Virtual Library

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    ES08 - Critical Concerns in Screening (ID 11)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Screening and Early Detection
    • Presentations: 7
    • Now Available
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      ES08.01 - Participation of the Target Population in Lung Cancer Screening (Now Available) (ID 3191)

      13:30 - 15:00  |  Presenting Author(s): Robin Cornelissen

      • Abstract
      • Presentation
      • Slides

      Abstract

      Participation of the Target Population in Lung Cancer Screening

      Robin Cornelissen, MD, PhD.

      Erasmus MC cancer institute

      Rotterdam, The Netherlands

      The two largest randomized controlled trials performed, The National Lung Screening Trial (NLST) and the Nederlands-Leuvens Longkanker ScreeningsONderzoek (NELSON) 1,2, proved that lung cancer screening using low dose CT scan, resulted in a significant reduction in lung cancer mortality. Following the results of the NLST trial, lung cancer screening was initiated in the United States and Canada. However, the uptake of lung cancer screening is poor, with only 3% to 4% of all eligible persons participating in the implemented screening program 3. Given more recent positive results of the NELSON study that were presented at the World Conference on Lung Cancer last year in Toronto, lung cancer screening is now considered in many countries across the globe. This low uptake of lung cancer screening is however a cause of concern.

      The reasons for the low participation rate are multi-factorial. The novelty of the lung cancer screening program is such a factor, resulting in lower uptake and might be the easiest one to address. The identification of the target population is more challenging due to the fact that the population to be screened is more defined than just age and sex. In addition, the lower socioeconomic status, which presents a significant portion of the to be screened population, and those who face barriers to care present a major challenge for implementing a successful screening program with a satisfactory uptake rate.

      Several strategies have been proposed to improve lung cancer screening uptake.

      In the socioeconomically deprived and heavy smoking communities, lung cancer is perceived as an uncontrollable disease 4, while cure rates in yearly screening programs lead to a cure in the majority of patients when lung cancer is detected 5,6. Therefore, public awareness of the curability of lung cancer when screening programs are implemented could boost the participation rate.

      Mobile lung cancer testing in supermarket car parks proved to be a successful pilot 7. This strategy avoids difficulties relating to the distance of travel, lack of public transport available, and the cost of either the journey itself or hospital parking. This strategy is currently explored in a larger cohort.

      One potential intervention that is being evaluated in clinical trials to improve the uptake and implementation of lung cancer screening is a patient navigator. A navigator can be a layperson, a medical assistant, or a nurse who will directly contact potential candidates for lung cancer screening for enrollment 3.

      The Accelerate, Coordinate, Evaluate (ACE) Programme, initiated in the United Kingdom, is an early diagnosis of cancer initiative focused on testing innovations that either identify individuals at high risk of cancer earlier 8. This program consists of several individual programs in different regions of the UK, of which The Liverpool Healthy Lung Programme is a participant. Among other goals, this initiative tries to improve uptake in the hard to reach cohort. They used general practitioners’ records to invite participants meeting the criteria to a ‘Lung Health Check’. This ‘Lung Health Check’ is a novel approach that may overcome or minimize the emotional barriers associate with the term “lung cancer screening”. This method resulted in an uptake level up to 40% 9. This initiative is an example that a higher uptake rate is indeed possible, even in the hard to reach population.

      At the IASLC World Conference on Lung Cancer in Barcelona, the issues regarding participation of the target population in lung cancer screening will be addressed and possible strategies will be discussed to overcome these challenges. As lung cancer screening is yet to be implemented in the majority of countries worldwide, we now have a unique opportunity to test and apply these strategies to successfully implement lung cancer screening in order to reduce lung cancer mortality.

      References

      1. The National Lung Screening Trial Research Team. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening. N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873

      2. Koning HD, Aalst CVD, Haaf KT, Oudkerk M. PL02.05 Effects of Volume CT Lung Cancer Screening: Mortality Results of the NELSON Randomised-Controlled Population Based Trial. J Thorac Oncol. 2018;13(10):S185. doi:10.1016/j.jtho.2018.08.012

      3. Triplette M, Thayer JH, Pipavath SN, Crothers K. Poor Uptake of Lung Cancer Screening: Opportunities for Improvement. J Am Coll Radiol JACR. 2019;16(4 Pt A):446-450. doi:10.1016/j.jacr.2018.12.018

      4. Quaife SL, Marlow LAV, McEwen A, Janes SM, Wardle J. Attitudes towards lung cancer screening in socioeconomically deprived and heavy smoking communities: informing screening communication. Health Expect Int J Public Particip Health Care Health Policy. 2017;20(4):563-573. doi:10.1111/hex.12481

      5. Survival of Patients with Stage I Lung Cancer Detected on CT Screening. N Engl J Med. 2006;355(17):1763-1771. doi:10.1056/NEJMoa060476

      6. Jonnalagadda S, Bergamo C, Lin JJ, et al. Beliefs and attitudes about lung cancer screening among smokers. Lung Cancer Amst Neth. 2012;77(3):526-531. doi:10.1016/j.lungcan.2012.05.095

      7. Wise J. Mobile lung cancer testing in supermarket car parks is to be expanded. BMJ. 2017;359:j5450. doi:10.1136/bmj.j5450

      8. Proactive Approaches to Individuals at High Risk of Lung Cancer; Accelerate, Coordinate, Evaluate (ACE) Programme. V1.1a.; 2018. https://www.cancerresearchuk.org/sites/default/files/ace_proactive_lung_report_with_economic_evaluation_final_version_1.1a.pdf. Accessed July 9, 2019.

      9. Ghimire B, Maroni R, Vulkan D, et al. Evaluation of a health service adopting proactive approach to reduce high risk of lung cancer: The Liverpool Healthy Lung Programme. Lung Cancer. 2019;134:66-71. doi:10.1016/j.lungcan.2019.05.026

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      ES08.02 - Nodule Growth Assessment (Now Available) (ID 3192)

      13:30 - 15:00  |  Presenting Author(s): Matthijs Oudkerk

      • Abstract
      • Presentation
      • Slides

      Abstract

      In the past 15 years several lung cancer screening trials have been performed in Europe1. Experts involved in these trials recently published a position paper in the Lancet Oncology2.

      Several conclusions and recommendations were drawn to enable a smooth and timely implementation of lung cancer screening in Europe. The experts made a strong and conditional argument on the methodology of lung cancer screening by low-dose computed tomography (CT). Quality control by regular CT phantom testing enabling standardization of CT data acquisition as well as benchmarking of CT software post processing and data analysis are mandatory. It is promoted to execute the CT screening Q/A control through national reference centers similar to the organizational structure of breast screening programs. In this manner the CT screening programs can be implemented in a responsible way avoiding the detrimental side effects of too high false positive CT outcome rates on the one hand and keeping up the most effective lung cancer early detection rate on the other hand.

      Apart from the acquisition protocol, the CT lung nodule analysis methodology is a critical factor for successful implementation of CT lung cancer screening 3. The diameter based NLST protocol used a 4 mm threshold (~ 30 mm3) as significant suspicion for malignancy. This approach yielded a positive rate of approximately 27% in the baseline round with a very low positive predictive value for lung cancer of 3.8%4. The NELSON study introduced a nodule volume analysis and a volume doubling time methodology with 2 CT measurements with a 3-month interval to calculate the volume doubling time as a biomarker for growth rate in indeterminate nodules. This approach resulted in a 2.6% positive rate in the baseline round with a high positive predictive value for lung cancer of approximately 36%, which is within the criteria needed for lung cancer screening implementation3. In the meantime, a ten times higher threshold of 8 mm (~300 mm3) was recommended to correct the high false positive rate of the NLST diameter methodology by several international societies5. After the publications of the NELSON data on increased lung cancer probability in baseline nodules at a threshold of 100 mm3the US guideline recommendations shifted from 300 mm3to 100 mm3(~ 6mm)6. A direct comparison of diameter and volume protocols cannot be performed through the assumption that all nodules are spherical. While this approach was chosen in a recent publication of the IELCAP investigators7, even the slightest correction for the assumption of sphericity reveals the substantial inferiority of diameter protocols. At follow-up CT examination at annual incident screen new nodules represent a high lung cancer probability at lower volumes than at baseline screen8,9. The upper threshold is at 200 mm3as indication for further clinical workup while new nodule at incident screen between the 30-200 mm3are classified as indeterminate and need a repeat scan at 3 months to calculate the volume doubling time. Lung cancer screening should be integrated in a defined national program and therefore opportunistic screening is not recommended. Calcium scoring as a screening methodis not yet established as a validated tool for early detection of coronary artery disease and the outcomes of the ROBINSCA study (risk or benefit in screening for cardiovascular disease www.robinsca.nl) are being awaited. Thus, so far, it is not indicated as a combined clinical routine screening methodology since ECG triggering is mandatory10. Non-triggered CT coronary artery calcium scoring will result in high false negative percentages. A lower CT radiation exposure threshold at a DLP of 50 mGy or 0.6 mSv is defined to assure the calibration of the quantitative imaging biomarkers for lung nodule detection. Lower radiation doses will induce false negative and unreliable growth rate results.

