 - 10:40  |  Presenting Author(s): Anne Claire Toffart  |  Author(s): Natacha Denis, Matteo Giaj Levra, Linda Sakhri, Michaël Duruisseaux, Julian Pinsolle, Léonie Ferrer, Denis Moro-Sibilot, Jean-François Timsit

      • Abstract
      • Presentation
      • Slides

      Background

      End-of-life communication is crucial, particularly for cancer patients. In usual practice, advanced care planning discussions with the patients are uncommon and rarely documented. The aim of this study was to investigate the impact of advanced care planning on intensity of care in cases of organ failure in lung cancer patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This prospective study was performed at the Grenoble University Hospital in France. Consecutive patients hospitalized in thoracic oncology unit between 01/28/2014 and 03/31/2016 were included and followed up to 12/31/2016. At each hospital admission, lung cancer patients benefited from advanced care planning. We defined 3 intensities of care: intensive care, maximal medical care and exclusive palliative care. The propositions of care could be modified during the hospitalization. Patients’ wishes should be received.

      4c3880bb027f159e801041b1021e88e8 Result

      Data of 715 hospitalizations corresponding to 473 patients were studied. Hundred fifty nine patients had a second hospitalization and 69 a third. At first admission, 247 (52%) patients had a performance status of 0 to 2, 186 (39%) were not yet treated for the cancer and 165 (35%) in progression. Main reasons of admission were an acute disease (n=208, 44%) and supportive care of cancer symptoms (n=167, 35%).

      During the three first admissions, 173 (25%) patients developed an organ failure. Among them, 56 (32%) had intensive care proposition, 104 (61%) maximal medical care, and 13 (7%) exclusive palliative care. Median time between admission and organ failure was 9 days [IQR 25%-75%, 3-13]. All patients benefited from intensity of care equal or lower than the proposed intensity of care. Among patients planed for intensive care, 17 (30%) patients received intensive care, 22 (39%) maximal medical care and 17 (30%) exclusive palliative care. Thirteen of the 39 patients not admitted in ICU despite organ failure and previous proposition of intensive care were considered too well by the oncologist. Patients’ wishes were recorded for 158 (91%) patients, and a discussion about end of life conditions was led with 116 (73%) patients or families.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In case of organ failure, an advanced care planning appears helpful to provide reasonable intensity of care. The proposition of care seems to be adapted to the patient’s general condition and cancer characteristics. 3/4 of the patients with an organ failure benefited from a discussion about end of life conditions.

      ClinicalTrials.gov Identifier: NCT02852629

      Funding from the publicly funded nonprofit organization Cancéropole Lyon Auvergne Rhône-Alpes (CLARA).

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA14.03 - Aggressiveness of Cares on the Month Before Death of Patients with Lung Cancer: A French National Database Survey (ID 12005)

      10:40 - 10:45  |  Presenting Author(s): Olivier Bylicki  |  Author(s): Charlène Tournier, florence Canoui-Poitrine, Cecile Blein, Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Background

      Prior studies have demonstrated that high-intensity end of life (EOL) cares improves neither survival nor quality of life for cancer patients. The National Quality Forum endorses markers of poor EOL care for cancer patients but there is little data’s concerning lung cancer patients (1). The aim of this study was to assess, the quality of management during the last month of life of lung cancer patients managed in France and factors associated EOL aggressiveness.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Using a French hospital discharge database (PMSI, Programme de Médicalisation des Systèmes d’Information), all patients with lung cancer who died between January 1, 2010 and December 31, 2011 (cohort 1) and between January 1, 2015 and December 31, 2016 (cohort 2) were identified through the International Classification of Diseases 10th version (ICD-10). Aggressiveness of EOL cares was assessed by the following criteria’s 1) chemotherapy administrated within last 14 days of life (DOL); 2) > 1 hospitalization within 30 DOL; 3) ICU admission within 30 DOL; and 4) Palliative care < 3 days before death. Multivariate analysis was performed to identify individual determinants EOL aggressiveness.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 90,827 incident adult patients were identified (cohort 1: 43,862, cohort 2: 46,965): men: 74%, median age: 67 years], metastatic at diagnosis: 70%; 57% have at least one marker of aggressiveness of EOL cares (repeated hospitalizations: 49%, ICU admissions: 12%, chemotherapy within 14 DOL: 9%, palliative care < 3 days before death: 5%). A significant increase was observed between 2010/2011 and 2015/2016 for repeated hospitalizations (48% vs 51%, p<.001) and ICU admissions (11% vs 13%, p<.001); the two other markers have remained stable. In multivariate analysis of cohort 2, the risk of aggressiveness of care in EOL was increased by the presence of COPD (OR: 1.08, 95%CI: 1.02-1.14) and a management in an anti-cancer center (OR: 2.32,95%CI 2.05-2.61) while advanced age (OR: 0.51, 95%CI 0.47-0.55), female sex (OR: 0.86 95%CI: 0.82-0.90), malnutrition (OR: 0.72, 95%CI:0.68-0.76) were protective factors for EOL aggressiveness of cares.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Despite growing focus on providing appropriate EOL cares, in this analysis 57% of deceased lung cancer patients in France received aggressive EOL cares. Research must be undertaken to better identify patients at risk of aggressive EOL cares and to improve the quality of cares of last days of life these patients.

      1.McNiff KK, . Measuring supportive care in medical oncology practice: lessons learned from the quality oncology practice initiative. JCO 2008;

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA14.04 - Discussant - MA 14.01, MA 14.02, MA 14.03 (ID 14636)

      10:45 - 11:00  |  Presenting Author(s): Gouri Shankar Bhattacharyya

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA14.05 - Social Isolation Increases Psychological Distress in Patients With NSCLC (ID 11959)

      11:00 - 11:05  |  Presenting Author(s): Cheryl Ho  |  Author(s): Bonnie Leung, Jonn Wu, Janessa Laskin, Heather Rennie, Alan Bates

      • Abstract
      • Presentation
      • Slides

      Background

      The Psychosocial Screen for Cancer (PSSCAN-R) questionnaire is a validated screening tool used to identify the psychosocial needs of patients with cancer. The questionnaire assesses patients’ perceived social supports and identifies patients at risk for developing psychological distress. The study goal was to examine patients with NSCLC who reported risk factors for social isolation and their risk for developing psychological distress.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients with NSCLC referred to BC Cancer from 2011-2015 who completed a prospective PSSCAN-R questionnaire at the time of first visit were included in the study. Perceived social support questions include: if patients live alone, lost a life partner recently, have no help with IADLs, have no regular contact with friends and family or have no emotional support from others. Demographics were collected retrospectively. Chi-squared test and logistical regression were used to compare patient groups based on age, gender and perceived social support factors.

      4c3880bb027f159e801041b1021e88e8 Result

      The study cohort was comprised of 4428 patients who completed the PSSCAN-R questionnaire. Female 50%, patients ≥65 years 69%, live alone 29%, lost life partner 13%, no help with IADLs 9%, no regular contact 3% and no emotional support 5%.table1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Female patients and patients younger than 65 are more at risk for developing moderate to severe anxiety and depression. Lack of perceived social support also contributes to the risk of developing psychological distress. In addition to developing gender and age-based resources for patients addressing their psychosocial needs, greater efforts in assessing patients’ perceived social supports and allocating community and institutional resources to isolated patients should also become an important part of the patients’ comprehensive and holistic care.

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      MA14.06 - Predictors of Financial Toxicity, an Under-Recognized Patient-Reported Outcome (ID 13571)

      11:05 - 11:10  |  Presenting Author(s): Doreen Anuli Ezeife  |  Author(s): Josh Morganstein, Sally C Lau, Jennifer Law, Lisa Le, Penelope Bradbury, Geoffrey Liu, Frances A Shepherd, Natasha B Leighl

      • Abstract
      • Presentation
      • Slides

      Background

      In contemporary cancer care, financial distress has been established as a clinically relevant patient-reported outcome (PRO) associated with worse mortality and quality of life, but remains under-recognized by health care providers. Our goal was to define predictors of patient financial toxicity (FT) in a public healthcare system.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Patients with advanced lung cancer were recruited from outpatient clinics at the Princess Margaret Cancer Centre (Toronto, Canada). FT was measured with the validated Comprehensive Score for Financial Toxicity (COST) instrument, an 11-item survey scored from 0-44 with lower scores reflecting worse financial well-being. Data on patient and treatment characteristics, total out-of-pocket costs (OOP) and extended insurance coverage (EIC) were collected. Associations between variables and COST score were evaluated using multivariable regression analyses.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 249 patients approached, 200 (80%) participated. Median age of the cohort was 65 years; 44% were male, 36% immigrants, 67% employed or on pension, with median OOP between $1000-5000 CAD. Median COST score was 21 (range 0-44). FT was associated with age, with patients <65 years reporting greater FT than older patients (COST 18 vs. 25; P<0.0001). Employed patients or those receiving pension income reported less FT than unemployed patients (22 vs. 19; P=0.01). Less FT occurred in patients with EIC compared to those without (23 vs. 19; P=0.03). Patients with higher OOP reported more FT (P<0.0001). Patients on clinical trials reported less FT than others (25 vs. 20; P=0.04). In multivariable linear regression, younger age was a predictor of higher FT, when adjusting for income, employment status, OOP and EIC (P<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      Age is a predictor of FT in the Canadian (Ontario) public healthcare system, with younger lung cancer patients reporting greater financial distress. This study highlights priority patient populations where FT should be routinely assessed and appropriate resources for support offered.

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      MA14.07 - The Impact of Socioeconomic Status and Geographic Location on Palliative Chemotherapy Uptake in Patients with Metastatic NSCLC  (ID 13098)

      11:10 - 11:15  |  Presenting Author(s): Zamzam Salam Al-Hashami  |  Author(s): Bonnie Leung, Janessa Laskin, Jonn Wu, Heather Rennie, Alan Bates, Cheryl Ho

      • Abstract
      • Presentation
      • Slides

      Background

      Socioeconomic status (SES) and geographic factors may impact patient treatment choices. Canada has a publically funded health care system and in BC, there are 35 community oncology network sites that delivery treatment in patients’ local communities. We studied the impact between SES and geographic location upon delivery of chemotherapy/survival in metastatic NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      All patients with metastatic NSCLC referred to BC Cancer centres from 2011-2015, who completed a prospective Canadian Problem Checklist questionnaire at the time of their first visit and for which chemotherapy data was available were included in the study. The CPC assesses patient distress in 6 domains including practical aspects of cancer care. The Postal Code Conversion File Plus uses data from Statistics Canada 2011 census to determine population size and income quintiles. Baseline characteristics and chemotherapy treatments were collected retrospectively. Univariate analysis using the Chi-squared test and Fisher’s exact test were used for analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      1113 patients were included with median age of 69 years, 54% female and 77% were former/current smoker and 47% received palliative chemotherapy. Uptake of chemotherapy did not differ between lowest + mid-lowest 44%, middle 51% /mid-highest + highest 49% income quintiles (p=0.18). Chemotherapy use was also similar between patients reporting financial concerns 50% versus none 47% (p=0.51). Uptake of chemotherapy was lower in patients who lived in rural communities population<10 37% (P 0.00), 10K-1.5M 41%, >1.5 million 53% (p<0.001). Chemotherapy use was lower for patients with concerns about getting to appointments (39% vs 49%, p=0.008) or accommodations (33% vs 48%, p=0.012).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This dataset provide evidence that patients from rural communities were less likely to receive palliative chemotherapy treatment for metastatic NSCLC in BC despite the availability of multiple local community oncology services. SES did not appear to impact the proportion of patients treated, congruent with a government funded health care system. An in depth assessment of distances to local cancer services and treatment delivery is warranted to investigate these differences and their effect on mortality.

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      MA14.08 - Discussant - MA 14.05, MA 14.06, MA 14.07 (ID 14637)

      11:15 - 11:30  |  Presenting Author(s): Christos Chouaid

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA14.09 - Mortality of Lung Cancer as a Second Primary Malignancy among Cancer Survivors: A Study of Surveillance, Epidemiology, and End Results Database (ID 11862)

      11:30 - 11:35  |  Presenting Author(s): Lei Deng  |  Author(s): Huan Song, Zhengrui Xiao, Changchuan Jiang, Qian Wang, Haiying Cheng, Donghao Lu

      • Abstract
      • Presentation
      • Slides

      Background

      Cancer survivors are at increased risk of developing a second primary malignancy, including lung cancer. However, the prognosis of lung cancer as a second primary malignancy (lung-2) remains largely unknown.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Primary lung cancer patients diagnosed from 1988 to 2014 in the SEER program were included. Lung-2 was ascertained by a previous diagnosis of primary malignancy in SEER. Hazard ratios (HRs) of overall and lung cancer specific mortality were estimated among patients with lung-2 compared to lung-1.

      4c3880bb027f159e801041b1021e88e8 Result

      679,541(88.8%) and 85,758 (11.2%) patients were identified as lung-1 and lung-2, respectively. The median time from first primary malignancy to lung-2 diagnosis was 4.8 years. Compared to lung-1, patients with lung-2 were more likely to be diagnosed at localized stage, with smaller primary tumor, and treated with surgery. Lung-2 patients were at lower risk of lung cancer specific mortality in the first five years (HR 0.77, 95% CI 0.76 - 0.78 at < 1 year; HR 0.87, 95% CI 0.86 - 0.89 from 1 to < 5 years) but at higher risk thereafter. Patients with lung-2 were associated with reduced risk of overall mortality during the first year after diagnosis (HR 0.91, 95% CI 0.91 - 0.92), but with significantly increased risks thereafter.

