Virtual Library

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    GR02 - Improving Patients Quality of Life During Treatment of Metastatic Disease (ID 30)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Advanced NSCLC
    • Presentations: 4
    • Now Available
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      GR02.01 - How Can We Incorporate Exercise Practices into Patient's Lives? (Now Available) (ID 3304)

      15:15 - 16:45  |  Presenting Author(s): Clarissa Mathias

      • Abstract
      • Presentation
      • Slides

      Abstract

      Physical activity is any movement using skeletal muscles. There have been over 16 studies examining physical activity and lung cancer risk, 12 cohorts and four case-control studies have examined the association between physical activity and lung cancer. When stratifying by study design, the pooled risk reduction amongst the 12 cohort studies is 23%, and amongst 4 case-control studies, a pooled risk reduction of 38%1. Among In a meta-analysis of 11 studies comparing highest versus and lowest levels of leisure-time physical activity, including odds ratios from studies in which the association between physical activity and cancer prevention was adjusted for smoking intensity: moderate-intensity physical activity was associated with a statistically significant risk reduction in lung cancer incidence, OR=0.87 (95% CI: 0.79–0.95), and vigorous-intensity physical activity was associated with a statistically significant risk reduction in lung cancer incidence, OR=0.70 (95% CI: 0.62–0.79).

      During exercise, particularly moderate-intensity aerobic exercise, T-cell populations transiently, NK cell populations and activity, and neutrophil quantity and activity transiently rise2. Exercise or physical activity haves a profound effect on macrophage physiology, including phagocytosis, chemotaxis, metabolism and anti-tumor activity. In murine models of acute exercise, peritoneal macrophage phagocytosis was increased in vitro, relative as opposed to sedentary conditions3. Although these effects are transient during an acute bout of exercise, the repetitive effects may produce a cumulative (training) effect. Chronic bouts of physical activity have been associated with an inverted ‘J-curve’ such that optimal immune function is achieved with moderate-intensity physical activity and sedentary and vigorous-intensity below optimal immune-system function.

      Physical activity is also a useful adjunct to improve the deleterious sequelae experienced during cancer treatment including fatigue, muscular weakness, deteriorated functional capacity, and many others. There is a growing base of evidence that suggests engaging in exercise, such as brisk walking, yields fewer symptoms and side effects during treatment and retards delays the rate at which physiologic systems are affected4. The mechanistic models hypothesized that includes pathways relating to sex hormones, metabolic hormones, inflammation and adiposity, immune function, oxidative stress, DNA repair, and xenobiotic enzyme systems. During cancer treatment, deconditioning of the cardiovascular and pulmonary system is common and is associated with diminished levels tolerance to of physical activity. However, it appears that the adaptive capacity of the cardiorespiratory system to exercise training remains intact during treatment. Among In a meta-analysis of 17 high-quality studies, aerobic fitness—a marker of cardiorespiratory function—improved significantly in cancer survivors during treatment over the exercise intervention period. Muscle Ffatigue and muscle weakness are also common sequelae of cancer treatment, but may be amenable to exercise training. A meta-analysis of randomized controlled trials concluded that both upper body and lower body strength improve as a result of exercise training during cancer treatment, with d=0.39 (95% CI: 0.12–0.65), and d=0.24 (95% CI: 0.07–0.41), respectively5. Strength improvements in the absence of muscle hypertrophy suggest that the adaptations resulting from strength training may be largely attributable to neural adaptations from better motor unit activation (recruitment, discharge rate), synchronization, and cross education. Neural adaptations occur early on in aduring a strength training program and may explain strength improvements in most short-term training studies. Mmoderate intensity activity may optimize immune activity and promote an anti-inflammatory state. Several biomarkers of immunologic function and inflammation exist including neutrophil and lymphocyte counts, natural killer cell activity, C-reactive protein, IL-6, IL-10, and TNF- alpha. It remains unclear what benefits exercise may have on immune system function after cancer treatment6.

      Despite the large volume of studies examining muscular strength among cancer survivors during treatment, few studies have examined the role of strength training among those with cancer cachexia7. It is interesting, Interestingly, given the success of resistance training among cancer survivors, to increaseincreasing upper and lower body strength that use of this modality among cancer survivors with cachexia is not more commonly studied.

      Despite the favorable profile of physical activity along the cancer continuum, many research gaps still exist. Elucidating the optimal dose of physical activity necessary to maximize the reduction in cancer risk of cancer and the optimal dose of physical activity necessary to improve specific physiologic systems, or treatment-specific side effects is warranted. In July 2010, an expert panel from the American College of Sports Medicine reviewed current studies of exercise training and cancer survivorship and released a roundtable consensus statement, concluding that exercise training is “safe during and after cancer treatments and results in improvements in physical functioning, quality of life, and cancer-related fatigue”8.

      Incorporation of exercise practices should, therefore, be advised and stimulated to prevent lung cancer, decrease treatment related side effects, rehabilitate survivors and possibly help during the cachexia period. Interaction between medical oncologists, thoracic surgeons, pulmonologists, physical therapist and sports medicine experts is mandatory for an optimal design of needed trials that will answer several opened questions related to this topic.

      References

      1. Emaus A et al. Physical activity and lung cancer prevention. Recent Results Cancer Res. 2011; 186:101–133

      2. Shephard RJ et al. Effects of exercise and training on natural killer cell counts and cytolytic activity: a meta-analysis. Sports Med. 1999; 28(3):177–195

      3.Woods JA, et al. Exercise-induced modulation of macrophage function. Immunol Cell Biol 78: 543-553, 2000

      4. Schmitz KH, et al. American college of sports medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc. 2010; 42(7):1409–1426

      5. Speck RM, et al. An update of controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. J Cancer Surviv. 2010; 4(2):87–100

      6. McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer. 2008; 8(3): 205–211

      7. Bossola M, et al. Cancer cachexia: it’s time for more clinical trials. Ann Surg Oncol. 2007

      8. Schmidt KH, et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med Sci Sports Exerc 42: 1409-1426, 2010

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      GR02.02 - What is the Best Management of Targeted Therapy Toxicity? (Now Available) (ID 3305)

      15:15 - 16:45  |  Presenting Author(s): Glenwood D. Goss

      • Abstract
      • Presentation
      • Slides

      Abstract

      GR02.02 - What Is the Best Management of Targeted Therapy Toxicity?

      15:35 - 15:55 | Presenting Author(s): Glenwood D. Goss

      Over the past decade, the discovery of oncogenic driver mutations in NSCLC and the subsequent advent of targeted therapies against these genomic alterations have significantly altered the management of adenocarcinoma of the lung for a significant proportion of patients. While most oncogenic driver mutations are rare, some exist in up to 50% of specific demographic groups, and together, oncogene-driven disease represents the majority of adenocarcinoma cases (1). Targeted therapies permit directed anti-neoplastic efficacy, with less systemic adverse events than chemotherapy. However, these agents are not without their own unique toxicities that must be managed for optimal drug compliance and therapeutic benefit. This talk will focus on the management of toxicities resulting from the targeting of aberrant pathways and common driver mutations in adenocarcinoma of the lung.

      We define targeted agents as pharmaceutical interventions directed specifically at one or more of the actionable genomic alterations that result in oncogenic phenotypes (proteins, signalling, etc.). Given the breadth of agents to be tested in this indication, the primary focus of the talk will be on approved (versus experimental) and commonly used agents, including small molecules and antibodies, but not antibody-drug conjugates. Genomic alterations to be addressed include at minimum the ERBB family of genes, KRAS, ALK, ROS-1, PI3K, VEGF and BRAF.

      For each agent directed against one of these aforementioned alterations, we will approach management of toxicity by contrasting the normal function of the pathway with adverse events associated with inhibition of this pathway. The management of the most frequent and serious adverse events of the pathway blockade will be the focus of the presentation.

      In conclusion, targeted therapies have had a profound impact on progression-free survival in a significant proportion of patients with metastatic adenocarcinoma of the lung, however they can be associated with a unique set of significant toxicities. The appropriate management of these toxicities may often determine whether a patient derives benefit or not from a targeted therapy, as toxicities can impact dose, frequency of delivery and compliance. Moving forward, increasing the specificity of targeted genomic alteration blockade is required to limit unwanted effects on wild-type proteins. The future of targeted therapy mandates that we devise newer agents with minimal toxicity.

      1. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014 Jul 31;511(7511):543–50.

      2. Kowanetz M. Vascular Endothelial Growth Factor Signaling Pathways: Therapeutic Perspective. Clin Cancer Res. 2006 Sep 1;12(17):5018–22.

      f1_sml.pngf2_sml.jpg

      Image 1: known (red) and putative (blue) driver mutations in adenocarcinoma of the lung, TGCA sample (1)

      Image 2: VEGF signaling in cancer and targets of inhibition.(2)

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      GR02.03 - What Is the Best Management of Immunotherapy Toxicity? (Now Available) (ID 3306)

      15:15 - 16:45  |  Presenting Author(s): Jean-Marie Michot

      • Abstract
      • Presentation
      • Slides

      Abstract

      Introduction.

      The consultations and advices of the organ specialists for immune-related adverse events (irAEs) management can be of great help. The oncologist who uses the immune-checkpoint inhibitors (ICIs) should in his clinical practice be surrounded by different organ specialists that will support him in the management of irAEs1–3.

      Although guidelines provide detailed algorithms for the management of irAEs4–6, few studies have assessed the real-life medical need of the oncology community. We propose here to report the activity of the immunoTOX assessment board to point the medical needs of oncologists in real life.

      Patients and methods.

      Organization of the immunoTOX assessment board.

      The ImmunoTOX assessment board is an academic group of physicians based at Gustave Roussy, Villejuif and at Paris-Sud University AP-HP Hospital, bringing together physicians specialized in the management of immunological toxicities1. Are present oncologists, pharmacovigilance pharmacists, internists and various specialists from expert bodies in the management of immunological toxicities (dermatologist, nephrologist, gastroenterologist, cardiologist, rheumatologist, hepatologist, neurologist, ear nose and throat specialist, ophthalmologist, hematologist, lung specialist and endocrinologist)

      Results.

      Over the period studied, 398 requests were sent to the immunoTOX board, for 356 patients. The median time between the occurrence of irAE and the immunoTOX board discussion was 35 days (IQ 13-72). The main requests to the immunoTOX board were about a diagnostic opinion on the relationship between immunotherapy and the side effect (n = 148, 37% of cases), followed by an opinion on the possibility of reintroduction the ICI in a patient after previous irAE (n = 109, 27% of cases), followed by an opinion about the management of a complex immunological toxicity (n = 100, 25% of cases), and by the possibility of starting an ICI in a patient with comorbidities (n = 41, 10% of cases).

      A certain or probable or possible causal relationship between immunotherapy and side-effect was found in 273/356 (77%) of patients. Among the 273 irAEs investigated, the main organ categories were distributed in the lung (n = 58, 21.2%), the gastrointestinal tract (n = 36, 13.2%), the liver (n = 33, 12.1%). %), musculoskeletal (n = 27, 9.9%) and nervous system (n = 23, 8.4%) (figure 1A).

      diapositive1.jpg

      The question of retreatment was 27% of the requests addressed to the immunoTOX board. The question of retreatment involved the possibility of resuming immunotherapy after prior irAE, which was grade 1-2 in 49% of cases and grade 3-4 in 51% of cases. The immunoTOX board gave a favorable recommendation for retreatment with caution for use in 65% of cases, a notice for maintaining temporary hold in 15% of patients, and a notice in favor of permanent discontinuation in 20% of cases.

      The requests question of the possibility of initiation of immunotherapy in a patient with comorbidities was one in ten. In patients with comorbidities, the immunoTOX board was in favor of initiating immunotherapy and recommended a precaution for use without formal contraindication in 93% of cases.

      Conclusion.

      The Immunotox board highlights the prominent real-life medical needs in the field of management of immunological toxicities. Questions rely mainly on toxicities affecting lung, digestive tract, hepatic and neuro-muscular system. When discussing a readministration or initiation of ICI in patients with autoimmune comorbidities, the Immunotox board was generally not opposed to give immunotherapy. A model of multidisciplinary management with oncologists working in close collaboration with organ specialists may guarantee to the patient the access to the ICI. This report will provide a basis of medical needs to define future strategies in prospective clinical trials of immunological toxicities management.

      Acknowledgement: The author thank the patients and their families and all investigators and site personnel. The authors thank Janine Nda, Cécile Geniez and Stéphanie Demirdjian and Sandrine Thorel for their assistance in management of patients.

      Figures legends.

      Figure 1. Distribution of irAEs organ categories (figure 1A) and irAEs types (figure 1B) registered by the immunoTOX board assessment. In the figure 2A are showed irAEs with occurrence ≥ 3.

      Figure 2. Characteristics of immune-related adverse events registered by the immunoTOX board assessment (among the 273 irAEs registered by the immunoTOX assessment board).

      CLS: Capillary leak syndrome

      CRS: Cytokine Release syndrome

      HPD: Hyperprogressive disease

      Hem-irAEs: Haematological immune-related adverse events

      irAEs: Immune-related adverse events

      References.

      1 Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper. Ann Oncol Off J Eur Soc Med Oncol ESMO 2016; 27: 559–74.

      2 Naidoo J, Zhang J, Lipson EJ, et al. A Multidisciplinary Toxicity Team for Cancer Immunotherapy–Related Adverse Events. J Natl Compr Canc Netw 2019; 17: 712–20.

      3 Cappelli LC, Shah AA, Bingham CO. Immune-Related Adverse Effects of Cancer Immunotherapy— Implications for Rheumatology. Rheum Dis Clin N Am 2017; 43: 65–78.

      4 Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol Off J Am Soc Clin Oncol 2018; : JCO2017776385.

      5 Haanen JB a. G, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol Off J Eur Soc Med Oncol 2017; 28: iv119–42.

      6 Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017; 5: 95.

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      GR02.04 - Immunotherapy: Hyperprogression and Treatment Beyond Progression (Now Available) (ID 3307)

      15:15 - 16:45  |  Presenting Author(s): David R Gandara

      • Abstract
      • Presentation
      • Slides

      Abstract

      Hyperprogression/Fast Progression and Treatment Beyond Progression: Unresolved Issues with Checkpoint Immunotherapy

      David R Gandara, MD

      University of California, Davis Comprehensive Cancer Center

      Sacramento, CA

      The tidal wave of checkpoint immunotherapy (CPI) over the last few years has both opened up a myriad of new treatment options for patients with lung cancer. There are many unique aspects of these PD-1- and PD-L1-directed therapies, turning oncologists into both immunologists and endocrinologists, to better manage a large variety of immune related adverse events. This presentation with address two other aspects of CPI which currently remain both poorly understood and controversial: Hyperprogression/Fast Progression and Treatment Beyond Progression.

      Hyperprogression/Fast Progression (HPD/FP): A phenomenon of accelerated tumor growth, termed hyperprogressive disease (HPD), has been reported in patients receiving checkpoint inhibitor therapy. HPD has been defined as a ≥ 2-fold increase in tumor growth rate (TGR) from baseline to first evaluation, by comparison with pre-treatment Alternate criteria describing rapid progression on CPI therapy have also been described. Whether HPD is unique to CPI remains unclear, as do associated predictive factors. We developed an alternative approach termed fast progression (FP), in order to study this phenomenon retrospectively in prior Phase III trials of CPI. In addition to CT-confirmed rapid early tumor growth, FP includes early death due to PD from cancer. Using these FP criteria, we analyzed data from the Phase III OAK study, demonstrating equivalent rates of FP with atezolizumab versus docetaxel. However more patients met criteria for FP by TGR increase with atezolizumab. Further, FP was not associated with previously reported predictive factors. This presentation will update those results as well as other new data regarding the HPD/FP phenomenon.

      Treatment Beyond Progression (TBP): Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. This effect explains the discordance between relatively modest response rate/progression free survival and more impressive overall survival in multiple CPI trials in advanced NSCLC. Presumptive benefit of TBP with CPI therapy has been observed in multiple tumor types including melanoma, renal cancer and NSCLC, leading the FDA to call for randomized trials designed to study this phenomenon. We studied TBP in the Phase III OAK trial of atezolizumab versus docetaxel, and reported that post-PD efficacy was consistent with a positive benefit-risk profile of atezolizumab TBP in patients performing well clinically at the time of PD. INSIGNA, a recently activated joint ECOG-SWOG Phase III study, is the first prospective trial to include an arm evaluating TBP. This presentation will discuss the biologic rationale for TBP with CPIs and detail other recently published data.

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    IBS03 - Personalized Management of Elderly Patients with Stage III NSCLC (Ticketed Session) (ID 34)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 2
    • Now Available
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      IBS03.01 - Managing Locally Advanced NSCLC in the Elderly in 2019 (Now Available) (ID 3322)

      07:00 - 08:00  |  Presenting Author(s): Corey Jay Langer

      • Abstract
      • Presentation
      • Slides

      Abstract

      Managing Locally Advanced NSCLC in the Elderly in 2019

      Alternative title: Personalized Management of Elderly Patients with Stage III NSCLC

      Corey J. Langer, MD, FACP

      Director of Thoracic Oncology

      Abramson Cancer Center

      Professor of Medicine

      Perelman School of Medicine

      University of Pennsylvania

      Philadelphia, PA 19104

      In the management of locally advanced (LA) non-small cell lung cancer (NSCLC), at least 10 studies over the past 25 years have shown superiority for chemoradiation over radiation (XRT) alone; more recently, concurrent chemoradiation has proven superior to sequential or asynchronous chemotherapy followed by XRT. Retrospective analyses evaluating outcomes in the elderly receiving these regimens have generally demonstrated similar progression-free (PFS) and overall survival (OS) compared to their younger counterparts on study, albeit with increased toxicity.1,2,3 Generally, those over 70 years of age were under-represented on these trials compared to the NSCLC population at large - while more than 40% of those diagnosed with LA-NSCLC were 70 years of age or older, fewer than 20% of those enrolled on relevant clinical trials were elderly.4 Virtually all of the earlier efforts were cisplatin-based, which made the routine use of this approach in elderly patients outside of clinical trials somewhat problematic, particularly in the face of age-associated co-morbidities that might preclude or limit the application of platinating agents. Since the beginning of the new millenia, non-cisplatin regimens, generally using weekly carboplatin in combination with a taxane or other partner agents active in NSCLC have been shown to yield “equivalent” efficacy with less toxicity. For elderly patients treated outside of a clinical trial, I generally favor weekly carboplatin (AUC 2) coupled with weekly solvent-based paclitaxel (45-50 mg/m2) in conjunction with a minimum dose of 60 Gy administered over a 6-7 week period. At least one trial from Japan conducted exclusively in the elderly with LA-NSCLC showed superior OS for concurrent XRT and low dose daily carboplatin vs XRT alone with median survival of 22.4 mos compared to 16.5 mos in the control group (HR 0.64).5 However, monotherapy with carboplatin during XRT is not considered the standard approach in LA-NSCLC.

      The only randomized trial to compare cisplatin- to carboplatin-based combinations in LA-NSCLC was a Japanese study which randomized patients to either MVP during thoracic XRT or to weekly carbo and either irinotecan or paclitaxel; this study showed virtually no difference in long term outcome (18 to 20% 5 year survival), with pacitaxel/carboplatin proving better tolerated.6 These results are dissatisfying, but clearly better than historic controls with XRT alone (5-7% 5 year OS). To date, unfortunately, in North American, we have no prospective, randomized, head-to-head comparisons of cisplatin based treatment vs. paclitaxel/carboplatin or other carboplatin-based regimens in stage IIIA/B NSCLC. Retrospective data from the VA and the SEER database, however, suggest little difference in long term OS.7 The results of RTOG 0617 would tend to validate paclitaxel/carboplaitn as a "viable" regimen in "good prognosis" LA-NSCLC pts with median survival in the 23 to 29 month range for weekly paclitaxel/carboplatin during radical XRT, with no advantage for 74 Gy over 60 Gy or the addition of cetuximab.8 More recently, the PACIFIC trial showed that patients with LA-NSCLC who received “consolidative” durvalumab, a PDL1 inhibitor, for up to a year, after responding to or stabilizing on concurrent chemoradiation, could enjoy a three-fold increase in PFS (16.8 vs 5.6 mos) and a 10% absolute improvement in OS (66.3% vs 55.6%).9 These benefits were both statistically significant (HR 0.68) and clinically meaningful; and the PACIFIC regimen featuring concurrent chemo-radiation followed by durvalumab has emerged as the “standard of comparison” if not the “standard of care” in fit individuals with LA-NSCLC, regardless of age. Of note, the HR for OS benefit in PACIFIC in those 65 years of age and older was 0.76 (95% CI: 0.55 - 1.05) vs 0.62 (95% CI: 0.44- 0.88) for patients under 65. Whether this approach should be applied to patients whose tumors do not harbor PDL1 expression or whose tumors have an oncogenic driver such as EGFR mutations remains controversial.

      References:

      1. Rocha-Lima, C et al, Cancer 2002

      2. Langer, C et al, ASCO 2002

      3. Schild, S et al, JCO 2002

      4. Auperin et al, JCO 2010

      5. Atagi et al, Lancet Oncology, 2012

      6. Yamamoto et al, JCO 2010

      7. Santana-Davila, R et al, JCO 2015

      8. Bradley, J et al, Lancet Oncology 2015

      9. Antonia, S et al, NEJM 2018

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      IBS03.02 - Surgery for Elderly Patients with Stage III Non-Small-Cell Lung Cancer (NSCLC)? (Now Available) (ID 3323)

      07:00 - 08:00  |  Presenting Author(s): Bernward Passlick

      • Abstract
      • Presentation
      • Slides

      Abstract

      Surgery for elderly patients with stage III Non-Small-Cell Lung Cancer (NSCLC)?