      References

      1 An update on the European Lung Cancer Screening Trials and Comparison of the Lung Cancer Screening Recommendations in Europe . Han et alJournal of Thoracic Imaging 2019; 34(1): 65–71.

      2 European position statement on lung cancer screening Oudkerk M Devaraj ALancet Oncology 2017 Dec;18(12):e754-e766.

      3 Management of lung nodules detected by volume CT scanning van Klaveren R Oudkerk M et al N Engl J Med. 2009 Dec 3;361(23):2221-9.

      4 Reduced lung-cancer mortality with low-dose computed tomographic screening Aberle DR et al N Engl J Med 2011 Aug 4;365(5):395-409.

      5 CT screening for lung cancer: alternative definitions of positive test result based on the national lung screening trial and international early lung cancer action program databases Yip R Henschke CI Radiology 2014 Nov;273(2):591-6.

      6 Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017 Mac Mahon H Radiology: Volume 284: Number 1—July 2017

      7 CT screening for lung cancer: comparison of three baseline screening protocol Henschke CI et al Eur Rad 2018 Dec 3

      8 Occurrence and lung cancer probability of new solid nodules at incidence screening with low-dose CT: analysis of data from the randomised, controlled NELSON trial Walter JE Heuvelmans MA et al Lancet Oncology 2016 Jul;17(7):907-916.

      9.Persisting new nodules in incidence rounds of the NELSON CT lungcancer screening study Walter JE Heuvelmnans MA Thorax. 2018 Dec 27

      10 Can nontriggered thoracic CT be used for coronary artery calcium scoring? A phantom study Xueqian Xie et al Medical Physics, Vol. 40, No. 8, August 2013

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      ES08.03 - The Magnitude of the Benefit (Now Available) (ID 3193)

      13:30 - 15:00  |  Presenting Author(s): David F. Yankelevitz

      • Abstract
      • Presentation
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      Abstract

      Why do people get screened? The obvious answer is so that cancer can be detected early with a view towards a higher chance of cure with early treatment. Therefore the critical questions that must be addressed relate to the risk of cancer over time and then, how likely cure will be when screen-detected versus clinically detected. Current approaches to evaluate screening have relied on randomized controlled trials with a view towards demonstrating that a benefit actually exists but are not designed to quantify the magnitude of the benefit. Current trial designs have limited rounds of screening and long-term follow up after screening has stopped. When these parameters change, the results of the trial will also change. Several approaches currently exist to estimate that critical parameter regarding the curability of screen detected lung cancer. This includes modeling approaches which can use data extracted from a variety of sources, they can also be measured directly as was done in the I-ELCAP study which measures directly the reduction in case fatality rate by using long term survival as a measure of cure, and an additional approach would be to screen continuously in the context of a clinical trial and measure the reduction in mortality after several years of screening where the benefit of screening reaches its maximum and becomes equivalent to the reduction in case fatality rate. When applied to lung cancer it can be shown that this benefit is far greater than the 20% so commonly reported and instead is in the 60=80% range for cure. Were this to be fully understood the entire rationale behind requiring shared decision making would be called into question as it was thought that the balance between benefits and harms was so tenuous that shared decision making was necessary.

      When considering whether a particular type of screening is to be considered beneficial there is also a tendency to compare different types of screening and seeing how many screens are necessary to save a life. Here to, this approach suffers from the same mistake. Each of those screening exams estimates this number based on their own randomized trial and each of these differ in terms of the design parameters, therefore the comparisons are essentially meaningless.

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      ES08.04 - Management Algorithms (Now Available) (ID 3194)

      13:30 - 15:00  |  Presenting Author(s): Claudia I Henschke  |  Author(s): Rowena Yip, Teng Ma, Samuel Miguel Aguayo, Javier Zulueta, David Yankelevitz

      • Abstract
      • Presentation
      • Slides

      Abstract

      Introduction

      Clinical management decisions arising from the first, baseline round of screening for lung cancer are most challenging, as nodules that are seen for the first time may have accumulated over a lifetime and almost all of them are of no clinical concern [1]. In contrast, new or changing findings on subsequent annual repeat low-dose CT scans (LDCTs) have much greater clinical significance.

      Efficiency is particularly important in the baseline round in order to minimize unnecessary harms caused by work-up within the 12 months after the baseline LDCT. Potential workup includes surgery, biopsies, and diagnostic tests requiring intravenous injection (e.g., PET scans, contrast CT). Biopsies and surgery have greater risks than LDCT, and thus the management protocols should aim to minimize these higher risk procedures as much as possible [2]. It is also important not to discourage participants undergoing the baseline round from future participation in annual rounds as these provide the real benefit of annual LDCT screening.

      Methods

      We compared the efficiency of three published baseline LDCT screening protocols [2], the International Early Lung Cancer Action Program (I-ELCAP) [3], American College of Radiology (ACR)-LungRADS [4], and the European Consortium protocols [5] for participants 50 years of age or older with at least 20 pack-years of smoking.

      The three protocols provide recommendations for immediate workup, 3-month and 6-month LDCT as shown in Table 1 [1]. The three protocols use the diameter of the entire solid and nonsolid non-calcified nodule (NCN), but differ for part-solid NCNs. For part-solid NCNs, I-ELCAP uses the diameter of the solid component [6], while ACR-LungRADS uses both the entire diameter of the part-solid NCN as well as the diameter of its solid component. The European Consortium protocol determines the volume of a solid NCN using their software [5], but also specifies the equivalent diameter values for the entire part-solid and nonsolid NCNs as volumetric measurements for these are problematic as was recognized [5]. Measurement error and rounding of measurements are also an important consideration [7,8].

      Efficiency was defined as an efficiency ratio (ER): the number of participants recommended for a particular workup divided by the resulting number of participants diagnosed with lung cancer [2]. An ER of 1 would mean that each recommended workup resulted in a diagnosis of lung cancer. An optimum ER has not been established for lung cancer, but it has been suggested that for lung surgery, a rate of 10% for non-malignant resections is desirable (9), this would be an ER of 1.1. In breast cancer biopsies which have a much lower risk than lung biopsies, it is recommended that 40% of biopsies should be negative to ensure sufficient workup to diagnose breast cancers early enough this would represent an ER of 1.4

      Results

      Table 1 provides the frequency of following the recommendations, the number of cancers diagnosed and the ER for each protocol. In summary, I-ELCAP recommendations had the lowest ER values for overall, immediate and delayed workup, and for potential biopsies.

      Discussion

      All three protocols used LDCT to guide evaluation of NCNs, particularly for the smaller NCNs. LDCT is a very low risk test as it requires no injection of contrast, the radiation dose is deemed “small” and “hypothetical” by the American Association of Physicists in Medicine [10], and the charge for a LDCT is 10-20 times lower than for a PET scan. This underscores the recognition that LDCT is a very useful tool for identifying growth at a malignant rate prior to further invasive testing.