      Table Hazard ratios (HRs) of overall and lung cancer specific mortality among patients with lung-2

      N (%) of patients

      From 0 to <1 year after diagnosis

      From 1 year to < 5 years after diagnosis

      From 5 years to 10 years of follow-up after diagnosis

      N (IR)

      HR (95% CI) *

      N (IR)

      HR (95% CI)*

      N (IR)

      HR (95% CI)*

      Overall mortality

      First primary lung cancer

      679,541

      383,208 (99.9)

      1.00

      135,513 (29.3)

      1.00

      16,821 (9.8)

      1.00

      Second primary lung cancer

      85,758

      44,288 (84.1)

      0.91 (0.91-0.92)

      20,073 (29.4)

      1.10 (1.08-1.12)

      3,133 (14.6)

      1.32 (1.27-1.37)

      Lung cancer specific mortality

      First primary lung cancer

      679,541

      325,633 (84.9)

      1.00

      111,348 (24.1)

      1.00

      8,147 (4.7)

      1.00

      Second primary lung cancer

      85,758

      31,247 (59.3)

      0.77 (0.76-0.78)

      12,485 (18.3)

      0.87 (0.86-0.89)

      1,158 (5.4)

      1.10 (1.03-1.17)

      N, number of deaths; IR, incidence rate per 100 person-years

      * HR was adjusted for age and calendar period at diagnosis, sex, race, cohabitation status, percentile of cost of living and high-school education in county of residence, tumor stage, histology, tumor grade, surgery, radiation therapy, and chemotherapy.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung-2 is associated with favorable lung cancer specific and overall survival within early period of diagnosis. Inferior overall survival afterwards cannot be attributed to aggressiveness of lung-2, highlighting the importance of managing first malignancy and comorbidities.

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      MA14.10 - QTc Interval-Prolonging Medications in Lung Cancer: Implications for Clinical Trial Eligibility and Routine Clinical Care (ID 12305)

      11:35 - 11:40  |  Presenting Author(s): David E Gerber

      • Abstract
      • Presentation
      • Slides

      Background

      Concomitant medication use, including agents that prolong the QTc interval, may exclude cancer patients from clinical trials. To estimate potential impact on accrual, we determined the prevalence of QTc-prolonging medication prescriptions in a national patient cohort.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We identified adult patients in the United States Veterans’ Affairs system diagnosed with lung cancer 2003-2016. QTc-interval prolonging medications and risk category were obtained from CredibleMeds®. We calculated prevalence of prescriptions for QTc-prolonging medications with known or possible risk of torsades de pointes (the most common criteria employed as trial exclusion criteria) in the 3 months up to and including date of cancer diagnosis. Rates across patient groups and time periods were compared using Chi-square test.

      4c3880bb027f159e801041b1021e88e8 Result

      280,068 patients were included in the study. Mean age was 70 years, 98% were male, and 72% were white. Overall, 29.7% were prescribed a QTc-prolonging medication. Patients receiving QTc-prolonging medications were marginally younger (mean age 68.9 years versus 70.9 years; P<0.001) and more likely to be black (14.1% versus 11%; P<0.001). The most commonly prescribed QTc-prolonging medications were antimicrobials (14.0%), psychiatric agents (10.2%), antiemetics (2.6%), and cardiovascular medications (1.7%). Seven percent of patients were prescribed two or more QTc-prolonging medications. Over the period of study, the rate of QTc-prolonging medication use increased 20% (25% in 2004 versus 31% in 2016; P<0.001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      A substantial and growing proportion of individuals with lung cancer are prescribed QTc-prolonging medications. These prescriptions may limit eligibility for clinical trials and complicate the administration of standard cancer therapies. Given the prevalence of chronic and/or multiple QTc-prolonging medication prescriptions, it may be challenging to address this obstacle to trial enrollment simply through prescription substitution or discontinuation. Further research into the actual clinical risks and optimal management of QTc-prolonging medications in cancer populations is warranted.

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      MA14.11 - Factors Associated with Early Mortality in Non-Small Cell Lung Cancer Patients Following Systemic Anti-Cancer Treatment (ID 12970)

      11:40 - 11:45  |  Presenting Author(s): Amanda Jane Williams Gibson  |  Author(s): Haocheng Li, Adrijana D'Silva, Roxana A. Tudor, Anifat A. Elegbede, Shannon Mary Otsuka, Winson Y Cheung, Gwyn Bebb

      • Abstract
      • Presentation
      • Slides

      Background

      To determine a 30-day mortality rate benchmark and assess factors associated with early mortality of non-small cell lung cancer (NSCLC) patients following receipt of systemic anti-cancer therapies (SACT).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In a 10-year population-based analysis, NSCLC patients receiving SACT in 2005-2014, with or without other treatments, and captured in the Glans-Look Lung Cancer Database, which contains demographic, clinical, pathological, treatment and outcome data were reviewed. 30-day mortality after most recent SACT cycle was calculated, and end-of life (EOL) regimen changes in the last 14 days of life were identified. Univariate analysis and multivariable logistic regression were used to identify demographic, tumor or treatment-related factors that correlated with mortality risk.

      4c3880bb027f159e801041b1021e88e8 Result

      1044 eligible NSCLC patients receiving at least one cycle of SACT in 2005-2014 were identified. 51% were female, 62% adenocarcinoma, 79% current/former smokers, 83% advanced stage at diagnosis, and 77% receiving palliative-intent treatment. 233 (22.3%) deaths occurred ≤ 30 days following SACT receipt, and 32 (13.7%) EOL regimen changes identified. Risk of early mortality decreased for never-smokers and those receiving SACT between 2010-2014, and increased in association with male gender, advanced disease at diagnosis, palliative-intent treatment, and use of EGFR-targeting agents. No factors were associated with a decreased risk of EOL regimen change. (Table 1). The predominant SACT-modality among those experiencing 30-day mortality was EGFR-targeting agents (54%).
      abstract #12790 table.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our findings from a real-world population identify several factors which affect the risk of early mortality in NSCLC patients following SACT, and establish a 30-day mortality benchmark for Canadian NSCLC populations. Evolving SACT modalities may facilitate an increased use of SACT at EOL and associated early mortality; however, in this cohort, decreased early mortality risk in the 2010-2014 timeframe suggests concomitant evolution of decisions regarding EOL SACT and/or palliative and EOL care may be underway at our centre, but represents an area for ongoing investigation.

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      MA14.12 - Discussant - MA 14.09, MA 14.10, MA 14.11 (ID 14638)

      11:45 - 12:00  |  Presenting Author(s): Amanda Tufman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA21 - Molecular Subtyping, CBL3, and Non Coding RNA (ID 924)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/25/2018, 15:15 - 16:45, Room 205 BD
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      MA21.01 - Cbl Mutations (mt) as Important Mediators of Oncogenic RTK Signaling in NSCLC (ID 12377)

      15:15 - 15:20  |  Presenting Author(s): Rebecca Feldman  |  Author(s): Ari M. Vanderwalde, Stephen V Liu, Martin Frederik Dietrich, Shirish Gadgeel, Wolfgang M. Korn, Jorge Nieva, Alexander Spira, Edward S Kim

      • Abstract
      • Presentation
      • Slides

      Background

      Casitas B-lineage lymphoma (Cbl), an E3 ubiquitin ligase, selectively regulates receptor tyrosine kinase (RTKs), e.g. EGFR, MET. Cbl loss of function (LOF) mt can can prevent ubiquitination of EGFR and potentiate EGFR signaling. Cbl mt have been described in cases of EGFR-TKI resistance but because EGFR signaling can activate signaling of fusion kinases and other ERBB family members, the implications of Cbl mt warrant broad characterization

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Biopsies from NSCLC pts tested with Next-Generation Sequencing on a 592-gene panel (Illumina NextSeq, ArcherDx) were analyzed retrospectively. Cbl domains of interest: LOF [tyrosine kinase binding (TKB), linker (L), ring finger (RF) and ubiquitin-associated (UBA)] and unclear function [N-terminal (NT) and proline-rich (PR)]. Chi-square analysis was used to compare co-alteration rates.

      4c3880bb027f159e801041b1021e88e8 Result

      Among 4,484 NSCLC pts’ tumors (50% M/50% F; age range: 20-90, profiled 11/16-12/17), 222 had Cbl mt (5%), of which 65 (29% of mt, 1.4% of cohort) were LOF: 13% TKB (29), 7% L (15), 5% RF (13), and 3.6% UBA (8). Cbl LOF mt were primarily observed in adenocarcinomas (48/65), metastatic sites (35/65) and equal between M/F. Cbl mt in other domains: 23% PR (51) and 14% NT (31). Co-mutation distribution is shown in table below. Cbl LOF mt that disrupt Cbl function (H398N, S407C, C396R, Y371D, T377I/H) or interactions w/ RTK (S216G, P288S, F325L) co-occurred w/ oncogenes in nine pts: EGFR (L858R, S768I, exon19del+T790M), ERBB3 (V104M, G284R), EML4-ALK (n = 2), CD74-ROS1 (n = 1), and HER2 (D1125E).

      LOF

      WT

      Oncogene

      pos/total (%)

      P

      ERBB3 mt

      2/65 (3.1)

      6/4329 (0.1)

      < 0.001

      EGFR mt

      3/65 (4.6)

      491/4329 (11.3)

      0.08

      METex14

      0/65 (0)

      100/4329 (2.3)

      0.2

      ROS

      1/60 (1.7)

      22/3976 (0.6)

      0.2

      KRAS mt

      14/65 (21)

      1242/3086 (29)

      0.2

      BRAF V600E

      0/65 (0)

      56/4312 (1.3)

      0.3

      ALK

      2/60 (3.3)

      97/4175 (2.3)

      0.6

      ERBB4 mt

      0/65 (0)

      6/4329 (0.1)

      0.7

      HER2 mt

      1/65 (1.5)

      58/4328 (1.3)

      0.9

      8eea62084ca7e541d918e823422bd82e Conclusion

      Regulation of RTK signaling through Cbl-mediated degradative pathways represents an important node for dysregulation in cancer. Presence of Cbl LOF mt in oncogene-driven tumors may provide a bypass signaling-enabled molecular landscape. Further analysis of the role of Cbl LOF mt in de-novo or acquired TKI resistance in pts identified is planned.

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      MA21.02 - Identification of an E2 Ubiquitin Conjugase CDC34 That Competes With E3 Ligase c-Cbl to Stabilize EGFR and Promotes Lung Carcinogenesis (ID 12416)

      15:20 - 15:25  |  Presenting Author(s): Guangbiao Zhou  |  Author(s): Xin-Chun Zhao, Yun-Chao Huang

      • Abstract
      • Presentation
      • Slides

      Background

      The ubiquitin (Ub)-proteasome system (UPS) is the principal pathway for diverse intracellular protein degradation, in which the E2 ubiquitin-conjugating enzymes play critical roles by transferring the Ub on their conserved cysteine residue to the ε-amino group of lysine residues on substrates.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      To systematically identify ubiquitin pathway genes that are critical to lung carcinogenesis, we used a highthrough-put silencing method to knockdown 696 genes in non-small cell lung cancer (NSCLC) cells, and investigated the significance of the candidates in patient samples, cellular and animal models.

      4c3880bb027f159e801041b1021e88e8 Result

      We identified 31 candidates that were required for cell proliferation in two NSCLC lines, among which the E2 ubiquitin conjugase CDC34
      represented the most significant one. CDC34 was elevated in tumor tissues in 67 of 102 (65.7%) NSCLCs, and smokers had higher CDC34 than nonsmokers. The expression of CDC34 was inversely associated with overall survival of the patients. Forced expression of CDC34 promoted, whereas knockdown of CDC34 inhibited lung cancer in vitro and in vivo. CDC34 bound EGFR and competed with E3 ligase c-Cbl to inhibit the polyubiquitination and subsequent degradation of EGFR. In EGFR-L858R and EGFR-T790M/Del(exon 19)-driven lung cancer in mice, nockdown of CDC34 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor formation.

      8eea62084ca7e541d918e823422bd82e Conclusion

      These results demonstrate that an E2 enzyme is capable of competing with E3 ligase to inhibit ubiquitination and subsequent degradation of oncoprotein substrate, and CDC34 represents an attractive therapeutic target for NSCLCs with or without drug-resistant EGFR mutations.

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      MA21.03 - Heterogeneity in MET Copy Number and Intratumoural Subsets in Pleomorphic Lung Carcinoma: Implications for MET Directed Therapy in NSCLC (ID 13061)

      15:25 - 15:30  |  Presenting Author(s): Adam Januszewski  |  Author(s): Yu Zhi Zhang, Wei-Chin Chang, Ute Laggner, Alex Bowman, Toyin Adefila-Ideozu, William OC Cookson, Miriam F Moffatt, Andrew G Nicholson, Anne Bowcock, Sanjay Popat

      • Abstract
      • Presentation
      • Slides

      Background

      Pleomorphic Lung Carcinoma (PC) is a rare subtype of NSCLC poorly responsive to systemic therapy. Both epithelial and sarcomatoid phenotypes exist, suggesting an important role of epithelial-to-mesenchymal transition. We aimed to determine MET copy number (CN) within individual tumour components and establish its correlation with immunohistochemistry (IHC) expression.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histopathological assessment and diagnosis was confirmed for 57 cases of resected PCs from the Royal Brompton Hospital Biobank. DNA was isolated from multiple regions and MET copy number determined by digital droplet PCR (ddPCR). IHC using c-MET (EP1454Y) and H-scores were assigned independently by two histopathologists.