      Bernward Passlick Department of Thoracic Surgery

      University of Freiburg

      About 40 % of the patients with newly diagnosed Non-small-Cell Lung cancer are between 65 to 75 years old and more than 15 % are older than 75 years at the time of diagnosis. Elderly patients have in general a reduced cardiopulmonary performance status, including a higher risk for ischemic heart disease and COPD. Furthermore higher co-morbidity can be expected (renal, metabolic, and cerebral).

      The major question whether surgery should be offered to patients of more than 70 years are whether there is a higher morbidity and mortality in elderly patients and the second question is, whether curative surgery approach is worthwhile in patients over 75 years.

      The question whether a higher age is associated with a higher morbidity in elderly patients has been investigated by different studies, most of them with a retrospective design. While in older studies from the 80-ies of last century (i.e. lung cancer study group) there was an elevated mortality in patients over 70 years, this was not true anymore in publications from the late 90th of last century and current publications: For example in a recent publication from the Japanese association of chest surgeons the postoperative mortality was 2 % in patients between 70 - 79 years old and it was 2.2 % in patients over 80 years old. Furthermore, there is only a little influence of the age with respect to the postoperative lung function parameters.

      If we try to analyze whether surgery is worthwhile in elderly patients, we have to realize that men who are now 85 years old have a mean life expectancy of 5.3 years and women of 6.3 years. Furthermore, there is no survival difference in surgically treated patients for stage III lung cancer which are younger or older than 70 years old. In a Japanese study patients over 80 years have achieved a long term survival of more than 50 % after surgery for lung cancer. Limited resections can be successfully performed in patients with limited cardio pulmonary function parameters.

      In summary, the morbidity and mortality in elderly patients is not elevated after surgery and the median cancer specific long term survival is not different as compared to younger patients.

      References:

      1. Castillo MD et al., Curr Opin. Anaesthesiol. 2007; 20, 4

      2. Okami J et al. JThorac Oncol. 2009, 4, 12 47

      3. Cerfolio RJ et al. Ann. Thorac. Surg. 2006; 82, 424

      4. Sullivan V et al. Chest 2005: 128, 2671

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    IBS13 - How to Identify and Manage Toxicity in Stage III (Ticketed Session) (ID 44)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Treatment of Locoregional Disease - NSCLC
    • Presentations: 2
    • Now Available
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      IBS13.01 - Radiation Related Toxicities in Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC) (Now Available) (ID 3354)

      07:00 - 08:00  |  Presenting Author(s): Alexander Sun

      • Abstract
      • Presentation
      • Slides

      Abstract

      Dr. Alexander Sun, MD, FRCPC

      Addie MacNaughton Chair in Thoracic Radiation Oncology

      Princess Margaret Cancer Centre/University of Toronto

      Lung Cancer Site Group Leader, Radiation Medicine Program

      Associate Professor, University of Toronto

      Principal Investigator for PMH – RTOG/NRG Oncology

      Co-Chair, Lung Disease Site Committee, Canadian Cancer Trials Group (CCTG)

      Radical radiotherapy is uesd as definitive therapy in locally advanced non-small cell lung cancer (LA-NSCLC), either alone or in combination with chemotherapy and/or surgery. However, definitive doses of radiotherapy are associated with potential toxicity related to the organs at risk (OAR). The major OAR’s related to radical radiotherapy for LA-NSCLC include the lung and esophagus. Therefore, we need to be able to identify and manage radiation pneumonitis and esophagitis during and after a course of definitive radiotherapy.

      For good performance status, unresectable stage III NSCLC, radical radiotherapy is delivered either concurrently or sequentially with chemotherapy to total doses of 60Gy or higher. Although the best outcomes have been obtained with concurrent chemoradiotherapy, higher rates of toxicity have also been observed. With the advent of the establishment of adjuvant durvalumab after definitive concurrent chemoradiotherapy, the management of pneumonitis in particular has become even more of a challenge given the potential overlapping toxicities. For poorer performance status patients, radical radiotherapy may be used alone.

      For resectable patients with LA-NSCLC, radical radiotherapy can be given concurrently with chemotherapy prior to surgical resection as part of trimodality therapy. In other instances, radical radiotherapy can be given adjuvantly post-operatively for positive margins and can be considered in pathological N2 disease.

      Prophylactic Cranial Irradiation (PCI) has also been delivered in LA-NSCLC, although mostly in clinical trials as PCI has not been established as part of routine standard of care in stage III NSCLC.

      In this session, a discussion as well as case presentations will be used to illustrate how to identify and manage the above toxicities in stage III NSCLC.

      References (max 10)

      Baker S, Fairchild A. Radiation-induced esophagitis in lung cancer. Lung Cancer: Targets and Therapy 2016:7 119–127. (Review Article).

      Mehmood Q, Sun A, Becker N, et al. Predicting Radiation Esophagitis Using 18F-FDG PET During Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer. J Thorac Oncol. 2016: 1;11(2):213-21.

      Verma V, Simone CB, Werner-Wasik M. Acute and Late Toxicities of Concurrent Chemoradiotherapy for Locally-Advanced Non-Small Cell Lung Cancer. Cancers. 2017; 9:120. (Review Article).

      Jain V and Berman AT. Radiation Pneumonitis: Old Problem, New Tricks. Cancers (Basel). 2018 Jul 3; 10(7). (Review Article).

      Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med 2018; 2018 Sep 25.

      Shaverdian, N, Lisberg AE, Bornazyan, K et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: A secondary analysis of the KEYNOTE-001 phase I trial. Lancet Oncol. 2017, 18(7), 895–903.

      Chuzi S, Tavora F, Cruz M, et al. Clinical features, diagnostic challenges, and management strategies in checkpoint inhibitor related pneumonitis. Cancer Manag Res. 2017;9:207-213. (Review Article).

      Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011; 29: 279–86.

      Le Pechoux C, Sun A, Slotman BJ, et al. Prophylactic cranial irradiation for patients with lung cancer. Lancet Oncol 2016; 17(7): e277–293. (Review Article).

      Sun A, Hu C, Wong SJ, et al. Prophylactic Cranial Irradiation vs Observation in Patients With Locally Advanced Non-Small Cell Lung Cancer: A Long-term Update of the NRG Oncology/RTOG 0214 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2019 Mar 14.

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      IBS13.02 - Surgical Management for Perioperative Complications in Advanced Lung Cancer After Chemoradiotherapy (Now Available) (ID 3355)

      07:00 - 08:00  |  Presenting Author(s): Hiroshi Date

      • Abstract
      • Presentation
      • Slides

      Abstract

      Complete resection of residual lung tumor after induction or definitive chemoradiotherapy may be indicated for selected patients with advanced lung cancer. However, perioperative complication is a great concern. Here, we present videos of four cases requiring surgical intervention for perioperative complications.

      Case 1

      A 59-year-old man was diagnosed with squamous cell carcinoma invading right diaphragm, left atrium and subcarinal lymph node (cT4N2M0). After induction chemoradiotherapy, he was downstaged to cT4N1M0 and underwent right thoracotomy. We realized that the tumor was invading liver through diaphragm. During partial hepatectomy, IVC was injured and massive bleeding occurred. Cardiopulmonary bypass was established and left lower lobectomy with combined resection of diaphragm, liver and left atrium was performed.

      Case 2

      A 50-year-old man was diagnosed with unresectable left upper lobe squamous cell carcinoma invading aorta and #6 lymph node (cT4N2M0). Definitive chemoradiotherapy significantly shrank the tumor. One year later, he was referred to us for salvage surgery. At thoracotomy, we found no fissure between the left upper and lower lobes. The left basal bronchus was accidentally stabled by false recognition of lingula bronchus. The staple lines were removed, and the basal bronchus was reconstructed by end-to-end anastomosis. Then the left upper lobectomy with combined resection of aortic adventitia was performed.

      Case 3

      A 69-year old man was diagnosed with right lower lobe adenocarcinoma with right #2 lymph node metastasis (cT2N2M0). After induction chemoradiotherapy, he underwent uneventful left lower lobectomy with extensive hilar and mediastinal lymph node dissection. He developed radiation pneumonitis and received steroid treatment. On day 52, he readmitted due to sever cough, fever and purulent sputum. Bronchoscopic examination showed left lower bronchial fistula (Figure 1). He underwent urgent right middle lobectomy. The stamp of the bronchus intermedius was covered with omental flap. figure 1.jpg

      Case 4

      A 55-year-old man underwent a right upper sleeve lobectomy for T2N1M0 squamous cell carcinoma originating in the right upper lobe and developed a symptomatic anastomotic stenosis at two months postoperatively (Figure 2a). He required repeated bronchoscopic dilations to relieve his symptoms, which at 1 year postoperatively were complicated with a perforation of the right middle lobe bronchus. Emergent completion pneumonectomy and auto-transplantation of the right lower lobe were performed. Satisfactory bronchial healing was obtained (Figure 2b).figure 2.jpg

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    IBS24 - Optimal Immunotherapy Sequence in Stage IV NSCLC (Ticketed Session) (ID 55)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Immuno-oncology
    • Presentations: 2
    • Now Available
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      IBS24.01 - IO/CT First line Always (Now Available) (ID 3389)

      07:00 - 08:00  |  Presenting Author(s): Jhanelle Elaine Gray  |  Author(s): Sonam Puri

      • Abstract
      • Presentation
      • Slides

      Abstract

      Combination therapy with anti-programed death protein (ligand) 1 inhibitor (PD-1/PD-L1) and platinum-doublet chemotherapy (CT) plus/minus vascular endothelial growth factor inhibition (VEGFi) has recently emerged as the standard first-line treatment for patients with metastatic non-small cell lung cancer (mNSCLC) without a targetable oncogene. The rationale for using the immunotherapy chemotherapy (IO-CT) combination comes primarily from a clinical effort to improve the efficacy of the first-line treatment of mNSCLC by combining two independently active therapies with non-overlapping toxicity profiles. Additional proof-of-principle comes from pre-clinical studies showing synergy between checkpoint inhibitors (CPIs) and CT through platinum mediated immunomodulation of the tumor microenvironment.1, 2

      Several randomized phase II-III clinical trials have evaluated the combination of platinum doublet CT with CPIs for first line therapy of mNSCLC (Table 1). Pembrolizumab (anti-PD-1) plus platinum-pemetrexed was the first IO-CT combination with promising activity in this setting as noted in the phase II KEYNOTE021 trial.3 This led to further evaluation of the combination in the phase III KEYNOTE189 trial 4 that compared platinum-pemetrexed with pembrolizumab or placebo in treatment naïve patients with non-squamous mNSCLC .The results showed a significant overall survival (OS) benefit with the pembrolizumab combination that was seen irrespective of the PD-L1 tumor proportion score (TPS) and persisted at the updated follow up analysis despite cross over to IO in 54% patients in the placebo-CT arm.5 Similarly, the KEYNOTE407 trial enrolled untreated patients with stage IV squamous NSCLC, and noted superior outcomes with the combination of pembrolizumab plus carboplatin-(nab) paclitaxel versus placebo-carboplatin-(nab)paclitaxel.6 These two trials have established pembrolizumab plus platinum CT as the preferred therapy for previously untreated patients with non-squamous and squamous mNSCLC, and both regimens are currently approved by the FDA for histology specific, front-line treatment of stage IV NSCLC. Additional trials have been conducted comparing the combination of atezolizumab (anti-PD-L1) plus platinum- (nab)paclitaxel versus placebo-CT for the first-line treatment of non-squamous (IMpower 130, IMpower150) and squamous (IMpower131) mNSCLC. While results of the IMpower130 study show an OS benefit of treatment with the atezolizumab-CT combination compared to CT alone 7, the IMpower131 trial showed a clear PFS benefit but no significant benefit in OS between the two arms.8 Interestingly, the potential benefit of adding VEGFi to IO-CT was explored in the IMpower150 trial. This complex, three arm trial compared the combination of atezolizumab, carboplatin, paclitaxel and bevacizumab (ABCP) and atezolizumab, carboplatin, paclitaxel (ACP) to carboplatin, paclitaxel and bevacizumab (BCP) in CT naïve, non-squamous, mNSCLC. The trial also enrolled a subset of patients with EGFR or ALK mutations who had failed standard tyrosine kinase therapies, a population of patients that historically have a poor response to treatment with CPIs and are otherwise excluded from majority of the IO or IO-CT combination trials. The results showed a survival benefit of the four-drug regimen (ABCP vs BCP) in both the EGFR/ALK WT and mutated population, highlighting the potential role of VEGFi in improving response to CPIs, especially in oncogene driven mNSCLC.9

      Coming back to the question “should IO-CT be first line always?” The answer is yes, for the majority of eligible mNSCLC patients with no targetable mutations. mNSCLC is an aggressive malignancy associated with high mortality, and multiple trials have shown that many patients do not have the opportunity of receiving 2nd line treatment.5,10 Platinum based CT has been the first-line treatment of choice for mNSCLC for many years. In the last decade, IO has revolutionized the treatment of advanced lung cancer. Recent data (Table 1) clearly demonstrates superior and durable clinical outcomes with the combination of platinum-based CT doublets and CPIs compared to CT alone in both squamous and non-squamous mNSCLC. These combinations are safe with little additive toxicity and should be adopted as routine standard of care therapies in the frontline setting, especially in high disease burden and PD-L1 TPS ≤1. However, there is variability in outcomes based on histological subtypes of mNSCLC and the different IO-CT combinations (Table 1). New trial design strategies are needed to determine the benefit of IO-CT versus IO alone, especially in patients with borderline performance status or PD-L1 TPS ≥50%. Additionally, it is also important to determine the subgroup of patients with the highest likelihood of benefit from addition of VEGFi to IO-CT.

      References

      1.Galluzzi L et al. Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015;28(6):690-714.

      2. Pfirschke C, Engblom C, Rickelt S, et al. Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. Immunity. 2016;44(2):343-354.

      3. Langer CJ et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous NSCLC: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497-1508.

      4. Gandhi L et al. Pembrolizumab plus Chemotherapy in Metastatic NSCLC. NEJM. 2018;378(22):2078-2092.

      5. Gadgeel S et al. JCO 2019, 37. (suppl; abstr 9013).

      6. Paz-Ares L et al. Pembrolizumab plus Chemotherapy for Squamous NSCLC. NEJM. 2018;379(21):2040-2051.

      7. West H et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic NSCLC(IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019.

      8. Jotte R et al. IMpower 131. JCO 2018, 36. (suppl;abstr LBA900)

      9. Socinski MA et al. Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC. NEJM. 2018;378(24):2288-2301.

      10. Reck M et al. Pembrolizumab vs. Chemotherapy for PD-L1-Positive NSCLC. NEJM. 2016;375(19):1823-1833.

      Table 1: Summary of key phase III first line IO-CT trials in mNSCLC

      Trial name

      Histology

      Treatment

      Cross over allowed

      Results

      KEYNOTE189

      Non squamous

      Pembrolizumab + Carboplatin/Cisplatin + pemetrexed vs placebo+ carboplatin/cisplatin+ pemetrexed

      Yes

      OS

      22.0 m vs 10.7 m

      (HR 0.56, 95% CI 0.45-0.70), p < .00001

      PFS

      (HR 0.48, 95% CI 0.40-0.58, p < .00001)

      IMpower150

      Non squamous

      Arm 1: Atezolizumab, carboplatin, paclitaxel and bevacizumab (ABCP)

      Arm 2: Atezolizumab, carboplatin, paclitaxel (ACP)

      Arm 3: Carboplatin, paclitaxel and bevacizumab (BCP)

      No

      Arm 1 vs. Arm 3

      ABCP vs BCP

      OS

      19.2m vs 14.7m

      (HR:0.78, 95%CI 0.64-0.96) p=0.02

      PFS

      8.3m vs 6.8m

      (HR:062, 95%CI 0.52-0.74), p<0.001

      IMpower130

      Non squamous

      Atezolizumab+ carboplatin +nab paclitaxel vs. carboplatin+ nab paclitaxel

      Yes

      OS

      18.6m vs. 13.9m (HR:0.79 95% CI 0.64-0.98), p=0.033

      PFS

      7m vs 5.5m (HR:0.64, 95%CI 0.54-0.77), p<0.0001

      KEYNOTE407

      Squamous

      Pembrolizumab + carboplatin+(nab) paclitaxel vs. Placebo + carboplatin+(nab) paclitaxel

      Yes

      OS:

      15.9m vs.11.3m (HR:0.64, 95% CI:049-0.85), p<0.001

      PFS: 6.4mvs.4.8m (HR:0.56, 95% CI:045-0.70), p<0.001

      IMpower131

      Squamous

      Atezolizumab+ carboplatin+ (nab) paclitaxel vs. carboplatin+ (nab) paclitaxel

      No

      OS

      14.9m vs 13.9m (HR=0.96, 95%CI 0.78-1.18), p=0.69

      PFS

      6.3m vs 5.6m (HR=0.71, 95% CI 0.60-0.85), p=0.0001

      Checkmate227

      Both

      Arm 1: Nivolumab + ipilimumab

      Arm 2: Nivolumab + platinum doublet chemotherapy

      Arm 3: platinum doublet chemotherapy

      NA

      Arm 2 vs Arm 3

      PFS

      5.6m vs 4.7m (HR:0.74 95%CI 0.58-0.94)

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      IBS24.02 - IO Followed by Chemo or Chemo Followed by IO (Now Available) (ID 3390)

      07:00 - 08:00  |  Presenting Author(s): Barbara Melosky

      • Abstract
      • Presentation
      • Slides

      Abstract

      IBS24 - Optimal Immunotherapy Sequence in Stage IV NSCLC

      Barbara Melosky

      Immunotherapy Followed by Chemotherapy or Chemotherapy Followed by Immunotherapy

      For our patients presenting with stage IV advanced NSCLC, the goals of therapy are primarily palliative. These goals need to be carefully balanced to meet the individual needs of each patient: while we want to keep our patients living as long as possible, we also want to provide them with the highest quality of life. Many patients with advanced NSCLC are treated with the combination of immunotherapy and chemotherapy. This comes at a cost of toxicity and may not be the best strategy for long term survival. We need to compare the evidence to determine which agent, immunotherapy or chemotherapy, to use first in patients with stage IV advanced NSCLC without a targetable mutation (wild-type).

      Immunotherapy followed by Chemotherapy

      Numerous phase III trials have compared immunotherapy to chemotherapy for patients with stage IV NSCLC. Some of the trials to be discussed include KEYNOTE 0241, KEYNOTE 1892, KEYNOTE 4073, KEYNOTE 0424, CheckMate 2275 and MYSTIC6. For each trial, the outcomes and side effect profiles will be presented, and the different trials will be compared.

      OR

      Chemotherapy followed by Immunotherapy

      Immunotherapy agents were initially studied after patients progressed on a platinum doublet. Trials to be discussed include CheckMate 0177 (squamous), CheckMate 0578 (non-squamous), KEYNOTE 0109, and OAK10. Again, outcomes and side effect profiles will be presented with a view to identifying which patients will experience the greatest benefit from this strategy.

      Conclusion & Key Points

      The increasing percentage of long term survivors in lung cancer is unprecedented and strengthens the argument that sequencing is important.

      While the evidence is clear that immunotherapy is the best choice for patients who express high PD-L1 or have high tumour mutational burden (TMB), evidence is less clear for how to treat patients without these biomarkers.

      IO followed by Chemo

      Chemo followed by IO

      Biomarkers

      PD-L1 expression, high TMB

      PD-L1 non-expressors, low TMB, non-selected population

      Evidence to support

      KEYNOTE 024//042, CheckMate 227, MYSTIC

      CheckMate 017/057, KEYNOTE 010, OAK

      References

      1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. J Clin Oncol 2019; 37:537.

      2. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018; 378:2078.

      3. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018; 379:2040.

      4. Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet 2019.

      5. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med 2018; 378:2093.

      6. Peters S, Cho BC, Reinmuth N, et al. Tumor mutational burden (TMB) as a biomarker of survival in metastatic non-small cell lung cancer (mNSCLC): Blood and tissue TMB analysis from MYSTIC, a Phase III study of first-line durvalumab ± tremelimumab vs chemotherapy. AACR 2019; #CT074.

      7. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373:123.

      8. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373:1627.

      9. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomized controlled trial. Lancet 2016; 387:1540.

      10, Rittmeyer A, Barlesi F, Waterkamp D, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 2017; 389:255.