      The main point is that the definition of a “positive result” needs to be continually reevaluated and updated in light of emerging technology and evidence from ongoing screening programs with the goal of reducing unnecessary invasive procedures for non-malignant pulmonary NCNs, which will markedly reduce the concerns about potential harms and increase the benefit by early diagnosis and treatment of small, early curable lung cancers.

      References

      1. Henschke CI, Salvatore M, Cham M, Powell CA, DiFabrizio L, Flores R, et al. Baseline and annual repeat rounds of screening: implications for optimal regimens of screening. Eur Radiol. 2018; 28:1085-1094.

      2. Henschke CI, Yip R, Ma T, Aguayo SM, Zulueta J, Yankelevitz DF, for the I-ELCAP Investigators. CT screening for lung cancer: comparison of three baseline screening protocols. Eur Radiol 2018; 29:3321-3322.

      3. International Early Lung Cancer Action Program protocol. (2016) www.IELCAP.org/sites/default/files/I-ELCAP-protocol.pdf Accessed June 27, 2019

      4. American College of Radiology (ACR). Lung CT screening reporting & data system (Lung-RADS Version 1.0). https://www.acr.org/Quality-Safety/Resources/LungRADS

      5. Oudkerk M, Devaraj A, Vliegenthart R, Henzler T, Prosch H, Heussel CP, et al. European position statement on lung cancer screening. Lancet Oncology 2017; 18: e754-e766.

      6. Henschke CI, Yip R, Wolf A, Flores R, Liang M, Salvatore M, et al. CT screening for lung cancer: part-solid nodules in baseline and annual repeat rounds. AJR Am J Roentgenol 2016; 11:1-9.

      7. Radiologic Society of North America Quantitative Imaging Biomarkers Alliance (QIBA) Calculator. (2017) http://accumetra.com/solutions/qiba-lung-nodule-calculator. Accessed May 1, 2018.

      8. Li K, Yip R, Avila R, Henschke CI, Yankelevitz DF. Size and growth assessment of pulmonary nodules: consequence of the rounding. J Thorac Oncol 2016; 12: 657-62.

      9. Flores R, Bauer T, Aye R, et al. Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer. J Thorac Cardiovasc Surg. 2014; 147:1619-26.

      10. American Association of Physicists in Medicine. AAPM Position Statement on Radiation Risks from Medical Imaging Procedures. https://www.aapm.org/org/policies/details.asp?id=406&type=PP Accessed June 27, 2019

      ch_management protocol-table.png

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      ES08.05 - Advances in Artificial Intelligence - How Lung Cancer CT Screening Will Progress? (Now Available) (ID 3195)

      13:30 - 15:00  |  Presenting Author(s): Debora Gil  |  Author(s): Antoni Rosell

      • Abstract
      • Presentation
      • Slides

      Abstract

      Predictive models for personalized medicine (also known as radiomics) is a recent discipline that uses sophisticated image analysis and artificial intelligence (AI) methods to obtain quantitative image-based features that correlate to final diagnosis and treatment outcome [1].

      The application of radiomics in lung cancer screening can represent a critical shift in this field. Some recent studies, like [2-3], show that radiomic features (including tumor shape descriptors and texture analysis) extracted from CT scans have significantly better predictive value than volumetry alone (AUC= 0.9 vs 0.74). Texture analysis reflects tumour heterogeneity and has recently introduced in PET images. In fact, PET texture analysis has demonstrated its value in establishing survival [4], predicting distant metastasis [5], detecting mutations and establishing radiotherapy doses [6]. However, and despite the promising results, there are some limitations like the low reliability of heterogeneity parameters in tumours with small volume, the low repeatability and reproducibility of textural features in the clinical setting and the limitation of the analytic methods.

      A multi-radiomic model that could integrate morphological features from the CT together with biological characteristics from the PET and clinical risk factors (age, smoking history, contact with asbestos or family cancer background), would become a highly accurate diagnostic and prognostic method and, thus, make lung cancer screening programs cost-effective. However, in order that radiomics become the cornerstone for clinical decision-making, new machine learning and statistical strategies adapted to the specific requirements of clinical applications should be formulated.

      A main pitfall in current state of the art AI methods is the use of generic machine learning and statistical tools borrowed from other fields of application which fall short under clinical conditions [7]. Predictive radiomic models for personalized medicine should address several specific challenges different from the ones common to other application areas of artificial intelligence. First, models should collect and integrate diverse multimodal data sources in a quantitative manner that delivers unambiguous clinical predictions. Second, models should also be easily interpreted from a clinical point of view to allow the analysis of the clinical factors that have an impact on the clinical decision. Third, predictions should be robust concerning data uncertainties due to the impact of collection conditions (like acquisition parameters or variability in manual annotations) and the presence of rare and/or outlying cases, which become highly influential for minority classes lead to overfitting.

      This work reviews state-of-the-art AI methods for radiomics, the specific challenges that they must face in medical imaging applications and the latest advances for reliable personalized early diagnosis of lung cancer.

      References

      [1] P Lambin, et al, Radiomics: the bridge between medical imaging and personalized medicine, Nature Reviews,12, 749-53, 2017.

      [2] Hawkins et al. Prediction of pathological nodal involvement by CT-based Radiomic features of the primary tumor in patients with clinically node-negative peripheral lung adenocarcinomas, Med. Phys. 45 (6), 2018.

      [3] Peikert T et al. Novel high-resolution computed tomography-based radiomic classifier for screen-identified pulmonary nodules in the National Lung Screening Trial, PLOS ONE 13(10), 2018.

      [4] Ohri N, Duan F, Snyder BS, Wei B, Machtay M, Alavi A, et al. Pretreatment 18F-FDG PET textural features in locally Advanced non-small cell lung cancer: secondary analysis of ACRIN 6668/RTOG 0235. J Nucl Med.57:842–8, 2016.

      [5] Wu J,Aguilera, et al. Early-stage non-small cell lung cancer: quantitative imaging characteristics of (18)F fluorodeoxyglucose PET/CT allow prediction of distant metastasis. Radiology, 281:270–8, 2016.

      [6] Yip SS, et al. Associations between somatic mutations and metabolic imaging phenotypes in non-small cell lung cancer. J Nucl Med. 58:569–76, 2017.

      [7] JP. Cohen et al, Distribution matching losses can hallucinate features in medical image translation, MICCAI 2018.

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      ES08.06 - Cost Effectiveness of Comprehensive Screening and Smoking Cessation Programmes (Now Available) (ID 3196)

      13:30 - 15:00  |  Presenting Author(s): Bruce Pyenson

      • Abstract
      • Presentation
      • Slides

      Abstract

      There is broad consensus that lung cancer screening with low-dose CT is cost-effective. However, there has been slow take-up in the US where it is covered by commercial insurance and by the federal Medicare program.

      One way to optimize LC screening is to consider screening as part of an integrated program that specializes in population health for the cluster of smoking-related illness. There are four components of this,

      LC screening centers can provide high-quality screening and systematic follow-up and appropriate referrals

      Imaging for LC screening can quantify cardiac calcification, COPD, and osteoporosis, all of which may be associated with smoking

      LC screening centers can operate as a center for smoking cessation, exercise counseling, and adherence support

      For the 1.5 million annual indeterminant pulmonary nodules in the US, LC screening centers can provide appropriate follow-up. The vast majority of such cases receive no follow-up.

      There are both economic and financial consequences for integrated screening. The economic consequences are measured in cost-effectiveness. The financial consequences are attracting high-utilizing people away from lower-quality providers, which can offset the loss of income from treating late stage lung cancers.