      4c3880bb027f159e801041b1021e88e8 Result

      Cases: median age 66 years, 36.2% T3, 41.4% T2 and 13.8% T1. In the epithelial areas, adenocarcinoma was the most common (45.6%) followed by undifferentiated NSCLC (22.8%) and squamous (17.5%): in pleomorphic areas, mixed giant/spindle cell (35%), spindle cell (31%) and giant cell (26%). MET-CN gain by ddPCR was seen in 25/58 (44%) of cases (CN>2.3). 3/58 (5%) had CN>5. There was a significantly higher MET-CN in pleomorphic compared to epithelial areas (2.7 versus 2.2 P = 0.046). While this did not correlate with c-MET IHC, an H-score of >223 had 75% sensitivity and 52.4% specificity for MET-CN >5.0 (Figure).

      met expression in pc2.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      There is intra-tumoral heterogeneity in MET-CN between tumoural subsets. This may account for the development of pleomorphic phenotypes in PC. Consequently MET-directed therapies such as crizotinib may be highly effective only against the MET-amplified component in PC and may not impact on overall tumoural control due to minimal efficacy in the non-amplified epithelial component. MET expression using IHC does not correlate with MET-CN determined by ddPCR, although may provide a screening tool for MET amplification. MET aberrations are potentially druggable and therefore this has implications for sampling and MET testing.

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      MA21.04 - Discussant - MA 21.01, MA 21.02, MA 21.03 (ID 14626)

      15:30 - 15:45  |  Presenting Author(s): Ravi Salgia

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA21.05 - Comprehensive Genomic Characterization and Prognostic Nomogram Developed by 295-Gene Panel Targeted Sequencing (ID 13664)

      15:45 - 15:50  |  Presenting Author(s): Bin Zhang  |  Author(s): Lianmin Zhang, Tengfei Zhang, Dongsheng Yue, Chenguang Li, Zhenfa Zhang, Jun-Yi Ye, Hongming Wang, Shannon Chuai, Changli Wang

      • Abstract
      • Presentation
      • Slides

      Background

      The genomic landscape of lung cancer has been thoroughly studied in the western population. But comprehensive genetic profiling reports have been limited for the Chinese patients. Here we conducted deep targeted sequencing on a large cohort of Chinese treatment-naïve lung cancer patients and identified novel molecular patterns. We developed nomogram models for prognosis prediction by integrating genetic and clinical characteristics and aim to explore more precise models for risk stratification beyond TNM staging.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was a retrospective study, enrolling diagnosed lung cancer patients at Tianjin Medical University Cancer Institute & Hospital from 2009 to 2012. We developed genomic landscape by targeted sequencing using a panel consisting of exons and critical introns of 295 cancer-related genes. Nomogram models were established to provide risk stratification in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients

      4c3880bb027f159e801041b1021e88e8 Result

      513 tumor tissue samples were collected at very beginning of treatment (stage I, n=193; stage II, n=140; stage IIIA, n=140; stage IIIB, n=5; stage IV, n=28; unknown, n=7). The most frequently mutated oncogenic genes in LUAD were EGFR (55%) and KRAS (11%), compared to 14% and 33% in TCGA. Heterogeneity existed in terms of mutual exclusive and co-occurrent mutated gene pairs between LUAD and LUSC. In LUAD, pairs with most significant exclusivity was EGFR/KRAS and co-occurrent was NOTCH3/GRIN2A, whereas the most significant concurrent gene pair in LUSC was ZNF703/FGFR1. To predict survival, our nomograms identified that, in stage I-IIIA LUAD and LUSC, mutated TET2 contributed to more favorable DFS while mutations in EPHA3 and ETV5 indicated better OS. Stage and mutated KRAS were associated with inferior DFS and OS (DFS, n=222, c-index=0.714; OS, n=308, c-index=0.706). In the T1+2&N0&M0 subgroup, which is considered clinically low risk for relapse, older patients who carry BRCA2 mutations were found to strongly correlate with poor DFS (n=121, c-index=0.709), while age and mutated KRAS were distinct indicators of inferior OS (n=163, c-index=0.725). The calibration for survival probability displayed well agreement between nomogram prediction and actual outcomes. Stratification of different risk groups based on nomogram prediction displayed significant differences among Kaplan-Meier curves for survival outcomes (p<0.0001).

      8eea62084ca7e541d918e823422bd82e Conclusion

      This is the so far largest cohort of Chinese lung cancer patients with comprehensive genomic profiling reported. We revealed unique molecular profiles than TCGA and distinct mutual exclusivity and co-occurrence patterns between LUAD and LUSC. In addition, the nomogram models show promise of more precise prognostic prediction of NSCLC patients when integrating genetic information with clinical characteristics.

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      MA21.06 - Proteins Associated with Survival Differ Depending on Molecular Subtypes, and Mutational- and Smoking-Status In NSCLC Biopsies (ID 13769)

      15:50 - 15:55  |  Presenting Author(s): Ann Rita Halvorsen  |  Author(s): Mads Haugland Haugen, Åsa Kristina Øjlert, Steinar Solberg, Lars Jørgensen, Gunhild M Mælandsmo, Odd Terje Brustugun, Åslaug Helland

      • Abstract
      • Presentation
      • Slides

      Background

      Purpose: Proteins are the functional players driving both normal and disease physiology. The proteomic changes observed in lung cancer may be a consequence of mutations in essential driver-genes. The purpose of this study was to identify proteins in lung cancer biopsies associated with survival in groups stratified by smoking status, and EGFR-, TP53- and KRAS-mutations.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We have performed a profiling of 295 cancer relevant proteins, of which 60 were in a phosphorylated state, using reverse phase protein arrays (RPPA). We analyzed biopsies from 80 lung cancer patients (adenocarcinoma) and correlated the protein expression pattern with progression free survival (PFS) based on mutational- and smoking-status.

      4c3880bb027f159e801041b1021e88e8 Result

      Spearman correlation analysis revealed a higher number of proteins with significant association to PFS (p<0.05) among the wild type samples compared to the mutated samples. High expression of protein kinase C (PKC) and the isoforms alpha, beta and delta, included the phosporylated state, showed the strongest association with better PFS, especially in the wild type samples. Ten proteins were associated with PFS in never-smokers, where eight of these were unique for this group.

      Unsupervised hierarchical clustering separated the samples into four subclusters, each enriched with one of the three molecular subtypes TRU, PI and PP (Comprehensive molecular profiling of lung adenocarcinoma, Nature, 2014). Subcluster 2 contained two smaller clusters (2a and 2b) enriched with samples of subtype PP, where subcluster 2a was associated with poor PFS (p=0.003, Figure 1).

      heatmap_subtypes_mod.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      As of today, we do not have any effective treatment targeting KRAS- and TP53- mutated cells. This study shows that expression of specific proteins and phospho-proteins associated with PFS differ depending on molecular subtype, and mutational- and smoking-status. Proteins associated with PFS may serve as therapeutic targets to circumvent treatment resistance.

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      MA21.07 - A Nation-Wide Population-Based Mapping of Targetable Alterations in Smoking-Independent Lung Cancer (ID 13145)

      15:55 - 16:00  |  Presenting Author(s): Maria Planck  |  Author(s): Annette Salomonsson, Annika Patthey, Christel Reuterswärd, Mats Jönsson, Johan Botling, Hans Brunnström, Aziz Hussein, Nastaran Monsef, Cristian Ortiz-Villalon, Bengt Bergman, Luigi De Petris, Kristina Lamberg, Anders Vikström, Gunnar Wagenius, Annelie Behndig, Eva Brandén, Mikael Johansson, Hirsh Koyi, Johan Staaf

      • Abstract
      • Presentation
      • Slides

      Background

      Smoking is by far the most important cause of lung cancer. However, lung cancer among never-smokers is common and increasing [1]. A smoking-independent subgroup of lung adenocarcinoma with certain molecular and clinical features exists [2-3]. Therefore, as 1st project within the Swedish Molecular Initiative against Lung cancer (SMIL) we aim to characterize never-smoking lung cancer for etiological, diagnostic and therapeutic purposes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Through the Swedish National Lung Cancer Registry [1], we identified all individuals who underwent surgery for lung cancer in Sweden 2005-2014 and who were registered as never-smokers (n=540). At each study site (n=6), clinical data were reviewed by a thoracic oncologist/pulmonologist through patients’ medical charts and archived tumor tissues were retrieved and reviewed by a thoracic pathologist. For subsequent studies, we extracted DNA and RNA (using the Qiagen AllPrep kit for FFPE tissue) and constructed tissue microarrays. As a first pre-planned analysis, we performed fusion gene mapping using an RNA-based NanoString nCounter Elements assay, as previously described [4].

      4c3880bb027f159e801041b1021e88e8 Result

      In the first 212 (out of 540) analyzed samples, we detected 17 fusions involving ALK, 8 involving RET, and 2 involving NRG1. In addition, MET exon 14 skipping was found in 17 samples. In total, these findings involved 21% of analyzed cases. Additional results from further studies on the cohort will be presented.

      8eea62084ca7e541d918e823422bd82e Conclusion

      SMIL is an ongoing nation-wide molecular research collaboration on lung cancer where we currently collect one of the largest never-smoking lung tumor cohorts worldwide. From the first pre-planned analyses, we conclude that, in a population-based cohort of early stage lung cancer from never-smokers, druggable oncogenic fusions are frequent.

      References

      1. http://www.cancercentrum.se/vast/cancerdiagnoser/lunga-och-lungsack/kvalitetsregister

      2. Staaf J, Jönsson G, Jönsson M, Karlsson A, Isaksson S, Salomonsson A,Pettersson HM, Soller M, Ewers SB, Johansson L, Jönsson P, Planck M. Relation between smoking history and gene expression profiles in lung adenocarcinomas. BMC Med Genomics. 2012 Jun 7;5:22.

      3. Karlsson A, Ringnér M, Lauss M, Botling J, Micke P, Planck M, Staaf J. Genomic and transcriptional alterations in lung adenocarcinoma in relation to smoking history. Clin Cancer Res. 2014 Sep 15;20(18):4912-24.

      4. Lindquist KE, Karlsson A, Levéen P, Brunnström H, Reuterswärd C, Holm K, Jönsson M, Annersten K, Rosengren F, Jirström K, Kosieradzki J, Ek L, Borg Å, Planck M, Jönsson G, Staaf J. Clinical framework for next generation sequencing based analysis of treatment predictive mutations and multiplexed gene fusion detection in non-small cell lung cancer. Oncotarget. 2017 May 23;8(21):34796-34810.

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      MA21.08 - Discussant - MA 21.05, MA 21.06, MA 21.07 (ID 14628)

      16:00 - 16:15  |  Presenting Author(s): Siddhartha Devarakonda

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA21.09 - Differential Gene Expression in Tumor and Normal Tissue Reveals New Insights in the Biology of Non-Small Cell Lung Carcinoma. (ID 13341)

      16:15 - 16:20  |  Presenting Author(s): Alan Spatz  |  Author(s): Vladimir Lazar, Eitan Rubin, Katherine D. Lach, Hangjun Wang, Andreas Papadakis, Roy Moscona, Patricia Jimenez, Goulnar Kasymjanova, Victor Cohen, Jason S Agulnik, Leon van Kempen

      • Abstract
      • Presentation
      • Slides

      Background

      Effective use of targeted cancer therapies typically depends upon the identification of actionable genomics somatic alterations, benefiting only a minority of Non-Small Cell Lung Carcinoma (NSCLC) patients. To integrate transcriptomic assessment in cancer precision medicine, we have evaluated the mRNA expression levels in tumors and their matched normal lung tissues with the hypothesis that mRNA quantification in tumors relative to their matched normal tissue may better reveal small transcriptional differences that are associated with major biological effects.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The discovery set used 123 frozen macrodissected treament-naive NSCLC tumors and matched normal tissues from surgical resections performed at the Mutualiste Montsouris Institute (Paris, France), and the validation set used 143 FFPE macrodissected treatment-naive NSCLC tumors and matched normal tissues from surgical resections performed at the Jewish General Hospital (Montreal, QC, Canada). A pathology review was performed in all cases. In the discovery set, expression levels of 17,318 genes were analysed using an Agilent Technologies platform; in the validation set, the NanoString nCoutner technology was used with a customized 148 probeset that was designed according to the results of the discovery phase. The primary objective of the study was post-surgery progression-free survival (PFS). The secondary objectives were post-surgery overall survival (OS) and the identification of pathway-driven expression signatures.