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    MA02 - Miscellaneous Topics in the Management of Early Stage Lung Cancer (ID 116)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 12
    • Now Available
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      MA02.01 - Reccurrence Pattern After Adjuvant Customized Chemotherapy Based on BRCA Expression Level (SCAT Trial) (Now Available) (ID 2760)

      10:30 - 12:00  |  Presenting Author(s): Bartomeu Massuti  |  Author(s): José Miguel Sanchez, Manuel Cobo, Teresa Moran, Jose Luis Gonzalez Larriba, Isidoro Barneto, Javier De Castro Carpeno, Lara Iglesias, Miguel Angel Muñoz, Guillermo López-Vivanco, Dolores Isla, Rafael López, Ramon De Las Penas, Delvys Rodriguez-Abreu, Angel Artal, Emilio Esteban, Mariano Provencio, Eva Pereira, Jose Sanchez-Payá, Rafael Rosell

      • Abstract
      • Presentation
      • Slides

      Background

      •Postop platinum-based CT improves outcomes in completely resected NSCLC with nodal involvement, (St II-IIIA). Customization is feasible in adjuvant setting (tissue availability) . Analysis of expressionin genes involved in DNA repair could be use to select CT regiment. •BRCA1 plays an important role in DNA repair pathways and functions as a differential regulator of response to cisplatin and antimicrotubuleagents. SCAT trial results found that for low BRCA1 levels subgroup Cis-Gemcitabine was superior to Cis-Docetaxel and in high BRCA1 levels subgroup Docetaxel single agent without platinum achieved similar survival to Cis-Doc. Analysis of recurrence pattern in different subgroups of the trials has been performed

      Method

      From Jun/2007 to May/2013 591 patients were screened and 500 p were included (108 in Control arm treated with Cisplatin-Docetaxel and 392 in Experimental arm treated with Cisplatin-Gemcitabine, Cisplatin-Docetaxel or Docetaxel alone according terciles BRCA1 expression level). With a cut-off September 30th 2018 and a median follow-up of 60 months, recurrence pattern are analysed in each arm and subgroup treatment and comparison are made for incidence of risk of recurrence, single/multiple recurrence, thoracic/extrathoracic and site of metastases (liver, bone, brain)

      Result

      Cumulative recurrence 232/456 evaluable patients (p) (50.8%). Recurrence were seen in 182/354 patients treated in experimental arm and in 50/102 p treated in the control arm (RR 1.04; 0.83-1.30) (p=0.672). Majority of recurrences 159/232 (68.5%) were single site recurrence. Intrathoracic recurrences in 121/232 (52%) while extrathoracic metastatic disease 111/232 (47.8%). No significant differences were seen for single/multiple, intra/extrathoracic recurrences between experimental and control arm. More frequent distant metastatic sites were: bone (42 p), brain (38 p) and liver (11 p) In the experimental group between different treatments no significant differences were found for the overall metastatic rate or for the single/multiple, intrathoracic/extrathoracic recurrences. For specific metastatic sites related to experimental treatment a significant reduction of risk of brain metastases were found in the experimental group with high level BRCA1 treated with Docetaxel single agent (p=0.0016)

      Conclusion

      For NSCLC resected patients with lymph node involvement (Stages II-IIIA) risk of recurrence remains high with cumulative rate > 50%. There were no differences in the Relative Risk (1.04) of recurrence when control and experimental arm are compared. Majority of recurrences were single site (68.5%) and intrathoracic (52%) but distant metastases developed in 47.8% os p. More frequent metastatic site was bone, followed by brain and liver. Brain metastases risk were significant lower for patients with low BRCA1 expression treated with single agent Docetaxel

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      MA02.02 - Toxicity of Lung SABR in Patients with Coexisting Interstitial Lung Disease (Now Available) (ID 586)

      10:30 - 12:00  |  Presenting Author(s): Tobias Finazzi  |  Author(s): Merle Ronden, Esther Nossent, Hilâl Tekatli, Idris Bahce, Ben Slotman, Femke Spoelstra, Suresh Senan

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with lung tumors and coexisting interstitial lung disease (ILD) are at increased risk of toxicity following stereotactic ablative radiotherapy (SABR). We report on our institutional experience with SABR in such patients.

      Method

      Institutional patients undergoing lung SABR with coexisting ILD were identified. ILD subtypes were determined by a pulmonologist specializing in ILD. From late 2015, patients were routinely counseled about the increased treatment risks. Magnetic resonance (MR-)guided SABR was used to reduce target volumes from 2016. Overall and progression-free survival (OS, PFS) were estimated using the Kaplan-Meier method, and dosimetric predictors of radiation pneumonitis (RP) were analyzed based on total lung minus planning target volumes (PTV).

      Result

      Twenty-four SABR patients treated for lung cancer (n=22) or metastasis (n=2) between 2007-2018 were identified. Median patient age was 74 years, and the commonest ILD diagnosis was idiopathic pulmonary fibrosis. The commonest fractionation schemes were 60 Gy in 8 fractions (n=11), or 55 Gy in 5 fractions (n=6), and SABR was delivered on a Linac (n=17) to a motion-encompassing internal target volume, or with MR-guided SABR (n=7). At median follow-up of 36.9 months (95% CI, 15.8 to not reached), median OS and PFS were 16.6 and 13.3 months, respectively, and 12-month local control was 88.9%. Five patients (20.8%) developed grade ≥3 RP, of which 3 (12.5%) were fatal. Patients with grade ≥3 RP had a higher total lung V20Gy, and a higher ipsilateral and total mean lung dose (MLDEQD2; Fig. 1) than those without (p <.05).

      figure 1.png

      Conclusion

      Our findings confirm that ILD patients have a poor prognosis and are at high risk for developing severe RP following SABR. Treatment should be preceded by patient counseling by an experienced ILD team. Careful attention must be given to limiting lung doses, and MR-guided SABR is our preferred approach in such patients.

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      MA02.03 - Impact of Coexisting Interstitial Lung Disease on Resected Non-Small Cell Lung Cancer Patients (Now Available) (ID 1237)

      10:30 - 12:00  |  Presenting Author(s): Jin Gu Lee  |  Author(s): Seong Yong Park, Chang Young Lee, Kyoung Shik Narm, Seung Hwan Song

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with interstitial lung disease(ILD) have higher incidence of lung cancer. Treatment for this group is challenging, and long term outcome is poor. We investigated the outcome of patients with lung cancer and ILD after surgical resection, along with risk factor of survival and acute exacerbation.Patients with interstitial lung disease(ILD) have higher incidence of lung cancer. Treatment for this group is challenging, and long term outcome is poor. We investigated the outcome of patients with lung cancer and ILD after surgical resection, along with risk factor of survival and acute exacerbation.

      Method

      Between Januery 2002 and August 2016, total 3413 patients underwent pulmonary resection for lung cancer, among them 74 patients had combined ILD. The demographics, operative and survival data were reviewed.

      Result

      Mean age was 68±7 years-old for 74 ILD patients. 51 (68.9%) patients received video-assisted thoracic surgery (VATS). Lobectomy and sublobar resection were performed to 58 (78.4%) and 15 (20.3%) patients, respectively. 30 (41.5%) patients experienced respiratory complication during early postoperative period. 30-, 90- days mortality and 5-year survival rate were significantly worse than patients without ILD in the same study period (8.1%, 21%, and 21.2% vs. 1.3%, 3.1%, and 73.8%, respectively, p<0.001). Patients with ILD who experienced respiratory complication showed significantly worse 5-year survival than those who has not (18.2% vs. 44.9%, p<0.001). The leading cause of death was cancer related (47.8%), followed by postoperative complications (23.9%). Among 23 patients who received adjuvant therapy, 10 patients died during or shortly after adjuvant therapy. Open thoracotomy (HR 4.02, p=0.017) was risk factor for respiratory complication. Sublobar resection showed similar survival rate in each stage (stage I, p=0.825 and stage II-III, p=0.633) and lower rate of respiratory complication than lobectomy, although statistically not significant (26.7% vs. 43.1%, p=0.246).

      Conclusion

      Interstitial lung disease increased the risk of pulmonary resection for lung cancer. Thoracotomy was associated with higher rate of respiratory complication. Sublobar resection showed similar survival with lower respiratory complication rate compared to lobectomy. Adjuvant therapy should be considered after careful weighing of risk and benefit.

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      MA02.04 - Discussant - MA02.01, MA02.02, MA02.03 (ID 3718)

      10:30 - 12:00  |  Presenting Author(s): Yaxing Shen

      • Abstract

      Abstract not provided

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      MA02.05 - Patient Selection and Early Clinical Outcomes of MR-Guided SABR in 54 Lung Tumors (Now Available) (ID 1318)

      10:30 - 12:00  |  Presenting Author(s): Tobias Finazzi  |  Author(s): Cornelis Haasbeek, Femke Spoelstra, Miguel Palacios, Marjan Admiraal, Anna Bruynzeel, Ben Slotman, Frank Lagerwaard, Suresh Senan

      • Abstract
      • Presentation
      • Slides

      Background

      Magnetic resonance (MR-)guided stereotactic ablative radiotherapy (SABR) with daily replanning was performed for patients in whom treatment delivery was challenging due to tumor location, motion or pulmonary comorbidity. We describe patient characteristics and early clinical outcomes using this novel approach.

      Method

      50 consecutive patients (54 lung tumors) underwent MR-guided SABR at a single center between 2016-2018 for either primary lung cancer (n = 29 tumors) or lung metastases (n = 25). Patients had one or more factors predisposing to toxicity, including a central tumor location (n = 27 patients), previous thoracic radiotherapy (n = 17), and interstitial lung disease (n = 7). A daily 17-second breath-hold MR scan was acquired in treatment position, followed by on-table plan adaptation. Gated delivery was performed using repeated breath-holds under continuous MR-guidance. Local control, overall (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, with PFS defined as time to disease progression or death from any cause.

      Result

      Breath-hold SABR delivery was well tolerated, with all but one patient completing the planned schedule. With daily replanning, a biologically equivalent dose (BED10Gy) ≥100Gy to 95% of the planning target volume was delivered in 51 tumors (94%). Median follow-up was 15.8 months (95% CI, [11.4-22.5]). Local control, OS and PFS at 12 months were 93.4%, 86.7% and 58.4%, respectively (Fig. 1). In-field recurrences developed in 2 patients who were re-irradiated for a local recurrence after previous SABR, and one marginal recurrence was observed. Overall rates of any grade ≥2 and ≥3 toxicity were 24% and 4%, respectively. No grade ≥4 toxicity was seen. Commonest toxicities were grade ≥2 radiation pneumonitis (8%) and chest wall pain (8%; including one rib fracture).

      figure 1.png

      Conclusion

      Early follow-up of the largest patient cohort to date undergoing thoracic MR-guided SABR indicates low toxicity rates, and promising local tumor control.

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      MA02.06 - Dose-Volume Factors Predicting Airway Stenosis After SBRT for Ultra-Central Lung Tumors (Now Available) (ID 1454)

      10:30 - 12:00  |  Presenting Author(s): Andrew Jackson  |  Author(s): Chunyu Wang, Ellen Yorke, Daphna Geldblum, Aditya Apte, Jie Yang, Andreas Rimner, Abraham J Wu

      • Abstract
      • Presentation
      • Slides

      Background

      The safety of SBRT is uncertain for ultra-central tumors (near the proximal airways or esophagus). One potential toxic effect of ultra-central SBRT is stenosis of the proximal airways, which can lead to airway obstruction and lung collapse. Predictors of such toxicity in this population are urgently needed. We therefore studied dose-volume correlates of airway stenosis after ultra-central SBRT.

      Method

      88 patients with tumors abutting the proximal bronchial tree (PBT) or PTVs overlapping esophagus (n = 76 and 23; 11 met both criteria) were included. 53 (60%) had primary/locally recurrent lung cancer, and 35 had lung metastases. All had 5, 8 or 15 fractions of image-guided radiotherapy with BED ≥84Gy (α/β=10). The lobar bronchi (LB) were contoured from the takeoff from the main bronchus to the bifurcation into segmental bronchi. The primary endpoint was grade 2 or higher lobar bronchial stenosis (LBS), defined as radiographic evidence of narrowing or complete obstruction of at least one lobar bronchus (CTCAE v4). Dose-volume histograms (DVHs) using linear-quadratic equivalent doses in 2 Gy fractions were calculated for the LB with α/β = 3 Gy. Mean equivalent doses (MEDs) to the LB were tested for correlation with LBS using a Cox proportional hazards model, and the log rank test with patient data split at the median value of the MEDs to the LB. Statistical significance was defined as p < 0.05.

      Result

      Median follow up was 14.3 months. There were 24 cases of LBS (27%). Median time to onset of LBS2+ was 8.6 months after end of treatment (range 2-19 months). LBS was significantly correlated with MED to the LB (p = 0.02). Incidence of LBS was significantly different in patients with MED to the LB < or > the median value of 35.4 Gy (p = 0.004 log-rank test), with actuarial rates of 19% and 55% respectively at 14 months, and 19% and 70% respectively at 24 months; and with raw rates of 15.9% and 38.6% respectively.

      Conclusion

      We observed a high rate of lobar stenosis after ultra-central SBRT. Incidence of lobar stenosis was significantly correlated with dose to the lobar bronchi. In particular, mean equivalent dose to the lobar bronchi was significantly correlated with LBS. Our analysis suggests that limiting the mean equivalent dose to the lobar bronchi to < 35.4 Gy results in a two year actuarial incidence of LBS of <19%, and a raw incidence <16%.

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      MA02.07 - A Phase I Trial of an Immune Checkpoint Inhibitor Plus Stereotactic Ablative Radiotherapy in Patients with Early Stage Non-Small Cell Lung Cancer (Now Available) (ID 1967)

      10:30 - 12:00  |  Presenting Author(s): Megan Eileen Daly  |  Author(s): Arta Monir Monjazeb, Amin Mirhadi, David Eastham, Frances Lara, Jonathan Wesley Riess, Ellen A Wiegner, Karen Kelly

      • Abstract
      • Presentation
      • Slides

      Background

      Stereotactic ablative radiation therapy (SABR) is the standard-of-care for medically inoperable, early stage non-small cell lung cancer (NSCLC), but regional and distant failures remain problematic. Based on in vivo preclinical data showing synergy between radiation and immune checkpoint inhibitors (ICI) and the known efficacy and mild toxicity profile of ICI in Stage III and IV NSCLC, we conducted a phase I study to determine the safety, tolerability and maximum tolerated dose of neoadjuvant, concurrent, and adjuvant atezolizumab with SABR for high risk early stage NSCLC (NCT02599454).

      Method

      Eligible patients had histologically confirmed T1-3 NSCLC with one or more features predictive of increased recurrence risk: diameter ≥1 cm, SUV ≥6.2 on FDG PET, or moderately/poorly differentiated histology. Patients were medically inoperable or refused surgery, and had a Zubrod PS ≤2. Patients received 6 cycles of atezolizumab IV in 21 day cycles. A 3+3 dose finding design was employed with three dose levels: 3 mg/kg, 10 mg/kg, and 1200 mg flat dosing. SABR was delivered starting cycle 3 to 50 Gy over 4-5 fractions. Patients were restaged after cycle 2, prior to SABR. Dose limiting toxicity (DLT) was assessed during the first 9 weeks of treatment.

      Result

      From April 2016-June 2018, a total of 15 patients enrolled, with 12 evaluable for DLT assessment. Three patients chose to discontinue treatment due to travel issues (1 pt), a COPD exacerbation (1 pt) and grade 2 liver function tests (LFTs) (1 pt). One patient on dose level 2 developed DLT, a grade 3 rash requiring discontinuation of protocol therapy. No other DLTs occurred, resulting in a recommended dose of 1200 mg for future studies. Eleven patients completed protocol treatment. Other grade 3 toxicities include transient lymphopenia in 4 patients. One patient each developed grade 2 pneumonitis, grade 2 hypothyroidism, and grade 2 hyperthryoidism. Three patients had a radiographic partial response and 1 patient had a minor response following 2 cycles. No patient had progressive disease prior to SABR. Results of correlative blood and tissue studies will also be reported.

      Conclusion

      Neoadjuvant, concurrent, and adjuvant atezolizumab in combination with SABR for early stage NSCLC is well-tolerated, with radiographic PR prior to SABR in 25% of our cohort. Overall efficacy data is premature. Enrollment to an expansion cohort is ongoing, and this combination will be tested in an upcoming randomized phase III trial SWOG/NRG S1914.

      This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Lung Cancer Research Program under Award no. W81XWH-15-2-0063.

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      MA02.08 - Discussant - MA02.05, MA02.06, MA02.07 (ID 3719)

      10:30 - 12:00  |  Presenting Author(s): Mireia Serra-Mitjans

      • Abstract
      • Slides

      Abstract not provided

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      MA02.09 - Prognostic Impact of Immune Cell Biomarkers in Surgically Resectable Non-Small Cell Lung Cancer (Now Available) (ID 2646)

      10:30 - 12:00  |  Presenting Author(s): Stephanie Tuminello  |  Author(s): Rajwanth Veluswamy, Francesca Petralia, Pei Wang, Raja Flores, Maaike Van Gerwen

      • Abstract
      • Presentation
      • Slides

      Background

      Immune cells within the tumor microenvironment (TME) play an important role in the development, progression and eventual outcomes of non-small cell lung cancer (NSCLC). The relative balance of immune effector and regulatory cell subpopulations may tilt the TME to be either detrimental or supportive of tumorogenesis and will have a profound impact on the tumor’s eventual destiny. In early-stage lung cancer, the role of individual immune cell subtypes in the TME on survival outcomes following surgical resection is unknown.

      Method

      This project made use of The Cancer Genome Atlas (TCGA) Program data. We computed sample-specific scores for different immune cells using xCell, a new model for estimating different immune cell types from RNAseq data, for all stage I-IIIA NSCLCs. Then, we assessed the association between each cell type and survival with Cox Regression, while adjusting for important clinical variables (i.e., stage, age, gender, smoking status). We stratified the analysis according to histological subtype.

      Result

      There were 910 surgically resected early-stage NSCLC analyzed, of which 438 were adenocarcinomas (LUADs) and 472 were squamous cell (LUSC) samples. Higher levels of natural killer cells, neutrophils, and mast cells within tumors were associated with significantly improved survival in LUAD patients, whereas no immune cell type was associated with survival for LUSC patients or the combined analysis.

      Figure 1: Adjusted Survival According to Estimated Immune Cell Infiltration

      figure 1 adjusted survival according to estimated immune cell infiltration.png

      Hazard ratios are adjusted for stage, gender, age and smoking status

      Conclusion

      Innate and adaptive immune cells within the TME may have prognostic value in early-stage NSCLC patients undergoing surgical resection. However, the role of individual immune cells may vary according to histological subtype. Prospective research should continue to assess the association of the immune cell composition of the TME with clinical outcomes.

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      MA02.10 - Different Prognostic Impact of Lymphovascular Invasion Between Lobectomy and Sublobar Resection in Stage IA Non-Small Cell Lung Cancer: A Propensity Score–Matched Analysis (Now Available) (ID 2905)

      10:30 - 12:00  |  Presenting Author(s): Jae Kwang Yun  |  Author(s): Geun Dong Lee, Yooyoung Chong, Yong Ho Jeong, Sehoon Choi, Hyeong Ryul Kim, Yong-Hee Kim, Dong Kwan Kim, Seung-Il Park

      • Abstract
      • Presentation
      • Slides

      Background

      Lymphovascular invasion (LVI) has been reported as a risk factor in patients with stage I Non-Small Cell Lung Cancer (NSCLC). Although lobectomy is a standard treatment, sublobar resection may be performed in patients with stage IA NSCLC. This study aimed to evaluate the prognostic effect of LVI in stage IA patients who underwent lobectomy and sublobar resection.

      Method

      We retrospectively reviewed data from 2134 patients with stage IA NSCLC from 2007 to 2016. By using the Cox proportional hazard regression model, we calculated the prognostic impact of LVI quantitatively. To reduce the effects of observed confounding between LVI-positive and negative patients, propensity score matching (PSM) was applied in patients with lobectomy and sublobar resection, respectively.

      Result

      Among patients with stage IA NSCLC (n=2134), 184 (8.6%) were pathologically diagnosed with LVI, which were 144 (8.9%) in lobectomy group (n=1614) and 40 (7.7%) in sublobar resection group (n=520). In multivariable analysis, LVI was a significant risk factor for both overall survival (OS) and recurrence-free survival (RFS) (OS: hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.39–2.96; p < .001; RFS: HR, 2.31; 95% CI, 1.68–3.17; p < .001). After PSM, the prognostic impact of LVI was shown much greater in patients with sublobar resection (HR = 1.77 and 2.51 for OS and RFS) than those with lobectomy (HR = 4.93 and 4.25 for OS and RFS).

      Conclusion

      The presence of LVI significantly affected OS and RFS in stage IA NSCLC patients. Survival outcomes were more affected by the presence of LVI in patients with sublobar resection than those with lobectomy. Subsequent completion lobectomy could be considered in patients diagnosed with LVI after sublobar resection.

      figure_revised.jpg

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      MA02.11 - Adjuvant Chemotherapy Following SBRT for Early Stage Non-Small Cell Lung Cancer (NSCLC) in Older Patients (Now Available) (ID 1981)

      10:30 - 12:00  |  Presenting Author(s): Apar Kishor Ganti  |  Author(s): Adams Kusi Appiah, Vinicius Ernani, Chi Zhang, Weining Zhen, Alissa Marr, Lynette Smith

      • Abstract
      • Presentation
      • Slides

      Background

      Adjuvant chemotherapy following surgery has been shown to be beneficial in NSCLC >4 cm in size, regardless of age. We have recently shown that adjuvant chemotherapy improves overall survival following stereotactic body radiotherapy (SBRT) in patients with tumors ≥4 cm in size. We aim to evaluate the role of adjuvant chemotherapy following SBRT in older patients (>70 years) with early stage NSCLC.

      Method

      Patients (>70 years) diagnosed with clinical stages I-II NSCLC (AJCC 7th Edition) from 2004 to 2013, who received SBRT, were identified using the National Cancer Database (n=7,934). The Kaplan-Meier method was used to estimate overall survival (OS) distributions and the log-rank test was used to compare distributions by treatment strategy. Clinical stages I and II were subdivided according to the TNM staging and log-rank tests was used to compare survival distributions by treatment strategy within each subgroup.

