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
    • Now Available
    • 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 (Now Available) (ID 11378)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Advance care planning (ACP) at its most basic level is a process of a capable person planning for future health care needs and deciding on a substitute decision maker to make health care decisions for them in the event that they become incapable. Over the past several years advance care planning has broadened its definition from a process of a legal document driven approach to one that is individualized, supports patient autonomy and includes a relational approach to ACP. This consensus definition (Sudore et al 2017) is inclusive of engaging adults at any age or stage of illness and their families into conversations that focuses on their goals, values, and preferences for future health care to ensure that patients receive care that is consistent with these values and preferences. It may also include choosing and preparing a trusted person (s) to act on their behalf in the event that they are no longer able to speak for themselves. This definition can also help support clinicians in clinical practice.

      Lung cancer is the most commonly diagnosed cancer worldwide with eighty five percent of patients being diagnosed at an advanced stage of illness. Despite recent advances in lung cancer treatment it is the leading cause of death from cancer for both men and women in the world. In addition to a significant symptom burden, high mortality and morbidity, patients are faced with complex decisions regarding treatment options, future care and end of life care decisions. Initiating ACP conversations early in a patient’s illness trajectory and revisiting at transition points in a patient’s illness has the potential to ensure they receive care that is consistent with their values, goals and preferences. These conversations may also alleviate the burden on family and reduce conflict with the health care team when patients’ wishes, values and goals are known and honoured.

      There is overwhelming evidence in the literature that the fear of destroying a patient and family’s sense of hope is one of the primary deterrents for health care clinicians engaging in ACP discussions. Other identified barriers to ACP in the literature are health care clinicians lack of knowledge about ACP, a lack of skills and confidence in how and when to start these discussions, the fear of causing distress and doing harm, a lack of time and a lack of support from their health care team. A common misconception is that most patients with advanced cancer or advanced illness will talk about ACP related issues if they feel it is important thus putting the onus on the patient rather than the health care clinician (Detering et al 2016, Schickedanz et al 2009). Studies show that a large percentage of nurses and physicians hold the belief that advance care planning conversations should be brought up by the patient and not the care provider as this indicates a readiness to engage in the planning process (Johnson et al 2015).

      Patient factors to consider prior to initiating an ACP conversation are the patient’s readiness and motivation to discuss advance care planning, that families and trusted others can be a motivator or a barrier to ACP and that patients prefer that these conversations are initiated with the health care team that knows them the best. Patients may not initiate these conversations thinking it may not apply to them if their health care team has not initiated the conversation (Sudore et al 2018, Johnson et al 2015).

      Emerging questions and concerns amongst health care clinicians are; what communications skills are needed, what constitutes an ACP conversation, who should have these conversations, what is the best time in a patient’s illness and how do I prepare for it. One of the first things to consider before engaging patients in ACP conversations is to assess your own communication skills and readiness followed by assessing for patient’s readiness and motivation. The timing of ACP conversations is important and should be individualized, it may include family or trusted others in the discussion and it should be voluntary. Paying attention to cues from patients can lead to the unplanned conversations. Cues may be implicit or explicit and patients may say…“I always want to be involved in decisions about my treatment and care”, “I want everyone to respect what’s important to me”, “I worry that what I want and don’t want will be overlooked”, “I am starting to wonder how long I may have to live” and “I don’t want to be a burden to my family”. The use of patient’s own words can help to guide the conversation.

      Clinician skills are important to have successful conversations that result in positive patient outcomes. Clinicians should have knowledge of ACP, be able to establish a therapeutic alliance, create a safe space for expression of emotion as ACP conversations can be difficult and emotional for the patient, family and the health care clinician, tailor the discussion to individual needs and determine what the patient and family know about the illness and what they know about ACP, an educational approach may be useful.

      Communication skills and tools can help to support clinicians in their practice. The use of open ended questions or phrases can to help to start the conversation. Some examples are; what is your understanding of your illness, how do you like information to be communicated to you, what brings quality to your life, what do you value most in your life, and is their someone in your life that you trust to make health care decisions for you if you are not able to speak for yourself?

      The success of having these unplanned conversations relies on knowing the literature, knowing the patient, knowing yourself and having the courage to do it.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Approximately 12,000 Australians are diagnosed with lung cancer each year and lung cancer continues to be the fifth most commonly diagnosed cancer in Australia [1]. Most lung cancers are diagnosed at an advanced stage and prognosis remains poor, with approximately 15% of patients surviving five years post-diagnosis [1]. Lung cancer research in Australia is also poorly funded [3].

      Patients with lung cancer experience high levels of distress with prevalence of anxiety and depression ranging from 20% to 50% [3 4]. Lung cancer patients, especially older men with lung cancer, have been identified as having one of the highest rates of suicide within the cancer population [5]. Lung cancer patients have significantly more unmet needs than other cancer patients [6]. Unmet needs have been associated with increased fatigue, bothersome symptoms, and lower satisfaction with health care increased intrusive cancer-related worries and poor quality of life[7]. Lung cancer also impacts on family members and loved ones and carer distress often parallels the patients’ distress. Lung cancer carers are at a higher risk of mental health problems such as depression and have more psychiatric sessions than other cancer carers [8].

      Stigma also affects 95% of people with lung cancer. Stigma can be either internal (felt stigma) or external (enacted stigma). Australians have been found to be less sympathetic to lung cancer patients than people from other countries[9]. This is largely due to the association between smoking and lung cancer [10, 2]. The stigma that surrounds lung cancer contributes to underreporting of symptoms, delayed help-seeking and people with lung cancer feeling disregarded by health professionals and receiving suboptimal treatment. Up to 11% of lung cancer patients have not seen a lung cancer specialist and 33% have not received cancer-specific treatments after initial diagnosis [11]. Caregivers also attribute more fault and blame towards patients with lung cancer for their illness and are less empathic potentially providing less effective homecare [12]

      To improve outcomes for lung cancer patients, the Lung Foundation Australia has identified five key areas of focus, including increased research funding, reducing the stigma surrounding lung cancer, improving early detection, implementing a national screening strategy and improving access to best practice treatments[2].

      Australian Institute of Health and Welfare 2017. Cancer in Australia 2017. Cancer series no.101. Canberra: AIHW.

      Lung Foundation Australia (2016) Improving outcomes for Australians with lung cancer, Lung Foundation Australia.

      Zabora J, BrintzenhofeSzoc K, Curbow B, et al. (2001) The prevalence of psychological distress by cancer site. Psychooncology, 10(1):19-28.