      4c3880bb027f159e801041b1021e88e8 Result

      A set of highly expressed genes correlated with post-surgery PFS. Details of the prognostic signature will be presented at the meeting. Importantly, mRNA levels in normal tissues were highly variable between individuals. Organ matched reference enabled to control for the noise signals related to individual background genetic variability. The cell cycle G2/M checkpoint was the most significantly deregulated expression pathway in this cohort; nine genes in the signature are involved in this pathway and were upregulated in tumors, dependending on their histology: CHEK1, TOP2A, AURKA, CDC2, PLK1, CDC2, CDC25A, CDC25B, and CDC25C. CHEK1 is a pivotal gene in regulating the G2/M cell cycle pathway that triggers the double-strand base excision repair in which the main effector is PARP1. CHEK1 was overexpressed in 86% of adenocarcinomas, versus 42% for PARP1.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Conventional transcriptomic approaches using expression metrics obtained in tumor pools may miss important changes due to individual variability in non-tumoral tissue.The present work illustrates that paired matched tumor and normal tissues can identify new key genes involved in the biology and pathogenesis of NSCLC, and opens new avenues for integrating transcriptomic investigations in the precision medicine arena.

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      MA21.10 - Large-Scale Discovery of Novel Human Oncofetal Transcripts in Lung (ID 13552)

      16:20 - 16:25  |  Presenting Author(s): Brenda C. Minatel  |  Author(s): Victor D Martinez, Adam P Sage, Erin A Marshall, Tomas Tokar, Daiana D. Becker-Santos, Wendy P. Robinson, Igor Jurisica, Wan Lam

      • Abstract
      • Presentation
      • Slides

      Background

      Oncofetal genes are those expressed during both embryogenesis and tumourigenesis, but silenced in normal adult tissues. Although most described oncofetal genes have been shown to play important roles in tumour development and display potential as diagnostic and prognostic markers, this area of research remains largely unexplored. The advent of high-throughput technologies has not only allowed for large-scale discovery of biomarkers, but has also highlighted the role of non-coding RNAs from tissue development to malignant transformation. Small non-coding RNAs (sncRNAs, e.g., miRNA, snoRNA, piRNA, snRNA) are key players in gene-regulatory networks, and have shown promise as fluid-based biomarkers. In this study, we performed a comprehensive characterization of the sncRNA transcriptome of fetal, non-malignant and tumour lung tissues to identify development-associated (oncofetal) sncRNAs with roles in lung cancer, including the discovery of previously unannotated miRNAs.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Here, 209 paired non-malignant/tumour lung samples from two cohorts (BCCA, n=118 and TCGA, n=91) and 25 fetal lung samples were analyzed through the platform miRMaster. This platform aligns sequence reads to the hg38 genomic build, quantifies known sncRNA species and predicts novel miRNA candidates using the mirDeep2 algorithm. The sncRNA species that had no significant alterations in expression between fetal and tumours samples, but displayed significant differential expression between fetal/non-malignant and tumour/non-malignant tissues were classified as oncofetal sncRNAs. The biological relevance of the oncofetal sncRNAs and the novel miRNA candidates was investigated by gene-target prediction and pathway enrichment analyses, using mirDIP, IID and pathDIP databases.

      4c3880bb027f159e801041b1021e88e8 Result

      Our study provides the first large-scale characterization of the lung sncRNA transcriptome in fetal, non-malignant and tumour tissues. In particular, we discovered the expression of 464 novel miRNA candidates and identified a large subset of oncofetal sncRNAs. Target prediction analysis showed that the novel miRNA candidates discovered in all lung tissues are involved in cellular processes associated with cell proliferation, migration and survival, including the Wnt, MAPK and Notch signaling pathways, which are known to be associated with the development and progression of lung cancer. Additionally, oncofetal sncRNAs were found to be associated with cell cycle control and differentiation, highlighting the functional relevance of these molecules.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have not only expanded the lung sncRNA transcriptome, but also revealed the expression of a large number of sncRNAs relevant to lung tumourigenesis that are not expressed in normal adult tissues. Our results will aid in the development of more accurate fluid-based biomarkers for the early-detection of lung cancer.

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      MA21.11 - Epigenomic Mapping of Cell-Free DNA in Patients with Non-Small Cell Lung Cancer (ID 14055)

      16:25 - 16:30  |  Presenting Author(s): Christine M Bestvina  |  Author(s): Jordan Karpus, Xiao-long Cui, Claire Oosterbaan, Brian Won, Chuan He, Jyoti Patel

      • Abstract
      • Presentation
      • Slides

      Background

      Epigenetic modifications such as DNA methylation play an important role in human cancers, and have been implicated in tumor progression and drug resistance. Prior studies suggest 5-hydroxymethylcytosine (5hmC) has many important regulatory functions, given the colocalization of 5hmC within regulatory regions such as transcription factor binding sites, promotors and enhancers. Elevated 5hmC levels have been associated with increased gene expression. Genome-wide mapping of 5hmC has been performed in several different cells and tissues including brain and bone, though this has not previously been studied in lung cancer. It is possible the 5hmC profile can serve as a valuable biomarker for diagnosis, assessment for resistance, and surveillance for recurrence in non-small cell lung cancer (NSCLC).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      This was an exploratory study with a primary objective to perform genome-wide 5-hydroxymethylcytosine profiling of circulating cell-free DNA (cfDNA) in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer. Thirty-three different patient samples were collected from 32 different patients with advanced NSCLC with a known EGFR mutation by prior tissue genotyping such as FoundationMedicine or cfDNA such as Guardant. Samples were classified as “controlled” if the disease burden was stable or decreasing, versus “uncontrolled” if disease burden was increasing. Patients ranged from previously untreated to heavily pretreated. Full profiling of 5hmC in cfDNA was performed.

      4c3880bb027f159e801041b1021e88e8 Result

      A difference in modification between “controlled” and “uncontrolled” disease was found in 311 differentially modified regions (p<0.01), and in 189 differentially modified genes(p<0.01).

      bestvina_iaslc_5_4_18.jpg

      Figure 1: Degree of methylation of a) 311 differentially modified regions b) 189 differentially modified genes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In a retrospective analysis, a strong correlation exists between the methylation of specific regions and genes and the state of disease control. Future research should focus on if 5hmC profiling can be used to monitor disease status, to predict response to treatment, or alongside ctDNA for diagnostic accuracy.

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      MA21.12 - Discussant - MA 21.09, MA 21.10, MA 21.11 (ID 14630)

      16:30 - 16:45  |  Presenting Author(s): Geoffrey Liu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA24 - Genomic Evolution, KEAP 3 and More Non-Coding RNA (ID 928)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 12
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD
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      MA24.01 - Genomic Evolution Trajectory Depicts Invasiveness Acquisition from Pre-invasive to Invasive Adenocarcinoma (ID 11840)

      10:30 - 10:35  |  Presenting Author(s): Chao Zhang  |  Author(s): Zhi Xie, Fang-ping Xu, Jian Su, Song Dong, Qiang Nie, Yang W. Shao, Qing Zhou, Jin -Ji Yang, Xue-ning Yang, Xu-Chao Zhang, Yi-Long Wu, Wen-Zhao Zhong

      • Abstract
      • Presentation
      • Slides

      Background

      Accumulation of molecular abnormalities may depict evolution trajectories of tumor initiation and development. However, the genomic profile of early stage adenocarcinoma and molecular mechanism of invasiveness acquisition from pre-invasive to invasive adenocarcinoma remains barely explored.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We simultaneously collected 20 patients with adenocarcinoma in situ (AIS) (n=5), minimally invasive adenocarcinoma (MIA) (n=5) and stage IA adenocarcinoma (lepidic/acinar predominant) (n=10). Whole exon sequencing (WES) was performed in pre-invasive adenocarcinoma with multi-region specimens and stage IA adenocarcinoma. Analysis of genomic alteration among different pathological status was performed and tumor mutation burden (TMB) was calculated as well as six mutation types individually. Enriched pathways of each pathology were measured through KEGG analysis.

      4c3880bb027f159e801041b1021e88e8 Result

      Baseline characteristics was generated through heatmap with smokers (2/20, 10%) and EGFR mutation (13/20, 65%) among whole population. AIS/MIA indicated much lower number of mutations than invasive adenocarcinoma (IAC) while TMB revealed the same trend without statistical significance. Multi-region sequencing showed high heterogeneity of single nucleotide variation (SNV) in AIS and MIA. Unique SNV presented dominant proportion in initial status. Cluster analysis showed higher copy number variation in AIS/MIA than IAC with cell adhesion molecules (CAMs) enriched in AIS/MIA while variety pathway enrichment in IAC through KEGG analysis. C>A transversions held major proportion in early stage adenocarcinoma and a significant increase in the proportion of C>T and C>G mutation was exhibited when evolving into IAC.

      图片1.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Intratumor heterogeneity may occur in the very beginning of adenocarcinoma. High copy number variation was dominant event for AIS/MIA while higher tumor mutation burden was seen in IAC. Tobacco signature encompassing C>A transversions dominates the early development of adenocarcinoma and APOBEC signature may play a potential role in acquisition of cancer invasiveness.

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      MA24.02 - Genomic Alterations in Lung Adenocarcinoma Precursor Lesions (ID 13037)

      10:35 - 10:40  |  Presenting Author(s): Dennis Wigle  |  Author(s): Michael K. Asiedu, Nanette Reed, MC Aubry, Anja C Roden

      • Abstract
      • Presentation
      • Slides

      Background

      Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) are thought to be precursor lesions of invasive disease. Genomic alterations in these lesions have not been described.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Genomic analysis including whole genome and exome sequencing, and SNP array analysis were performed on 9 AIS and 18 MIA pathologically confirmed samples to identify single nucleotide variants (SNVs), structural variations and copy number variations. Mutation significance and signature analysis were determined by MutSig and NMF analyses. Pathway analysis was performed using ingenuity IPA.

      4c3880bb027f159e801041b1021e88e8 Result

      The range of mutation burden for AIS and MIA was 0.7 to 12/Mb with a median of 1.7/Mb. This compared to a mean of 7.2/Mb for invasive lung adenocarcinoma. Significantly mutated genes identified in AIS and MIA were ELAVL4, LIN37, XCL1, ELK3, RPS9, FBXO2, HLA-B and MYOG, which affected pathways regulating ESR1, ELAVL1 and TP53. Genes with recurrent mutations included MTPN, CDC27, GGT2, CTBP2, EGFR, NCOR1 and TGIF1 and implicated EGFR, MYC and MAPK1 pathways. Somatic mutations were characterized by C>T and T>C transition signature, whereas CNV analysis found high concentrations of copy number amplifications at 6p21.3 to 6p22.1, 8q24.12 to 8q24.3 and at 21q22.3. There were comparable structural variations in the AIS cases compared to MIA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In contrast to hypothesized models of tumor progression, AIS and MIA can harbor significant genomic alterations and tumor mutation burden. These observations challenge the notion of accumulating mutation burden during the progression to invasive disease. The finding of high mutation burden in some of these precursor lesions also suggests the intriguing concept of immunotherapeutic options for either treatment or chemoprevention.

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      MA24.03 - Biologic Profiling of Pre-Metastatic Niche in Completely Resected Pathological Stage I Non-Small Cell Lung Cancer (ID 13081)

      10:40 - 10:45  |  Presenting Author(s): Tomohito Saito  |  Author(s): Hironori Ryota, Mitsuaki Ishida, Kento J Fukumoto, Hiroshi Matsui, Yohei Taniguchi, Hiroaki Yanagimoto, Koji Tsuta, Tomohiro Murakawa

      • Abstract
      • Presentation
      • Slides

      Background

      Despite refinement of treatment strategy for non-small cell lung cancer (NSCLC), pathological Stage I NSCLC still develops recurrent disease in approximately 20% of patients even after complete resection. Recently, tumor microenvironment which promotes distant metastasis, or 'pre-metastatic niche', has been indicated to play pertinent roles in postoperative recurrence of cancer. Our aim is to investigate biologic profiles of pre-metastatic niche in pathological Stage I NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eighteen (12.7%) of 141 patients with pathological Stage IA or IB NSCLC who underwent R0 lobectomy between Jan. 2008 and Dec. 2013 developed distant metastasis postoperatively. From archived formalin-fixed paraffin-embedded specimens, these 18 cases of postoperative distant metastasis and matched cases were selected for total RNA extraction. To overcome inherent bias in selecting control patients, one-to-one matched pairs were created using propensity score matching of which model included age, sex, smoking history, and pathological stage. The samples with inadequate mRNA quality/ quantity were excluded. Gene expressions were detected by nCounter (NanoString Technologies, WA, USA) with PanCancer Immune Profilling Panel and PanCancer Progression Panel. Detected expressions were then analyzed and compared between the two groups by nCounter Advanced Analysis (version 2.0.115). Genes with unadjusted P-value < 0.01 were regarded as candidates for further investigation

      4c3880bb027f159e801041b1021e88e8 Result

      From preliminary comparative study on 6 paired cases, distant metastasis group showed upregulations of TPM2, CCL21, SOX2, CXCL12, EGFL7, PTGDS, BGN, PS8L1, ID4 and TGFB, whereas it showed downregulations of MTOR and CCL8 compared to recurrence-free group.

      In LATE-BREAKING ABSTRACT, we will report following results:

      1) Complete dataset of the comparative analysis including all pairs with adequate mRNA.

      2) Immunohistochemstry and/or in situ hybridization of the candidate genes/proteins on pathological sections.volcano plotnew.annotationearly.rec.png

      8eea62084ca7e541d918e823422bd82e Conclusion

      Biologic profilings of brain metastasis from NSCLC may subsequently help to understand underlying mechanism of postoperative distant metastasis and ultimately lead to novel targeted therapy.