      Result

      There were 3991 male patients (50.3%), and 6219 (78.4%) had stage I disease. Among stage I patients, 670 (10.8%) received adjuvant chemotherapy (defined as chemotherapy within 90 days of completion of SBRT), compared to 742 stage II patients (43.3%) received adjuvant chemotherapy. Median OS was better with SBRT in patients with stage I disease (25.2 vs. 19.9 months; p<0.001); while patients with stage II NSCLC had better OS with SBRT + chemotherapy (19.9 vs. 14.6 months; p<0.001). On multivariate analysis, after adjusting for age, gender and facility type, patients with stage I NSCLC who received SBRT alone had better overall survival [HR for death: 0.79 (95% CI, 0.73, 0.87)]. SBRT alone was associated with an increased risk of death in patients with stage II disease [HR: 1.37 (95% CI, 1.23, 1.53). When patients with N0 disease were evaluated based on tumor size, those with tumors ≥4 cm had better OS with SBRT + chemotherapy (18.5 vs. 15.5 months; p=0.003). In contrast, patients with tumors <4 cm did better with SBRT alone (median OS of 24.1 vs. 20.3 months; p<0.001)slide1.jpg

      Conclusion

      Adjuvant chemotherapy following SBRT is associated with improved OS in patients >70 years of age and tumors ≥4 cm in size or lymph node involvement.

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      MA02.12 - Discussant - MA02.09, MA02.10, MA02.11 (ID 3720)

      10:30 - 12:00  |  Presenting Author(s): Yaxing Shen

      • Abstract

      Abstract not provided

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    MA04 - Models and Biomarkers (ID 122)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 12
    • Now Available
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      MA04.01 - Development of an in Vivo Platform to Identify Novel Mechanisms Governing Lung Cancer Response to Immunotherapy (Now Available) (ID 714)

      13:30 - 15:00  |  Presenting Author(s): Kelsie L Thu  |  Author(s): Shawn P Kubli, Andrew C Wakeham, Andrew J Elia, Tak Mak

      • Abstract
      • Presentation
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have emerged as a promising therapy for the treatment of advanced stage lung cancer. While these agents elicit durable responses in some patients, most do not respond. An improved understanding of the mechanisms governing ICI response in a complex in vivo setting has potential to reveal novel therapeutic combinations to enhance ICI efficacy and associated biomarkers indicative of response. We have developed a syngeneic lung tumour model for in vivo CRISPR/Cas9 screens to deduce novel tumour-intrinsic mediators of response to anti-PD1 therapy.

      Method

      To delineate physiologically relevant ICI response mechanisms, an in vivo, syngeneic and orthotopic lung tumour model with an intact immune system is required. For this purpose, we have developed the KRAS-mutant Lewis Lung Carcinoma (LLC) model. Flow cytometry and immunohistochemistry were used to characterize immune cell composition in resected tumours and in vivo experiments were conducted to determine the effects of anti-PD1 treatment on LLC tumour growth.

      Result

      Luciferase-tagged LLC cells were implanted into the lungs of syngeneic C57BL/6 mice using orthotopic injection and mice reached humane endpoints 10-14 days post injection. Immunophenotyping of dissociated tumours revealed changes in the proportions of myeloid and lymphocyte populations relative to tumour-naïve lungs. CD8+ T-cells were present and tumour cells expressed PDL1 suggesting LLC has the capacity to respond to ICI. Consistent with these observations, orthotopic LLC growth was delayed in mice treated with anti-PD1 therapeutic antibody compared to anti-IgG2a isotype control, demonstrating that LLC is an appropriate model for identifying mechanisms that confer sensitivity and/or resistance to ICI therapy. Based on these findings, we generated LLC-Luciferase cells stably expressing Cas9. Since genome-wide screens are not feasible with this in vivo tumour model, we are synthesizing a custom, focussed guide RNA (gRNA) library. Genomic analyses have identified ~500 candidate immunomodulatory genes expressed in LLC and clinical lung tumours that will be targeted to determine the effects of inactivating these candidates on anti-PD1 response.

      Conclusion

      This platform will enable high-throughput genetic screens to elucidate novel tumour-intrinsic determinants of ICI response in vivo. Our discoveries will have potential to inform novel biomarkers predictive of response, and putative targets for new combination therapies to enhance the anti-tumour effects of ICIs. Collectively, this work will improve our understanding of the biological mechanisms governing ICI sensitivity, thereby stimulating the development of new strategies to maximize therapeutic benefit from ICIs in lung cancer patients.

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      MA04.02 - Molecular Profiling of Adenocarcinoma and Squamous Cell Lung Cancer at Single Cell Resolution (Now Available) (ID 1358)

      13:30 - 15:00  |  Presenting Author(s): fengying Wu  |  Author(s): Yayi He, Zhou Yiqi, Anwen Xiong, Jia Yu, Wei Li, Nan Fang, Caicun Zhou

      • Abstract
      • Presentation
      • Slides

      Background

      Adenocarcinoma and squamous are two main subgroups of lung cancer: adenocarcinoma (ADC) accounts for 30-50% and squamous cell carcinoma (SCC) accounts for nearly 30% of all cases respectively. ADC and SCC have different pathological phenotypes and respond differently to various therapies, including immunotherapy. However, the underlying molecular mechanism of such differentiated drug responses still needs to be further characterized.

      Method

      To achieve high resolution of both tumor cells and their tumor microenvironment (TME), we used single cell RNA sequencing method to characterize ADC and SCC tumors from Stage IV NSCLC patients. Tissue biopsy samples from 21 patients (12 patients with ADC, 9 with SCC) were collected. For each sample, single cell RNA sequencing was performed on an average of 1930 cells. A graph-based clustering approach was used to classify cells into different cell types based on their gene expression patterns. The cellular subtypes of both cancer cells and TME in ADC and SCC samples were analyzed.

      Result

      ADC and SCC show distinct patterns at single cell resolution. Cancer cells from all ADC patients form two closely related clusters, while cancer cells from SCC patients show high intra-and inter-patient heterogeneity. Gene Ontology (GO) analysis demonstrated that ADC samples are enriched in genes of neutrophil degranulation and activation, while SCCs are enriched in genes related to epidermal cell differentiation and glutathione metabolic process. Genes related to cancer progression and metastasis, such as LSD1 and FASCIN, are normally expressed at higher level in SCC than in ADC. Furthermore, ADC samples contain higher percentage of a specific myeloid cell population, while SCC has higher percentage of fibroblasts, demonstrating the difference also in TMEs of ACD versus SCC.

      Conclusion

      The significantly higher level of heterogeneity for SCC can be a possible reason for poor responses to standard lung cancer therapies, including immunotherapy. Accurate characterization of SCC with single cell resolution could hold the key to more effective therapeutic strategies.

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      MA04.03 - Lung Tumorspheres Characterization Reveals Cancer Stem-Like Cells Potential Targets and Prognostic Markers in Non-Small Cell Lung Cancer (Now Available) (ID 2269)

      13:30 - 15:00  |  Presenting Author(s): Alejandro Herreros-Pomares  |  Author(s): Eloisa Jantus-Lewintre, Silvia Calabuig-Fariñas, Juan Diego De-Maya-Girones, Rut Lucas, Ana Blasco, Ricardo Guijarro, Miguel Martorell, Eva Escorihuela, María Dolores Chiara, Elena Durendez-Saez, Carolina Gandia, Rafael Sirera, Rosa Farràs, Carlos Camps

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) is the leading cause of death cancer-related worldwide due to late diagnosis and high resistance against treatments. This resistance has been associated to cancer stem-like cells (CSCs), a highly tumorigenic subpopulation for which the identification of targets and biomarkers is still under development.

      Method

      Tissue samples from 8 NSCLC patients were successfully established and cultured using a sphere-forming assay for CSCs enrichment. Adherent counterparts were used as differentiated control cells. Proliferation, chemorresistance, invasion and differentiation capacities were tested in vitro, whereas tumor initiation capacity was determined in vivo. The expression of 44 CSCs-related genes was assessed by qPCR and protein expression of the best contributors to distinguish adherent cells from tumorspheres was determined by immunoblot and immunofluorescence. The prognostic role of these genes was evaluated in a cohort of 661 resected NSCLC patients from TCGA and validated in an independent cohort of 114 resected lung adenocarcinoma patients.

      Result

      Patient-derived tumorspheres showed unlimited exponential growth, high resistance against chemotherapy, great invasion and differentiation capacities in vitro in addition to a higher tumorigenic potential than adherent cells in vivo. The expression of 17 genes was significantly overexpressed in lung tumorspheres, being NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 the best contributors. Proteins encoded by these genes were consistently increased in tumorspheres from adenocarcinoma patients and showed differential localization and expression patterns. The expression of CDKN1A, SNAI1 and ITGA6 was associated to prognosis based on Cox regression analysis (Z-score > 1.5), so their absolute regression coefficients from a multivariate model were used to calculate a gene expression score. Kaplan-Meier survival analysis showed that patients with high score have shorter OS in the entire cohort [37.7 vs. 60.4 mo., p = 0.001] and the adenocarcinoma subcohort [36.6 vs. 53.5 mo., p = 0.003], but not in squamous cell carcinoma one. Multivariate analysis indicated that this gene expression score was an independent biomarker of prognosis for OS in both, the entire cohort [HR: 1.498; 95% CI, 1.167-1.922; p = 0.001] and the adenocarcinoma subcohort [HR: 1.869; 95% CI, 1.275-2.738; p = 0.001]. The prognostic value of this score was confirmed in an independent cohort of 114 lung adenocarcinoma patients (42.90 vs. NR mo, p = 0.020).

      Conclusion

      Proteins encoded by NANOG, NOTCH3, CD44, CDKN1A, SNAI1, and ITGA6 are potential targets against lung CSCs. Elevated gene expression levels of CDKN1A, SNAI1 and ITGA6 are associated with worse prognosis.

      Funded by CB16/12/00350 from CIBEROnc, PI12-02838, and PI15-00753 from ISCIII and Fundacion Arnal Planelles.

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      MA04.04 - Discussant - MA04.01, MA04.02, MA04.03 (Now Available) (ID 3730)

      13:30 - 15:00  |  Presenting Author(s): David Santamaria

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA04.05 - Deciphering the Molecular Mechanisms Underlying the Progression of Bronchial Premalignant Lesions (Now Available) (ID 2108)

      13:30 - 15:00  |  Presenting Author(s): Evgeny V. Denisov  |  Author(s): Polina A. Gervas, Anastasia A. Ponomaryova, Anastasia A. Schegoleva, Tatiana S. Gerashchenko, Artem M. Kiselev, German M. Demidov, Alexey A. Zarubin, Liliya S. Lyapunova, Sergey P. Kovalenko, Olga V. Cheremisina, Sergey A. Tuzikov, Olga V. Pankova, Nadezhda V. Cherdyntseva, Vladimir M. Perelmuter

      • Abstract
      • Presentation
      • Slides

      Background

      The mechanisms underlying the progression of bronchial lesions to squamous cell lung cancer remain undefined. Previously, we hypothesized that bronchial lesions presented individually or combined with each other in the bronchi of non-small cell lung cancer (NSCLC) patients mirror the different scenarios of the premalignant process: individual basal cell hyperplasia (iBCH) – the stoppage at hyperplasia, BCH plus squamous metaplasia (SM) – the progression of hyperplasia to metaplasia, and SM plus dysplasia – the progression of metaplasia to dysplasia. In this study, we aimed to assess the molecular profile of BCH, SM, and dysplasia depending on their co-occurrence in the bronchi of NSCLC patients and to identify mechanisms that are involved in the different scenarios of the premalignant process.

      Method

      The samples of lung tissue were obtained at a distance of 4-5 cm from the tumor during surgery of 21 NSCLC patients. Normal bronchial epithelium, BCH, and SM, as well as dysplasia, were isolated from tissue sections using laser microdissection PALM (Carl Zeiss). The microdissected samples underwent whole genome (One Step WGA, Bioron) and transcriptome (Ovation PicoSL WTA System V2, Nugen) amplification and sequenced using the SeqCap EZ Human Oncology Panel (Roche) and profiled using SurePrint G3 Human GE v2 8x60K microarrays (Agilent). Additionally, the samples were sequenced using the Pico Methyl-Seq Library Prep Kit (Zymo Research). Changes in gene expression were confirmed using immunohistochemical staining.

      Result

      Genetic alterations were observed already at the early stages of the premalignant process in the bronchial epithelium; however, their number varied from sample to sample. For example, one case of BCH showed more than 10 deleterious mutations in the GRM5, MAML2, SP1, ETV4, and other genes, whereas other BCHs carried single alterations. No significant differences were found in the mutational landscape between the iBCH and BCH combined with SM. Bisulfite sequencing demonstrated significant changes in the methylation status of the SAPCD2 and ST14 genes in BCH. Importantly, these changes differed between various forms of BCH. Sequencing of SM and dysplasia is in progress and results will be presented later. Gene expression profiling showed differences in the activity of immune response genes between the iBCH and BCH combined with SM and the cell cycle and cilium assembly genes between SMs co-presented with BCH and dysplasia. Overall, the transcription profile of SM co-presented with BCH was closer to BCHs, whereas SM co-detected with dysplasia was similar to dysplasia. Several genes were identified to be expressed specifically in different forms of BCH and SM, among which CCDC114, MAP7D2, and LIFR were confirmed by immunohistochemistry. The loss of CCDC114 and MAP7D2 in SM may serve as an indicator of its progression to dysplasia.

      Conclusion

      Taken together, this study demonstrates the significant differences between various types of BCH and SM. These differences support the hypothesis that the isolated and combined forms of the bronchial lesions mirror the different scenarios of the premalignant process as well as explore the mechanisms underlying the progression of hyperplasia and metaplasia to dysplasia.

      The study was supported by RFBR (#17-29-06002) and the Russian President Fellowship (#SP-1549.2018.4).

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      MA04.06 - Lung Epithelium Whole Transcriptome Signatures That Reflect Incident Lung Cancer Case-Control Status (Now Available) (ID 2526)

      13:30 - 15:00  |  Presenting Author(s): Simon D Spivack  |  Author(s): Xiao Dong, Miao Kevin Shi, Weiguo Han, Steven Keller, Alex Maslov, Yousin Suh, Jan Vijg

      • Abstract
      • Presentation
      • Slides

      Background

      BACKGROUND: Focusing early detection and prevention efforts on those at high risk for lung cancer is central to leveraging such strategies. Notably, that risk persists even after removal of a lung cancer, as reflected in lung recurrences, which are common, and usually occur remote from the surgical removal site. This implies risk for future incident lung cancer is represented in the biology of broad areas of lung epithelium, before, during, and after diagnosis. Given that somatic mutations in the bronchial tree are known to persist for decades, there is a suggestion that smoking transforms the entire epithelium at several somatic and gene regulatory levels. We hypothesize that the normal lung epithelium contains expression and epigenetic epithelial signatures that are representative of donor case-control status, that is poised for carcinogenesis.

      Method

      METHODS: As a first step, in order to identify differentially expressed genes (DEGs) associated with aging, smoking and cancer case-control status, we analyzed RNA-seq transcriptome data of laser capture microdissected (LCM) bronchial and alveolar epithelium separately, in paired tissue sets of 40- and 74 respective individuals, summarized here. Read count was the main normalization variable. We also measured differentially methylated sites (DME) by whole genome bisulfite genome sequencing (WGBSeq), covering >60% of the genome/methylome [as of this deadline, these methylome data are not yet fully analyzed].

      Result

      RESULTS: Mean subject age for 77 total subjects was 65 (+/-9.9), 19% current-, 76% former, 5% never smokers. For each cell type, we modeled gene expression level as a result of aging, gender, smoking and case-control status. We put all four clinical variables age, gender, smoking status, case-control status) along with cell type (alveolar/bronchial) into the model, to avoid potential confounding effects. We discovered 175 DEGs discriminating case-control status (FDR p<0.05) in alveolar and bronchial cells combined, and 420 case-control DEGs with bronchial cells alone. Bronchial cells displayed 31 DEGs discriminating current versus former smokers (FDR-adjusted P<0.05). Gene ontology (David) clusters for case-control discrimination in these “normal” bronchial epithelia included energetics pathways (GO 0042776/0006754; ATP biosynthesis) as well as transcriptional and translational regulation pathways; KEGG clusters also included oxidative phosphorylation pathways (hsa00190), among others.

      Conclusion

      CONCLUSION: There is a donor case-control discriminant expression signature for human lung bronchial captured cells, emphasizing bioenergetically-deranged metabolic pathways, among others. If confirmed in larger studies that measure deranged metabolites directly, metabolomics biomarkers representing bioenergetics and other pathways may serve to define those individuals whose epithelia is tilted toward carcinogenesis, and therefore are at increased risk for lung cancer.

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      MA04.07 - Inhibition of CXCR2+ Neutrophil Migration as a Targeted Therapy in KRAS-Driven Lung Adenocarcinoma (Now Available) (ID 2914)

      13:30 - 15:00  |  Presenting Author(s): Meghan De Meo  |  Author(s): Roni F. Rayes, Simon Milette, Mara Vagai, Mariana Usatii, Arvind Chandrasekaran, Betty Giannias, France Bourdeau, Christopher Moraes, Sidong Huang, Daniela Quail, Logan Walsh, Veena Sangwan, Nicholas Bertos, Sophie Camilleri-Broet, Philippe Broet, Pierre O Fiset, Jonathan Cools-Lartigue, Lorenzo E. Ferri, Jonathan D. Spicer

      • Abstract
      • Presentation
      • Slides

      Background

      Lung adenocarcinoma (LUAD) accounts for 40% of all lung cancer cases. Although driver mutations in the K-RAS oncogene occurs in 25% of all LUAD cases, to date, there are no available targeted therapies. Infiltrating neutrophils in LUAD are indicative of the worst survival outcomes. The C-X-C motif chemokine receptor 2 (CXCR2) mediates their recruitment to the tumour microenvironment where they promote a pro-tumorigenic environment. CXCR2 ligand expression is higher in KRAS-driven LUAD compared to the other most frequently mutated oncogenes. Therefore, we hypothesize that K-RAS-driven LUAD may be the best candidate for a CXCR2 targeted treatment strategy.

      Method

      The PREdiction of Clinical Outcomes from Genomic Profiles (PRECOG) is a dataset of gene expression and survival outcome. The dataset includes data from approximately 18 000 human patients with 39 different malignancies. The dataset was used to determine whether high neutrophil infiltration, CXCR2 expression and CXCR2 ligand expression were associated with poor survival outcomes in LUAD. A 100 patient LUAD tissue microarray was built and stained for neutrophil elastase and CXCR2 by immunohistochemistry. Kaplan-Meier curves were used determine the effect of high neutrophil or CXCR2+ cell infiltration in the LUAD tumour microenvironment on survival outcome. The Cancer Cell Line Encyclopedia (CCLE) is an online dataset that provides gene expression and genotype data from 947 human cancer cell lines (36 cancer types). Expression data of all LUAD cell lines (n=70) from CCLE was obtained for all known CXCR2 ligands. The expression of CXCR2 ligands in K-RAS, EGFR, ALK and ROS-1-driven LUAD cell lines was compared. Microfluidics devices were used to compare the neutrophil recruitment to K-RAS, EGFR, ALK and ROS-1-driven LUAD cell lines. The neutrophil recruitment to each of the cell lines was compared in the presence and absence of CXCR2 inhibition.

      Result

      Using the PRECOG dataset, we found that CXCR2 expression in neutrophils is at least 18-fold greater than its expression in other immune cell types. Using all the LUAD cell lines (n=70) available on the CCLE, we found that K-RAS-driven LUAD is the highest CXCR2 ligand expresser as compared to EGFR, ALK and ROS1-driven LUAD. Moreover, using PRECOG, we found that poorer survival outcome is associated with high expression of eight out of nine known CXCR2 ligands (p < 0.05). In addition, high neutrophil infiltration in LUAD is associated with the worst survival outcome compared to other immune cell infiltrates (p < 0.001). In accordance with the PRECOG data, the presence of infiltrating neutrophils in a 100 patient LUAD tissue microarray is associated with poorer survival outcome when compared to patients with no infiltrating neutrophils (p < 0.05). Neutrophil migration to K-RAS, EGFR, ALK and ROS1-driven LUAD cell lines was examined in microfluidics devices and found to be highest in K-RAS-driven LUAD. CXCR2 inhibition reduced neutrophil migration only in K-RAS-driven lung adenocarcinoma (p < 0.05).

      Conclusion

      CXCR2 inhibition could be an exciting potential targeted treatment for patients with K-RAS-driven LUAD. CXCR2 inhibition is in clinical trials for metastatic melanoma, pancreatic, breast and head and neck cancer. Current evidence suggests that CXCR2 inhibition is safe and tolerable.

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      MA04.08 - Discussant - MA04.05, MA04.06, MA04.07 (Now Available) (ID 3731)

      13:30 - 15:00  |  Presenting Author(s): Triantafillos (Lakis) Liloglou

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA04.09 - Study of Exosomes in NSCLC for Biomarkers Searching (Now Available) (ID 2417)

      13:30 - 15:00  |  Presenting Author(s): Elena Durendez-Saez  |  Author(s): Silvia Calabuig-Fariñas, Cristian Suarez, Marais Mosqueda, Sandra Gallach, Eva Escorihuela, Andrea Moreno, Susana Torres, Alejandro Herreros-Pomares, Álvaro González, Ernesto De La Cueva, Eva Serna, Jesus M Paramio, Eloisa Jantus-Lewintre, Carlos Camps

      • Abstract
      • Presentation
      • Slides

      Background

      Exosomes are small membranous vesicles secreted by a most type of cells (especially in tumoral processes), around 40-130 nm of size, that carry relevant information to distant tissues and being able to modulate its physiology. Exosomes have been detected in different clinical samples and may play a key role in NSCLC, participating in several processes such as horizontal transfer of RNA from tumor to microenvironmental cells, angiogenesis, pre-metastatic niche formation, immunosuppression; and could also be key elements in stem cell differentiation (from different origins).