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      ES08.07 - System Approach to Screening Management (Now Available) (ID 3197)

      13:30 - 15:00  |  Presenting Author(s): Anthony P Reeves

      • Abstract
      • Presentation
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      Abstract

      IASLC ES08 - Critical Concerns in Screening 2019

      System Approach to Screening Management

      Anthony P. Reeves

      School of Electrical and Computer Engineering

      Cornell University

      Screening seeks to identify a specific disease or set of diseases at an early stage where therapy can be most effective. It involves application of a medical test or tests to a group of asymptomatic individuals at-risk for the disease. Only a very small fraction of the tested population will be expected to have the target disease. Thus, a system for managing the screening process focuses on a single complex protocol and differs significantly from the more traditional medical practice that has a focus on symptomatic diseases and medical conditions. Very high compliance with the protocol and timeliness in follow up actions are critical to extract the maximum benefit of the screening process and avoid unnecessary actions on the majority of the participants that do not have the disease.

      System requirements for Lung Cancer Screening

      Screening involves detection of early stage asymptomatic disease and timely follow-up to provide the maximum therapeutic benefit of early stage detection. This requires a system to track participants throughout the screening process, from initial contact to documentation of screening results to follow-up. To maintain the highest degree of quality and timeliness, the screening management system should be comprehensive for all the digital data in the screening program and incorporate the screening protocol in its design.

      For lung cancer screening (LCS), the web-based I-ELCAP management system was implemented in 2000 [1] with integration of all screening functions into a single system, including: scheduling, data collection, follow-up, patient reports and QA reports. This system includes structured reports for all patient interactions and medical events. The screening protocol is built in to the system; hence, there are real-time checks on adherence to the screening protocol. Any deviations from the protocol, such as a missing report or appointment schedule are flagged for attention. In addition, the management system includes all acquired digital images linked to the patient records; physicians may review images from within the system. Finally, the system includes computer image analysis methods for automated pulmonary nodule detection and for nodule growth rate assessment.

      Additional findings and Computer Aided Diagnosis

      Since that early system implementation in 2000, the importance of additional findings for other organs visible in the chest CT scans have become apparent. The radiological structured reporting requirements have been increased to include findings of the heart, and the lungs (emphysema, COPD) which, with lung cancer, covers the three main causes of death for the high-risk screening population. The detailed reporting of the CT scan reading, especially once the initial baseline scan has been read, places an increased burden on the radiologist. To improve the program quality and to address the reading issues a number of additional automated computer analysis functions have been integrated into the system, Reeves et. al. (2017) [2]. These include measures for: coronary calcium, heart size, the aorta, pulmonary hypertension, emphysema, major airways, bone mineral density from thoracic vertebra, breast density, and liver density. In addition, an automated quality assessment of the CT scan itself is reported.

      The role for AI in screening management

      Recent advances in AI technology, including deep learning with convolutional neural networks, have increased the capabilities of computer aided diagnostics. A landmark paper by Gulshan et. al. (2016) [3] showed that an automated end-to-end review of eye fundus images for diabetic retinopathy to determine if a follow-up action was indicated could be effectively accomplished without requiring a human read of the images. Following this work a commercial product for this task is now available. A recent paper by Ardila et. al. (2019) [4] showed that, for LCS CT scans, a similar approach with a more complex system could be used for predicting cancer events in a manner similar to LungRADS. A challenge with this LCS study, compared to Gulshan diabetic retinopathy study, is the cost and reporting complexity of the former for training data. While the Gulshan study was prospective and trained on over 120,000 cases, the Ardila study was retrospective with a subset of the NLST data of around 10,000 cases and only considered lung cancer. These methods employ the natural advantage of computer analysis with respect to human readers in attention to detail and lack of fatigue. Further, modern AI methods when appropriately designed, can assimilate data from millions of cases, far beyond human capacity. Efficient large-scale documentation methods have been developed to address the data issue for LCS [2] in which over 25,000 cases have been documented for multiple diseases.

      These studies move us closer to the point where the majority of the CT image report for LCS could be automatically completed and the role of the physician focused to reviewing a small number of the most significant findings.

      References

      1. Reeves, A. P., Kostis, W. J., Yankelevitz, D. F., and Henschke, C. I. A web-based database system for multi-institutional research studies on lung cancer. RSNA 87th Scientific Meeting 221 (Nov. 2001), 372

      2. Reeves, A. P., Xie, Y., and Liu, S. Large-scale image region documentation for fully automated image biomarker algorithm development and evaluation. Journal of Medical Imaging 4, 2 (2017), 024505.

      3. Gulshan, V., Peng, L., Coram, M., Stumpe, M. C., Wu, D., Narayanaswamy, A., ... & Kim, R. (2016). Development and validation of a deep learning algorithm for detection of diabetic retinopathy in retinal fundus photographs. Jama, 316(22), 2402-2410.

      4. Ardila, D., Kiraly, A. P., Bharadwaj, S., Choi, B., Reicher, J. J., Peng, L., ... & Naidich, D. P. (2019). End-to-end lung cancer screening with three-dimensional deep learning on low-dose chest computed tomography. Nature medicine, 1.

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    IS01 - Symposium by Bayer Healthcare Pharmaceuticals: Precision Medicine: Optimizing The Approach To Lung Cancer Through Testing (Not IASLC CME Accredited) (ID 365)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS03 - Symposium by Takeda Oncology: Current Treatment Landscape And Unmet Needs In ALK+ NSCLC (Not IASLC CME Accredited) (ID 367)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS05 - Symposium by Springer Healthcare: Simplifying The Sequencing Of Treatment In NSCLC Patients With No Actionable Mutations (Not IASLC CME Accredited) (ID 369)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS06 - Symposium by F. Hoffmann-La Roche: How Immunotherapy Is Continuing To Revolutionise First-Line Lung Cancer Care (Not IASLC CME Accredited) (ID 370)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    IS11 - Symposium by F. Hoffmann-La Roche: Waking Up To Precision Medicine In NSCLC (Not IASLC CME Accredited) (ID 375)

    • Event: WCLC 2019
    • Type: Industry Symposia & Workshops
    • Track:
    • Presentations: 0
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    MA01 - Oligometastatic Disease (ID 114)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Oligometastatic NSCLC
    • Presentations: 12
    • Now Available
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      MA01.01 - Safety of Pembrolizumab Combined with Stereotactic Ablative Body Radiotherapy (SABR) for Pulmonary Oligometastases (Now Available) (ID 2187)

      10:30 - 12:00  |  Presenting Author(s): Shankar Siva  |  Author(s): Mathias Bressel, Sherene Loi, Shahneen Sandhu, Ben Tran, Jennifer Mooi, Jeremy Lewin, A Azad, D Colyer, Mark Shaw, Sarat Chander, Katherine Cuff, Simon Wood, Nathan Lawrentschuk, Declan Murphy, David Pryor

      • Abstract
      • Presentation
      • Slides

      Background

      Pembrolizumab has demonstrated safety and efficacy in a broad range of tumors. However, safety concerns exist around the combination of pembrolizumab and high dose radiotherapy to the lung, particularly as both have independent risk of pneumonitis. In this interim analysis we assess the safety profile of combination pembrolizumab and SABR to pulmonary oligometastases.

      Method

      As part of the ongoing prospective dual-institutional RAPPORT clinical trial (clinicaltrials.gov ID NCT02855203), patients with 1-5 oligometastases from renal cell carcinoma were enrolled between Nov 2016- April 2019. All participants had ECOG performance status 0-1, and signed informed consent. Patients with at least 1 lung oligometastasis were included in this analysis. All patients were planned for a single fraction of 20Gy SABR to each lung oligometastasis, followed 5 days (+/-3 days) later by 8 cycles of 200mg i.v. 3-weekly pembrolizumab (total 24 weeks). When SABR dose constraints were not achievable, conventional hypofractionated radiotherapy could be delivered. At least 1 oligometastasis needed to receive SABR. Adverse events (AEs) were recorded using CTCAE V4.03 until 30 days post last dose of pembrolizumab, and late AEs atrributable to SABR for 24 months after SABR.