      Futher details will be added in LATE-BREAKING ABSTRACT.

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      MA24.04 - Discussant - MA 24.01, MA 24.02, MA 24.03 (ID 14606)

      10:45 - 11:00  |  Presenting Author(s): Udayan Guha

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA24.05 - Baseline Spatial Heterogeneity of T790M in Tyrosine Kinase Inhibitor Naïve EGFR-Mutant Lung Adenocarcinomas (ID 14171)

      11:00 - 11:05  |  Presenting Author(s): Michael Cabanero  |  Author(s): James Kuo, Ni Liu, Ming Sound Tsao

      • Abstract
      • Presentation
      • Slides

      Background

      Despite a good initial response, most epidermal growth factor receptor EGFR-mutant lung adenocarcinomas develop resistance after treatment with 1st and 2nd generation tyrosine kinase inhibitors (TKIs). Approximately 50-60% of resistance can be attributed to the EGFRT790M mutation, which provides a higher affinity ATP binding site that outcompetes TKIs and restore constitutive kinase function. Although classically thought of as de novoacquisition, the presence of T790M has been shown to exist in some tumors before TKI-therapy. Obtaining a spatial map of T790M in TKI-naïve tumors can provide insight into development of this type of resistance.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eight cases of TKI-naive primary lung adenocarcinoma resections that were later found to be positive for T790M post-treatment with TKI were collected from 2004 to 2012. Initial pre-treatment tumor surgical resections were used for DNA extraction. Two tumor sections per case were divided into equal grid-like regions of approximately 8x8 mm2. The number of grids ranged from 16 to 32 per case, based on tumor size (0.8 cm to 6.5 cm). Digital droplet polymerase chain reaction was used to genotype the sensitizing EGFR-mutations and T790M mutations at each region. Allelic frequencies (AF) of the mutations were measured. Recurrence free interval, defined as surgical resection date to date of recurrence detection, and total duration of TKI-therapy were extracted from medical records.

      4c3880bb027f159e801041b1021e88e8 Result

      All eight cases of TKI-naïve EGFR-mutant lung adenocarcinomas were positive for T790M at baseline. T790M tumor burden, defined as the mean allelic frequency of T790M, ranged from 0.17% to 40.15% across the tumors. Three main patterns of distribution were observed. In two cases, T790M was present at low level (<1% AF) prevalence throughout the entire tumor. Five cases were characterized by the presence of distinct sub-clonal region, defined as T790M AF high in one or adjacent regions surrounded by regions with low or zero T790M AF. In one case, T790M was the predominant clone with T790M AF closely matching sensitizing EGFR-mutation AF. T790M tumor burden was not associated with either tumor size or recurrence free interval.

      8eea62084ca7e541d918e823422bd82e Conclusion

      T790M tumor cells exist prior to TKI-therapy in a majority, if not all, EGFR-mutated lung adenocarcinoma that developed T790M mutation as the resistance mechanism to EGFR TKI therapy, rather than by de novo acquisition during TKI-therapy exposure. However, pre-treatment T790M tumor burden did not appear to be associated with recurrence free survival, although this requires more cases for confirmation.

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      MA24.06 - Long Non-Coding Rna Expression Patterns Delineate Infiltrating Immune Cells in the Lung Tumour Microenvironment (ID 13978)

      11:05 - 11:10  |  Presenting Author(s): Adam P Sage  |  Author(s): Kevin W. Ng, Erin A Marshall, Katey S.S. Enfield, Greg L. Stewart, Spencer D. Martin, Brenda C. Minatel, Carolyn J Brown, Ninan Abraham, Wan Lam

      • Abstract
      • Presentation
      • Slides

      Background

      The tumour microenvironment is characterized by complex interactions between different cell types, including immune cells that may exhibit pro- or anti-tumour effects. Sequencing and deconvolution techniques present opportunities to identify immune cell composition of bulk tumour data; similarly, these have renewed an interest in the non-coding transcriptome and its regulation of immune- and tumour-biology. Numerous long non-coding RNAs (lncRNAs; >200nt) have emerged as regulators of tumour initiation, progression, and metastasis. Additionally, several immune-related lncRNAs mediate fine-level regulation to balance pro- and anti-inflammatory phenotypes; yet, the landscape of lncRNA expression in human immune cells remains uncharacterized. Thus, delineating these multifaceted regulatory networks is critical to cancer immunology, particularly in immunogenic malignancies such as lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      RNA-sequencing data of purified immune-cell subsets (CD8+ T, CD4+ T, B, Monocytes, Neutrophils, and Natural Killer) obtained from flow-sorted healthy peripheral blood samples were probed for lncRNA expression. Sequencing reads were aligned to the hg38 reference genome and quantified to Ensembl v89, yielding 4919 expressed lncRNAs. These immune-associated lncRNAs were correlated with immune cell infiltrate in tumour and paired non-malignant lung adenocarcinoma samples (n=54, The Cancer Genome Atlas) as estimated by the proportion of consistent immune-associated methylation profiles, denoted by leukocytes unmethylation for purity (LUMP) scores.

      4c3880bb027f159e801041b1021e88e8 Result

      We observed that lncRNA expression patterns display a greater degree of cell-type specificity than protein-coding genes in immune cells. In fact, 676 lncRNAs had detectable expression in exclusively one cell type. We uncovered previously-uncharacterized lncRNAs that have expression patterns suggestive of immune-regulatory roles. Compared with lung tumour samples, 19 immune-associated lncRNAs were significantly negatively correlated with LUMP scores (r<-0.400, BH-p<0.0100), 17 of which were also strongly positively correlated with CD45 gene expression (r>0.400, BH-p<0.0100) suggesting expression from immune rather than tumour cells. For instance, the lncRNA USP30-AS1 is significantly downregulated in tumours (average fold-change=2.96, BH-p=6.88*10-13), suggesting its relevance to tumour biology; however, higher transcript expression is correlated with decreased LUMP score (r=-0.685, BH-p=1.02*10-4), illustrating its specificity to immune cells.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Here, we present an atlas of cell-type specific lncRNAs in human immune cells. Our data suggest a functional relevance of lncRNAs to the biology of the tumour microenvironment, and the necessary consideration of tumour purity when examining non-coding RNA expression in order to avoid conclusions confounded by immune cells in bulk tumour data. Thus, we provide a resource for further elucidation of genomic links between immune and malignant cells, which may aid the development of future prognostic and therapeutic strategies.

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      MA24.07 - A Novel cis-Acting lncRNA Controls HMGA1 Expression in Lung Adenocarcinoma (ID 13979)

      11:10 - 11:15  |  Presenting Author(s): Adam P Sage  |  Author(s): Greg L. Stewart, David A. Rowbotham, Katey S.S. Enfield, Erin A Marshall, Victor D Martinez, Christine Anderson, Wan Lam

      • Abstract
      • Presentation
      • Slides

      Background

      High mobility group A1 (HMGA1) chromatin remodeling protein is enriched in several aggressive cancer types, including NSCLC, where mRNA and protein expression are markedly increased. Additionally, high HMGA1 expression has been associated with poor overall survival and chemotherapy resistance. While HMGA1 is deregulated in lung cancer, the mechanisms that mediate its expression are only beginning to emerge. Long non-coding RNAs (lncRNAs), are a class of transcripts have been implicated in the onset of cancer-associated phenotypes in tumourigenesis and metastasis. Recently, an emerging class of lncRNAs - cis-acting - has been shown to regulate the expression of neighbouring protein-coding genes, including oncogenes and tumour suppressor genes. Thus, lncRNAs may represent novel actionable therapeutic intervention points in known cancer driving pathways. Here we investigate the role of a cis-acting lncRNA, RP11.513I15.6, its deregulation in NSCLC, and its relationship with HMGA1.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      LncRNA transcriptomes were deduced from RNA-sequences of 36 microdissected tumour and matched non-malignant tissues. Normalized sequence read counts were used to identify transcripts with significantly deregulated expression (Wilcoxon Signed-Rank Test, BH-p<0.05). Sequencing data obtained from The Cancer Genome Atlas were analyzed to validate these results. SiRNA-mediated knockdown of lncRNA candidates identified in these analyses were performed in a non-malignant lung epithelial cell line (BEAS-2B). Quantitative real-time PCR quantified the effects of lncRNA knockdown on the expression of neighbouring cancer-associated protein-coding genes.

      4c3880bb027f159e801041b1021e88e8 Result

      Our analyses identified RP11.513I15.6, an undescribed lncRNA neighbouring HMGA1, to be significantly downregulated in adenocarcinoma (>2-fold downregulation in 81.5% of cases). This observation was confirmed in our validation cohort. HMGA1 expression was found to be anticorrelated with RP11.513I15.6, as tumours with downregulated RP11.513I15.6 displayed significant overexpression of HMGA1. This suggested that this lncRNA may be a key negative regulator of HMGA1. In vitro experiments demonstrated siRNA-mediated inhibition of RP11.513I15.6 in immortalized lung epithelial cells resulted in a significant increase in the expression of HMGA1 mRNA and protein. Taken together, our results suggest that RP11.513I15.6 is a novel cis-acting lncRNA that negatively regulates HMGA1, and may contribute mechanistically to the maintenance of cancer phenotypes.

      8eea62084ca7e541d918e823422bd82e Conclusion

      We have discovered a novel, 18-fold downregulated transcript that is anti-correlated with expression of HMGA1, a well established oncogene. In vitro studies support the hypothesis that this transcript, RP11.513I15.6, is a cis-acting lncRNA as siRNA-mediated inhibition led to upregulation of neighbouring HMGA1. Characterizing this oncogene regulatory mechanism will not only further our understanding of cancer biology, but could uncover a novel therapeutic intervention point.

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      MA24.08 - Discussant - MA 24.05, MA 24.06, MA 24.07 (ID 14608)

      11:15 - 11:30  |  Presenting Author(s): Alice Berger

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA24.09 - Synergy Between the KEAP1/NRF2 and PI3K Pathways Drives Non-Small Cell Lung Cancer with an Altered Metabolism (ID 13734)

      11:30 - 11:35  |  Presenting Author(s): Sarah Ann Best  |  Author(s): David P Desouza, Ariena Kersbergen, Antonia N Policheni, Saravanan Dayalan, Dedria Tull, Vivek Rathi, Daniel H Gray, Matthew E Ritchie, Malcolm J McConville, Kate D Sutherland

      • Abstract
      • Presentation
      • Slides

      Background

      The lung is a highly oxidative environment, tolerated through the engagement of tightly controlled stress response pathways. A critical stress response mediator is the transcription factor Nuclear Factor Erythroid-2-Related Factor 2 (NFE2L2/NRF2), which is negatively regulated by Kelch-like ECH-Associated Protein 1 (KEAP1). Alterations in the KEAP1/NRF2 pathway have been identified in 23% of lung adenocarcinomas, suggesting that deregulation of the pathway is a major driver in lung cancer.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We generated a novel genetically engineered mouse model (GEMM) whereby Keap1 (Keap1f/f) and Pten (Ptenf/f) were conditionally deleted in the lung, utilising intranasal inhalation of Adenovirus-Cre. The effects on lung pathology were investigated using histopathology, metabolomics and flow cytometry.

      4c3880bb027f159e801041b1021e88e8 Result

      We found that, while loss of Keap1 alone displayed no abnormalities in the lung, loss of Keap1 combined with loss of the tumour suppressor Pten, promoted malignant transformation. We further monitored tumour progression and immune infiltration in the lung, and metabolite profile changes in the serum of the Keap1f/f/Ptenf/f mouse model. Notably, a tumour-specific metabolite signature was identified in the plasma of Keap1f/f/Ptenf/f tumour-bearing mice, which indicated that tumourigenesis is associated with metabolic reprogramming. Furthermore, the immune milieu was dramatically changed by Keap1 and Pten deletion, and tumour regression was achieved utilising immune checkpoint inhibition.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study highlights the ability to exploit both metabolic and immune characteristics in the detection and treatment of lung adenocarcinomas harbouring KEAP1/NRF2 pathway alterations.

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      MA24.10 - Interrogating the Metabolic Effects of Keap1 Inactivation in Adenocarcinoma (ID 13764)

      11:35 - 11:40  |  Presenting Author(s): Sarah Ann Best  |  Author(s): Sheryl Ding, Ariena Kersbergen, Boris Reljic, Kate D Sutherland

      • Abstract
      • Presentation
      • Slides

      Background

      The most frequently altered gene in lung adenocarcinoma (ADC) is the KRAS oncogene. There are currently no effective treatments to target KRAS-mutant ADC. Loss of function in Kelch-like ECH-associated protein 1 (KEAP1) is co-mutated in 18% of KRAS-mutant ADC and is mutually exclusive with inactivating mutations in Tumour protein 53 (TP53). KEAP1 is a negative regulator of the transcription factor NRF2, which regulates cellular antioxidant and metabolic pathways. Metabolic dysregulation is considered a hallmark of cancer cells, which utilize anaerobic glycolysis and anabolic glucose metabolism in preference to aerobic oxidative phosphorylation in a phenomenon termed the Warburg effect.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We interrogated the consequences of Keap1 loss in KrasG12D-induced ADC using conditional genetically engineered mouse models (GEMMs). To examine metabolic features unique to Keap1-mutant ADC, GEMMs with KrasLSL-G12D/+ alone or with either the p53flox/flox allele (Kras/p53) or Keap1flox/flox allele (Kras/Keap1) were investigated. Gene and protein expression of key enzymes involved in glucose metabolism were measured in spontaneous lung tumors. Glycolytic functional assays were performed in live FACS-isolated tumor cells using a novel protocol.