      The principal objective of this study was to analyze the exosomes cargo from NSCLC cell lines and primary cultures with diverse characteristics under different growth conditions: suspension cultures with cancer stem cells (CSCs) features and monolayer cultures.

      Method

      Primary cultures from resected NSCLC patients and NSCLC cell lines were successfully established. Differentiated tumor cells were cultured under adherent conditions (2D) whereas CSCs were established in suspension cultures (3D tumorspheres). Exosomes isolation was performed by ultracentrifugation. Exosomes characterization was carried out through nanovesicles tracking analysis (NTA) and electron microscopy; and the determination of surface markers through immunoblot and flow cytometry. Exosomal DNA was extracted in order to determine the mutational status of the EGFR and RAS genes by BEAMing Digital PCR (Sysmex). Transcriptomic analysis has been carried out from exosomal RNA through whole genome gene expression microarrays, (Affymetrix). The data was normalized by Robust Multi-Array Average (RMA) and analyzed using Transcriptome Analysis Console (TAC), MultiExperiment Viewer (MeV) software and Partek Genomics Suite. Statistical significance was established at (p ≤ 0.01).

      Result

      In reference to the characterization, NTA and electron microscopy showed that exosomes were obtained free of cellular debris and their size ranges from 108-125 nm, according to the size of tumor-derived microvesicles. Exosomal surface markers analyzed by immunoblot and flow cytometry were detected in samples, confirming proper isolation. Mutational analysis of EGFR and RAS genes performed on exosomal DNA shown the same pattern displayed by the origin cells. Transcriptomic analysis of the exosomal content showed that the expression of mRNAs, miRNAs and precursors were significantly different between 3D and 2D-derived exosomes. Finally, a pathway enrichment analysis was carried out to know in which biological processes (cancer-related) are involved.

      Significant differential expressions were also found between mRNAs, miRNAs and pre-miRs present in exosomes from adenocarcinoma (ADC) vs. squamous cell carcinoma (SCC). Interestingly, 7 miRNAs differentially expressed in exosomes (miR-200c; miR-29a; miR-339; miR-224; miR-31; miR-21; miR-33a) had already been identified as overexpressed in tumor tissue from NSCLC patients by our group. Moreover, miR-339 y miR-21 were related to prognosis (p < 0.05) in ADC group.

      Conclusion

      Differences in exosomal mRNA, miRNAs and pre-miRs expression have been observed between: i) lung-tumorspheres vs. more differentiated tumor cells and ii) ADC vs. SCC cultures. In addition, the same mutational pattern was detected in exosomes as compared with their parental cultures. Therefore, exosomes can be a useful source for biomarkers analysis in NSCLC.

      Supported by grant GV/2018/026, PI18/00266, & Asociación Española Contra el Cáncer (AECC Valencia).

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      MA04.10 - Development and Validation of a Gene Expression-Based Prognostic Signature in Early-Stage Squamous Cell Carcinoma of the Lung (Now Available) (ID 2643)

      13:30 - 15:00  |  Presenting Author(s): Pinaki Bose  |  Author(s): Anthony Boylos, Lars Frederick Petersen, Olga Kovalchuk, Igor Kovalchuk, Michelle L Dean, Doha Itani, Karen Kopciuk, Gwyn Bebb

      • Abstract
      • Presentation
      • Slides

      Background

      Squamous cell carcinoma of the lung (SqCCL) accounts for about 30% of all lung cancers and is usually associated with smoking. The clinical outcomes of early stage SqCCL are heterogeneous; while 60% of Stage I and II SqCCL patients never present with recurrence after surgery, the remaining will ultimately succumb to the disease. Therefore, a robust prognostication tool is an unmet clinical need. Here, we describe the development and validation of a gene expression-based prognostic signature in Stage I and II SqCCL patients.

      Method

      A total of 673 primary tumour samples obtained from surgically resected Stage I and II SqCCL patients were included in this study. The Cancer Genome Atlas (TCGA) cohort contained 365 patients with gene expression data generated using RNA sequencing (RNAseq). Five data sets (GSE30219, GSE37745, GSE50081, GSE4573, GSE14814) containing 308 patients profiled using Affymetrix microarrays were obtained from the Gene Expression Omnibus (GEO) database; batch effect mitigation of gene expression data was performed using ComBat. An additional cohort of consecutive Stage I and Stage II SqCLC patients was assembled at the Tom Baker Cancer Centre (TBCC), University of Calgary and gene expression was profiled using RNAseq. We performed a two-stage development of the gene signature by performing penalized elastic net Cox regression analysis in the TCGA training cohort followed by refinement of the gene list in the compiled GEO database patients. Final validation was performed using the in-house TBCC cohort. Progression-free survival (PFS) and overall survival (OS) were the primary and secondary outcomes of interest, respectively.

      Result

      All datasets used in this study were found to consist of patients with comparable clinical characteristics. A gene expression signature associated with PFS was developed in TCGA cohort that significantly stratified patients into high and low risk groups. The signature was refined in the complied GEO database cohort and validated in the U of C cohort. The signature also effectively stratified patients into high and low risk groups based on OS. We are currently performing multivariable analysis of the refined gene signature, adjusting for covariates of known prognostic value.

      Conclusion

      Our signature, if prospectively validated, will guide clinical decision making in SqCCL. Effective risk stratification using our signature may identify Stage I patients that will benefit from adjuvant therapy and stage II patients that could be spared adjuvant treatment following surgical resection.

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      MA04.11 - Biological and Prognostic Implications of the Long Non-Coding Transcriptome in Tumour-Infiltrating Immune Cells (Now Available) (ID 2838)

      13:30 - 15:00  |  Presenting Author(s): Kevin W Ng  |  Author(s): Adam Sage, Erin A Marshall, Katey SS Enfield, Wan Lam

      • Abstract
      • Presentation
      • Slides

      Background

      The lung tumour microenvironment is defined by complex infiltration patterns of immune cells which can contribute to both tumour progression and rejection. The advent of targeted immunotherapies has transformed cancer therapy, leading to durable regression even in late-stage lung tumours. Single-cell RNA sequencing and deconvolution of bulk tumour samples have provided insight into the transcriptomes of tumour-infiltrating immune populations and the regulatory networks that promote cytotoxicity and exhaustion transcriptional programs. Long non-coding RNAs (lncRNAs) have emerged as master regulators of gene expression in tumour cells, but their role in immune cells remains undercharacterized. We sought to delineate lncRNA expression profiles in healthy and lung tumour-infiltrating immune cells in order to better understand transcriptional reprogramming in tumour-infiltrating immune cells and to explore their potential as biomarkers of patient outcome and response to immunotherapy.

      Method

      RNAseq profiles of flow-purified adaptive and innate immune subsets were analysed for lncRNA expression, yielding 4919 expressed lncRNAs. Immune lncRNAs were then mapped to tumour and paired non-malignant lung adenocarcinoma samples (TCGA n=108, BCCA n=72) and associated with infiltrating immune populations by deconvolution and methylation-based purity scores. Associations with tumour immunogenicity were assessed by somatic mutational load and expression of tumour-associated antigens. Immune-specific expression of lncRNAs was confirmed in an external single cell RNAseq dataset of lung adenocarcinomas (n=5).

      Result

      We found that lncRNA expression patterns display markedly greater cell-type specificity than protein-coding genes in healthy samples, supporting their role in cell-intrinsic transcriptional regulation. 323 immune lncRNAs were differentially expressed in lung tumours compared to matched non-malignant tissue, with enriched expression of immune lncRNAs in tumours with high antigenic load. Many of these genes were positively correlated with CD45 expression and negatively correlated with tumour purity, suggestive of immune cell-restricted expression patterns. Furthermore, a substantial proportion of these genes showed decreased expression in microdissected tumour samples, suggesting that immune-derived lncRNAs may account for gene expression patterns observed in bulk tumour data. We validated these findings in a scRNAseq dataset and analysed co-expression patterns of immune lncRNAs with immune cell markers in order to identify specific immune cell phenotypes and assess the interaction of immune lncRNAs with cytotoxicity and exhaustion transcriptional networks. We identify immune lncRNAs which may regulate expression of important immune genes related to NK and CD8+ T cell cytotoxicity, as well as immune lncRNAs which predict patient outcome and response.

      Conclusion

      We present an atlas of lncRNAs expressed in innate and adaptive immune cells, emphasizing the multifaceted roles of lncRNAs in homeostasis and anti-tumour immunity. We highlight the potential of immune infiltrate to confound differential expression analysis of bulk tumour RNAseq data, with consideration needed for tumour purity and immune infiltration levels. Our data provide a resource that will facilitate further identification of functionally and clinically useful lncRNAs.

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      MA04.12 - Discussant - MA04.09, MA04.10, MA04.11 (Now Available) (ID 3732)

      13:30 - 15:00  |  Presenting Author(s): Alfonso Calvo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA16 - Prioritizing Use of Technology to Improve Survival of Lung Cancer Subgroups and Outcomes with Chemotherapy and Surgery (ID 142)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 12
    • Now Available
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      MA16.01 - Project PRIORITY: A Patient-Founded and Patient-Driven Research Partnership on Real-World Data on EGFR-Positive Lung Cancer (Now Available) (ID 2918)

      15:45 - 17:15  |  Presenting Author(s): Ivy Elkins  |  Author(s): Upal Basu Roy, Anita Figueras, Teri Kennedy

      • Abstract
      • Presentation
      • Slides

      Background

      Despite increases in PFS in EGFR-positive lung cancer patients due to EGFR TKIs, patients eventually develop resistance to these drugs. Project PRIORITY (Patient Reported Initiative On Resistance, Incidence, Treatment studY) is a patient-founded and patient-driven longitudinal study aimed at understanding unmet needs of the global EGFR-positive lung cancer community.

      Method

      A comprehensive 103-question, IRB-approved patient-facing survey about the diagnostic and treatment journey of patients (including risk factor exposure, treatments, symptom and side-effect management, access to biomarker testing and clinical trials) was developed with input from US FDA statisticians and expert clinicians, and then pilot-tested among English-speaking patients both locally and internationally. Differences between US and international participants were analyzed by Chi-square (for categorical variables) and ANOVA.

      Result

      Of the 253 respondents, 27.7% were international participants. In line with previous studies with EGFR patients, participants reported low rates of active tobacco exposure (16.4%) and high rates of second-hand tobacco exposure (34.7%). Also, first-line use of afatinib (OR = 2.5, p <0.05) and erlotinib (OR = 3.3, p< 0.05) were associated with the development of a T790M mutation reflecting similarity in clinical characteristics.

      US participants were more likely to report childhood exposure to secondhand smoke, family history of cancer (other than lung cancer), use of more than one line of therapy, and combination first-line therapy (P<0.05 for all variables).

      International participants were more likely to report first-line treatment with 1st/2nd generation TKI, less use of tissue and plasma NGS, lower clinical trial participation, and more use of whole-brain radiation for brain metastasis (P<0.05 for all variables).

      priority abstract figure.jpg

      Conclusion

      This first-of-its-kind international study provides a comprehensive picture of the treatment of EGFR-positive lung cancer patients in the real-world setting and highlights the existence of diagnostic (low NGS rates) and treatment gaps (low clinical trial participation and different treatment sequencing) both within the US and internationally.

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      MA16.02 - T790M Allelic Fraction Level Did Not Correlate Survival in T790M Positive NSCLC – Observations from an Early Access Program (Now Available) (ID 1809)

      15:45 - 17:15  |  Presenting Author(s): Oscar Siu Hong Chan  |  Author(s): Kwok Chi Lam, Victor Lee, Shi Fung Nyaw, Mei Wan Rebecca Yeung

      • Abstract
      • Presentation
      • Slides

      Background

      Osimertinib is an irreversible third-generation EGFR-TKI indicated for patients with metastatic EGFR T790M mutation positive NSCLC after progression of initial TKI therapy. An early access program (EAP) was started in 2015 providing ethical access of Osimertinib to patients with metastatic NSCLC running out of treatment options in Hong Kong. As some prior data suggested that T790M allele fraction (AF) correlated survival outcomes in patients receiving Osimertinib, we try to validate it with data from this EAP. Survival outcomes and safety data of Osimertinib in the real world practice under this EAP were also analysed. (NCT03219970)

      Method

      This retrospective analysis included EAP patients who had advanced or metastatic NSCLC harbouring EGFR T790M mutation that progressed on prior TKI ± chemotherapy. EAP subjects received Osimertinib at 80mg daily until disease progression, intolerable toxicities or death. The T790M mutation can be assessed by any approved molecular tests in any specimen types.

      The AF levels in patients with T790M mutation confirmed by quantitative plasma genotyping (QPG) using ddPCR technique of the same vendor were retrieved. The primary objective was to assess the relationship of post-Osimertinib overall survival (OS) and T790M AF level. Secondary objectives included investigator-assessed response, time to discontinuation (TTD) of Osimertinib, safety (Osimertinib-related adverse events of special interest, AESIs) and OS of all EAP participants.

      Result

      From Sep 2015 to Feb 2017, 156 patients enrolled in the EAP and received treatment. At time of data cut-off (11 Oct 2018), 74 (47%) were alive. Median follow-up was 23.4 (range: 1–30) months, median age 62 years, 62% female, 26% ECOG PS ≥2, 96.8% with metastatic disease. Besides T790M, 56% of patients had exon 19 deletions and 41% had exon 21 L858R mutations.

      Ninety-one patients had QPG using ddPCR method with AF data. OS, best response rate and TTD were not significantly related to T790M AF level as a continuous variable (p=0.20; hazard ratio 1.022, 95% CI 0.989 to 1.057), confirmed through sensitivity analysis with different AF threshold values.

      The investigator assessed best response rate was 41.7% (65/156) and disease control rate was 62.2% (97/156). Median TTD was 15.77 (12.43, 18.98) months. Median OS was 21.88 (95% CI 19.14–26.21) months. AESIs were reported in 7.7% of patients overall: 5.8% QTc prolongation and 1.9% pneumonitis.

      Conclusion

      T790M AF level did not correlate with TTD and OS in this EAP cohort but the limitations should not be overlooked. The survival outcomes concurs other reported series.

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      MA16.03 - Big Data Analysis for Personalized Medicine in Lung Cancer Patients (Now Available) (ID 2532)

      15:45 - 17:15  |  Presenting Author(s): Maria Torrente  |  Author(s): Beatriz Núñez-García, Fabio Franco, Virginia Calvo De Juan, Ernestina Menasalvas, Alejandro Rodríguez-González, Consuelo Parejo, Mariano Provencio

      • Abstract
      • Presentation
      • Slides

      Background

      The use of Big Data in healthcare is in its early days, and most of the potential for value creation remains unclaimed.

      Electronic Health Records (EHR) contain a large amount of information about the patient's condition, which can potentially revolutionize the clinical practice, such information is seldom considered due to the complexity of its extraction and analysis. We report on a first integration of an NLP framework for the analysis of clinical records of lung cancer in Puerta de Hierro University Hospital (HUPHM).

      Method

      A cohort of 1000 patients diagnosed of non-small cell lung cancer (NSCLC) from 2009 to 2018 at HUPHM were included in this observational study. Unstructured clinical data were obtained from the EHR. The semantic indexing and the information analysis was performed by the Politecnica University of Madrid, using Big Data and machine learning techniques. Clinical notes were converted into usable data, and combined with genomic data, images and bibliography, such as PubMed or Drugbank.

      Result

      A total of 251.730 documents were analyzed (240.851 notes and 10.879 reports). These heterogeneous sources of information were analyzed and integrated in an interactive user interface (Figure 1). As a result, all this large amounts of data turns into actionable and exploitable information for clinicians and authorities for planning public health policies and also create new clinical trials.

      The interactive platform will allow the clinician obtain immediate and personalized information of each patient and will elaborate predictive models for long survivors, identify risk patients, reduce overtreatments, etc.

      Conclusion

      By using Big Data we will be able to exploit large amounts of clinical information and combine them with multiple databases developing interactive user interface, increasing lung cancer knowledge and directing medicine towards a more personalized one.

      This work was supported by the EU H2020 programme, under grant agreement Nº 727658 ( Project iASiS).

      captura de pantalla 2019-04-10 a las 21.07.09.png

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      MA16.04 - Discussant - MA16.01, MA16.02, MA16.03 (Now Available) (ID 3783)

      15:45 - 17:15  |  Presenting Author(s): Sukhmani Padda

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA16.05 - Wearable Technology for Preconditioning Before Thoracic Surgery: A Feasibility Study (Now Available) (ID 2642)

      15:45 - 17:15  |  Presenting Author(s): Yogita S. Patel  |  Author(s): Danielle Hylton, Matthew Rok, Marla Beauchamp, Joshua Wald, Lawrence Mbuagbaw, Christian Finley, John Agzarian, Yaron Shargall, Christine Fahim, Wael C. Hanna

      • Abstract
      • Presentation
      • Slides

      Background

      Preconditioning before surgery can lower complication rates, but there are significant barriers to its adoption in the lung cancer population, which is characteristically older, suffers multiple comorbidities, and is averse to exercise. In an effort to overcome these barriers, we designed Move For Surgery (MFS), a home-based, preoperative preconditioning program which involves aerobic exercise using wearable technology and deep breathing exercises. We aimed to test the feasibility of MFS in preparation for a randomized controlled clinical trial.

      Method

      In this prospective feasibility study, patients undergoing resection for NSCLC were preoperatively enrolled and provided with a wearable activity tracker (Fitbit) and a booklet describing various aerobic exercises, deep breathing exercises, and nutritional and smoking cessation tips. The daily step count, sleep cycle, and calories burned were synced and tracked remotely. Daily step goals were set by increasing the participants’ baseline step count by 600 steps each week until the day of surgery. Participants were encouraged and motivated to reach their daily step goal by daily automatic reminders through the Fitbit. Participants completed the EQ-5D-5L health-related quality of life instrument at baseline and on the day of surgery. Data is presented as mean +/- SD and median (range). Continuous variables were compared using Student’s t-test, and categorical variables were compared using Chi-square or Fischer’s exact test, with a level of significance p<0.05.

      Result

      Of the 40 patients screened, 62.5% (25/40) were eligible and enrolled. Of the 15 not eligible, 80% (12/15) did not have a smartphone. Participants (n=25) were enrolled from 11/2017 to 07/2018. Median age was 62 (33-82) and 72% (18/25) were women. The mean predicted FEV1 and DLCO were 88.9% +/- 23.4% and 74.9% +/- 19.8% respectively. Participants spent a median of 25 days (8-55) on trial, and wore their Fitbits 90.0% +/- 25.2% of the time. The mean baseline daily step count for this cohort was 7,586 +/- 4,082, and the participants were able to achieve the daily step goal in 40.8% +/- 30.0% of the time. Participants with higher baseline step counts (≥6,000/day) were more likely to achieve the daily step goals (52.2% vs 20.5%; p=0.0083). Significant improvement was seen in the overall health component of the EQ-5D-5L from before the intervention (76.4 +/- 15.45) to after the intervention (80.4 +/- 14.57; p=0.03). Overall, 96.0% (24/25) of the participants completed the recommended deep breathing exercises, 100% (25/25) recommended MFS for future patients, and 96.0% (24/25) stated they will buy their own Fitbits and continue this lifestyle post-surgery.

      Conclusion

      A preoperative preconditioning trial with wearable technology prior to lung cancer resection is feasible based on encouraging enrollment rates, use of the device, and goal achievement, but it is only applicable to participants with smart devices. MFS motivates patients to undergo preconditioning before lung cancer resection and to continue with a healthy lifestyle after surgery. A revision of the daily step goal is required to improve compliance. A randomized trial is in progress to determine the impact of MFS on postoperative outcomes in the thoracic surgery population.

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      MA16.06 - Deterioration in Health-Related Quality of Life Diminishes Benefit of Lung Cancer Resection in Older Adults (Now Available) (ID 2875)

      15:45 - 17:15  |  Presenting Author(s): Jae Y. Kim  |  Author(s): Andrew M Blakely, Hengrui Hu, Lennie Wong, Dan J Raz, Loretta Erhunmwunsee, Virginia Sun

      • Abstract
      • Presentation
      • Slides

      Background

      Outcomes of oncologic resection are related to tumor biology as well as patient-reported health factors. However, data regarding changes in functional status and health-related quality of life (HRQOL) before and after lung surgery are currently lacking.

      Method

      We identified lung cancer patients from the SEER-Medicare Health Outcomes Survey (MHOS) linked database. HRQOL survey data captured physical/mental health, activities of daily living (ADLs), and medical comorbidities. Patients who underwent surgery with 1) baseline HRQOL survey prior to cancer diagnosis and 2) follow-up survey at least one year after diagnosis were selected. Patient, disease, and HRQOL measures were analyzed using Cox proportional hazards regression in regard to overall survival (OS) and disease-specific survival (DSS).