      Linden W, Vodermaier A, Mackenzie R, et al. (2012) Anxiety and depression after cancer diagnosis. Prevalence rates by cancer type, gender, and age. J Affect Disord 141:343–51.

      Urban D, Rao A, Bressel M, et al. (2013) Suicide in lung cancer: who is at risk? Chest;144(4):1245-52.

      Hill, K. M., Amir, Z., Muers, M. F., Connolly, C. K., & Round, C. E. (2003). Do newly diagnosed lung cancer patients feel their concerns are being met? European journal of cancer care, 12(1), 35-45.

      Li J, Girgis A. (2006). Supportive care needs: are patients with lung cancer a neglected population? Psycho-Oncology, 15(6):509-16

      Akechi T, Akizuki N, Okamura M, et al. (2006). Psychological distress experienced by families of cancer patients: preliminary findings from psychiatric consultation of a Cancer Center Hospital. J Clin Oncol 36(5):329–332.

      An Ipsos MORI report for the Global Lung Cancer Coalition. Global perceptions of lung cancer. June 2010. https://www.ipsos-mori.com/Assets/Docs/Polls/sri_global-perceptions-of-lung-cancer_16june2010.pdf

      Chambers, S.K., Dunn, J., Occhipinti S. et al (2012). A Systematic Review of the Impact of Stigma and Nihilism on Lung Cancer Outcomes. BMC Cancer, 12:18

      Vinod, S. K., O'Connell, D. L., Simonella, L., Delaney, G. P., Boyer, M., Peters, M., ... & Armstrong, B. (2008). Gaps in optimal care for lung cancer. Journal of Thoracic Oncology, 3(8), 871-879.

      Lobchuk, M. M., McClement, S. E., McPherson, C., & Cheang, M. (2008). Does blaming the patient with lung cancer affect the helping behavior of primary caregivers? In Oncology nursing forum 35,(4) 681-9.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Special Needs and Wellness in Lung Cancer Patients - European Perspective

      Early palliative care among patients with metastatic lung cancer can lead to improvements in various aspects such as quality of life, emotional stability and supportive environment. An integrative care, which combines the standard medical treatments of a palliative care, is considered to be the optimal care.

      The Palliative care discipline aims to improve patients’ quality of life and support their families, as they face a life-threatening illness. A key ingredient of this approach is the ability to identify and to map patients' needs and to address them in a holistic and systematic way. Each individual patient may have different needs, which include symptoms management, patient and family coping, information, social support, etc.

      This type of care requires the involvement of multidisciplinary team including Oncologist, Radiation unit, palliative team, Psychologist, social worker, spiritual guidance, community services such as home care unit or family physician, inpatient departments and day care treatment units. The need for multi-team effort makes the task of coordination and integration significantly challenging. In order to achieve this goal, the role of the nurse coordinator is both to be the actual coordinator of the various disciplines involved, as well as to mediate the massive amount of information to the patient and his main caregivers. Performing these tasks can reduce patients' confusion, frustration and exhaustion, and remove bureaucratic barriers.

      As part of this mission, the nurse coordinator builds a treatment plan with the patients and his / her family and main caregivers. During the dialogue, the nurse coordinator informs them about the various aspects of the diagnosis, treatment and the variety ways of coping. In addition, the nurse coordinator is responsible to implementing this multidisciplinary plan.

      One of the main challenges is maintaining the palliative treatment through a long term illness. As cancer medications might prolong life expectancy and improve patient's well – being, the sense of urgency of palliative care decreases along the patient's journey, despite its utmost importance in prevention of and coping with a commonly seen future deterioration.

      Whereas in Israel and some European countries the "nurse-coordinator" is inseparable unit in lung cancer case management, other sites are still in the process of adopting this approach.

      In my talk I will demonstrate this approach through a patient case From Sheba Medical Center in Ramat Gan, Israel.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      The reality of lung cancer stigma is tangible and has a profound impact on people living with this disease. Further, stigma remains a highly significant barrier to fulfilling the clinical promise of advancements in lung cancer treatment, early detection, and reduced lung cancer burden.1-2 Lung cancer stigma can have far-reaching effects that range from reduced involvement in interventions targeting prevention and early detection efforts such as smoking cessation and screening, impaired patient-clinician communication, delayed access to diagnosis and treatment, negative psychosocial responses, and even more broadly, to limited public support of and actual research funding. The phenomenon of lung cancer stigma is multilevel involving that of the individual, persons in the individuals’ immediate environment, persons in the healthcare system, and society at large, which shapes public perceptions and decisions that impact lung cancer patients (e.g., public attitudes, media campaigns, policy, research funding). Stigma is mainly social in nature. It is commonly a perceived or felt stigma as well as internalized by the individual patient influencing patient behavior. The stigma of lung cancer is perpetuated by the public’s perception that this is a ‘smoker’s only’ disease. However, many people are not aware that approximately 20% of lung cancer patients diagnosed each year are never smokers.3 It is imperative that innovative and novel approaches to changing the public perception of lung cancer and its associated stigma are pursued. If you have lungs, you can get lung cancer. As opposed to the prevailing perspective of blame that highlights a lifestyle choice fueled by addiction (i.e., smoking), we need to change the public conversation around lung cancer to one that focuses on early diagnosis, treatment, research dollars that match the magnitude of this deadly disease, and compassion. Comprehensive tobacco control efforts over the past five decades have been lauded as one of the leading public health successes. Specifically, restrictions to smoking in public buildings and spaces, increased tobacco-related taxation, and public health national media campaigns primarily delivered through fear-based messaging have all led to diminished social acceptance of smoking as an appropriate lifestyle behavior. Collectively, this has contributed to the overall success of decreasing U.S. adult smoking rates from 43% in 1964 to the current 15.5% U.S. adult smoking rate.4 Unfortunately, the demonization of tobacco has had the unintended consequence of stigmatizing the disease of lung cancer negatively impacting those at risk for and living with the disease.

      Just as the stigmatization of lung cancer did not happen in isolation, addressing this phenomenon requires broad strokes, so to speak, to change the public conversation about lung cancer. We have a unique opportunity to leverage social media platforms like Twitter, Facebook, and Instagram to change this conversation by crafting messaging that empowers rather than further stigmatizes both patients living with lung cancer as well as those at risk. The purpose of this presentation will be to discuss: (1) social media as a platform to change the public dialogue around lung cancer, and subsequently, its associated stigma; (2) how successful traditional population-based marketing can be adapted to the social media platform to target stigma; and (3) future directions in this new communication landscape for evidence-based psychosocial interventions targeted toward decreasing lung cancer stigma.