      4c3880bb027f159e801041b1021e88e8 Result

      Major alterations in glycolytic function were identified as unique features of Keap1 inactivation in lung adenocarcinomas carrying oncogenic activation of Kras. Loss of Keap1 function in Kras-mutant ADC therefore created a pro-oncogenic metabolic environment to drive lung tumourigenesis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Targeting metabolic dependency in KRAS-mutant tumors may provide a unique method of treating this aggressive subset of lung ADC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA24.11 - Loss of Tumour Suppressors is Adequate and Sufficient to Drive Lung Cancer in CRISPR/Cas9 Mice. (ID 14026)

      11:40 - 11:45  |  Presenting Author(s): Paola A Marignani

      • Abstract
      • Presentation
      • Slides

      Background

      In non-small cell lung carcinoma (NSCLC), loss-of-function (LOF) mutations are found in tumour suppressors, highlighting the importance of these genes in the aetiology of lung cancer. The major tumour suppressors (TS) associated with the development of lung cancer are p53, and the kinase LKB1. Unlike oncogenes that have been successfully exploited therapeutically, LOF alterations in TS are difficult to exploit. The goal of our research is to understand how the loss of TS function allows for metabolic and epigenetic adaptation that favour conditions for tumour growth.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We developed a CRISPR/Cas9 mouse model of lung cancer representative of tumour suppressors lost in NSCLC. Since LKB1 and p53 are two of the most common LOF tumour suppressors found in NSCLC along with activating mutations in Kras, we used a Cre-dependent Cas9 mouse to create mice that simultaneously lack pulmonary Lkb1 and p53 along with activating KRasG12D. Here, we evaluated the development of lung cancers in the context of metabolism and epigenetic marks.

      4c3880bb027f159e801041b1021e88e8 Result

      The metabolic profile of lung tumours harvested from CRISPR/Cas9 mice was significantly different from the mTOR and metabolic profile of lungs harvested from control mice, favouring a switch from glycolysis to mitochondrial metabolism. Epigenetic marks; acetylation and methylation modifications to histones 3 (H3) and H4 were significantly different compared to control mice, indicative of poor prognosis.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our study is the first to characterize a new CRISPR/Cas9 mouse model for lung cancer that leverages the loss of two common tumour suppressor proteins associated with lung cancer; Lkb1, and p53. We show that the simultaneous loss of these TS leads to activation of mTOR and pro-survival pathways sustained by metabolic adaptation. Further to this, we observe epigenetic marks that agree with poor prognosis. We conclude from our study that patients with lung cancers that lack expression of LKB1 are likely to respond favourably to interventions that simultaneously target aberrant metabolism with modifiers of tumour epigenetic landscape. Our findings suggest that loss of LKB1 expression serves as a marker for NSCLC.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      MA24.12 - Discussant - MA 24.09, MA 24.10, MA 24.11 (ID 14609)

      11:45 - 12:00  |  Presenting Author(s): Vladmir Cláudio Cordeiro De Lima

      • Abstract
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      Abstract not provided

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    MS07 - Antibody-Drug Conjugates in Advanced NSCLC (ID 786)

    • Event: WCLC 2018
    • Type: Mini Symposium
    • Track: Advanced NSCLC
    • Presentations: 4
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 205 BD
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      MS07.01 - Basic Science (ID 11428)

      13:30 - 13:50  |  Presenting Author(s): David E Gerber

      • Abstract
      • Presentation
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      Abstract not provided

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      MS07.02 - Pharmacology (ID 11429)

      13:50 - 14:10  |  Presenting Author(s): Christian Rolfo

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      Abstract not provided

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      MS07.03 - Clinical Data (ID 11430)

      14:10 - 14:30  |  Presenting Author(s): Thomas E. Stinchcombe

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      Abstract not provided

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      MS07.04 - Future Directions (ID 11431)

      14:30 - 14:50  |  Presenting Author(s): Silvia Novello  |  Author(s): Annapaola Mariniello

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      Abstract not provided

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    MTE08 - Enhancing the Nurse's Role in Tobacco Prevention and Cessation: New Challenges (Ticketed Session) (ID 818)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Nursing and Allied Professionals
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 07:00 - 08:00, Room 205 BD
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      MTE08.01 - Enhancing the Nurse's Role in Tobacco Prevention and Cessation: New Challenges (ID 11560)

      07:00 - 08:00  |  Presenting Author(s): Linda Sarna

      • Abstract
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      Abstract not provided

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    MTE15 - Who is Too High Risk for a VATS Resection? (Ticketed Session) (ID 825)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/25/2018, 07:00 - 08:00, Room 205 BD
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      MTE15.01 - Identifying High Risk Patients: What Makes a Patient Too High Risk for Surgery and Who Decides? (ID 11572)

      07:00 - 07:30  |  Presenting Author(s): Hisao Asamura

      • Abstract
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      Abstract not provided

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      MTE15.02 - Who is Too High Risk for a VATS Resection? (ID 11573)

      07:30 - 08:00  |  Presenting Author(s): Pieter E. Postmus

      • Abstract
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      Abstract not provided

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    MTE25 - Enhancing the Care of Your Older Adult Population with Lung Cancer (Ticketed Session) (ID 835)

    • Event: WCLC 2018
    • Type: Meet the Expert Session
    • Track: Nursing and Allied Professionals
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 07:00 - 08:00, Room 205 BD
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      MTE25.01 - Enhancing the Care of Your Older Adult Population with Lung Cancer (ID 11591)

      07:00 - 08:00  |  Presenting Author(s): Martine Puts

      • Abstract
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      Abstract not provided

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 8
    • Moderators:
    • Coordinates: 9/24/2018, 10:30 - 12:00, Room 205 BD
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      OA03.01 - The Immunophenotyping and Genomic Characteristics of Pulmonary Sarcomatoid Carcinoma: Pleomorphic, Spindle Cell and Giant Cell Carcinoma (ID 12239)

      10:30 - 10:40  |  Presenting Author(s): Chunyan Wu  |  Author(s): Likun Hou

      • Abstract
      • Presentation
      • Slides

      Background

      Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small cell lung cancer (NSCLC) and comprises a diagnostically and therapeutically challenging group of tumors. We explored the immunohistochemical characteristics and genetic profiles of PSC (except carcinosarcoma and pulmonary blastoma)

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A total of 432 cases with surgically resected undifferentiated NSCLC (121 solid adenocarcinomas (ADC), 98 non-keratinizing squamous cell carcinomas (SQC), 118 large cell carcinomas (LCC) and 95 sarcomatoid carcinomas) were reviewed. Expression of epithelial-mesenchymal transition (EMT) markers (Cytokeratin (CK), Vimentin (Vim) and zinc-finger E-box binding homeobox 1 (ZEB1)) were studied by immunohistochemistry. 8 therapeutically-relevant genetic alterations(EGFR/BRAF/KRAS/HER2/MET exon 14 mutations and ALK/ROS1/RET fusion)of sarcomatoid carcinomas were detected by Capture-based targeted sequencing

      4c3880bb027f159e801041b1021e88e8 Result

      The expression of CK was almost positive in ADC, SQC and LCC, which of sarcomatoid component (SC) of PSC was observed positively only in 80/95(84.2%). Although vim expression was higher (88/95, 92.6%) in SC, it was also positive in ADC (37/121, 30.6%), SQC (14/98, 14.3%), LCC (12/118, 10.2%), respectively. In the contrast, SC was detected with 100% ZEB1 expression in PSC (95/95). ZEB1 expression was focal positive only in 1 cases of SQC (1/98, 1.0%). In ADC and LCC, no ZEB1 expression was found. The expression of ZEB1 had higher specificity (99%) and sensitivity (100%) than Vim expression in SC of PSC. The most frequent mutation genes were KRAS (18/58, 31.0%), EGFR (6/58, 10.3%), MET exon 14 (7/58, 12.0%) and no BRAF/HER2/ALK/ROS1/RET alteration were detected.

      8eea62084ca7e541d918e823422bd82e Conclusion

      ZEB1 was a useful differential diagnostic marker for PSC. Targeted mutations testing may be useful for classifying and managing PSC patients.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.02 - Nationwide Comparative Study Of PD-L1 IHC Assays on Lung Cancer: Initial Report Of LC-SCRUM-IBIS Project (ID 11321)

      10:40 - 10:50  |  Presenting Author(s): Noriko Motoi  |  Author(s): Genichirou Ishii, Yuichiro Hayashi, Koji Tsuta, Kiyotaka Yoh, Shingo Matsumoto, Koichi Goto

      • Abstract
      • Presentation
      • Slides

      Background

      Precision medicine requires accurate biomarkers for appropriate therapeutic decision. PD-L1 IHC is a predictive biomarker for immune checkpoint inhibitor (ICI), however, the complexity of PD-L1 IHC system could make interpretations confusion in practice. In this study, we compared four PD-L1 IHC systems using real-world clinical samples to reveal their properties and capability of harmonization as a part of nationwide immuno-oncology biomarker study of lung cancer (LC-SCRUM-IBIS).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Out of 1635 lung cancer patients enrolled in LC-SCRUM-Japan, four PD-L1 IHC assays (22C3, 28-8, SP263 and SP142) and whole-exome sequencing (WES) were analyzed in addition to NGS mutation screening by the Oncomine™ Comprehensive Assay (OCA). Planned accrual is 1000. IHC was evaluated by three certified lung pathologists independently. Three-tier scoring system (cutoff value of 1, 50%) applied for tumor cell (TC) in all assays, and TC+IC scoring algorism in SP142, according to the manufactural instruction. We calculated Spearman’s correlation coefficient and kappa value among TC proportion and the original protocol’s criteria of each assays. Discordant rate among assays was examined.

      4c3880bb027f159e801041b1021e88e8 Result

      486 patients (438 nonsmall, 48 small cell carcinoma) completed IHC study analysis from February to December 2017.

      Compared to 22C3, TC-score of 28-8 (kappa value 0.896) were and SP263 (0.729) showed good, and SP142 resulted slight (0.159) correlations. SP142-tc+ic score showed fair correlation with 22C3/28-8/SP263 TC-scores (kappa= 0.213/ 0.241/ 0.291, respectively).

      Our results showed substantial reproducibility of TC score among observers across different IHC assays (range of kappa: 0.675 – 0.837). Inter-observer concordance of the SP142-IC score was also acceptable (kappa 0.591-0.779). Of note, within 22C3 positive group (>1%), 4.5/15.6/67.7/55.0 % of 28-8/SP263/SP142-tc/SP142-(tc+ic) resulted in negative, respectively, indicating a risk of lower category switching for SP263 and SP142 compared to 22C3 and 28-8. A subset (8.3%) of 22C3-negative group resulted in SP142-positive and all such discrepancy was due to IC-positivity.

      There was no significant association between each PD-L1 expression and TMB by WES and OCA. Out of 77 patients treated with ICI, most responders (11/17, 65%) had PD-L1 high expression.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results revealed an excellent/moderate/slight correlation between 22C3 and 28-8/SP263/SP142. SP142-positive-cases were fewer and more rigorous than the other three assays. A subset of lung cancer showed IC-only PD-L1-positivity. Inter-observer reproducibility was substantial for TC and moderate for IC. The scoring algorism affected concordance trend in a modest way. For harmonization, we should aware of each assays properties. PD-L1 IHC is not a perfect but a feasible biomarker for patients’ selection of ICI therapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      • Abstract
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      Background
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each developed as predictive biomarker for specific anti PD1/PD-L1 immunotherapies. The Blueprint (BP) phase 1 comparability study demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells (TPS), while the SP-142 PD-L1 assay appeared to stain a lower percentage of tumor cells when compared to the other assays. The first part of BP phase 2 (BP2A) re-affirmed these findings in a larger cohort of ‘real life’ specimens scored by 24 experienced pulmonary pathologists, and also showed that the 73-10 assay developed for avelumab showed greater sensitivity than all other assays to detect PD-L1 on tumour cells. BP2A also demonstrated generally excellent inter-observer agreement for tumor cell PD-L1 scoring using both glass slides and digital images, with slightly lesser agreement for the cytology samples included in the study cohort. Inter-observer agreement for immune cell scoring on glass or digital slides was poor. Phase 2B of Blueprint (BP2B) aimed to compare PD-L1 scoring on triplet samples representing large tumor resection blocks, small biopsy samples and fine needle aspirate cell blocks prepared from the same tumor. a9ded1e5ce5d75814730bb4caaf49419 Method
      Triplet samples of large resected tumor block, small biopsy sample and fine needle aspirate cell block (the latter two taken from the resected tumour specimen) were gathered from 31 resected primary lung cancers (17 adenocarcinomas, 12 squamous cell carcinomas, and 2 large cell carcinomas). Sections from all 93 blocks were stained with the pharmDx 28-8 and 22C3, the FDA-approved SP142 and SP263, or clinical trial associated 73-10 PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. All H&E and PD-L1 IHC slides were scanned and digital images were used to score all cases by the same 24 pathologists involved in BP2A. As before, tumor cells PD-L1 staining were scored as continuous variable and into 7 cut-off-defined categories, as used in various immune checkpoint inhibitor trials. Immune cells were not scored. 4c3880bb027f159e801041b1021e88e8 Result
      The data reaffirm the relative comparability of 28-8, 22C3 and SP263 assays across the range of scores; SP142 assay scores were lower, those for 73-10 higher. Inter-observer agreement between readers ranged from moderate to near perfect (Kappa-Fleiss (K-F) scores generally >0.7); best overall agreement was on aspirates. Overall, the agreement between scores on the different sample types from the same tumor was good (most K-F scores >0.7); aspirates showed no significant difference from biopsy samples or whole surgical blocks. In contrast to biopsies and surgical blocks, scores could, however, not be rendered in about 14% of aspirate sections. 8eea62084ca7e541d918e823422bd82e Conclusion
      The results of BP2B confirms earlier results and also demonstrate comparable performance for fine needle aspirates in those cases where TPS scores were possible. 6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.04 - Discussant - OA 03.01, OA 03.02, OA 03.03 (ID 14550)