      Result

      Overall, 138 patients were evaluated, of whom 67 (49%) were male. Mean age at diagnosis was 74 years. The majority of patients were Caucasian (n=112, 81%). Disease extent was localized for 75 (54%), regional for 58 (42%), and distant for 5 (4%). In general, the cohort experienced a decline in physical HRQOL, mental HRQOL, and ADLs; and an increase in the number of major comorbidities (see Table). Median OS was 74 months. Decreased OS was independently associated with male sex (HR 1.7, p=0.03), more advanced disease (regional vs. localized: HR 1.8; distant vs. localized: HR 2.1; p=0.04), and decline in ADLs (HR 1.8, p=0.02). Decreased DSS was independently associated with male sex (HR 2.2, p=0.03), more advanced disease (regional vs. localized: HR 2.9; distant vs. localized: HR 3.1; p=0.01), and decline in mental HRQOL (OR 2.1, p=0.02).

      table.png

      Conclusion

      The potential survival benefit of lung resection for malignancy is diminished by declines in physical and mental health. Among older surgical patients at risk for functional and HRQOL deterioration, identification and mitigation of such deterioration may in turn optimize oncologic outcomes.

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      MA16.07 - Implementation of a Smartphone App to Face Postoperative Period in Patients with NSCLC Undergoing Lung Resection Surgery (Now Available) (ID 1028)

      15:45 - 17:15  |  Presenting Author(s): Carlos Alfredo Fraile Olivero  |  Author(s): Lucia Milla Collado, José Ramón Jarabo Sarceda, Elena Fernández Martín, Carlos Cerdan Santacruz, Joaquin Calatayud Gastardi, Ana María Gómez Martínez, Pedro Daniel Arribas Manzanal, Passio Santos Capa, Micaela Martínez Tardido, Veronica Alen, Florentino Hernando-Trancho

      • Abstract
      • Presentation
      • Slides

      Background

      Preoperative patient education and counseling helps to set expectations about surgical procedure and to prepare for it. Thoracic surgery procedures are related to postoperative complications and strategies to reduce them begin prior to surgery. Lung expansion maneuvers, the importance of early ambulation and pain control are best taught before the procedure. The aim of this prospective study was to implement the use of a smartphone application in a cohort of patients undergoing lung resection surgery and describe their feedback results.

      Method

      We created a Smartphone application as a multidisciplinary tool including: peri-operative medical advice (stop smoking, mouth health, early mobilization and pain control) (Fig1), ten chest physical exercises (with animated images) and programmable Smartphone daily notifications. Complete information to download, set up and interaction with the software was given to patients. A Multiple-Choice-Question survey was applied to patients at the moment of hospital discharge in order to evaluate their experience. This prospective and observational study included clinical data and results of surveys applied.

      image1 (3).png

      Result

      A total of 68 patients interacted with the application before surgery and answered the survey after the procedure. Median age was 66.5 years and 67.6% were males. Of them, 51 patients (75%) considered the content “very compressible”. 54 patients (79.4%) considered “positive” the contribution of the application to face the postoperative period. Additionally, 31 patients (45.6%) deemed “appropriate” the quantity of time and physical effort needed to complete the interaction with the tool and reach the goals.

      Conclusion

      This is the first smartphone application created by thoracic surgeons to improve patient´s education and helps them to prepare for surgery. This new technological tool was successfully implemented in our thoracic surgery department. For patients, it is easy to download, setup and contents comprehensible information that contributes to face positively the postoperative period with an adequate physical effort and quantity of time.

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      MA16.08 - Discussant - MA16.05, MA16.06, MA16.07 (Now Available) (ID 3784)

      15:45 - 17:15  |  Presenting Author(s): Sabita Jiwnani

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA16.09 - Clinical Practice and Outcomes in Patients with Stage III Unresectable Non-Small-Cell Lung Canceran Academic Centre, Canada (Now Available) (ID 818)

      15:45 - 17:15  |  Presenting Author(s): Jason Scott Agulnik  |  Author(s): Goulnar Kasymjanova, David Small, Carmela Pepe, Lama Sakr, Victor Cohen, Magali Lecavalier, Hangjun Wang, Alan Spatz, Manjusha Hurry, Ryan Walton

      • Abstract
      • Presentation
      • Slides

      Background

      The prognosis of patients with stage III unresectable non-small cell lung (NSCLC) cancer is poor: five-year OS is only 19-24% for stage IIIA and 7- 9% for stage IIIB. In light of the approval of immunotherapy maintenance treatment, after completion of CRT, we undertook a retrospective study to characterize management and report outcomes of patients with stage III, unresectable NSCLC treated with chemoradiation (CRT) at the Jewish General Hospital, Montreal.

      Method

      Patients diagnosed with stage III unresectable NSCLC,and treated with combined CRT, either concurrent (cCRT) or sequential (sCRT) treatment,between January 2007 to December 2018 were included in the study. Overall survival was calculated using the Kaplan-Meier approach and calculated from the start of radiotherapy. Physician defined progression-free survival was calculated from the start of radiotherapy until documented progression based on radiologic assessment. A multivariate analysis using Cox regression was carried out to assess clinical factors impacting survival.

      Result

      134/263 patients were deemed unresectable and received combined CRT. 124/134 (92.5%) received CRT as initial treatment and 10(7.5%) received CRT after progression to stage 3 post surgery for an earlier stage NSCLC.114/134 received cCRT and 20/134 received sCRT. Patients on cCRT were significantly younger with a slight prevalence of non-squamous histology and had N1 or single station N2 disease.Median OS (mOS) was 18.7 months (95%CI, 12.4-24.8) for the overall cohort; mOS in cCRT of 23.3 months (95%CI,14.3-32.2) was significantly better compared to 11.33 months with sCRT (95% CI, 10.2-24.8 p=0.01). PFS was slightly better in patients with cCRT (7.97mo, 95%CI 1.75-11.18) compared to sCRT (5.26mo, 95% CI 4.06-6.48 p=0.08).86/134 (64%) progressed and received subsequent therapy: 49 (57%)-chemotherapy alone, 15 (17.4%)–radiation alone, 13 (15.1%)-immunotherapy and 9 (10.5%)-targeted therapy.In multivariate analysis, the tumor size (HR 1.5, 95%CI 1.08-1.97) and nodal status (HR 2.5, 95%CI 3.34-4.74) were the only prognostic factors for OS. Gender, age, ECOG, smoking status, histology, chemotherapy protocol, subsequent therapy, mutation status and cCRT were not statistically significantin multivariate analysis. cCRT was not significant, likely due to patient selection.

      Conclusion

      Unresectable stage III NSCLC is a heterogenous group that is challenging to manage. Combined CRT has beenthe standard of care for this group of pts. In our patient cohort, a trend of improved survival was seen in the cCRT group. Tumor size and nodal status were prognostic factors for OS. Future studies evaluating survival with newer IO therapies is of interest.

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      MA16.10 - Antioxidative Effect of Erdosteine on Platinum-Based Doublet Chemotherapy Induced Nephrotoxicity (Now Available) (ID 1080)

      15:45 - 17:15  |  Presenting Author(s): Chang Youl Lee  |  Author(s): Seung Hun Jang, Myung-Goo Lee

      • Abstract
      • Presentation
      • Slides

      Background

      Many classes of antineoplastic agents including the platinum coordination complexes are also known to generate free radicals which have a role in the side effects of chemotherapy. Despite the introduction of new treatments including target and immunotherapy, platinum-based doublet chemotherapy is one of the most widely used and most potent chemotherapy drugs to treat lung cancer patients especially with small cell lung cancer. However, side effects in normal tissues and organs, notably nephrotoxicity in the kidneys, limit the use of platinum-based doublet chemotherapy. There are several experimental evidences which support the protective effect of erdosteine in acute injury induced by a variety of pharmacological or noxious agents, mediated by products of oxidative stress. Erdosteine is a multifactorial drug currently used in lung disease. In the last decade, data from several studies to the possible antitussive and anti-inflammatory properties of erdosteine and an indirect anti-inflammatory mechanism of action related to the ROS scavenging activity was suggested. The purpose of this study is to investigate whether erdostein can reduce the renal toxicity of lung cancer with platinum-based doublet chemotherapy by antioxidant role.

      Method

      This study was a prospective, randomized, double-blind clinical trial on 153 patients with lung cancer(small cell lung cancer and non-small cell lung cancer). Patients who was treated with platinum-based doublet chemotherapy were randomly assigned into 2 groups of intervention(erdostein) group and control(non-erdostein) subjects regardless of the type of lung cancer. Intervention group took erdosteine 600 mg orally twice a day. We measured CCr, serum/urine NGAL, serum/urine Cystatin C, urine KIM-1 of the lung cancer patients who underwent platinum-based doublet chemotherapy to assess renal injury. And also we measured the activity of specific antioxidant enzymes, such as catalase and superoxide dismutase to evaluate oxidative stress. Serum and urine samples were collected from the patient before and after chemotherapy.

      Result

      There was no significant difference of renal status between intervention and control groups at baseline. However, Statistically there was a significant decline in CCr among control group regardless of the type of lung cancer and the resimen of chemotherapy. NGAL expression of blood and urine was decreased in intervention group (especially patient treated with cisplatin and small cell lung carcer patients) but Cystatin C levels showed no difference between two groups. The decrease in urinary KIM-1 after cisplatin-based doublet chemotherapy in intervention group were observed compared to control group. Superoxide dismutase levels of serum were approximately increased to twice the initial level to the level measured after chemotherapy in the treatment group while the level of catalase did not change significantly in both the groups.

      Conclusion

      These results show that erdosteine may be a promising drug for protection against platinum-based doublet chemotherapy-induced nephrotoxicity, especially for patients with cisplatin-based doublet chemotherapy and small cell lung cancer. However, further studies with different dose of erdosteine are warranted for clarifying the issue.

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      MA16.11 - Early and Late Survival Comparison Between Oncological Versus Non-Oncological Patients Admitted to a General Intensive Care Unit in Chile (Now Available) (ID 1948)

      15:45 - 17:15  |  Presenting Author(s): Suraj Rajesh Samtani  |  Author(s): Rene Lopez, Jeronimo Graf, Jose Miguel Montes, Rodrigo Perez

      • Abstract
      • Presentation
      • Slides

      Background

      Cancer patients are a heterogeneous population and usually admission to ICU units was discouraged due to negative outcomes. In the past years, literature supports the admission at ICU for oncological patients that need invasive mechanical ventilation (IMV) with new admission policy known as the ICU-trial, with aim to recognize a group of patients that may benefit of limited time of intensive support and treatment. The purpose of this trial is to describe the characteristics and overall survival of a prospective cohort of invasive mechanical ventilation (IMV) patients admitted to an ICU of Clinica Alemana.

      Method

      This is an observational, prospective and analytical cohort study conducted in Clínica Alemana de Santiago. We included patients with cancer > 18 years old, with baseline Eastern Cooperative Oncology Group (ECOG) performance status classification from 0 to 3, who were admitted to ICU and needed IMV between October 2017 and February 2019. Demographic, physiologic, laboratory, clinical and treatment data were extracted prospectively in a database-updated daily. Survival data was obtained from national death registry database.

      Result

      A total of 1,490 patients were admitted between October 2017 and February 2019. A total of 358 patients (24%) had oncological diagnosis and 100 patients were supported with IMV. According to ICU plan, 76 patients were treated as full code and 24 patients as ICU-trial. Among all IMV patients ICU mean of length of stay (LOS) was of 7 days. At the comparison between oncological vs non-oncological patients, APACHE II score and the first-day SOFA score were not statistically different between both groups. Among oncological patients, 73,3% of patients were ECOG 1 and solids tumors were more common than hematological malignancies (90% vs 10%). Lung and digestive cancer were the most frequent malignancies. Full code management was the most frequent strategy at ICU admission in comparison to ICU-trial (76% vs 24%). Survival at day 28 between oncological and non-oncological patients was 76.3% vs 79.3% respectively (p=0.588). However, survival was significantly different at day 90 (64.3% vs 78.8% respectively, p=0.015) and at end of following period (52% vs 76.2% respectively, p<0.001). Remarkably, survival adjusted by cox regression showed a significant lower survival in oncological patients with ECOG 2 and ECOG 3 while the patients with ECOG 0 and 1 had a similar survival to non-oncological patients. According to ICU plan management statistically significant difference was observed in the group of oncological patients with higher survival in full code vs ICU-trial (59.5% vs 29.2% respectively, p=0.015) with a hazard ratio 0.52 [0.28-0.94].

      Conclusion

      Our data suggest that in oncological patients the short-term survival is determined for severity of the critical illness and the late survival is lower respect to non-oncological patients if poor performance status is documented. In patients with cancer admitted under ICU-trial criteria and supported with invasive mechanical ventilation a late survival close to 30% was observed. Similar to previous studies, our study emphasizes that ICU admission should not be limited only on the basis of a patient having a neoplastic disease and different variables should be considered from patient to patient.

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      MA16.12 - Discussant - MA16.09, MA16.10, MA16.11 (Now Available) (ID 3785)

      15:45 - 17:15  |  Presenting Author(s): Apar Kishor Ganti

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA19 - Looking at PROs in Greater Detail - What Patients Actually Want and Expect (ID 147)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment in the Real World - Support, Survivorship, Systems Research
    • Presentations: 12
    • Now Available
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      MA19.01 - Empirical Identification of Distress Clusters in Lung Cancer Patients (Now Available) (ID 2085)

      11:30 - 13:00  |  Presenting Author(s): Mary Ellen Hand  |  Author(s): Teresa Lillis, Mary M. Pasquinelli, Zane Deliu, Christine Weldon, Julia Trosman, Lawrence Eric Feldman, Michael Huber

      • Abstract
      • Presentation
      • Slides

      Background

      Screening for distress from the time of diagnosis is emerging as standard cancer care. Although there is heterogeneity in patients’ experience of distress, identification of subgroups of patients with unique distress profiles may inform interventions for distressed patients. Accordingly, we aimed to identify unique subgroups of patients based on their distress screening responses from a large sample of newly diagnosed lung cancer patients across two urban academic medical centers in Chicago, IL.

      Method

      Lung cancer patients (N=596) were screened for distress at their diagnostic visit between (2/22/16 – 8/14/18) with the Coleman Foundation “Patient Screening Questions for Supportive Care” tool; a 34-item screener that identifies patient needs across psychological, physical, family/caregiver, and treatment and care concerns. A Two-Step cluster analysis was conducted to identify natural clusters of patients based on similar responses to distress screening items.

      Result

      Cluster analysis results revealed a two-cluster outcome: “High Distress” (N=332) and “Low Distress” (N=264). The items that best distinguished High Distress patients from Low Distress patients were concerns about cancer stage/diagnosis, concerns about prognosis/long-term outcome, concerns about treatment options, and having higher average number of total concerns. Cancer stage at screening was not predictive of cluster membership. Demographic characteristics, descriptive statistics, and group difference tests for survey items by cluster and for the total sample are presented in Table 1.

      Conclusion

      More than half of lung cancer patients were grouped as experiencing high distress on screening. While cancer stage was not predictive of high distress grouping, concerns about stage, treatment, and prognosis were most predictive of high distress cluster membership. An intervention to improve communication between providers and patients about these concerns may reduce distress.

      Table 1

      High Distress (N=332/55.7%)

      Low Distress (N=264/ 44.3%)

      Total Sample (N=596)

      Significance

      Tests

      Demographics

      Age

      M=65.75 (SD=9.95)

      M=66.25 (SD=9.71)

      M=65.97 (SD=9.84)

      F=.39 (p>.05)

      Female

      N=171 (51.5%)

      N=144 (54.5%)

      N=315 (52.9%)

      χ2=.55 (p>.05)

      Race/Ethnicity

      χ2=30.83 (p<.01)

      White

      N=124 (37.3%)

      N=154 (58.3%)

      N=278 (46.6%)

      p<.01

      African American

      N=161 (48.5%)

      N=72 (27.3%)

      N=233 (39.1%)

      p<.01

      Other

      N=47 (14.2%)

      N=38 (14.4%)

      N=85 (14.3%)

      p>.05

      Stage IV

      N=160 (48.2%)

      N=118 (44.7%)

      N=278 (46.6%)

      χ2=.72 (p>.05)

      Physical & Psychological Health

      Psychological Distress (PhQ-4)

      M=3.55 (SD=3.63)

      M=1.56 (SD=2.14)

      M=2.67 (SD=3.29)

      F=58.86 (p<.01)

      Pain

      M=5.13 (SD=4.76)

      M=4.76 (SD=3.45)

      M=4.99 (SD=3.66)

      F=1.04 (p>.05)

      Fatigue

      M=8.56 (SD=5.31)

      M=7.63 (SD=4.74)

      M=8.15 (SD=5.01)

      F=4.34 (p<.05)

      Physical Activity

      M=12.63 (SD=7.74)

      M=16.70 (SD=8.52)

      M=14.42 (SD=8.33)

      F=35.55 (p<.01)

      Concerns

      Practical Concerns

      Childcare

      N=8 (2.5%)

      N=2 (.8%)

      N=10 (1.7%)

      χ2=2.43 (p>.05)

      Food & Housing

      N=58 (17.8%)

      N=13 (5.0%)

      N=71 (12.2%)

      χ2=22.06 (p<.01)

      Transportation

      N=72 (22.0%)

      N=14 (5.4%)

      N=86 (14.7%)

      χ2=31.29 (p<.01)

      Work/School

      N=19 (5.9%)

      N=8 (3.1%)

      N=27 (4.7%)

      χ2=2.49 (p>.05)

      Paying for Medication

      N=79 (24.1%)

      N=35 (13.6%)

      N=114 (19.5%)

      χ2=10.19 (p<.01)

      Family/Caregiver Concerns

      Children

      N=46 (18.7%)

      N=18 (8.0%)

      N=64 (13.6%)

      χ2=11.58 (p<.01)

      Partner

      N=51 (20.9%)

      N=24 (10.6%)

      N=75 (15.9%)

      χ2=9.37 (p<.01)

      Caregiver

      N=23 (9.5%)

      N=8 (3.5%)

      N=31 (6.6%)

      χ2=6.91 (p<.01)

      Ability to have children

      N=8 (3.3%)

      N=2 (.9%)

      N=10 (2.1%)

      χ2=3.35 (p>.05)

      Family

      N=62 (25.6%)

      N=24 (10.5%)

      N=86 (N=18.3%)

      χ2=18.07 (p<.01)

      Treatment & Care Concerns

      Cancer Diagnosis & Stage

      N=303 (93.5%)

      N=8 (3.3%)

      N=311 (55.1%)

      χ2=453.34(p<.01)

      Prognosis & Long-term Outcome

      N=312 (95.7%)

      N=37 (15.4%)

      N=349 (61.6%)

      χ2=378.04 (p<.01)

      Treatment Options

      N=246 (75.7%)

      N=11 (4.6%)

      N=257 (45.4%)

      χ2=282.43 (p<.01)

      Communicating treatment wishes

      N=165 (52.1%)

      N=7 (2.9%)

      N=172 (30.8%)

      χ2=155.09 (p<.01)

      Physical Health Concerns

      Breathing

      N=160 (64.3%)

      N=78 (35.5%)

      N=238 (50.7%)

      χ2=38.77 (p<.01)

      Constipation

      N=86 (43.4%)

      N=41 (20.0%)

      N=127 (31.5%)

      χ2=25.63 (p<.01)

      Diarrhea

      N=47 (27.0%)

      N=17 (8.5%)

      N=64 (17.1%)

      χ2=22.68 (p<.01)

      Fevers

      N=22 (13.3%)

      N=4 (2.1%)

      N=26 (7.2%)

      χ2=16.72 (p<.01)

      Nausea/Vomiting

      N=66 (33.7%)

      N=16 (8.1%)

      N=82 (20.8%)

      χ2=39.15 (p<.01)

      Sleep

      N=137 (59.3%)

      N=58 (27.4%)

      N=195 (44.0%)

      χ2=45.79 (p<.01)

      Urination

      N=46 (26.1%)

      N=12 (6.0%)

      N=58 (15.5%)

      χ2=28.79 (p<.01)

      Chewing/Swallowing

      N=49 (27.1%)

      N=18 (9.1%)

      N=67 (17.7%)

      χ2=21.01 (p<.01)

      Mouth Sores

      N=24 (14.5%)

      N=13 (6.6%)

      N=37 (10.2%)

      χ2=6.18 (p<.05)

      Dry Mouth

      N=116 (53.2%)

      N=51 (24.5%)

      N=167 (39.2%)

      χ2=36.76 (p<.01)

      Swollen Arms or Legs

      N=76 (39.6%)

      N=21 (10.5%)

      N=97 (24.7%)

      χ2=44.49 (p<.01)

      Feeling full quickly or swollen abdomen

      N=57 (32.0%)

      N=18 (9.2%)

      N=75 (20.1%)

      χ2=30.35 (p<.01)

      Sexual Intimacy or Functioning

      N=54 (28.3%)

      N=17 (8.4%)

      N=71 (18.0%)

      χ2=23.37 (p<.01)

      Dry/Itchy or Blistered Skin

      N=94 (46.3%)

      N=43 (20.7%)

      N=137 (33.3%)

      χ2=30.37 (p<.01)

      Tingling in hands/feet

      N=84 (43.5%)

      N=33 (16.8%)

      N=117 (30.1%)

      χ2=32.93 (p<.01)

      Appearance

      N=31 (19.35)

      N=14 (7.2%)

      N=45 (12.7%)

      χ2=11.52 (p<.01)

      Use of Alcohol or Drugs

      N=3 (2.0%)

      N=1 (.5%)

      N=4 (1.2%)

      χ2=1.59 (p>.05)

      Total # of Concerns

      M=7.84 (SD=3.71)

      M=2.53 (SD=2.47)

      M=5.49(SD=4.16)

      F=400.82 (p<.01)

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      MA19.02 - Psychological Distress in Never, Ex, Current, and Passive Smokers Diagnosed with Lung Cancer - Analyses from the EnRICH Program (Now Available) (ID 461)

      11:30 - 13:00  |  Presenting Author(s): Bea Brown  |  Author(s): John Simes, Michael Boyer, Phillip Hogg, Anthony Joshua, Jane Young, Christopher Brown

      • Abstract
      • Presentation
      • Slides

      Background

      Lung cancer is associated with greater psychological distress than any other cancer. In Australia, the prevalence of anxiety and depression in those with lung cancer is nearly 30% higher than the average of other major cancers. More than 50% of patients experience distress, anxiety and/or depression, resulting in diminished quality of life (QoL), and a fourfold increase in likelihood of suicide than the general population.