      References

      1. Jacobsen MM, Silverstein SC, Quinn M, et al. Timeliness of access to lung cancer diagnosis and treatment: A scoping literature review. Lung Cancer. 2017;112:156-164. doi:10.1016/j.lungcan.2017.08.011.

      2. Hamann HA, Ostroff JS, Marks EG, Gerber DE, Schiller JH, Lee SJC. Stigma among patients with lung cancer: a patient-reported measurement model. Psychooncology. 2014;23(1):81-92. doi:10.1002/pon.3371.

      3. American Cancer Society. Lung cancer risks for never smokers. https://www.cancer.org/latest-news/why-lung-cancer-strikes-nonsmokers.html. Accessed June 26, 2018.

      4. National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The Health Consequences of Smoking—50 Years of Progress. Centers for Disease Control and Prevention (US); 2014. http://www.ncbi.nlm.nih.gov/pubmed/24455788. Accessed June 24, 2018.

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

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Malignant pleural mesothelioma (MPM) is an aggressive, rare cancer due to exposure to and inhalation of asbestos (Odgerel et al 2017). Incidence is higher in certain occupational groups including asbestos mining and disposal and construction industries (Rake et al 2009). Rates vary within and across countries. The UK has approximately 2700 new diagnosis a year, one of the highest internationally. Rates of MPM show no signs of reducing and global incidence and burden is likely to be underreported due to poor data capture in some countries. Whilst asbestos use has drastically reduced in developed countries, significant amounts of asbestos are still used in India, China, Russia, and some developing countries (Frank&Joshi 2016)

      The latency period for MPM varies from 30 and 50 years with an average of 40. Occasionally exposure to diagnosis can be 10 years or less, but this is uncommon.

      MPM is an incurable cancer but there are new treatments offering promise in terms of length of life and palliation of symptoms. New radical surgical procedures are being performed and novel drug treatments provide better patient outcomes. In addition there are new procedures for the consequences of MPM such as trapped lung and malignant pleural effusion (MPE).

      Although showing no signs of the global burden reducing, and the increase of new treatment and procedures, there is little research exploring the experience of living with mesothelioma from the perspective of the person with the disease and their family. This presentation will shine a light on existing research, and provides us with an understanding of the experiences of living with MPM. It will draw on the wider literature as well as recent and current studies being conducted by the author and colleagues. International literature will be included but many references will be to the UK context.

      The journey of the person with MPM will provide the structure for the presentation. Starting with the long road to diagnosis, the experiences of coming to terms with and understanding the diagnosis will be considered. This will be followed by research on people’s experiences of treatment and trials and care related to end of life. An underpinning theme will be balancing the bleak with the positive.

      The diagnostic process is a challenging experience for patients. Many people describe it as a long and winding road, full of dead ends and false trails, as other possible diagnosis are offered prior to confirmation of MPM. For others whose first symptom is a MPE the distress of the symptoms are compounded by the shock of being delivered a terminal diagnosis. Although challenging, for some actually getting a diagnosis confirmed has the benefit of the end of uncertainty.

      Understanding and coming to terms with a MPM diagnosis is fraught and perplexing. Not only is the diagnosis life limiting, it was due to exposure to asbestos many years ago. The extent to which people remember and expected consequences of this exposure will impact upon ability to accept the diagnosis.

      It is not uncommon for people to have never heard of MPM and people can struggle to understand the nature of the tumour and their prognosis. Many people see cancer as a solid tumour or lump, so a diffuse cancer such as MPM is difficult for people to understand. Balancing the needs of patients and family members can be difficult especially if they conflict in terms of the nature of information and the time in the pathway it is requested. Prognostic facts are an example as patients and family carers may differ when and if they want such information.

      For those with a MPE, there is an urgency to have that treated. Unless the MPE and related symptoms are addresses, people are unable to assimilate information about the underlying diagnosis of MPM. This highlights the importance of timing related to information delivery.

      As new treatments become available, this will increase the information burden for patients. There are also challenges regarding decision making and tolerating the burden of treatments and interventions (Hughes&Arber 2008, Clayson et al 2005). People will have to understand procedures and eligibility criteria for treatments and face the consequences of being eligible or not eligible. Finding themselves not eligible can be experienced as a ‘failure’ as well as a loss of hope. For those receiving aggressive treatments they will have to endure any potential side effects and consequences.

      Legal and compensation processes add additional challenges to the patient journey. Again there may be a time pressure for people to resolve this for family members before the person with MPM dies (Hughes&Arber 2008).

      Finally research findings regarding end of life are considered, including the access to timely palliative care, pressures on family members in coping with MPM as an industrial disease requiring post-mortem and coroner involvement (Clayson et al 2005).

      Psychosocial impacts emerge across the pathway as patient’s and carers deal with stress, shock, changes to identify, relationships and the demands of managing uncertainty.

      Throughout the pathway, research indicates the need for people with MPM to balance out the bleak with the positive (Taylor 2018). Understanding this can help health professionals better meet the needs of patients and family.

      Much of the research on MPM experience highlights the enormity and range of information people have to take on board. Some of this has a time pressure as it is linked to treatment or trial decisions.

      In conclusion, the contribution of Relationship-centred care’ (RCC) will be considered. This expands on and enhances the notion of person-centred care. The proposition is that RCC will help address the complex and challenging nature of improving the MPM patient and carer experiences (Taylor et al 2018).

      The experience of patient and family carers experiences of MPM is relatively unexplored. We need more evidence to help us understand what is important to them and how care priorities can best be met. At the impact of increased asbestos use in developing countries emerges, with an increase in asbestos related diseases, research to illuminate patients perspectives and experiences in those nations will be required.

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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
    • Now Available
    • 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 (Now Available) (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. (Now Available) (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 (Now Available) (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 (Now Available) (ID 14636)

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

      • Abstract
      • Presentation
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      Abstract not provided

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      MA14.05 - Social Isolation Increases Psychological Distress in Patients With NSCLC (Now Available) (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 (Now Available) (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  (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (ID 14638)

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

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      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
    • Now Available
    • 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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (ID 14628)

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

      • Abstract
      • Presentation
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      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. (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 205 BD
    • +

      MA24.01 - Genomic Evolution Trajectory Depicts Invasiveness Acquisition from Pre-invasive to Invasive Adenocarcinoma (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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.