      11:00 - 11:15  |  Presenting Author(s): Julien Adam

      • Abstract
      • Presentation
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      Abstract not provided

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      OA03.05 - Characterization of the Immunologic Intra-Tumor Heterogeneity in Early Stages of Non-Small Cell Lung Cancer by Multiplex Immunofluorescence (ID 13334)

      11:15 - 11:25  |  Presenting Author(s): Alejandro Francisco Cruz  |  Author(s): Edwin Roger Parra, Mei Jiang, Junya Fujimoto, Santhoshi N. Krishnan, Souptik Barua, Arvind Rao, Chi-Wan Chow, Carmen Behrens, Neda Kalhor, Annikka Weissferdt, John V Heymach, Stephen Swisher, Boris Sepesi, Jack Lee, Cesar Moran, P. Andrew Futreal, Jianjun Zhang, Ignacio I. Wistuba

      • Abstract
      • Presentation
      • Slides

      Background

      Recurrence of non-small cell lung carcinoma (NSCLC) is associated with genetic and epigenetic intra-tumor heterogeneity (ITH). The interaction between malignant cells, stromal cells, and tumor-associated immune-cells (TAICs), such as T-cell lymphocytes (TCLs) and tumor-associated macrophages (TAMs), is important for progression of NSCLC and the characterization of the immunologic ITH might be relevant to predict recurrence in surgically treated patients at early stages of NSCLC. The aim of this study was to characterize the immunologic ITH of primary NSCLC tumors at early stages using image analysis and multiplex immunofluorescence (mIF) approaches.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Eight cases of stage IA and 8 cases of stage IB surgically resected NSCLC (11 adenocarcinomas, ADCs; and 5 squamous-cell carcinomas, SCCs) with a history of early recurrence were selected for this preliminary analysis. FFPE blocks were obtained and consecutive sections were stained with two panels of mIF for immune profiling, panel 1: pan-cytokeratin (AE1/AE3), PD-L1, PD-1, CD3, CD8, and CD68; panel 2: AE1/AE3, CD3, CD8, granzyme-B (GB), CD45RO, and FOXP3. Three not adjacent, intra-tumor regions (3mm2 each) per case were randomly selected after gridding the whole tumor section. A total of 41 intra-tumor regions were scanned by Vectra multispectral-microscope and analyzed using InForm-software. TAICs were quantified in epithelial and stromal compartments from each intra-tumor region. G-Cross AUC (area under the curve) was computed for specific intervals of distances between TAICs and malignant cells. Median distance between TAICs and malignant cells within each region was calculated.

      4c3880bb027f159e801041b1021e88e8 Result

      The median density of TCLs and TAMs were 1527 cells/mm2 and 635 cells/mm2, respectively, without significant differences between histologic subtypes. TCLs were predominantly concentered in stromal compartment (median, 2222 cells/mm2) compared with epithelial compartment (median, 332 cells/mm2). Percentage and density of TCLs and TAMs varied 4 and 8 times, respectively, between cases and regions. Non-cytotoxic T-cells and inactive cytotoxic T-cells were the most prevalent phenotypes. Higher density of TAMs and antigen-experienced TCLs were observed in stage IB than stage IA.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Characterization of immunologic ITH of NSCLC is able by mIF and image analysis with FFPE tumor tissue. There is variability of TAICs densities between regions from the same tumor and different subpopulations were observed. TAMs and exhausted T-cells were more prominent in stage IB (tumor >3cm) suggesting these cells may play an important role in recurrence. Ongoing studies with a larger cohort and comparison with non-recurrent surgically treated patients are warranted. Supported by CPRITRP160668 and UTLungSPORE grants

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.06 - Extraction of Radiomic Values from Lung Adenocarcinoma with Near-Pure Histological Subtypes (ID 13840)

      11:25 - 11:35  |  Presenting Author(s): Mong-Wei Lin  |  Author(s): Shun-Mao Yang, Li-Wei Chen, Hao-Jen Wang, Leng-Rong Chen, Kuo-Lung Lor, Yi-Chang Chen, Min-Shu Hsieh, Jin-Shing Chen, Yeun-Chung Chang, Chung-Ming Chen

      • Abstract
      • Presentation
      • Slides

      Background

      Histological subtypes of lung adenocarcinomas classified by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) system have been investigated using radiomic approaches. However, the results have had limitations since of invasive lung adenocarcinomas may be heterogeneous, with two or more subtypes. To reduce the influence of heterogeneity during radiomic analysis, computed tomography (CT) images of lung adenocarcinomas with near-pure adenocarcinoma subtypes were analyzed to extract representative radiomic features of different subtypes.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled 95 patients who underwent complete resection for lung adenocarcinoma and a pathological diagnosis of a “near-pure” (≥70%) IASLC/ATS/ERS histological subtype. Conventional histogram/morphological features and complex radiomic features (grey-level-based statistical features and component variance-based features) of thin-cut CT data of tumor regions were analyzed. A prediction model based on leave-one-out cross-validation (LOOCV) and logistic regression (LR) was used to classify all five subtypes and three pathologic grades (lepidic, acinar/papillary, micropapillary/solid) of adenocarcinomas. The validation was performed using 36 near-pure adenocarcinomas in a later cohort.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 31 lepidic, 14 papillary, 32 acinar, 10 micropapillary, and 8 solid adenocarcinomas were analyzed. With 21 conventional and complex radiomic features, for 5 subtypes and 3 pathological grades, the prediction models achieved accuracy rates of 84.2% (80/95) and 91.6% (87/95), respectively, while accuracy was 71.6% and 85.3%, respectively, if only conventional features were used. The accuracy rate for the validation set (n=36) was 83.3% (30/36) and 94.4% (34/36) in 5 subtypes and 3 pathological grades, respectively, using conventional and complex features, while it was 66.7% and 77.8% only using conventional features, respectively.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Lung adenocarcinoma with high purity histological subtypes demonstrates strong stratification of radiomic values, which provide basic information for accurate pathological subtyping and image parcellation of tumor sub-regions.

      figure for wclc 2018.png

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.07 - Three-Dimensional Immunofluorescence Analysis of Dynamic Vessel Co-Option of Spread Through Air Spaces (STAS) in Lung Cancer (ID 14318)

      11:35 - 11:45  |  Presenting Author(s): Yukako Yagi  |  Author(s): Rania G Aly, Kazuhiro Tabata, Natasha Rekhtman, Takashi Eguchi, Joseph Montecalvo, Katia Manova, Prasad S. Adusumilli, Meera Hameed, William D Travis

      • Abstract
      • Presentation
      • Slides

      Background

      STAS was identified, by the 2015 WHO classification, as a new method of invasion in lung adenocarcinoma, with poor prognosis. Blood vessel co-option is a mechanism by which spreading intraalveolar tumor cells connect to the surrounding vasculature to survive. The aim of this study was to visualize the dynamic mechanism of blood vessel co-option using a high resolution and high-quality 3D reconstruction, and multiplex immunofluorescence (IF).

      a9ded1e5ce5d75814730bb4caaf49419 Method

      A 3D reconstruction image of a case of invasive lung adenocarcinoma with extensive STAS was performed on the formalin fixed paraffin-embedded (FFPE) block. 150 serial sections were obtained by the automated sectioning system AS410 (DNS. Ltd, Japan), and stained with H&E (100 slides), and multiplex IF (30 slides) for CD31, type IV collagen, TTF-1 and E-Cadherin to assess the relation between STAS and the surrounding lung parenchyma and vasculature. The IF stained sections were scanned with 0.33um/pixel by Panoramic P250 Flash (3D Histech Ltd, Hungary) Whole Slide Imaging Scanner (WSI). The WSIs were reconstructed into 3D exported to Imaris 8.0 (Bitplane, MA, US) for signal assessment.

      4c3880bb027f159e801041b1021e88e8 Result

      Serial 3D image analysis identifies the presence of STAS mainly in the form of micropapillary clusters. The multiplex IF staining highlighted the co-option which was determined by the spread and then attachment of STAS (TTF-1 and E-Cadherin positive) to distant alveolar wall capillaries (CD31 positive) with preservation of the alveolar wall (figure). This relation between STAS and the surrounding lung parenchyma was visualized in all serial sections of the whole FFPE block thickness. 01s1632681_ cd31a488_ecada594_col4a647_ttfa546_65.5x2.jpg

      8eea62084ca7e541d918e823422bd82e Conclusion

      The survival of STAS, beyond the tumor edge, in lung adenocarcinoma is a viable mechanism for tumor recurrence. The combination of the high resolution and high-quality 3D reconstruction and multiplex immunofluorescence in our study, supports the concept that dynamic blood vessel co-option is a mechanism for STAS survival.

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      OA03.08 - Discussant - OA 03.05, OA 03.06, OA 03.07 (ID 14551)

      11:45 - 12:00  |  Presenting Author(s): David L. Rimm

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA09 - Prevention and Cessation (ID 909)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Prevention and Tobacco Control
    • Presentations: 8
    • Moderators:
    • Coordinates: 9/24/2018, 15:15 - 16:45, Room 205 BD
    • +

      OA09.01 - 5As to 3As: Evolution of the Systematic Approach to Smoking Cessation in Ontario’s Regional Cancer Centres (ID 14066)

      15:15 - 15:25  |  Presenting Author(s): William Kenneth Evans  |  Author(s): Erin Cameron, Mohammad Haque, Naomi Schwartz, Sahara Khan, Rebecca Truscott

      • Abstract
      • Presentation

      Background

      Smoking is responsible for approximately 30% of all cancer deaths in Canada, and more than 85% of lung cancer cases. Cancer patients who continue to smoke experience decreased treatment efficacy and safety, increased toxicities, greater risk of cancer recurrence and second primaries, poorer quality of life, and decreased survival. Evidence suggests that quitting smoking after diagnosis can significantly reduce these adverse effects. In 2012, Cancer Care Ontario (CCO) introduced a Framework for Smoking Cessation to be implemented across the province’s 14 Regional Cancer Centres (RCCs). In 2017, the Framework was revised from a 5As (Ask, Advise, Assess, Assist, Arrange) to a 3As (Ask, Advise, Act) brief intervention model.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      The transition to a 3As model was based on emerging evidence, feedback from CCO’s Smoking Cessation Advisory Committee and Regional Smoking Cessation Champions, as well as learnings from a preliminary program evaluation. The revised Framework recommended an “opt-out” approach to referring smokers to cessation services. Following an environmental scan and site visit with each RCC to assess the current state, site-specific action plans were developed to promote alignment with the revised Framework. Action steps were given priority ratings in the areas of data capture, referrals, and resources. Two phone calls were held with each RCC to monitor progress on action plan implementation. Knowledge translation resources were created to support healthcare providers’ uptake of the 3As model.

      4c3880bb027f159e801041b1021e88e8 Result

      Smoking cessation interventions are often perceived by health care providers as time-consuming; the 3As model made the intervention briefer but no less effective. Over 3,000 knowledge translation resources were distributed to support healthcare providers working directly with cancer patients, including pocket cards and posters with suggested scripts. While the revised Framework officially launched in April 2018, early adopters of the 3As model and opt-out approach have seen improved performance on the Accepted a Referral indicator (proportion of smokers who accepted a referral to cessation services). In 2017, one RCC’s rate tripled from 10.1% to 30.9% in 6 months, while another improved from 13.2% to 36.9% in the same period.