      Result

      20 patients with a combined total of 41 lung oligometastases were included in this analysis. The mean age was 61 years, with 15 (75%) male. The number of lung oligometastases were 1 in 9 (45%), 2 in 3 (15%), 3 in 6 (30%), 4 in 2 (10%) patients. SABR was delivered to 39 lung oligometastases (95%) and conventional radiotherapy to 2 oligometastases (5%) using 10 fractions of 3Gy. Twelve patients have completed all eight cycles of pembrolizumab, with five patients having ongoing treatment. Three patients ceased treatment early due to grade 3 pneumonitis (15%) after 3, 6 and 7 cycles of pembrolizumab respectively. These patients had 1, 2 and 1 lung oligometastases, respectively. The worst grade of any treatment related AEs was grade 3 in 4 pts (20%), with 3 attributed to both SABR and pembrolizumab, and 1 atributed to pembrolizumab alone. Three of the four grade 3 events were pneumonitis. A further 3 patients had grade 2 AEs(15%), and 8 patients had grade 1 AEs(40%). There were no grade 4 or 5 adverse events, and five patients (25%) had no treatment related adverse events.

      Conclusion

      SABR to lung oligometastases in combination with pembrolizumab was well tolerated, with clinically acceptable rates of grade 3 pneumonitis compared to historical rates reported with pembrolizumab monotherapy.

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      MA01.02 - Lung Stereotactic Body Radiotherapy and Concurrent Immunotherapy: A Multi-Center Safety and Toxicity Analysis (Now Available) (ID 597)

      10:30 - 12:00  |  Presenting Author(s): Sibo Tian  |  Author(s): Jeffrey M Switchenko, Pretesh R Patel, Joseph W Shelton, Shannon E Kahn, Rathi N Pillai, Conor E Steuer, Taofeek Owonikoko, Madhusmita Behera, Walter J Curran, Kristin A Higgins

      • Abstract
      • Presentation
      • Slides

      Background

      Radical treatment of metastases with stereotactic body radiotherapy (SBRT) in patients with advanced malignancies is an emerging treatment paradigm. SBRT is increasingly used in patients receiving immune checkpoint inhibition (ICI); however, limited toxicity data for this treatment approach exists. The purpose of this study was to evaluate the safety and tolerability of lung SBRT with concurrent ICI.

      Method

      Records from a single academic institution were reviewed to identify patients treated with lung SBRT and concurrent (within 30 days) ICI; a contemporaneous cohort receiving lung SABR without ICI were included as a reference cohort. Treatment-related adverse-effects (AE) occurring within 30 days (acute) and 180 days (subacute) of SBRT were graded via CTCAE v5.0.

      Result

      110 patients were included; 47 received SBRT with concurrent ICI (49 SBRT courses, 61 lesions) between August 2015 and January 2019. 63 received SBRT without ICI (68 courses, 79 lesions). For the SBRT+ICI cohort, median age at treatment was 64 years, median follow-up was 6.7 months. 70% were lung, 15% were melanoma, 6.4% were from head and neck primaries. 90% were treated for metastatic consolidation/oligo-progression, 10% received SBRT for locally advanced/recurrent disease. 65.3% of patients received prior RT. 36.7% received prior lung RT, 40% of which were overlapping. 67% received ICI monotherapy, 16% ICI/chemotherapy, and 16% ICI/ICI combinations. 24.5% received ICI between SBRT fractions; 38.8% received ICI both before and after SBRT. Grade 3 (G3) and any grade pneumonitis rates were 8.2% and 30.6%; there were no G4-5 events. ICI was discontinued due to toxicity in 22.4% of patients. Receipt of ICI/ICI combinations increased the risk of any grade pneumonitis (62.5% vs 24.4%, p=0.04); but not G3 pneumonitis. Risk of G3 pneumonitis was higher in the SBRT+ICI vs SBRT alone cohort (8.2 vs 0%, p=0.03); but not any grade pneumonitis (30.6% vs 29.9%, SBRT+ICI vs SBRT p=0.75). Median time to onset was 3.4 months from end of SBRT in both groups. Risk of G3 and any grade pneumonitis was not predicted by ICI agent, timing of ICI administration, prior RT, prior lung RT, lesion centrality, number of target lesions, or smoking status. Overall acute G3+ AE rates were 2% (SBRT+ICI) and 0% (SBRT). Subacute G3+ AEs occurred in 26.5% (SBRT+ICI) and 2.9% (SBRT) of patients.

      Conclusion

      Concurrent ICI, especially ICI/ICI combinations, increased the risk of G3 pneumonitis with lung SBRT. However, SBRT+ICI appears safe and tolerable compared to SBRT alone. Strategies integrating SBRT and ICI warrant additional investigation.

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      MA01.03 - Interim Safety Analysis of the Phase IB Trial of SBRT to All Sites of Oligometastatic NSCLC Combined with Durvalumab and Tremelimumab  (Now Available) (ID 2893)

      10:30 - 12:00  |  Presenting Author(s): Ticiana A. Leal  |  Author(s): Joshua M Lang, Zachary Morris, Jens Eickhoff, Anne M Traynor, Toby Campbell, Andrew Baschnagel, Michael Bassetti

      • Abstract
      • Presentation
      • Slides

      Background

      Oligometastatic NSCLC represents a unique subset of patients (pts) with limited burden of metastatic disease. Prior early studies have demonstrated that combining local ablative and systemic therapies in pts with oligometastatic disease leads to improved progression-free survival (PFS). The immunostimulatory effects of SBRT and potential synergy with immune checkpoint inhibitors has prompted enthusiasm in combining the two; however, the toxicity is unknown.

      Method

      In this phase Ib study, a cohort of 21 pts with oligometastatic NSCLC receive SBRT to all sites of disease between 30 and 50 Gy in five fractions and durvalumab 1500 mg IV + tremelimumab 75 mg IV every 4 weeks x 4 cycles in a sequential fashion, followed by durvalumab maintenance until progression, unacceptable toxicity or patient wishes. Eligible patients had 1-6 metastatic extracranial lesions, all of which were suitable for SBRT, ECOG performance status 0-1, no actionable driver mutation, and no prior immunotherapy.The primary endpoint is safety of this combination. The period for evaluating dose-limiting toxicities (DLTs) is from the time of first administration of SBRT until 28 days post completion of the first dose of durvalumab and tremelimumab. Grading of DLTs follows CTCAE version 4.03. A DLT will be defined as any Grade≥ 3 toxicity. Secondary endpoints include PFS and overall survival. Correlative studies of baseline TMB, PD-L1 expression on post-SBRT biopsy and immune biomarkers on circulating tumor cells will be correlated with outcomes. In this interim analysis, we assess the safety of the first nine patients enrolled.

      Result

      Nine pts enrolled from 2/2018-3/2019. Median follow-up: 2.8 months (range 1.5-8.2 months). Characteristics included: median age 72 years (range 56-81 years), female/male 2/7, squamous/nonsquamous 2/7, median number of sites treated 2, CNS involvement 3/9. Most toxicities were Grade (G) 1/ 2. Severe adverse events (AEs) included: G4 elevated CK (1). Severe immune-related (ir)AEs: G3 rash (1), G3 AST (2), G3 ALT (1), G3 amylase (1), G3 lipase (1). One DLT reported due to grade 3 AST > 7 days (recovered). One additional pt discontinued treatment due to grade 3 irAE. There were no treatment-related deaths. Two patients (22%) died of disease progression.

      Conclusion

      There were no unexpected safety signals in the first nine patients enrolled. The incidence of grade 3 or greater irAEs was similar to those seen in the treatment of advanced NSCLC, and no additional toxicity is observed with the addition of SBRT to date. The study continues to enroll and results will be updated.

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      MA01.04 - Discussant - MA01.01, MA01.02, MA01.03 (Now Available) (ID 3715)

      10:30 - 12:00  |  Presenting Author(s): Fiona McDonald

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA01.05 - Progress of Accompanying GGN Beyond Pulmonary Resection for Non-Small Cell Lung Cancer (Now Available) (ID 1525)

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

      • Abstract
      • Presentation
      • Slides

      Background

      The aim of this retrospective study was to review the natural course of synchronous ground-glass nodule (GGN), which was left after the curative resection of non-small cell lung cancer (NSCLC) in other lobe.