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

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

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

      • Abstract
      • Presentation
      • Slides

      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
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 205 BD
    • +

      MS07.01 - Basic Science (Now Available) (ID 11428)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      While in some cases antibodies that specifically bind tumor surface antigens can have therapeutic effects, many unmodified (naked) antibodies lack anti-cancer activity. Conjugation to cytotoxic drugs, radionuclides, or toxins can expand the utility of monoclonal antibodies and improve their potency. In this way, antibodies are employed as a means to target and deliver a toxic payload to the selected tissue. Factors critical to the success of antibody drug conjugates include the target antigen, antibody, linker, and payload. The target antigen should be overexpressed in the tumor relative to healthy tissue. The antibody should have high affinity and avidity for the targeted tumor antigen. The linker should be stable in circulation but must efficiently release the payload after internalization within the cancer cell. The payload should be a highly potent (picomolar range) cytotoxic agent with efficacy against the cancer under treatment, with a reproducible and optimal drug-to-antibody ratio (usually 3-4 drug molecules per antibody molecule), that does not meaningfully compromise the antibody’s biophysical and pharmacokinetic properties. The steps entailed in the mechanism of antibody-drug conjugate action include: (a) antigen binding; (b) antigen-antibody-drug conjugate complex internalization into endosomal vesicles; (c) processing along the endosomal-lysosomal pathway; (d) degradation in this acidic and proteolytic-rich environment; (e) intracellular release of cytotoxic compound. Antibody-drug conjugates may also retain antibody interactions with host immune effector functions, including antibody-dependent cellular cytotoxicity (ADCC). Mechanisms of resistance include (a) reduced target gene expression or presence of increased antigen mutations resulting in reduced target antigen on cell surface; (b) reduced antibody-drug conjugate internalization due to reduced cell surface trafficking or recycling; (c) multidrug resistance ransporter efflux out of the targeted cell.

      In addition to differential expression on tumor cells, antibody-drug conjugate target antigens need to (1) have an extracellular epitope amenable to specific antibody binding, and (2) be able to undergo internalization via receptor-mediated endocytosis into target cells, where the drug payload can be released. High-level expression is advantageous but not necessary. The higher the cell surface density of the target antigen, the more antibody-drug conjugate can be taken up and metabolized by the cell, to release the active cytotoxic agent. Rapid uptake of antibody-drug conjugate not only enhances efficacy, but also reduces opportunity for extracellular payload release. Antigens that are shed should be avoided.

      Antibody-drug conjugate technology has improved considerably in recent years. The employed antibodies are now chimeric, humanized, or fully human, and therefore less immunogenic than early murine antibodies. Efficient linkers (disulfide, dipeptide, hydrazine) have improved stability in circulation as well as better release of active drug within the tumor cell. Finally, highly potent agents with IC50 in the subnanomolar range (maytansine derivatives [DM1, DM4], auristatin [MMAE, MMAF], both of which are microtubule disrupting agents) have replaced conventional chemotherapy drugs such as doxorubicin, vinca alkaloids, and methotrexate.

      Despite the targeted nature of antibody-drug conjugates, toxicities may occur through multiple mechanisms: (1) Non-specific systemic release of the cytotoxic drug payload; (2) Non-selective cytoxicity of target-negative cells in proximity to target-positive cells (bystander effect); (3) internalization of the antibody-drug conjugate by target-negative cells. Prior experience has shown that unrecognized expression of target antigen on healthy tissue can result in profound toxicities: LewisY antigen (gastric mucosaàhemorrhagic gastritis); CD446v6 (deep layers of skinàfatal exfoliation); CA9 (intestinal mucosaàfatal gastrointestinal toxicity). Further complicating the development of antibody-drug conjugates, preclinical models may not adequately predict clinical activity and tolerability. In mouse models, the target antigen is not commonly expressed in host tissues, resulting in misleadingly favorable preclinical activity.

      As evidence of the inherent challenges facing antibody-drug conjugates, only two have been approved by the U.S. Food and Drug Administration: ado-trastuzumab emtansine (anti-HER2; for HER2-positive breast cancer) and brentuximab vedotin (anti-CD30; for Hodgkin’s lymphoma and anaplastic large-cell lymphoma). Target antigens relevant to non-small cell lung cancer under investigation include mesothelin (antetumab ravtansine), folate receptor (mirvetuximab soravtansine), sodium-dependent phosphate transporter (NaPi2b) (lifatuzumab vedotin; DNIB0600A), glycoprotein nonmetastatic B (gpNMB; osteoactivin) (glemtumumab vedotin), and epidermal growth factor receptor (depatuxizumab mafodotin), Perhaps the most developed antibody-drug conjugate in thoracic oncology, rovalpituzumab tersirine (Rova-T) targets delta-like ligand 3 (DLL3), which is highly expressed in approximately two-thirds of small cell lung cancer, but not NSCLC.

      Ultimately, several factors may influence the efficacy of an antibody-drug conjugate, among them target expression, sensitivity to the payload, and aspects of target biology that may impact internalization and intracellular trafficking. Revisiting longstanding principles of cytotoxic therapy may improve the performance of antibody-drug conjugates. These principles include the importance of combination therapies and the recognition that not all tumors are sensitive to microtubule-disrupting agents.

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      MS07.02 - Pharmacology (Now Available) (ID 11429)

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

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MS07.03 - Clinical Data (Now Available) (ID 11430)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Antibody drug conjugates (ADC’s) are currently being developed for several thoracic malignancies, and preliminary studies have revealed activity in patients with progressive disease after standard therapy for non-small cell lung cancer (NSCLC).

      Sacituzumab govitecan targets the Trop-2 which is overexpressed on many epithelial cancers compared to normal tissues and the antibody is bound to SN-38 which is the active metabolite of irinotecan.1,2 .A single arm phase 2 trial (n=54) investigated in patients with NSCLC with disease progression after at least one line of therapy. The ORR was 17%, median PFS was 5.2 months, and median OS was 9.5 months. The grade ≥ 3 adverse events observed were neutropenia, anemia, diarrhea, nausea, and fatigue. Trop-2 staining was not associated with benefit from therapy and the majority of patients had high Trop-2 staining.