      8eea62084ca7e541d918e823422bd82e Conclusion

      To improve program effectiveness, CCO’s smoking cessation initiative transitioned from a 5As to a 3As model and an opt-out referral process. Frontline staff have indicated a willingness to adopt the simplified approach, and early results show a promising increase in the number of smokers who are connected to smoking cessation services.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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      OA09.02 - Acceptance of Smoking Cessation Services in Cancer Care Ontario’s Lung Cancer Screening Pilot for People at High Risk (ID 13032)

      15:25 - 15:35  |  Presenting Author(s): William Kenneth Evans  |  Author(s): Gail Elizabeth Darling, Beth Miller, Erin Cameron, Monica Yu, Martin Tammemägi

      • Abstract
      • Presentation

      Background

      Participation in lung cancer screening can be a teachable moment for smoking cessation. Current smokers who attend for lung screening may also be motivated to quit. In June 2017, Cancer Care Ontario launched organized lung cancer screening at 3 pilot sites in Ontario with smoking cessation embedded in the screening pathway. Participants are recruited through primary care providers and public-facing messaging.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Smoking cessation services (SCS) are offered to all current smokers (anyone who smoked a cigarette in the past 30 days) interacting with the pilot. Individuals found ineligible for screening are offered a direct referral to the Canadian Cancer Society’s Smokers’ Helpline. Screen-eligible individuals are scheduled for smoking cessation counselling during their baseline low-dose computed tomography (CT) appointment, using an opt-out approach. Hospital-based SCS are provided by trained counsellors and consist of 10 minutes (minimum) of behavioural counselling, a recommendation or prescription for pharmacotherapy, and arrangements for proactive follow-up. The proportions of current smokers who accept referral to SCS and who attend hospital-based smoking cessation counselling are being monitored throughout the pilot. A participant satisfaction survey is completed after the screening appointment (if applicable). Data on quit rates, quit attempts, heaviness of smoking and relapse among screening participants is being captured.

      4c3880bb027f159e801041b1021e88e8 Result

      Between June and October 2017, 50% of the 1241 individuals who underwent risk assessment to determine eligibility for screening were current smokers. Of the 808 individuals eligible for screening, 63% were current smokers: 52% were male, (age 55-64, 61%; 65-74, 39%), 55% had a high school education or less. 27% of ineligible individuals were current smokers. 83% of all current smokers (regardless of screen-eligibility) accepted a referral to SCS. Of screen-eligible current smokers, 89% accepted hospital-based cessation counselling; 88% of those who had a baseline low-dose CT in the reporting period attended a hospital-based counselling session. 93% of survey respondents (response rate 56%) reported being satisfied with the smoking cessation counselling they received.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Acceptance of SCS by current smokers in Cancer Care Ontario’s lung cancer screening pilot is very high. A large majority of screened current smokers have attended a hospital-based counselling session, and satisfaction with this service was high. These findings suggest that an opt-out approach is acceptable to individuals motivated to attend a lung screening program. The final pilot evaluation in spring 2020 will evaluate the success of the smoking cessation initiative by assessing quit attempts, quit rates and relapse among screening participants.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA09.03 - Discussions Between Health Professionals and Smokers About E-Cigarettes: Results from the ITC Policy Evaluation Project (ID 13257)

      15:35 - 15:45  |  Presenting Author(s): Shannon Gravely  |  Author(s): James F Thrasher, K. Michael Cummings, Janine Ouimet, Ann McNeill, Gang Meng, Eric N. Lindblom, Ruth Loewen, Richard O’connor, Mary E. Thompson, Sara C. Hitchman, David Hammond, Bryan W. Heckman, Ron Borland, Hua Hie Yong, Tara Elton-Marshall, Maansi Bansal Travers, Coral Gartner, Geoffrey T. Fong

      • Abstract
      • Presentation

      Background

      The current scientific evidence on the effectiveness of e-cigarettes for smoking cessation is limited, but shows e-cigarettes may be at least as effective as nicotine replacement therapy (NRT), which is a standard treatment for cessation and broadly recommended by health professionals (HPs). E-cigarettes are now more popular for cessation than licensed NRT and prescription medications in countries such as England, the United States (US), and Canada; however, debate exists on whether HPs should advise smokers to use e-cigarettes, particularly for those who have medical comorbidities (e.g., chronic lung disease). The present study included smokers from four countries to examine: (1) the prevalence of: (i) HP advice to quit smoking, (ii) discussions about e-cigarettes, and (iii) recommendations to use e-cigarettes; and (2) smoker’s characteristics associated with discussing e-cigarettes and receiving advice to use them.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Data come from the 2016 International Tobacco Control (ITC) Policy Evaluation Project Four-Country Tobacco and E-cigarette Survey, which includes nationally representative samples of adult (≥18 years) smokers from Canada (n=1,922), the US (n=1,501), England (n=2,105), and Australia (n=1,038). Participants eligible for analysis had visited a HP in the last year.

      4c3880bb027f159e801041b1021e88e8 Result

      Among all smokers who visited a HP in the last year, 47.5% received advice to quit smoking, 6.8% reported discussing e-cigarettes, and 2.1% of smokers were recommended to use an e-cigarette (36.1% of those who had a discussion). Discussions and e-cigarette recommendation were more common among smokers who were: younger, highly educated, advised to quit smoking, more frequent e-cigarette users, positive about e-cigarettes, and believed that the public approved of vaping. While smokers with diabetes (p=0.026) or cancer (p=0.018) were more likely to discuss e-cigarettes with a HP, they were not more likely to be recommended to use them. Smokers with chronic lung disease were more likely to be recommended to use an e-cigarette than smokers without lung disease (p=0.026).

      8eea62084ca7e541d918e823422bd82e Conclusion

      These findings suggest that HPs are not taking advantage of discussions with smoking patients to encourage cessation, to provide information about different smoking cessation methods (e.g., suggest e-cigarettes as a cessation aid for smokers who are not willing or able to quit with other strategies), and to encourage smokers who are not inclined to quit to use e-cigarettes as a less-harmful alternative to smoking. More research is urgently needed to assess whether e-cigarettes are a viable alternative to cigarettes for people with lung disease to help them stop smoking and prevent further lung deterioration.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA09.04 - Discussant - OA 09.01, OA 09.02, OA 09.03 (ID 14562)

      15:45 - 16:00  |  Presenting Author(s): Betty Tong

      • Abstract
      • Presentation

      Abstract not provided

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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      OA09.05 - Potential Reduction in Lung Cancer Mortality in the US from 2015-2065: A Comparative Modeling Approach (ID 11662)

      16:00 - 16:10  |  Presenting Author(s): Jihyoun Jeon  |  Author(s): Theodore R. Holford, David T. Levy, Eric J. Feuer, Pianpian Cao, Jamie Tam, Lauren Clarke, John Clarke, Chung Yin Kong, Rafael Meza

      • Abstract
      • Presentation

      Background

      Tobacco control efforts implemented since the 1960s in the US have led to considerable reductions in smoking and smoking-related diseases including lung cancer. It is, however, unclear to what extent tobacco use and lung cancer mortality will be further reduced during the next half century due to control efforts that have already been implemented until 2015. To address this question, we developed simulation models that explicitly relate smoking temporal patterns to future lung cancer rates.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Four independent lung cancer natural history models were developed using US smoking (1964-2015) and lung cancer mortality (1969-2010) data. Each model projected lung cancer mortality by smoking status (ages 30-84) from 2015 to 2065 under a status quo scenario, in which current smoking patterns are assumed to continue into the future. Sensitivity analyses were conducted comparing optimistic and pessimistic assumptions relative to the status quo.

      4c3880bb027f159e801041b1021e88e8 Result

      Models validated well to observed lung cancer mortality. Under the status quo scenario, age-adjusted lung cancer mortality is projected to drop 79% from 2015 to 2065. Concomitantly, the annual number of lung cancer deaths is projected to decrease from 135,000 to 50,000 (63% reduction). Despite these decreases, 4.4 millions deaths from lung cancer are projected to occur in the US from 2015-2065.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Tobacco control efforts since the 1960’s will continue to lead to reductions in lung cancer rates well into the next half century. Nonetheless, additional prevention efforts are required to sustain and expand these gains, and further reduce the lung cancer burden in the US.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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      OA09.06 - Molecular Alterations and Estimated Indoor Radon in NSCLC Patients from the French National Cancer Institute Registry: Radon France Study (ID 14168)

      16:10 - 16:20  |  Presenting Author(s): Laura Mezquita  |  Author(s): Fabrice Barlesi, Edouard Auclin, David Planchard, Angela Botticella, Anas Gazzah, Pernelle Lavaud, Frank Aboubakar Nana, Cecile Lepéchoux, Benjamin Besse

      • Abstract
      • Presentation

      Background

      Radon is a radioactive gas, considered the leading cause of lung cancer in non-smokers. We assessed the correlation between the radon exposure areas in France and the molecular alterations nationally registered in non-small cell lung cancer (NSCLC) patients.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We retrospectively collected all NSCLC tested for EGFR, BRAF, HER2 and KRAS mutations (m) and ALK and ROS1 rearrangements (r) on the 28 French Plateform led by INCa (French National Cancer Institute). The prevalence of molecular alterations by region was correlated to the indoor radon risk area based on the official French (Institut de Radioprotection et de Sûreté Nucléaire, INSN, France). Paris and its region Ile-de-France were not included in this analysis due to its high rate of patients that are native from other regions.

      4c3880bb027f159e801041b1021e88e8 Result

      116.424 NSCLC were included. Overall, KRAS was positive in 27,7% (27.314/98.522), EGFR in 11,27% (13.125/116.424), ALK in 3,2% (2.928/91.291), BRAF in 2,3% (2.419/105.919), ROS1 in 1,12% (373/33.222) and HER2 in 0,8% (816/97.749) of all cases.

      We stratified the French regions in 3 areas based on their exposure to radon: high (Auvergne-Rhône-Alpes, Bretagne, Normandie, Pays de la Loire), intermediate (Bourgogne-Franche-Comté, Nouvelle Aquitaine, Occitanie, Provence-Alpes-Cote-d'Azur) and low explosure (Centre Val-de-Loire, Grand Est, Hauts de France). The prevalence of driver alterations (EGFR, BRAF, HER2 and ROS1 were significantly higher in high exposure area. The prevalence of KRAS mutations was significantly higher in low exposure area.

      Low risk

      Intermediate

      High

      P

      EGFR mutation

      1962 (10%)

      4338 (11%)

      4176 (11.4%)

      <0.0001

      ALK rearrangement

      577 (3.3%)

      1019 (3%)

      896 (3%)

      0.35

      BRAF mutation

      327 (1.8%)

      830 (2.4%)

      692 (2.4%)

      0.0001

      HER2 mutation

      109 (0.6%)

      266 (0.9%)

      252 (0.8%)

      0.01

      ROS1 rearrangement

      61 (0.9%)

      133 (0.9%)

      126 (1.3%)

      0.005

      KRAS mutation

      4717 (29.8%)

      9215 (28.2%)

      7895 (27%)

      <0.0001

      Molecular drivers*

      3037 (3.9%)

      6587 (4.4%)

      6142 (4.4%)

      <0.0001

      * EGFR, BRAF & HER2 mutations, ALK & ROS1 rearrangements; KRAS mutation excluded.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC molecular alterations that are linked to low tobacco consumption were higher in the French region with high radon exposure. Role of the radon in lung cancer carcinogenesis of specific molecular subtypes should be further explored.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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      OA09.07 - Association Between Outdoor Air Pollution And Lung Cancer in Female Never Smokers (ID 14485)

      16:20 - 16:30  |  Presenting Author(s): Renelle L Myers  |  Author(s): Michael Brauer, Sim Ladhar, Sukhinder Atkar-Khattra, John Yee, Cheryl Ho, Anna McGuire, Kyle Grant, Alex Lee, Barbara Melosky, Sophie Sun, Martin Tammemägi, Stephen Lam

      • Abstract
      • Presentation

      Background

      Long term exposure to ambient particulate matter (PM2.5) has been associated with an increased risk of developing lung cancer, and is estimated to be responsible for ~23% of global lung cancer deaths. No current lung cancer screening risk prediction model uses air pollution as an individual risk factor in its risk calculation. As smoking rates decrease globally, and air pollution increases, it is important to assess the effect of long term outdoor air pollution exposure on lung cancer risk especially in never smokers.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We enrolled 421 patients with newly diagnosed lung cancer presenting to BC Cancer and conducted a detailed residential history from birth to estimate their air pollution exposure since 1996 when accurate high-resolution concentration estimates of PM2.5 particulate matter derived from satellite observations and ground measurements became available. The average PM2.5 exposure was quantified by combining residential histories with exposure data.

      4c3880bb027f159e801041b1021e88e8 Result

      The demographics of the 262(62%) ever smokers, and 159(38%) never smokers with lung cancer are shown in Table 1. Median exposure of all cancer patients was 7.1 PM2.5 ug/m3 (IQR 6.8-7.3; Range 4.3-65.8). Of the ever smokers, 6.1% had a PM2.5 >10 ug/m3 whereas 15.1% of the never smokers had a PM2.5 >10 ug/m3. Among never smokers with lung cancer with high PM2.5 exposure >10 ug/m3, 74% were female and 83% were of Asian descent. Using a logistic regression model, we demonstrated a significant association between air pollution exposure and never smokers compared to ever smokers in women: Odds Ratioper_1_LN-transformed unit = 12.05 (p<0.001). This association was absent in males (interaction p=0.006).

      8eea62084ca7e541d918e823422bd82e Conclusion

      table1.jpgIn women with lung cancer, outdoor air pollution exposure was significantly higher in never smokers than in ever smokers. This association was not observed in men with lung cancer.

      6f8b794f3246b0c1e1780bb4d4d5dc53

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.

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      OA09.08 - Discussant - OA 09.05, OA 09.06, OA 09.07 (ID 14563)

      16:30 - 16:45  |  Presenting Author(s): Douglas Arenberg

      • Abstract
      • Presentation

      Abstract not provided

      Information from this presentation has been removed upon request of the author.

      Information from this presentation has been removed upon request of the author.