      Method

      Between 2008 and 2017, a prospectively collected retrospective data of 2276 patients who underwent curative resection for NSCLC was reviewed. Among them, GGN was detected in 126 patients beside resected lung. Defined by high-resolution computed tomography (HRCT) or thin-section of computed tomography (CT), twenty patients with nearly solid nodule or GGN with higher CT ratio (> 0.75) was excluded, thereafter the data of 98 patients (4.3%) was included in the study. Demographic data of patients including age, gender, and smoking history were collected for analysis. In addition, risk factor including characteristics of GGN, histopathology and staging of resected tumor, adjuvant treatment, and any other medical history were evaluated for risk factor analysis.

      Result

      Median duration of follow-up was 36 months (range; 11 – 120). The size of GGN has been decreased in 10 patients (10.2%), stationary 48 patients (50.0%), while an increasing in size of GGN was observed in 40 patients (40.8%). Among them, five patients were recommended reoperation (12.5%), and the other 35 patients were in clinical observation (87.5%). In mutivariate analysis, existence of solid component, smoking history, and multiple GGNs in one lobe were independent prognostic factor.

      table.png

      Conclusion

      During the follow-up, 40.8% of GGN showed a growth in size, emphasizing that patients with part-solid GGN and with smoking history should be in careful observation.

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      MA01.06 - Prognostic Factors of Oligometastatic Non-Small Cell Lung Cancer Following Radical Therapy: A Multicenter-Analysis (Now Available) (ID 3063)

      10:30 - 12:00  |  Presenting Author(s): Isabelle Opitz  |  Author(s): miriam Patella, Loic Payrard, Jean Yannis Perentes, Thorsten Krueger, Rolf Inderbitzi, Hans Gelpke, Sandra Schulte, Maja Diezi, MIchel Gonzalez, Walter Weder

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with oligometastatic non-small cell lung cancer (NSCLC) may benefit from radical therapy. We aimed to identify factors related to better prognosis, in a multicenter analysis of patients who underwent surgery of primary tumours, in combination with radical treatment of metastatic sites, and chemo- or chemoradiation.

      Method

      We retrospectively reviewed the records of oligometastatic patients who all underwent anatomical resection of primary tumor, treated at 4 centers, (August 2001-November 2018). Oligometastasis was defined as ≤5 synchronous metastases in ≤2 organs. Radical metastatic treatment was surgery (n=48), radiotherapy (n=36) or a combination (n=41). Univariate analysis and multivariate Cox proportional hazards model were used for identification of prognostic factors on overall survival (OS) and progression-free survival (PFS). Survival was estimated by Kaplan-Meier analysis. P-value < 0.05 was considered significant.

      Result

      We treated 125 patients; 72 (58%) were male, aged 60±9.8 years, with 88 (70%) adenocarcinoma, and following pathological (pN) stage: pNx: 1 (1%), pN0: 57 (46%), pN1: 23 (18%), pN2: 44 (35%). Brain metastasis was most common (n=76; 61%) followed by adrenal (n=13; 11%) and bone (n=12; 10%). Systemic therapy was administered in 102 (82%). Median follow-up was 60 months (95%, CI: 41-86).

      One-, 2-, 3-, and 5-years OS was 80%, 58%, 49% and 36% respectively. Several patient-related and treatment-related factors showed a correlation with OS at univariate analysis. Multivariate analysis showed that patients ≤60 years (HR 0.47, 95% CI:0.28-0.78, p=0.004), and/or pN0, compared to pN1,2 (HR 0.38, 95% CI: 0.22-0.66, p=0.001), had a significant survival benefit (Figure 1A). Bone metastasis were associated with worse prognosis (HR 2.122, 95% CI: 1.00-4.48, p=0.05).

      Twenty-eight patients were ≤60 years with pN0, and had 1- and 5-year survival of 100 and 83%.

      PFS at 1-, 2-, 3- and 5-years was 41%, 29%, 25% and 23% respectively. In the multivariate analysis, absence of mediastinal lymphnode involvement (HR: 0.483, 95% CI: 0.305-0.764, p=0.002) and surgical treatment of metastasis (HR: 0.553, 95% CI: 0.347-0.880, p=0.013) remained independently associated with better outcome (Figure 1B). The administration of treatments after first progression was strongly associated with better prognosis (HR: 0.252, 95% CI: 0.076-0.834, p=0.013).

      figure 1.jpg

      Conclusion

      Our experience demonstrates, in a multicenter setting, that radical treatment of selected oligometastatic NSCLC results in excellent 5-year survival. Nodal status correlates with both OS and PFS. Surgical metastasectomy appears to improve PFS, but multimodality treatment, especially in case of recurrence, remains mandatory.

      These data might contribute to develop future combined strategies in the era of immunotherapy.

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      MA01.07 - Prognostic Factors of Surgical Treatment in Non-Small Cell Lung Cancer (NSCLC) Patients in Oligometastatic Stage-M1b of Disease (Now Available) (ID 312)

      10:30 - 12:00  |  Presenting Author(s): Dariusz Adam Dziedzic  |  Author(s): Grabczan Wojciech, Rudzinski Piotr, Renata Langfort, Tadeusz Orlowski

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer in stage IV is rarely the subject of surgical treatment. Most cases are considered as inoperable and qualified for palliative treatment. Long-term results in this group of patients are poor despite systemic oncological treatment. A special group of patients are patients with a single metastasis beyond the lung (grade M1b), in which in some cases surgery may significantly improve the prognosis. The aim of the study was to determine the prognostic factors of surgical treatment of non-small cell lung cancer in stage IVA with a single distant metastasis (oligometastatic stage-M1b)

      Method

      A retrospective study was based on data from the National Register of Cancer of the Lung conducted by the Polish Group of Lung Cancer. The study included 387 patients (242 men and 145 women) between 41 and 87 years of age (median 60.4 +/- 8.4 years) with established NSCLC and single synchronous metastasis most often to: second lung (55.5%), brain (24.8%) and adrenal glands (14.5%). All patients underwent resection of the pulmonary parenchyma and resection of the metastatic focus. The size of the primary tumor was respectively: 1-2 cm in 16.0%, 2-3 cm in 26.4%, 3-5 cm in 23.5%, 5-7 cm in 12.4% 7-10 cm in 14 , 0% and over 10cm in 7.8%. The features of N0, N1, and N2 were diagnosed in 69.8%, 15.5% and 14.7% of patients respectively. Radical oncology R0, R1 and R2 were obtained in 96.1%, 2.1% and 1.8% of cases respectively. Anatomical resection was performed in 70% and minor resection in 30% of patients. Preoperative chemotherapy was used in 7.5% of cases, and postoperative in 21.2% of patients.

      Result

      The 5-year survival in the entire M1b group was 27.3%. Multivariate analysis showed that the negative prognostic factors were male gender (HR = 1.56, 95% CI-1.16-2.1, P <0.003), age> 50 (HR = 1.39, 95% CI-0.87-2.22, P <0.002), tumor size (HR = 34.32, 95% CI-2.39-7.82, P <0.001), feature N1 (HR = 1.53, 95% CI-1.02-2.29, P <0.04) and the N2 trait (HR = 2.71; 95% CI -1.8-4.06, P <0.001). Patients undergoing anatomical resection vs lower (HR = 0.5, 95% CI-0.35-0.72, P <0.001) and postoperative preoperative chemotherapy (HR = 0.69, 95% CI-0.48-0.97, P <0.034) have better prognosis. The number of lymph nodes removed during the procedure is also significantly affected - 5-year survival at 1-5 removed nodes was 24.6%, and in the case of 6-10 nodes 32.4%.

      Conclusion

      Surgical treatment of NSCLC in the M1b stage in a selected group of patients allows for the improvement of long-term results. Negative prognostic factors are gender, age, tumor size and metastases to lymph nodes. The scope of resection in this group of patients should be the same as in the lower stages with the predominance of anatomical resection and mediastinal lymphadenectomy. Post-operative chemotherapy may have a beneficial effect on long-term results.