      Telisotuzumab vedotin (ABBV-399) targets the c-Met protein and is conjugated to monomethyl auristatin E, a microtubule inhibitor.3 A phase 1 trial in metastatic solids tumor included an expansion cohort of in patients with NSCLC who were c-Met + (defined as IHC H-score of ≥ 150). An objective response was observed in three of 16 patients (18.8%) with c-Met positive NSCLC, and at week 12 six of 16 (37.5%) experienced disease control The treatment related adverse events observed (at all dose levels) were fatigue, nausea, neuropathy, decreased appetite, vomiting, and hypoalbuminemia. No responses were observed among patients with c-Met negative tumors.

      Ado-trastuzumab emtansine (T-DM1) is an ADC that uses the trastuzumab monoclonal antibody which targets the HER2 protein and delivers the maytansinoid antimicrotubule agent DM1. A single arm phase 2 trial investigated this agent in patients with HER2 positive NSCLC (defined as IHC score of 3+, IHC score or 2+ and FISH positivity, or HER2 mutation).4 Of the 15 patients enrolled 1 patient experienced a partial response (6.7%), the median PFS was 2.0 months, and median OS was 10.9 months. This study was terminated at the interim analysis since it did not meet the predefined efficacy criteria to proceed to the second stage. A phase 2 basket trial investigated T-DM1 in patients with HER2 mutant or amplified NSCLC.5 In the HER2 mutant cohort the ORR was 44% (8 of 18), median PFS was 5 months, and median OS was 11 months. In the HER amplified cohort the ORR was 50% (3 of 6), and the median PFS was 6 months, and the median OS was 12 months. The HER2 mutant cohort met the study’s primary end-point and the HER2 amplified cohort was expanded as per the Simon two-stage design. A phase 2 study investigated T-DM1 in patients with IHC 2+ or 3+ NSCLC, and each cohort was analyzed independently.6 Among the 29 patients enrolled on the IHC 2+ cohort no responses were observed, and the ORR in the IHC 3+ cohort was 20% (4 of 20). In the IHC 2+ cohort the median PFS and OS was 2.6 and 12.2 months respectively, and in the IHC 3+ cohort the median PFS and OS was 2.7 and 12.1 months, respectively. The grade ≥ 3 adverse events observed have been neutropenia, thrombocytopenia, anemia, fatigue, dyspnea, and hepatotoxicity, and have been consistent with the adverse events observed in breast cancer.

      These studies have revealed preliminary activity of ADC’s in patients NSCLC with disease progression after standard therapies. The rate of adverse events to the ADC’s are manageable. Refinement in the biomarker selection of patients for these therapies may improve the efficacy.

      1. Heist RS, Guarino MJ, Masters G, et al. Therapy of Advanced Non-Small-Cell Lung Cancer With an SN-38-Anti-Trop-2 Drug Conjugate, Sacituzumab Govitecan. J Clin Oncol. 2017;35(24):2790-2797.

      2. Gray JE, Heist RS, Starodub AN, et al. Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan. Clin Cancer Res. 2017;23(19):5711-5719.

      3. Angevin E, Kelly K, Heist R, et al. First-in-human phase 1, dose-escalation and -expansion study of ABBV-399, an antibody-drug conjugate (ADC) targeting c-Met, in patients (pts) with advanced solid tumors. Annals of Oncology. 2016;27(suppl_6):371P-371P.

      4. Hotta K, Aoe K, Kozuki T, et al. A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non-Small Cell Lung Cancer. J Thorac Oncol. 2018;13(2):273-279.

      5. Li BT, Shen R, Buonocore D, et al. Phase 2 Basket Trial of Ado-Trastuzumab Emtansine in Patients with HER2 Mutant or Amplified Lung Cancers. WCLC 2017: 18th World Conference on Lung Cancer in Yokohama, Japan. October 15-18. 2017.

      6. Stinchcombe T, Stahel RA, Bubendorf L, et al. Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC). Journal of Clinical Oncology. 2017;35(15_suppl):8509-8509.

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      MS07.04 - Future Directions (Now Available) (ID 11431)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Despite the success achieved by molecularly targeted agents in oncogene-addicted NSCLC over the past decade, patients inevitably develop acquired resistance with subsequent disease progression.

      Moreover, most lung tumors still do not present actionable targets derived by driver genetic alterations.

      To circumvent these issues, alternative strategies to target tumor cells have been studied.

      Antibody drugs conjugates (ADC) represent a novel class of anti-cancer treatment designed with the aim to combine the cytotoxic activity of chemotherapeutics with the selectivity of target agents, thus increasing the therapeutic interval of available compounds.

      The paradigm of ADCs is to convey cytotoxicity selectively into tumor cells, by way of a monoclonal antibody (MoAb) bound to cytotoxic chemicals via synthetic linkers. This complex is able to recognize tumor antigens which serve as Trojan horse for ADC internalization into cancer cell.

      To date, two ADCs have entered clinical practice, brentuximab vedotin for hematological malignancies and trastuzumab emtansine in advanced breast cancer overexpressing human epidermal growth factor receptor 2 (HER2) [1].

      In the field of thoracic malignancies, ADC research has focused on rarer “orphan” diseases, for which neither target therapies nor valuable second-line treatment options are available. In fact, the two ADCs currently underway in most advanced phases of clinical trials are rovalpituzumab tesirine for SCLC and anetumab emtansine for unresectable mesothelioma; however, with suboptimal early results [2;3].

      In NSCLC, no ADC has been experimented yet in phase III trials. However, several basket trials are currently evaluating anti-cancer activity and safety of ADCs mostly targeting HER2, Trop2 and NaPi2b, among others [4-6].

      In NSCLC treatment, as well as in other malignancies, ADC development has been limited by several factors.

      First, to realize a suitable ADC numerous criteria must be fulfilled [7].

      About the cytotoxin (also known as warhead), this must be a small molecule showing high potency, relative hydrophilicity and a lack of susceptibility to P-glycoprotein, which is a very common resistance mechanism for ADCs. Linkers connecting the MoAb to the warhead must be stable in blood, but they are also required to be able to release the drug inside the target cancer cells.

      Apart from these technical issues, which are underway of further improvement, the major unaddressed concern for ADCs in clinics may be finding the optimal antigen target. Cancer antigen must be transmembrane and able to internalize into the target cell after MoAb binding. Importantly, the ideal antigen should be tumor specific or at least with a minimal expression on healthy tissues, to reduce off-target toxicity. However, the type of non-cancerous cells on which the target antigen is exposed may also play a role in predicting ADCs toxicity. Because of the cell cycle-dependent mechanism of action, non-highly proliferating cells may be less vulnerable to the ADC cytotoxic damage. [8]

      Despite these limitations, the fact that the tumor target antigen is not required to drive tumor growth, constitutes an appealing advantage for ADCs application in malignancies lacking acknowledged driver mutations. In the context of thoracic cancers, squamous lung carcinoma or less differentiated entities would be amenable for greater research efforts in finding an adequate ADC antigen target.