      Lung cancer stigma, arising from presumption about tobacco exposure and associated smoking stigma, contributes to high levels of distress. A national survey found that more than a third (35%) of Australians believe those living with lung cancer “have only themselves to blame” and almost 40% indicated, before expressing concern, the first question they would ask someone diagnosed with lung cancer is whether they smoked. This stigma makes lung cancer patients reluctant to seek psychosocial support and reduces their sense of entitlement to care and empathy. However, approximately one fifth (21%) are life-long never-smokers.

      This study aimed to describe differences in levels of psychological distress in never-and ever-smokers enrolled in the Sydney Catalyst EnRICH Program, a prospective clinical cohort of patients with lung cancer in New South Wales, Australia.

      Method

      Measures: EnRICH incorporates patient-reported outcome measures (PROMs) that assess dimensions of anxiety, depression, emotional function, and psychological distress, namely, the: (i) EORTC QLQ-C30; and (ii) NCCN Distress Thermometer.

      Sample: All patients with newly diagnosed lung cancer presenting to study hospitals are eligible for the EnRICH cohort. Consenting patients who completed PROMs comprise the sample for the current analyses.

      Statistical Methods: Subscales of the QLQ-C30 reflecting overall QoL and emotional function, and scores on the NCCN Distress Thermometer, were compared between patient groups by smoking status. Groups were combined into never-smokers (never, passive) and ever-smokers (ex, current) for analyses. Mean differences and 95% confidence intervals were computed.

      Result

      Among 205 patients who completed PROMs (69% of consenting patients), there were 52 never-smokers, 5 passive-smokers, 161 ex-smokers and 52 current-smokers at the time of diagnosis. Emotional function was worse in never-smokers (ever=75.3, never=63.2, difference=12.1 points 95%CI 2.4-21.7). There were no differences in other subscales. Although numbers are small, passive-smokers had the lowest mean scores for emotional-, role-, and social-functioning (Figure 1). Distress thermometer scores were 1.2 points worse in never-smokers [95%CI (0.56-1.8)].

      everneverscales.png

      Conclusion

      Never-smokers had worse emotional function and higher distress than other lung cancer patients. If confirmed in larger studies, additional supportive care services may improve outcomes for these patients.

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      MA19.03 - Differences in Symptom Burden Between Responsive and Progressive Disease in Advanced Non-Small Cell Lung Cancer (aNSCLC) (Now Available) (ID 845)

      11:30 - 13:00  |  Presenting Author(s): George R Simon  |  Author(s): Loretta Ann Williams, Qiuling Shi, Belqis El Ferjani, Meita S Hirschmann, Darcy Ponce, Seyedeh S Dibaj, Sheenu Chandwani, Emily Roarty, Waree Rinsurongkawong, Jeff Lewis, Thomas Burke, Charles S Cleeland, Jack Lee, Jack Roth, Stephen Swisher, John Victor Heymach, Jianjun Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      We have established a real-world Advanced Non-Small Cell Lung Holistic Registry (ANCHoR) to assess how immunotherapy impacts treatment choice, clinical outcomes, and patient-reported outcomes (PROs) of aNSCLC. Our aim in this analysis was to assess the ability of the MDASI-LC to differentiate between patients who are responding or who are progressing during treatment.

      Method

      Between May 2017 and December 2018, patients with aNSCLC at a single institution were enrolled in ANCHoR and completed the MDASI-LC prior to therapy (PTT) and at routine clinic visits. The MDASI-LC consists of 16 symptom severity and 6 interference items rated on 0-10 scales (0 = no symptom or interference, 10 = worst imaginable symptom or complete interference). MDASI-LC scores from PTT to first recorded response determination (FRD) were compared by response group using linear mixed modeling (LMM).

      Result

      One hundred one patients completed the MDASI-LC PTT and at FRD. Mean patient age was 63.8 years (standard deviation = 10.29) and 55% were males. Fifty percent of patients received chemotherapy (CTX), 22% immunotherapy (IM), 19% CTX+IM or angiogenesis inhibitor, and 9% targeted therapy. Median time from PTT to FRD was 105 days (lower quartile = 63, upper quartile = 224). Forty-six percent of patients had a complete or partial response (RECIST criteria CR, PR), 14% had stable disease (RECIST SD), and 41% progressed (RECIST PD). LMM showed progressing patients had significantly more fatigue (estimated effect [est] =1.39; p = 0.031), sleep disturbance (est=1.37; p = 0.046), and drowsiness (est=1.33; p = 0.037) and reported significantly more interference with work (est=1.67; p = 0.016) over time than responding patients.

      Conclusion

      The MDASI-LC differentiated the symptom burden of patients with responding disease from that of patients with progressive disease. Patients with progressive disease had more fatigue, disturbed sleep, drowsiness, and greater interference with work than those with responsive disease. Further research is needed to determine if the MDASI-LC can predict response to therapy in patients and may be useful in delineating treatment benefit.

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      MA19.04 - Discussant - MA19.01, MA19.02, MA19.03 (Now Available) (ID 3796)

      11:30 - 13:00  |  Presenting Author(s): Gilberto Castro

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA19.05 - Improving Lung Cancer Outcomes and Quality in the US Community Setting with the Creation of Lung Cancer Centers of Excellence Program (Now Available) (ID 1939)

      11:30 - 13:00  |  Presenting Author(s): Amy Moore  |  Author(s): Luis Raez, Ray Osarogiagbon, Leah Fine

      • Abstract
      • Presentation
      • Slides

      Background

      The Addario Lung Cancer Foundation community hospital Centers of Excellence (COE) Program encourages community cancer centers in the US to implement ‘best practices’ across the lung cancer care continuum, including provision of coordinated, multidisciplinary care. By comparing performance metrics within and outside the network of COEs, the program seeks to ensure that lung cancer patients (pts) receive the highest quality of care in their local area whilst also enabling COE hospitals to gain insights that facilitate the rapid implementation of quality improvement cycles.

      Method

      The Impact Study was launched to conduct a comprehensive comparative analysis of COE member and non-member institutions across numerous quantitative and qualitative metrics from within the lung cancer care continuum. The 2018 analysis included 17 COE sites and 19 non-COE community hospitals representing approximately 5,000 pts in each cohort. The COE Impact study captured pts’ demographic and clinical information as well as performance metrics from early stage screening through late stage diagnosis and all aspects of pts’ care.

      Result

      Variable

      COE

      Non-COE

      P value

      # Cancer centers/hospitals

      17

      19

      Answers collected by nurse navigator

      41%

      100%

      <0.001

      Average # of hospital beds

      565

      342

      0.104

      Average # of lung cancer pts/institution

      497

      470

      0.968

      Lung cancer screening program

      94%

      42%

      0.001

      Endoscopic Bronchoscopy Ultrasound (EBUS)

      23%

      16%

      0.323

      Screening of pts for clinical trials

      81%

      35%

      <0.001

      Race: Caucasians

      81%

      37%

      <0.001

      Pathologist in tumor boards

      100%

      67%

      0.012

      ER visits the first 4 months of therapy

      14%

      32%

      0.022

      Molecular testing of pts with metastatic disease

      81%

      48%

      0.001

      Next generation sequencing

      58%

      22%

      0.009

      Conclusion

      Improved structure and processes of care delivery at COE hospitals may translate into improved quality of care, outcomes, and patient experiences. The Lung Cancer COE program, now including 38 community cancer centers encompassing 12,000 lung cancer patients, plans to conduct this study annually with prospective, longitudinal data collection for future trend analyses as a means of facilitating continuous quality improvement in community-level lung cancer care.

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      MA19.06 - Successful Development of Realtime Automatically Updated Data Warehouse in Health Care (ROOT-S) (Now Available) (ID 584)

      11:30 - 13:00  |  Presenting Author(s): Hyun Ae Jung  |  Author(s): Sunyoung Hong, JuYoun Park, MI RA Park, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park

      • Abstract
      • Presentation
      • Slides

      Background

      Clinical information is often not recorded in an organized way, and converting it to a structured format can be a time-consuming task that may not successfully capture all facets of the information. Clinical Data Warehouse is a real time database that consolidates data from a variety of clinical sources to present a unified view. However, the clinical data extracted from the CDW have not only structured data (SD) but also natural language (NP) generated during clinical practice, and there is a limitation that it is difficult to apply to clinical trials because it is not structured and formatted to find key-point contents. This study aims at developing a systematic and comprehensive cohort through an automatic real-time update system called CDW.

      Method

      The aim of this study was to evaluate clinical data of non-small cell lung cancer, small cell lung cancer, head and neck cancer, thymic cancer, and mesothelioma. In this study, we developed a unique algorithm that is optimized for each disease category using comprehensive natural language processing (NLP) systems and structured information from unstructured free text and structured data capture (SDC). We developed an algorithm using clinical information of patients diagnosed and treated during the past 10 years and designated validation sets of patients diagnosed and treated in 2018 for validation that these algorithms work automatically.

      Result

      We collected clinical data of 23,735 NSCLC patients, 2,077 SCLC patients, 5,032 head and neck cancer patients, 3,948 esophageal cancer patients, 747 thymic cancer patients and 138 mesothelioma patients diagnosed at Samsung Medical Center. We could demonstrate using the validation set that the program accurately extracts the data needed for the cohort of each cancer. The program is updated automatically every 24 hours, the source of each data is indicated separately, and the data that need to be integrated is transformed and systematically organized. The biggest advantage is that the scattered information is systematically integrated and automatically buildup to match the patient's cohort, so you can capture most updated survival or test results or treatment outcomes almost in real time. Data on the development of this program will be presented.

      Conclusion

      This study is the first study that successfully developed and validated real-time updated cohort using CDW. This study suggests a blueprint for constructing a big data -based cohort for clinical research and is expected to be a landmark trial. The detailed analysis of each cancer through the development of the program will be presented.

      wclc.png

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      MA19.07 - Testing an Optimal Care Coordination Model (OCCM) for Lung Cancer in a Multi-Site Study (Now Available) (ID 2659)

      11:30 - 13:00  |  Presenting Author(s): Matthew P Smeltzer  |  Author(s): Thomas Asfeldt, Nicholas Faris, Amanda Kramar, Christine Amorosi, Vikki G Nolan, Meredith Ray, Monique Dawkins, Mary Catherine Nalan, Walter Stevens, Lorna Lucas, Randall A Oyer, Christopher S Lathan, Ray Osarogiagbon

      • Abstract
      • Presentation
      • Slides

      Background

      Medicaid-insured lung cancer patients have worse outcomes than others. To address barriers to optimal care in the US Medicaid population, the Association of Community Cancer Centers (ACCC) created and tested the OCCM.

      Method

      The OCCM included 13 assessment areas: Patient Access to Care, Prospective Multidisciplinary Case Planning, Financial/Transportation/Housing, Care Coordination, Electronic Health Records, Survivorship Care, Supportive Care, Tobacco Cessation, and Clinical Trials. Each area had 5 defined levels of quality care delivery. With support from the Bristol-Myers Squibb Foundation, we pilot tested the model in 7 US cancer centers. Sites selected 1-2 assessment areas to evaluate using OCCM, developing relevant data benchmarks. Sites enrolled patients on Medicaid and Non-Medicaid controls. The ACCC team worked with each site to develop quality improvement projects with bi-weekly conference calls and 2 on-site visits. Data were collected and analyzed at a centralized data coordinating center. Statistical analyses were performed with Kruskal Wallis and chi-squared tests.

      Result

      Seven sites spanning 3,081 miles evaluated 10 of the 13 OCCM areas. Total enrollment was 927 patients (257 Medicaid/ 670 Non-Medicaid). The Medicaid population had an average age of 62 years, ranging from 58-68 across sites. The clinical stage distribution was 40% stage I/II and 60% stage III/IV. Medicaid patients were 47% adenocarcinoma histology, 29% squamous cell, 14% small cell, and 10% other. Sites differed by patient age (p=0.0041), race (p<0.0001), and smoking status (p=0.028).

      Three sites evaluated models for prospective multidisciplinary case planning for Medicaid patients including: bi-weekly tumor board (BTB), virtual tumor board (VTB), and multidisciplinary team huddle (MTH). VTB and MTH allowed for presentation of higher percentages of eligible patients (BTB: 23%, VTB: 100%, MTH: 100%, p<0.0001). BTB and MTH discussed all cases prospectively, while VTB achieved 80%. Median days from diagnosis to presentation were 18 (BTB), 14 (VTB), and 9 (MTH, p=0.14).

      Two sites evaluated smoking cessation programs. One, using trained cessation counselors, had 62% (18/29) active smokers, of whom 56% (10/18) expressed readiness to quit. Another site, using the freedom from smoking initiative, had 50% (11/22) active smokers and 55% (6/11) readiness to quit. 83% of those who started the cessation program quit smoking.

      Patient access to care was evaluated with timeliness of care metrics at two sites: one found 13 days (median) from lesion discovery to diagnosis and 21 days from diagnosis to treatment in Medicaid patients, which did not differ from Non-Medicaid controls (p=0.96 and 0.38). 94% met the site goal of treatment initiation within 45 days. Another site found 16 days (median) from discovery to diagnosis and 27 days from diagnosis to treatment (did not differ from Non-Medicaid controls, p=0.68 and 0.83).

      Conclusion

      Sites successfully used the OCCM to identify areas to improve and developed meaningful data benchmarks. The OCCM is a valuable tool for cancer centers to identify specific areas to target to improve lung cancer care delivery.

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      MA19.08 - Discussant - MA19.05, MA19.06, MA19.07 (Now Available) (ID 3797)

      11:30 - 13:00  |  Presenting Author(s): Riyaz Shah

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA19.09 - Assessing Clinical Frailty in Advanced Lung Cancer Patients - An Opportunity to Improve Patient Outcomes? (Now Available) (ID 2363)

      11:30 - 13:00  |  Presenting Author(s): Fabio Gomes  |  Author(s): Katie Baker, Jennifer Woods, Jonathan Bruce, Marie Eaton, Phill Higham, Laura Cove-Smith, Alex Garbett, Anthea Cree, Cassandra Ng, Fiona Blackhall, Neil Bayman

      • Abstract
      • Presentation
      • Slides

      Background

      The median age of non-small cell lung cancer (NSCLC) diagnosis in England is 73 years. At that age, 40% of the general population has some degree of clinical frailty which may impact survival, quality of life, anti-cancer treatment tolerability and access to clinical trials. However, clinical frailty is often not addressed or managed at the time of anti-cancer treatments. This project was designed to integrate frailty assessments and build frailty pathways within an advanced cancer care setting in order to better support patients and improve outcomes.

      Method

      This quality improvement project that used Plan-Do-Study-Act (PDSA) methodology. Phase one of the project focused on establishing a multidisciplinary team to integrate a frailty screening tool, the Rockwood Clinical Frailty Scale (CFS), into standard clinical practice. The primary aim was to implement and screen ≥80% of all new lung cancer patients at a high-volume tertiary cancer centre. The secondary aim was to explore the correlation of CFS with age, performance status (PS), treatment selection and systemic anti-cancer treatment (SACT) tolerability. Specialised training was provided to the clinical team and the CFS was integrated from 26/11/2018 on an electronic form routinely completed by clinicians. A digital dashboard was set-up to monitor real-time data and the frail group was defined as CFS score >3. Data cut-off for this analysis was 29-03-2019.

      Result

      335 lung cancer patients were screened using CSF by a team of 20 clinicians with a compliance rate of 89%. There was a strong correlation between PS and CFS (r= 0.77, p<0.01). The distribution of both CFS and PS correlated with ageing (r= 0.2 and r= 0.17, respectively; p<0.01). Patients ≥70 years were more likely to be frail (56% vs 40%; OR 1.4, 95%CI 1.2-1.7; p<0.01). Frailty reduced the likelihood of receiving any anti-cancer treatment by 20%. Amongst those who started SACT, patients classed as frail were less likely to go beyond the first cycle of treatment (64% vs 91%; OR 0.7, 95%CI 0.5-0.9; p<0.01).

      Conclusion

      CFS screening is feasible within a busy clinical practice when incorporated as a digital tool. CFS helps to identify patients who may potentially benefit from specialised frailty assessment and management. This could ultimately be used to better inform on treatment selection, and support requirements during treatment, to improve outcomes for patients in the future.

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      MA19.10 - Estimation of Quality-Adjusted Life Expectancy for Stage and Systemic Treatment in Non-Small Cell Lung Cancer in Rajavithi Hospital, Thailand (Now Available) (ID 585)

      11:30 - 13:00  |  Presenting Author(s): Sunatee Sa-nguansai  |  Author(s): Oranuch Kamnerdtong, Kunlatida Maneenil

      • Abstract
      • Presentation
      • Slides

      Background

      Owing to the high mortality and rapidly growing costs related to lung cancer, it is worth examining the health benefits of treatment in this cancer. This study attempts to quantify the real-life practice quality-adjusted life expectancy (QALE) of non-small cell lung cancer (NSCLC) patients with different stages and systemic treatments.

      Method

      This cross-sectional study was conducted by reviewing and collected quality of life (QoL) data from 256 eligible all stages NSCLC patients treated at Rajavithi hospital from May 1st to October 31st, 2018. The iSQoL statistical package was used to evaluate QALE compared with the reference Thai population in different stage of disease. For advanced stage, QALE was compared among treatment groups (chemotherapy and Epidermal growth factor receptor tyrosine kinase inhibitors; EGFR TKIs)

      Result

      The QALE for patients with early and advanced stage NSCLC were 4.49 ± 0.43 and 1.03 ± 0.08 QALY, with the corresponding loss-of-QALE were 14.02 ± 0.44 and 20.13 ± 0.09 QALY, respectively. The difference of QALE between early and advanced stage was 3.46 QALY (p<0.001).

      Based on systemic treatment in advanced stage, The QALE for patients who received chemotherapy and TKIs were 1.05 ± 0.08 and 2.19 ±0.28 QALY, with the corresponding loss-of-QALE were 20.48 ± 0.09 and 19.12 ± 0.29 QALY, respectively. The difference of QALE between treatment with chemotherapy and TKIs was 1.17 QALY (Figure, p=0.001).

      ca-lung_qale-results.dpi_300.jpg

      Conclusion

      The utility gained from treatment with TKIs in advanced NSCLC is substantial. Early stage had better QALE than advanced stage NSCLC patients.Future study will assess the cost-effectiveness of targeted therapy in Thailand.

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      MA19.11 - Population Based Analysis of End of Life Treatment Patterns in Thoracic Malignancies (Now Available) (ID 1154)

      11:30 - 13:00  |  Presenting Author(s): Graham Pitson  |  Author(s): Leigh Matheson, Peter Eastman, Margaret Rogers

      • Abstract
      • Presentation
      • Slides

      Background

      Active cancer treatment within the last month of life is unlikely to meaningfully benefit patients and ASCO guidelines recommend chemotherapy treatment rates be kept as low as possible. Patients with thoracic malignancies often have rapidly progressive disease and significant symptom burden and there is little population based data on patterns of care near end of life.

      Method

      The Evaluation of Cancer Outcomes Registry records clinical information on all newly diagnosed cancer patients within a region of Victoria, Australia. Core diagnostic, demographic, treatment and outcome details were extracted for all patients diagnosed from 2009-2015 with death data through to end of 2016. Patients with thoracic malignancies were further analysed for treatment patterns at end of life. Details of palliative radiotherapy (pRT) and active systemic treatment (AST – intravenous chemotherapy, targeted therapy and/or immunotherapy) were recorded for all patients. Details on oral chemotherapy and stereotactic radiotherapy were not recorded.

      Result

      The total cohort during the study period comprised 12760 patients. Of these, 1328 patients were recorded with a thoracic malignancy (TM) (non small cell lung cancer 82%, small cell lung cancer 10%, mesothelioma 7%) and 1118 of these died. At total of 39% (518) and 41% (538) of the 1328 TM patients received AST and pRT respectively at some point. Of these patients 15% (77/518) received AST and 23% (121/538) pRT within 30 days of death, compared with 7.0% (242/3436) (p<0.01) and 19% (178/965) (p=0.06) respectively for the total cohort excluding TM patients. Patients receiving AST within 30 days of death had a similar median age (66.7 vs. 67.8 years, p=NS) but shorter median survival from diagnosis (146 v. 281 days, p<0.01) than patients receiving final AST within 1-6 months. The frequency of some change in AST agents within the prior month was highest in the last month of life. The most common AST agents used in the final month of life were pemetrexed, etoposide and gemcitabine and most patients were treated with single agents. More pRT treatments were started in the last 30 days of life than in any other month near end of life. Patients receiving pRT in the last month of life also had a shorter median survival from diagnosis (113 v. 215 days, p<0.01) and the sites most commonly treated with pRT in the last month of life were chest/lung, spine and whole brain.