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      MA01.08 - Discussant - MA01.05, MA01.06, MA01.07 (Now Available) (ID 3716)

      10:30 - 12:00  |  Presenting Author(s): Corey Jay Langer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA01.09 - Concomitant SBRT and EGFR-TKI Versus EGFR-TKI Alone for Oligometastatic NSCLC: A Multicenter, Randomized Phase II Study (Now Available) (ID 2214)

      10:30 - 12:00  |  Presenting Author(s): Li Zhang  |  Author(s): Ping Peng, Yongshun Chen, Guang Han, Rui Meng, Sheng Zhang, Zhengkai Liao, Yujie Zhang, Juejun Gong, Chuangying Xiao, Xiyou Liu, Peng Zhang, Lu Zhang, Shu Xia, Qian Chu, Yuan Chen

      • Abstract
      • Presentation
      • Slides

      Background

      NSCLC patients harboring EGFR mutation generally develop resistance to EGFR TKI less than one year. Prior studies indicated that local consolidative therapy is associated with improved outcomes in patient with limited metastatic NSCLC. Radiotherapy is one of the ideal control methods for locally progressed patients, however, the optimal intervention time in order to slow the occurrence of EGFR-TKI resistance for advanced NSCLC patients with EGFR-sensitive mutations is still unclear. Our preliminary clinical and animal studies suggest that early combined radiotherapy prior to EGFR-TKI resistance can significantly improve the prognosis of patients. Our hypothesis is that the optimal intervention time of radiotherapy for EGFR mutation patients is 3 months after the beginning of EGFR-TKI.

      Method

      This is a prospective, multicenter, randomized controlled study to evaluate stereotactic body radiation therapy (SBRT) as a potential treatment for limited stage IV NSCLC (primary plus up to 3 metastatic sites) with sensitive EGFR mutation. The patients did achieve partial response or stable disease after three months treatment of the first-generation EGFR-TKI would be randomized to TKI combined SBRT (TS) or TKI alone. The primary endpoint was PFS (the time from the beginning of EGFR-TKI treatment to disease progression or death). The secondary endpoint was overall survival (OS) and safety. TKI wasn’t interrupted during the irradiation.

      Result

      A total of 61 patients were enrolled from Feb, 2017 to Jan, 2019. Median follow up was 22.3 months. Patients who TS (n: 30) had a significantly longer median PFS compared to those with TKI alone (n: 31) (PFS: 17.4 vs. 8.9 months P =0.042). T790M mutation was observed in 57.9% acquired resistance patients for TS group, and 39.3% for TKI alone group. Median PFS of T790M mutated patients was 17.4 months compared to 10.3 months of TKI alone group (P = 0.007). Multivariable analysis revealed that radiation fields were positively associated with PFS, 21.8 months for just primary tumor; 10.6 months for metastatic lesions and 18.3 months for primary and metastatic lesions (P= 0.006). OS data was not yet mature. None experienced >= grade 3 SBRT related toxicities.

      Conclusion

      A trend of improved long term PFS was noted in patients receiving SBRT for primary tumor combined EGFR TKI at the third month after the beginning of TKI. Moreover, this data suggested that benefit from radiation might be associated with delay the occurrence of T790M mutation. Further studies are required to investigate the molecular mechanisms underlying this association.

      Clinical Trial information: NCT03595644

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      MA01.10 - Additional Local Consolidative Therapy Showed Survival Benefit Than EGFR-TKIs Alone in Bone Oligometastatic Lung Adenocarcinoma Patients (Now Available) (ID 398)

      10:30 - 12:00  |  Presenting Author(s): Fang Hu  |  Author(s): Changhui Li, Jianlin Xu, Jindong Guo, Yinchen Shen, Wei Nie, Xiaoxuan Zheng, Lixin Wang, Hai Zhang, Baohui Han, Xueyan Zhang

      • Abstract
      • Presentation
      • Slides

      Background

      Whether epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) plus local consolidative therapy (LCT) has better survival benefit than EGFR-TKIs alone remains controversial in lung adenocarcinoma patients with EGFR mutation and bone oligometastases.

      Method

      We conducted a retrospective study to assess the effects of LCT on bone oligometastases lung adenocarcinoma patients with EGFR mutation. The primary endpoint was overall survival (OS); The secondary endpoints was progression-free survival (PFS).

      Result

      A total of 127 lung adenocarcinoma patients with EGFR mutation and bone oligometastases were identified. There were 65 patients received EGFR-TKIs alone (monotherapy group) and 62 patients received EGFR-TKIs plus local consolidative therapy (LCT) (combination group). Addition of LCT was associated with a significantly longer OS (36.3 vs. 21.0 months, P=0.01, hazard ratio [HR]=0.537, 95% confidence interval [CI]:0.360-0.801, p=0.01) and PFS (14.0 vs. 8.1 months, P=0.01, HR=0.613, 95%CI: 0.427-0.879, p=0.01) in the whole cohort (Figure 1). All subgroups showed OS benefit in faver of combination therapy except for PS scores greater than or equal to 2 group, and all subgroups analyzed derived PFS benefit in favor of combination therapy (Figure 2).

      Conclusion

      In patients with EGFR-mutant lung adenocacinoma and bone oligometastases, LCT plus EGFR-TKIs therapy was associated with significantly longer OS and PFS than EGFR-TKIs therapy alone, indicating that LCT plus EGFR-TKIs therapy might be a better therapeutic option for those patient population.

      figure 1.jpg

      figure 2.jpg

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      MA01.11 - Improving Survival in Lung Cancer Patients with Oligometastatic Disease Progression Using Stereotactic Body Radiation Therapy (Now Available) (ID 1836)

      10:30 - 12:00  |  Presenting Author(s): Luis Raez  |  Author(s): Miguel Castillo, Ana Botero, Aaron Falchook, Ignacio Castellon, Brian Hunis

      • Abstract
      • Presentation
      • Slides

      Background

      In patients (pts) with stage IV non-small cell lung cancer (NSCLC) receiving systemic therapy, stereotactic body radiation therapy (SBRT) can eliminate oligometastatic disease progression (OMP). This allows NSCLC pts to continue the same systemic therapy, and its is especially important when the therapy is well tolerated as is the case for many pts receiving immunotherapy (IMMUNO) and targeted therapy (TARGET). The purpose of this study is to quantify the progression free survival (PFS) and overall survival (OS) of pts receiving systemic therapy who experience OMP that is treated with SBRT, and subsequently continue the same systemic therapy.

      Method

      Retrospective review of one hundred pts with metastatic NSCLC undergoing chemotherapy (CHEMO), IMMUNO or TARGET that had OMP defined as less than 4 sites of metastasis and underwent SBRT were evaluated for PFS and OS. PFS1: Time between initiation of systemic therapy and development of OMP. PFS2: Time between OMP treated with SBRT and development of further PD requiring a change in systemic therapy. Pts received IMMUNO for second line and beyond. SBRT doses were determined based on the disease site and dose tolerance of the adjacent organs. SBRT was delivered in 1-5 fractions on consecutive days or every other day. Radiation dose was determined by target volume and adjacent dose-limiting organs.

      Result

      OMP presented as brain metastasis (BM) in 45 pts and extracranial metastasis (EM) in 55 pts. 34 pts were receiving CHEMO, 34 TARGET and 32 IMMUNO at the time of OMP. Pts with BM that received SBRT were able to continue the same therapy for a period of 6.5-9 extra months due to the control of BM. Pts with EM that have developed PD were able to continue the same therapy an 17-21 extra months due to the ablation of OMP by SBRT. For the entire cohort PFS was: 16.5m for BM and 34m for EM and the OS were: 31m and 53m respectively.

      Location of oligometastatic progression (OMP)

      Median PFS1

      Median PFS2

      PFS

      Median OS

      Extracranial (N=55)

      13

      21

      34

      53

      chemo

      7

      17

      24

      47

      Immuno

      13.5

      20.5

      34

      49

      Target

      12

      21

      33

      53

      Brain (N=45)

      9

      7.5

      16.5

      31

      Chemo

      5.5

      6.5

      12

      25.5

      Immuno

      7

      8

      15

      27

      Target

      11

      9

      20

      47

      Conclusion

      PFS and OS may be prolonged due to the use of SBRT in pts that develop OMP. This intervention allowed patients to continue with the same systemic treatment. Our CHEMO cohort is composed of long term survivors under therapy and may not represent the average PFS/OS of pts on CHEMO. Prospective trials are needed to verify these results.