      A further barrier to the design of viable ADCs is the unavailability of a reproducible, standardized and economic technique to identify and validate valuable target antigens. So far, the techniques used are immunohistochemistry or - more recently - functional genomic mRNA profiling, with the latter failing to localize the predicted protein into cancer cells [1].

      In NSCLC setting, concern is raised by the ruthless competition with the numerous systemic treatments already available or on study. A smart approach to find a place for ADCs in the NSCLC treatment algorithm, may be to explore combination strategies with drugs already on market. In the era of immune-oncology we are living, great attention is dedicated to combination strategies with immune checkpoint inhibitors (ICI). ADCs in most advanced phases of clinical experimentation are currently being tested in association with ICIs. Notably, a phase I/II trial of anetumab plus atezolizumab in advanced NSCLC patients has already been planned [9]. The supporting rationale is based on the demonstrated immunogenic cell death properties displayed by ADCs. Moreover, additional ADC immunogenicity is warranted by their antibody-dependent cell-mediated cytotoxicity potential. [10]

      A last and unsolved question regards tumor heterogeneity, which makes it unlikely to eliminate a whole neoplasm by using a single ADC target. As a future perspective, we could envision extensive tumor sequencing that allows for efficient antigen prediction and for the design of tailored ADCs targeting, contemporarily, multiple tumor specific antigens.

      Long and winding is the path for the ADC entry in NSCLC clinical practice. However, the rapidly evolving landscape in tumor sequencing and proteomics along with the clinical research experiences, may pave the way to find the most appropriate setting for ADCs in terms of manageable side effects and NSCLC patients’ selection.

      1. Moek KL, de Groot DJA, de Vries EGE et al. The antibody–drug conjugate target landscape across a broad range of tumour types. Ann Oncol. 2017 Dec 1;28(12):3083-3091.

      2. NCT02610140.

      3. NCT03061812.

      4. Hamilton EP, Barve MA, Bardia A et al. Phase 1 dose escalation of XMT-1522, a novel HER2-targeting antibody-drug conjugate, in patients with HER2-expressing breast, lung and gastric tumors. J Clin Oncol 36, 2018 (suppl; abstr 2546).

      5. Sands JM, Shimizu T, Garon EB et al. First-in-human phase 1 study of DS-1062a in patients with advanced solid tumors. J Clin Oncol 36, 2018 suppl; abstr TPS2605.

      6. NCT03319628.

      7. Beck A, Goetsch L, Dumontet C et al. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017 May;16(5):315-337.

      8. Damelin M, Zhong W, Myers J, Sapra P. Evolving Strategies for Target Selection for Antibody-Drug Conjugates. Pharm Res. 2015 Nov;32(11):3494-507.

      9. NCT03455556.

      10. Gerber, HP, Sapra P, Loganzo F et al. Combining antibody–drug conjugates and immune- mediated cancer therapy: what to expect? Biochem Pharmacol 2016. 102, 1–6.

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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
    • Now Available
    • 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 (Now Available) (ID 11560)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      The purpose of this presentation is to discuss strategies for enhancing the nurses’ role in tobacco control, including the implementation of smoking cessation interventions in oncology practice settings as part of routine care. The experiences of the Tobacco Free Nurses Initiative to accelerate nursing involvement in tobacco control in multiple countries will be used to illustrate key strategies.

      Healthcare professionals are effective in increasing quit attempts and long-term cessation; however, few patients receive the necessary support. Although more healthcare providers are identifying smoking status in the patient record and providing advice to quit, fewer actively assist patients who smoke with a quit attempt and arrange for follow-up. During this presentation, an evidence-based smoking cessation intervention based on the 5 As (i.e., Ask, Advise, Assess, Assist and Arrange) will be reviewed along with strategies for facilitating implementation in the clinical setting.

      The oncology team needs adequate knowledge and skills in the delivery of a tobacco dependence treatment intervention. Although many healthcare providers may know about the devastating health effects of smoking and tobacco use, including lung cancer, few received the necessary training to deliver an evidence-based intervention. Many educational resources are available as listed in Table 1.

      Basic content of educational programs to support delivery of a smoking cessation intervention includes information about health risks of smoking and exposure to secondhand smoke, nicotine dependence and withdrawal, health benefits of quitting, evidence-based methods for supporting tobacco dependence treatment including behavioral interventions (i.e., social support and skills training), identification of triggers for relapse and how to manage withdrawal symptoms and cravings, and knowledge of FDA-approved pharmacotherapy, including side effects and toxicity.

      With the advent of the electronic medical record (EMR), tobacco use is often included as core information at patient intake with reminders to providers increasing the rates of advice and assessment. The EMR may be tailored to include easy-to-use prepopulated “Smart sets” for intervention with information about approved medications and referral options as well as downloadable materials for patients and families. The EMR can push alerts to clinicians to prompt treatment. Inpatients who are identified as smokers can be offered nicotine replacement therapy (NRT) to alleviate withdrawal symptoms, regardless of their desire to quit long-term.

      Changes in the healthcare environment also can support implementation of these recommendations. These include adopting smoke-free policies in healthcare settings, beyond the inpatient hospital, and supporting quit efforts of healthcare providers. Although smoking is declining among healthcare providers, this may be an issue in some settings and in some geographic areas. Smoking of the healthcare provider has been associated with decreased interventions and confidence in providing a patient with intervention. Promoting the smoking cessation support services provides an opportunity to support the quit efforts of healthcare providers as well. Providers’ support of patient quit efforts is essential regardless of the smoking status of the individual clinician.