      Conclusion

      Patients with thoracic malignancies have higher rates of AST treatment within the last 30 days of life than other patients with cancer in the same geographic region. Those treated within 30 days of death also have shorter median overall survival and higher frequencies of changing AST agents or starting pRT, possibly suggesting aggressive, symptomatic and poorly responding disease.

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      MA19.12 - Discussant - MA19.09, MA19.10, MA19.11 (Now Available) (ID 3798)

      11:30 - 13:00  |  Presenting Author(s): Flavia Amaral Duarte

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS17 - Pathology of the Future (ID 80)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Pathology
    • Presentations: 5
    • Now Available
    • +

      MS17.01 - Role of Liquid Biopsy in the Pathology Diagnosis Workflow (Including DNA, RNA Ad Exosomes) (Now Available) (ID 3537)

      14:30 - 16:00  |  Presenting Author(s): Fernando Lopez-Rios

      • Abstract
      • Presentation
      • Slides

      Abstract

      Although liquid biopsy approaches have considerable potential to improve patient care, integrating them into the pathology diagnosis workflow could be a challenge. In the presentation I will address the most frequent barriers for inmediate implementation of the recommendations released by the IASLC and other academic groups. Briefly, plasma is preferred over serum for ctDNA and ctRNA extraction. The choice of analytical methodology should balance availability, cost, turnaround time, sensitivity and specificity. Recent cross-platform comparisons will be presented because technical factors could explain both discordance between assays and with tissue-based genotyping. The results of liquid biopsies should follow the standards of molecular pathology reporting. Taking into consideration that the number of pathology and biomarker reports per patient will be growing over the next few years, it is important to integrate all of them before discussion of treatment options take place at the molecular tumour board. The recent tier classifications of molecular alterations released by professional organisations could help implement this strategy.

      References

      Abbosh C, Birkbak NJ, Swanton C. Early stage NSCLC - challenges to implementing ctDNA-based screening and MRD detection. Nat Rev Clin Oncol 2018; 15: 577-586.

      Aggarwal C, Thompson JC, Black TA, et al. Clinical Implications of Plasma-Based Genotyping With the Delivery of Personalized Therapy in Metastatic Non-Small Cell Lung Cancer. JAMA Oncol 2018. doi: 10.1001/jamaoncol.2018.4305.

      Laufer-Geva S, Rozenblum AB, Twito T, et al. The Clinical Impact of Comprehensive Genomic Testing of Circulating Cell-Free DNA in Advanced Lung Cancer. J Thorac Oncol 2018; 13: 1705-1716.

      Leighl NB, Page RD, Raymond VM, et al. Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non-small Cell Lung Cancer. Clin Cancer Res 2019. doi: 10.1158/1078-0432.

      Li BT, Janku F, Jung B, et al. Ultra-deep next-generation sequencing of plasma cell-free DNA in patients with advanced lung cancers: results from the Actionable Genome Consortium. Ann Oncol 2019; 30: 597-603.

      Rolfo C, Mack PC, Scagliotti GV, et al. Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC. J Thorac Oncol 2018; 13: 1248-1268.

      Siravegna G, Marsoni S, Siena S, Bardelli A. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol 2017; 14: 531-548.

      Torga G, Pienta KJ. Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests. JAMA Oncol 2018; 4: 868-870.

      Sabari JK, Offin M, Stephens D, et al. A Prospective Study of Circulating Tumor DNA to Guide Matched Targeted Therapy in Lung Cancers. J Natl Cancer Inst 2018. doi: 10.1093/jnci/djy156.

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      MS17.02 - Major Pathological Evaluation in Neoadjuvant Immunotherapy (Now Available) (ID 3538)

      14:30 - 16:00  |  Presenting Author(s): Jose Ramirez

      • Abstract
      • Presentation
      • Slides

      Abstract

      The pathologists play different roles in the care of cancer patients. The main part of this activity is to make the diagnosis of the tumor type, followed by the support to the clinicians in the staging of the patient.

      In the group of patients that receive Chemotherapy (CT) and / or Radiotherapy (RT) before surgery, the pathologist has to evaluate the results of these treatments by evaluating the tumor bed and the response of the lung.

      There is a lot of experience in the literature referred to the different types of pathological response to lung cancer treatment after the use of either CT or RT. There are guidelines for the pathologists in order to give an objective evaluation of the treatment results (1). All of them ask the pathologists to evaluate the percentage of viable tumor cells, necrosis and stromal reaction. We can also find different attempts to find molecular markers useful for predicting survival after these traditional treatments (2).

      In order to have an objective evaluation of the lung cancer patients after CT in 2014 emerged the concept of Major Pathological Response (MPR) as a possible predictor of overall survival (3). This term was applied to describe those patients with a viability of 10% of the tumor cells after neoadjuvant CT. In this report, they propose the MPR as a surrogate endpoint. Since that, the concept of MPR has been used in different reports and assays, becoming a usual parameter for patients with lung resections after receiving chemotherapy.

      The percentage of viable cells became an important data that has to be evaluated with accuracy in order to avoid subjective results. One of the best ways is to use any of the commercial systems to make measurements on the slides. In our department, we use digital slides to get objective and reproducible data for this type of evaluation.

      The recent implementation of immunotherapy (IT) for NSCLC that is being applied to an increasing number of patients all over the world makes it necessary to study deeply its morphological effects over de tumor in lung specimens. As most of the patients will never go to the operating room, it becomes important to be aware of the limited knowledge that we have so far.

      There are some reports comparing the effects of the traditional chemotherapy with immunotherapy. One of these studies shows that the pathologist should look for the same features that are routinely evaluated in the cases after CT (4). The pathologist might evaluate the classic features (viable cells, necrosis and stromal reaction) and other characteristics such as macrophages, cholesterol clefts, lymphoid aggregates, giant cells and neovascularization. In this review, they did not find important differences between the type of morphological changes in both types of treatment, so they propose to use the same parameters in CT and in IT

      A recent report proposes the concept of Immuno related Pathological Response Criteria (irPRC) (5). They pay attention to the Immune activation with dense lymphoid infiltrate, macrophages and tertiary lymphoid structures as the main characteristics. They also evaluate the massive tumor cell death with destructive features such as cholesterol clefts and those indicative of tissue repair with neovascularization and fibrosis.

      Last year a review collected different assays done with neoadjuvant IT in patients with resectable lung cancer (6). There is no enough experience in these special groups of patients, as today the IT is given only to advanced lung carcinoma patients.

      Conclusions: At the present time there are no guidelines for the evaluation of lung tissues after IT. The pathologists have to be aware of the effects of these new biological treatments for lung cancer patients, in order to give as much information as possible in the short number of cases that are seen in the real clinical situation. The previous experience in resected lungs after neoadjuvant therapy is not enough to evaluate the cases after IT. The data obtained from these lung specimens have to give more information in order to improve the knowledge of the effects of these new therapies.

      References:

      1. Pataer A, Kalhor N, Correa AM et al. Histopathologic Response Criteria Predict survival of Patients with Resected Lung Cancer After Neoadjuvant Chemotherapy. J Thorac Oncol. 2012;7: 825–832.

      2. Pataer A, Shao R, Correa AM et al. Major pathologic response and RAD51 predict survival in lung cancer patients receiving neoadjuvant chemotherapy. Cancer Medicine 2018; 7(6):2405–2414.

      3. Hellman MD, Chaft JE, William NW et al. Pathologic response after neoadjuvant chemotherapy in resectable non-small cell lung cancers: proposal for the use of “major pathologic response” as a surrogate endpoint. Lancet Oncol. 2014 January ; 15(1): e42–e50.

      4. Weissferdt A, Sepesi B, Pataer A et al. Pathologic assessment following neoadjuvant immunotherapy or chemotherapy demonstrates similar patterns in non-small cell lung cancer (NSCLC). Ann Oncol 2018: 29(S8).

      5. Cottrell TR, Thompson ED, Forde PM et al. Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC). Annals of Oncology 2018; 29: 1853–1860.

      6. Owen D, Chaft JE. Immunotherapy in surgically resectable non-small cell lung cancer. J Thorac Dis 2018; 10(S3): 404-411.

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      MS17.03 - Quantitative Image Analysis, Image-Based Profiling Including 3D Digital Printing and AI (Now Available) (ID 3539)

      14:30 - 16:00  |  Presenting Author(s): Sylvie Lantuejoul

      • Abstract
      • Presentation
      • Slides

      Abstract

      Digital pathology and AI

      Digital pathology refers to the use of computer stations to analyze images of whole slides scanned at high resolution for teaching or research purposes; these images are analyzed by algorithms that allow standardization and reproducibility of the analyses. Recently, artificial intelligence has been used to build even more powerful algorithms. The idea is not to reproduce the visual analysis of pathologists but to improve it and to identify new predictive or prognostic morphological characteristics or to couple them with genomic analysis to better stratify tumours (1,2).

      Technical considerations

      The digital workflow requires specific equipement (slide scanner, image storage and digital pathology workstation). Image analysis needs well-standardized pre-analytical conditions, especially if IHC stainings are analyzed, where colour variations and absence of background noise must be controlled during different validation steps. Some methods exist to correct artifacts such as section fold, fuzzy area. SOPs (standardised operating procedures) and regulations must also be respected concerning the scanning platforms, which must be CE IVD or FDA approved, the construction of databases, anonymisation, sending and image analysis. Algorithms used for analyses perform different operations on digital images: quality improvement, filtering, recording and segmentation and they must also be validated by correlation measuring the reproducibility between pathologists and algorithms. In addition, The large amount of data requires significant computer processing with accelerated calculations by CNNs (Convolutional Neural Networks) and large image storage capacity.

      Applications :

      Quantitative analyses and Image-Based Profiling: most image analyses proposed by commercial softwares (VisionPharm, Definiens Tissue Studio, Indica Labs HALO), or open source softwares such as QuPath Open Source Software for Quantitative pathology or ImageJ, are area or cells-based measurements. Area- based measurements include quantification of stained zones (using IHC stain for example) ; cell_based measurements require segmentation steps to delineate tissue compartments, to distinguish for example tumor from begnin regions or to identify subcellular structures (such as nuclei). Some modules or algorithms are CE-IVD or FDA approved such as those used to quantify the expression of ER, PR, Her2 and KI67 in breast cancers. Other algorithms enable the estimation of the percentage of tumour cells before molecular analysis for the detection of genes mutations (Tissue Mark, Philipps pathology). They can also enable to localise and quantify the immune infiltrate ( CD3 and CD8+ T Cells) within the tumor stroma (Immunoscore , Laboratory of Integrative cancer Immunology INSERM Paris). Some machine Learning methods can also automatically differentiate tumor cells from stroma cells and inflammatory cells or identify lymph node metastases. In thoracic pathology, automated whole slide scoring of PDL1 has been proposed in NSCLC with an excellent agreement for tumor cells scoring and a good concordance for immune cells (3). Image based analysis has been used for quantification of immune checkpoints molecules co expression in NSCLC (4). Several studies have showed the interest of automatic image-based analysis for the optimization of histological or cytological classification of lung cancer and prediction of prognosis (5,6). Deep learning technology has been used to classify lung tumour subtypes from the virtual slides available in the TCGA (7), or to classifiy adenocarcinoma according to the predominant pattern with a kappa score of 0.525 and an agreement of 66.6% with three pathologists (8). Deep learning was also proposed for genomic profiling of tumours, with a prediction of STK11, EGFR, FAT1, SETBP1, KRAS and TP53 mutations from pathology images showing an AUCs ranging from 0.733 to 0.856 (9,10).

      Applications: 3D dimensions modeling and digital Printing

      Three-dimensional (3D) photogrammetry is a method of image-based modeling in which data points in digital images, taken from offset viewpoints, are analyzed to generate a 3D model. This technique can be used to generate 3D representation sof surgical specimens, for routine gross examination, in multidisciplinary meetings to improve clinicopathologic correlation between surgeon and pathologists, and for education purposes via 3D printing specimen models (11).

      References

      1. Niazi MKK, Parwani AV, Gurcan MN. Digital pathology and artificial intelligence. Lancet Oncol. mai 2019;20(5):e253‑61.

      2. Aeffner F, Zarella M, Buchbinder N, Bui M, Goodman M, Hartman D, et al. Introduction to digital image analysis in whole-slide imaging: A white paper from the digital pathology association. J Pathol Inform. 2019;10(1):9.

      3. Taylor CR, Jadhav AP, Gholap A, Kamble G, Huang J, Gown A, et al. A Multi-Institutional Study to Evaluate Automated Whole Slide Scoring of Immunohistochemistry for Assessment of Programmed Death-Ligand 1 (PD-L1) Expression in Non–Small Cell Lung Cancer: Appl Immunohistochem Mol Morphol. avr 2019;27(4):263‑9.

      4. Parra ER, Villalobos P, Zhang J, Behrens C, Mino B, Swisher S, et al. Immunohistochemical and Image Analysis-Based Study Shows That Several Immune Checkpoints are Co-expressed in Non–Small Cell Lung Carcinoma Tumors. J Thorac Oncol. juin 2018;13(6):779‑91.

      5. Yu K-H, Zhang C, Berry GJ, Altman RB, Ré C, Rubin DL, et al. Predicting non-small cell lung cancer prognosis by fully automated microscopic pathology image features. Nat Commun [Internet]. nov 2016 [cité 10 juin 2019];7(1). Disponible sur: http://www.nature.com/articles/ncomms12474

      6. Luo X, Zang X, Yang L, Huang J, Liang F, Rodriguez-Canales J, et al. Comprehensive Computational Pathological Image Analysis Predicts Lung Cancer Prognosis. J Thorac Oncol. mars 2017;12(3):501‑9.

      7. Khosravi P, Kazemi E, Imielinski M, Elemento O, Hajirasouliha I. Deep Convolutional Neural Networks Enable Discrimination of Heterogeneous Digital Pathology Images. EBioMedicine. janv 2018;27:317‑28.

      8. Wei JW, Tafe LJ, Linnik YA, Vaickus LJ, Tomita N, Hassanpour S. Pathologist-level classification of histologic patterns on resected lung adenocarcinoma slides with deep neural networks. Sci Rep [Internet]. déc 2019 [cité 10 juin 2019];9(1). Disponible sur: http://www.nature.com/articles/s41598-019-40041-7

      9. Coudray N, Ocampo PS, Sakellaropoulos T, Narula N, Snuderl M, Fenyö D, et al. Classification and mutation prediction from non–small cell lung cancer histopathology images using deep learning. Nat Med. oct 2018;24(10):1559‑67.

      10. Patil PD, Hobbs B, Pennell NA. The promise and challenges of deep learning models for automated histopathologic classification and mutation prediction in lung cancer. J Thorac Dis. févr 2019;11(2):369‑72.

      11. Turchini J, Buckland ME, Gill AJ, Battye S. Three-Dimensional Pathology Specimen Modeling Using “Structure-From-Motion” Photogrammetry: A Powerful New Tool for Surgical Pathology. Arch Pathol Lab Med. nov 2018;142(11):1415‑20.

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      MS17.04 - Multiplex Immunohistochemistry (Now Available) (ID 3540)

      14:30 - 16:00  |  Presenting Author(s): Ignacio Wistuba  |  Author(s): Edwin Parra, Alejandro Francisco Cruz

      • Abstract
      • Presentation
      • Slides

      Abstract

      Multiplexed imaging platforms to simultaneously detect multiple epitopes in the same tissue section emerged in the last years as very powerful tools to study tumor immune contexture. These revolutionary technologies are providing a deep methodology for tumor evaluation in formalin-fixed and paraffin-embedded (FFPE) to improve the understanding of tumor microenvironment, new targets for treatment, prognostic and predictive biomarkers, and translational studies. Multiplexed imaging platforms allow the identification of several antigens simultaneously from a single tissue section, core needle biopsies, and tissue microarrays. In recent years, multiplexed immunohistochemistry, immunofluorescence, mass spectometry and other imaging modalities have improved the abilities to characterize the different types of cell populations in malignant and non-malignant tissues, and their spatial distribution in relationship to clinical outcomes. Multiplexed technologies associated with digital image analysis software offer a high-quality throughput assay to study cancer specimens, inc;luding lung cancer, at multiple timepoints before, during and after treatment. The aim of this resentation is to provide a review of multiplexed tissue imaging applied to lung cancer focusing in the use of multiplex immunofluorescence with tyramine signal amplification staining for lung cancer immune profiling and translational research.

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      MS17.05 - Controversies in Pathologic Staging (Now Available) (ID 3541)

      14:30 - 16:00  |  Presenting Author(s): Masaya Yotsukura

      • Abstract
      • Presentation
      • Slides

      Abstract

      The 8th edition of the TNM classification system was implemented in January 2017, except in the United States, where it was delayed until January 2018. The 8th edition was proposed by the Staging and Prognostic Factors Committee (SPFC) of the International Association for the Study of Lung Cancer (IASLC), and accepted by the Union for International Cancer Control and American Joint Committee on Cancer. The SPFC’s proposed changes from the 7th to 8th edition were essentially based on prognostic data from the IASLC database, which included 70,697 evaluable patients with non-small cell lung cancer and 6,189 patients with small cell lung cancer.

      Although the TNM system is the result of a scientific analysis of the anatomical extent of the tumor, some of the classification points are still controversial.

      1. Ground glass opacity

      Regarding the T descriptor, the main issue revolves around ground glass opacity (GGO)-related matters. The invasive area can pathologically be well-defined under microscopic evaluation, sometimes in combination with Elastica van Gieson stain. However, the difference between pathological and clinical staging has been a problem. Clinical staging depends on how to measure the GGO component by computed tomography (CT), which has not been defined very well.

      Another point to be addressed related to GGO is the separation of GGO-containing tumors from solid tumors. For example, if a tumor has a solid component of 1.5 cm without any surrounding GGO component, it will be defined as clinical T1b, whereas if a tumor has a solid component of 1.5 cm along with 1.0 cm of surrounding GGO component (total tumor diameter of 1.5 + 1.0 = 2.5 cm), it would also be defined as clinical T1b. However, the malignant capacity of a purely solid tumor is reported to be worse than that of GGO-containing tumors. Thus, from a prognostic viewpoint, it might be better to consider these two types of tumors separately.

      2. Visceral pleural invasion

      Another controversy regarding the T descriptor in pathologic staging involves visceral pleural invasion (VPI). First, data should be collected using a standardized definition. A standardized definition of VPI was incorporated into the 7th edition of TNM and maintained in the 8th edition. PL1, 2, and 3 are pathologically evaluated based on tumor invasion to the elastic layer, pleural surface, and parietal pleura. In case of doubt regarding VPI, the use of elastic stains is recommended. The collection of data using this definition and the use of elastic stains are important for accurate evaluation in future revisions.

      Second, the difficulty of clinical evaluation of VPI might be a problem. In the current staging system, clinicians have to speculate on the presence of VPI, based solely on the findings of CT imaging. A clear imaging-based definition of VPI might be beneficial.

      Third, in the current staging system, interlobar PL3 is classified as T2a. Since little is known about the prognosis of this interlobar PL3, data should be collected for use in a future revision of the TNM classification.

      3. Nodal evaluation

      Regarding the N descriptor, as previously reported in the literature, tumors with nodal metastases to multiple lymph node stations have a worse prognosis than those with single-station metastasis. Counting the number of positive nodes instead of the number of stations might be considered as well, especially from the viewpoint of emphasizing prognostic impact. However, a standardized method for pathological nodal evaluation has been lacking. How should pathologic slides be made for an accurate evaluation of nodal status? The number of nodes that are incorporated on the same slide, and the number and depth of sections to be evaluated per slide, are not well defined. It is also not clear how to handle an intraoperatively separated node, when counting the number of metastatic nodes. It would be desirable to have some consensus about the evaluation methodology to achieve a more accurate prognostic analysis.

      4. Molecular information

      There are some disagreements about how to use molecular information, in relation to TNM classification. Over the past decades, dramatic advances have been made in the fields of molecular diagnosis and precision medicine. The therapeutic strategy has been developed in detail depending on the molecular status, especially in advanced tumors. Accordingly, the prognosis has been influenced by the molecular status of the tumor, and thus molecular biomarkers have become some of the most important prognostic factors.

      In principle, the TNM classification describes the anatomic extent of tumors, arranged according to prognostic differences. From the perspective of the prognostic impact, molecular biomarkers might be as important as TNM staging. The combination of molecular status and TNM classification could be considered. However, based on the principal concept of the anatomic classification of the TNM system, it might be better to consider molecular factors as a different methodology of the classification system. Further discussions will be needed regarding the relationship between molecular markers and the anatomic TNM classification system.

      These issues reflect only some of the controversies surrounding the TNM staging system. Along with other issues, they are expected to be discussed in detail in the SPFC meetings for the forthcoming update of the TNM classification system.

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

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

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      Method

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

      Result

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

      Conclusion

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

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

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      Method

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

      mesomics_example.png

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

      Biorepositories: French MESOBANK; LungNEN Network

      Result

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

      Conclusion

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

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

      LFC and MF co-supervised this work

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

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      Method

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

      Result

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

      Conclusion

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

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

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

      • Abstract
      • Presentation
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      Abstract not provided

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

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      Method

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

      Result

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

      Conclusion

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

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

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      Method

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

      Result

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

      abtract_figure.jpg

      Conclusion

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

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

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

      • Abstract
      • Presentation
      • Slides

      Background

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

      Method

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

      Result

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

      Conclusion

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

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

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

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      Abstract not provided

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

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

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      Abstract not provided

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