      Table 1. Resources to support implementation of tobacco dependence treatment in oncology clinical settings

      Title

      Organization

      Information

      Agency for Healthcare Research and Quality

      Treating Tobacco Use and

      Dependence: 2008 Update

      https://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/tobacco/index.html

      Section for clinicians and system decision makers, including systems change information for integration of tobacco dependence in clinical practice

      American Society of Clinical Oncology

      Tobacco cessation tools and resources

      https://www.asco.org/practice-guidelines/cancer-care-initiatives/prevention-survivorship/tobacco-cessation-control

      Comprehensive information regarding the 5 As for a cessation intervention and wide-ranging tobacco control policies

      Centers for Disease Control and Prevention

      Health Care Providers: How you can help patients quit

      https://www.cdc.gov/tobacco/campaign/tips/partners/health/hcp/index.html

      Provides general information for healthcare providers based on the Tips for Former SmokersRCampaign

      Centers for Disease Control and Prevention

      Smoking cessation and cancer

      https://www.cdc.gov/tobacco/campaign/tips/diseases/cancer.html

      Specific examples of the impact of smoking and exposure to second-hand smoke on cancer. Videos from the TIPs campaign with cancer to promote motivation to quit

      North American Quitline Consortium

      State telephone support lines for smoking cessation

      http://www.naquitline.org/

      Provides information about availability and details of telephone quitlines for smoking cessation across the United States including electronic referral, other resources, and availability of nicotine replacement

      Oncology Nursing Society

      Tobacco control policy recommendationsfor oncology nurses

      https://www.ons.org/advocacy-policy/positions/policy/tobacco

      Also endorsed by the International Society of Nurses in Cancer Care

      Smokefree partner toolkit

      Smoke-free.gov

      https://smokefree.gov/help-others-quit/health-professionals

      Provides comprehensive list of evidence-based resources, guides and government reports aimed for clinicians, including smokefree mobile interventions

      SRNT, Society for Research on Nicotine and Tobacco

      Resources for Clinicians

      https://www.srnt.org/?page=Resources_Clinicians

      Provides many science-based resources and a searchable index for abstracts related to cardiovascular disease

      Tobacco Free Nurses

      Resources for nurses to enhance to tobacco control

      https://tobaccofreenurses.org

      Multiple webcasts in different languages, including many focused on oncology nursing and tobacco control

      University of Wisconsin- Center for Tobacco Research and Intervention

      Providers overview of tobacco dependence treatment

      https://ctri.wisc.edu/providers/providers-overview/

      Offers tobacco treatment training through webinars, onsite videos or online programs.

      Updates on the evidence for electronic cigarettes, including vaping regulations by state

      References

      Treating Tobacco Use and Dependence:2008 Update. Clinical Practice Guideline.https://www.ahrq.gov/professionals/clinicians-providers/guidelines-recommendations/tobacco/index.html

      EK, Strouse R, Hall J, Kovac M, & Schroeder SA. (2010). National survey of U.S. health professionals’ smoking prevalence, cessation practices, and beliefs. Nicotine Tob Res, 12 (7), 724–733. doi: 10.1093/ntr/ntq071.

      Sharpe T, Alsahlanee A, Ward K & Doyle F. (2018). Systematic review of clinician-reported barriers to provision of smoking cessation interventions in hospital inpatient settings. J Smok Cessat, 1-11. Doi.10.1017/jsc.2017.25

      Sarna L, Bialous SA, Ong MK, Wells M, Kotlerman J. Increasing nursing referral to telephone Quitlines for smoking cessation using a web-based program. Nurs Res. 2012 Nov-Dec;61(6):433-40. doi: 10.1097/NNR.0b013e3182707237.

      Thomas D, Abramson MJ, Bonevski B, George J. System change interventions for smoking cessations. Cochrane Database Syst Rev.2017 Feb 10;2:CD010742. doi: 10.1002/14651858.CD010742.pub2.

      Boyle R, Solberg L, Fiore M. Use of electronic health records to support smoking cessation. . 2014 Dec 30;(12):CD008743. doi: 10.1002/14651858.CD008743.pub3. Review. PMID 25547090

      Rigotti NA, Regan S, Levy DE, Japuntich S, Chang Y, Park ER, Viana JC, Kelley JH, Reyen M, Singer DE. Sustained care intervention and postdischarge smoking cessation among hospitalized adults: a randomized clinical trial.JAMA.2014 Aug 20;312(7):719-28. doi: 10.1001/jama.2014.9237

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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
    • Now Available
    • 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? (Now Available) (ID 11572)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Thoracoscope is, by its original meaning, defined as an endoscope to observe intrathoracic space, just like a bronchoscope for bronchial lumen. But today this endoscope has been widely accepted as a surgical instrument to perform various kinds of intrathoracic procedures which had been otherwise done with open thoracotomy. Video-assisted thoracic surgery (VATS) has been expected to reduce the surgical burden, and already applied for the complex surgeries such as those for lung cancer. It is now a part of our routine procedures. However, despite the minimally invasiveness of the procedure, VATS may become a risky surgery in several special situations. Not only the surgeons, but also pulmonologist, medical oncologist, or radiation oncologist should know the nature of the surgery, and the situations in which VATS should be rather avoided. In this MTE sessions, I would like to present the special situations in which the VATS procedures are at too high risk, and therefore, and are not considered to be performed.

      HIGH-RISK SURGERY

      When dose the surgery become at high risk? In what situation, we should think the surgery is at high risk? Generally, there must be two kinds of situations each alone or both combined, which make the surgery at high risk. One is the patients at high risk for surgery even for a routine lobectomy, with a limited pulmonary reserve. The other is the difficult, complex surgery such as the extended pulmonary resection. Technical limitations of a VATS procedure are generally related to several different situations, which are described below. In this MTE session, I would like to focus upon the surgical, technical risks for the VATS procedures.

      VATS LUNG RESECTRIONS AT TECHNICALLY HIGH RISK

      2-1. DIFFICULT ONE-LUNG VENTILATION. One-lung ventilation, collapsing the one entire lung of the operative side, is an indispensable part of the stable VATS procedure. Thoracic cavity is usually filled with expanded lung, and only very limited space is left when the lungs are airated. To make VATS procedures possible, deflation (collapse) of the lung on affected side is indispensable, which provides the space for observation and working of surgical instruments. Therefore, for patients who do not tolerate to the one-lung ventilation because of the limited pulmonary reserve or previous history of lung resection, VATS is generally not indicated. For these patients, we consider routine open thoracotomy with intermittent collapse of the operative side of the lung.

      2-2. TIGHT ADHESIONS. Tight adhesions might exist within the thoracic cavity, especially for patients with the history of pleurisy or surgery. As seen previously, the working pleural space is an indispensable element of a VATS procedure. Surgeons are concerned about such history in case VATS resection is indicated. There are several types of adhesions which make VATS procedure difficult. Examples for these conditions are as follows:

      1) Previous pleurisy. If intrathoracic adhesion, mostly due to the previous pleurisy, is extensive, it is impossible to have an enough working space. In fact, lysis under thoracoscopy can be done, but it is usually time-consuming with significant amount of blood loss. There might be even a higher risk of damaging the visceral pleura and lung parenchyma, which may cause prolonged air leakage especially in the elderly with bullous lung. Therefore, except for a localized one, the extensive symphysis of pleura should be respected as a contraindication and a case which should be converted to the open thoracotomy.

      2) Adhesions at pulmonary hilum (“Frozen hilum”). In some cases with past history of infection such as tuberculosis, the hilar nodes are tightly adhesive to the bronchovascular structures. This is extremely difficult situation even for routine lobectomy. VATS resection for such cases are hardly considered.

      3) Previous thoracotomy. Major lung resection after previous lung resection involving the hilum (for example, a completion right lower lobectomy after middle lobectomy) is one of the most challenging surgery even by open thoracotomy. Also, for these operations, VATS resection is rarely indicated.

      2-3. COMPLEX PROCEDURES. Among various procedures in thoracic surgery, complex procedures are thought to be done safely by open thoracotomy, and not by VATS. These might include the following: such as bronchovascular plasty, combined resection with neighboring structures, pneumonectomy, and pleuropneumonectomy.

      2-4. OTHER SITUATIONS WHICH MAKE VATS PROCEDURE AT HIGH RISK

      1) Complex anatomical variation. When complex anatomical variations are found during the surgery, the procedure should be converted to open thoracotomy without hesitation.

      2) Large lesions. Any large intrathoracic mass, wherever it is located, have a trouble in being retrieved from the thoracic cavity. Not only they inevitably require enough extension of the trocar port or access thoracotomy, but also, they might be crushed during being extracted, which may result in tumor dissemination.

      3) Special locations. In the intrapulmonary and mediastinal lesions, there are special locations where the thoracoscopic instrumentation is quite difficult: Lesions located at mediastinal aspect of the lung, and those close to hilum. Mediastinal mass (swollen lymph nodes) adjacent to the vital structures such as great vessels is also least suitable for this technique because of danger of massive bleeding.

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

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

      • Abstract
      • Presentation
      • Slides

      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
    • Now Available
    • 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 (Now Available) (ID 11591)

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

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is the most common cancer around the world and it affects many older adults (1). With older age, the risk of treatment complications may rise. However, there is a lack of evidence on how to best treat older adults with cancer as this population has been severely under-represented in clinical trials. As patients age, their health and function can vary significantly, resulting in an increasingly heterogeneous population

      Lung cancer is the most common cancer around the world and it affects many older adults (1). With older age, the risk of treatment complications may rise. However, there is a lack of evidence on how to best treat older adults with cancer as this population has been severely under-represented in clinical trials. As patients age, their health and function can vary significantly, resulting in an increasingly heterogeneous population (3). Many older adults have other health and functional status impairments that may impact cancer treatment benefits and treatment risks.

      Several professional societies and organizations have recommended that for older adults with cancer for whom treatment is considered (3,4,5), comprehensive geriatric assessment (CGA) (consisting of the domains comorbidity, medication use, functional status, cognition, psychosocial wellbeing, social support, mobility/fall risk) should be conducted to help clinicians with the treatment selection and care during the treatment. Implementing a comprehensive geriatric assessment in the oncology setting can help the oncology team with 1) detecting additional health conditions, 2) the assessment data can be used to predict life expectancy; 3) the assessment data can be used to predict chemotherapy toxicity; 4) the assessment data can result in changing treatment plans; and 5) the assessment data can be used to potentially reducing toxicity (3,4,5). The randomized trial of Dr. Corre and his team showed that treatment selection for older adults with Non Small Cell Lung cancer (NSCLC) based on the CGA was associated with decreased treatment toxicity (6). This assessment should be followed up with a care plan to address the health and functional status issues identified. In this session we will review how to enhance the clinical care for your older adult with lung cancer.

      The learning objectives for this session are:

      1. To review the currently available evidence with regard to comprehensive geriatric assessment and management for your older adult with lung cancer patients including the Corre study.

      2. To review how you can improve the clinical care of your older adult with lung cancer (the who/what/how of CGA including which tools, domains, who does what as well as the top 10 clinical pearls).

      Reference list.

      1. Ferlay, J. et al. GLOBOCAN 2012v1.0, Cancer Incidence and Mortality Worldwide. IARC Cancer Base No. 11. Lyon, France: International Agency for Research on Cancer (2013).

      2. Santoni G, Angleman S, Welmer AK, Mangialasche F, Marengoni A, Fratiglioni L. Age-related variation in health status after age 60. PLoS One 2015;10(3):e0120077.

      3. Wildiers H, Heeren P, Puts M, et al. International Society of Geriatric Oncology consensus on geriatric assessment in older patients with cancer. J Clin Oncol 2014 August 20;32(24):2595-603.

      4. Mohile SG, Dale W, Somerfield MR, Hurria A et al. Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Chemotherapy: ASCO Guideline for Geriatric Oncology Summary. J Oncol Pract. 2018 Jun 22:JOP1800180. doi: 10.1200/JOP.18.00180. [Epub ahead of print]

      5. Hurria A, Wildes T, Baumgartner J et al. NCCN Clinical Practice Guidelines in Oncology. Older Adult Oncology. Version 1.2018. NCCN; 2018.

      6. Corre R, Greillier L, Le Caër H, et al. Use of a Comprehensive Geriatric Assessment for the Management of Elderly Patients With Advanced Non-Small-Cell Lung Cancer: The Phase III Randomized ESOGIA-GFPC-GECP 08-02 Study. J Clin Oncol. 2016 May 1;34(13):1476-83.

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    OA03 - Advances in Lung Cancer Pathology (ID 897)

    • Event: WCLC 2018
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 8
    • Now Available
    • 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 (Now Available) (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 (Now Available) (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
      • Presentation
      • Slides

      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 (Now Available) (ID 14550)

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

      • Abstract
      • Presentation
      • Slides

      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 (Now Available) (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

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

      6f8b794f3246b0c1e1780bb4d4d5dc53

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      OA03.08 - Discussant - OA 03.05, OA 03.06, OA 03.07 (Now Available) (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
    • Now Available
    • 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 (Now Available) (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

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      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 (Now Available) (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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      Information from this presentation has been removed upon request of the author.

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

      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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      OA09.04 - Discussant - OA 09.01, OA 09.02, OA 09.03 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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 (Now Available) (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.