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      MA01.12 - Discussant - MA01.09, MA01.10, MA01.11 (Now Available) (ID 3717)

      10:30 - 12:00  |  Presenting Author(s): Tomoyuki Hishida

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA23 - Preclinical Models and Genetics of Malignant Pleural Mesothelioma (ID 353)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 12
    • Now Available
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      MA23.01 - Phase II Trial of an Oral FGFR Inhibitor AZD4547 as Second or Third Line Therapy in Malignant Pleural Mesothelioma: Final Results of FRAME Study (Now Available) (ID 2208)

      14:30 - 16:00  |  Presenting Author(s): Wei-Sen Lam  |  Author(s): Anna K Nowak, Fred Chen, Sanjeevan Muruganandan, Sukyana Arunachalam, Melvin Chin, Michael Millward, Cathy Read, Kevin Murray, Jenette Creaney, Y C Gary Lee

      • Abstract
      • Presentation
      • Slides

      Background

      Treatment options are limited after first line platinum-based therapy for malignant pleural mesothelioma (MPM). FGFR-9 is a mitogenic ligand that activates the FGF-receptor (FGFR) family and is overexpressed in pleural fluid and tumour samples from mesothelioma patients. In mesothelioma mouse models, FGF-receptor inhibitors reduce tumour burden. Hence, we examined the efficacy of the FGFR tyrosine kinase inhibitor, AZD4547 as second/third line therapy in MPM.

      Method

      From April 2016 to January 2019, we conducted a single-site, single arm, open-label study of AZD4547 in patients with MPM. Eligible patients had histologically or cytologically confirmed mesothelioma, measurable disease and had progressed after first or second line therapy. Patients received oral 80mg twice-daily AZD4547 with protocol dose reductions as required. The primary end point was 6-month progression free survival (PFS6); key secondary endpoints included PFS, response rate, overall survival, and safety and tolerability. Using a Simons' two-stage design, 26 patients would be recruited to the first stage and the study would be declared negative if fewer than 7 (27%) of 26 patients achieved PFS6.

      Result

      24 patients (21 (87%) male), median age 69.5 (range 53-84) were recruited. Histological subtype was epithelioid (83.3%), biphasic (8.3%), sarcomatoid (8.3%). Most patients had one prior regimen (14; 58%). Common toxicities included grade 1 and 2 hyperphosphataemia, nail changes, stomatitis, and ophthalmological changes, consistent with reported toxicities of this drug class. No adverse events required hospitalisation. There were two partial responses (8%); 17 patients (70%) had stable disease (SD) for at least 6 weeks, and 5 patients (21%) had progressive disease as their best response. Three of 24 patients (12%) were progression free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and was discontinued once the criteria for progressing to stage 2 could not be met. Progression free survival was 3.9 months and overall survival was 9.3 months. One patient remained on study with SD for 16 months, experiencing ongoing grade 2 hyperphosphatemia, alopecia of body and facial hair and grade 2 onycholysis.

      Conclusion

      The FGFR inhibitor AZD4547 was ineffective for patients with MPM who had progressed on first or second line therapy. Continuous grade 2 cutaneous and ocular toxicities were observed with prolonged therapy

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      MA23.02 - CDK4/6 Inhibitors Show Antitumor Effects in Preclinical Models of Malignant Pleural Mesothelioma (Now Available) (ID 1866)

      14:30 - 16:00  |  Presenting Author(s): Elisabeth Aliagas  |  Author(s): Maria Martínez-Iniesta, Miguel Hernández, Ania Alay, David Cordero, Xavier Solé, Francisco Rivas, Anna Ureña, Noelia Vilariño, Cristina Muñoz-Pinedo, Alberto Villanueva, Ernest Nadal

      • Abstract
      • Presentation
      • Slides

      Background

      Novel therapeutic approaches are needed to improve the clinical outcome of patients with malignant pleural mesothelioma (MPM). In the current study, we investigate the antitumor activity of CDK4/6 inhibitors in preclinical models of MPM.

      Method

      MPM cell lines (H28, H226, H2052, H2452, MSTO-211H) and primary cultures (ICO_MPM1, ICO_MPM2, ICO_MPM3) were treated with abemaciclib or palbociclib for 24 and 72 hours. Cell viability was evaluated by cell counting and crystal violet assays. Cell death and cell cycle distribution were analyzed by flow cytometry and senescence was quantified by β-galactosidase expression. For transcriptomic studies, mRNA expression was assessed through RNA sequencing analysis. Gene set enrichment analysis (GSEA) was used to identify signaling pathways deregulated in MSTO-211H cells treated with CDK4/6 inhibitors. MSTO-211H cells were implanted subcutaneously in athymic mice that were randomly assigned to the following cohorts (n=7): i) vehicle; ii) cisplatin + pemetrexed; iii) palbociclib alone and iv) palbociclib + gemcitabine. Tumors’ size and mice weight was monitored during 4 weeks to evaluate efficacy.

      Result

      Treatment with abemaciclib or palbociclib at 100nM induced a significant decrease in cell proliferation (mean 50.9% ± 7.6; mean 47.3% ± 9.9, respectively) in distinct MPM cell models, including cells derived from patients who progressed to prior cisplatin and pemetrexed. Both CDK4/6 inhibitors induced G1-phase cell cycle arrest, while cell death was slightly affected (up to 1-5%). At concentrations ranging from 250 to 500nM, the percentage of senescent cells was increased after abemaciclib (15-26%) and palbociclib (18-25%) treatment in all the analyzed cell models. GSEA revealed that CDK4/6 inhibitors promote interferon signaling pathway and MHC presentation. In the in vivo experiment, a significant reduction in tumor growth was observed in response to palbociclib alone or combined with gemcitabine for 4 weeks (vehicle = 1335.8±586.4 mm3; cisplatin + pemetrexed= 726±573.5 mm3; palbociclib = 479±235.7 mm3; palbociclib + gemcitabine = 517±487.4 mm3; p< 0.05).

      Conclusion

      CDK4/6 inhibitors reduce cell proliferation in culture models of MPM mainly by blocking cell proliferation at G1 and by inducing senescence. Palbociclib alone or combined with gemcitabine reduces in vivo tumor growth of subcutaneously implanted MSTO-211H cells compared to chemotherapy.

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      MA23.03 - BAP1 Loss Induces Genome Instability Through BRCA1-Dependent and Independent Mechanisms in Mesothelioma (Now Available) (ID 1133)

      14:30 - 16:00  |  Presenting Author(s): Anita Singh

      • Abstract
      • Presentation
      • Slides

      Background

      Background

      BRCA1 associated protein 1 (BAP1) is a tumor suppressor that is the most frequently mutated in the majority of mesotheliomas. We have previously reported that loss of BRCA1 expression in mesothelioma is a common event, and mediates resistance to spindle checkpoint activator vinorelbine, a drug with relevance to treatment of mesothelioma. However, the loss of BRCA1 is unknown in mesothelioma. The aim of this study is to determine the functional relationship between BAP1 and BRCA1 and examine their role in vinorelbine resistance in mesothelioma cells.

      Method

      We conducted functional genetic analysis of BAP1 and BRCA1 in two MPM cell lines, MSTO and H2452, the latter carrying an inactivating A95D mutation in the UCH domain of BAP1. BAP1 knockdown was achieved by siRNA transfection, while BRCA1 knockdown was achieved by doxycycline induction of an integrated shRNA. Patient samples were processed for BAP1 and BRCA1 immunohistochemistry from MEDUSA cohort.

      Result

      Loss of BAP1 expression led to reduced expression of BRCA1, whereas knockdown of BRCA1 did not affect BAP1 expression. Treatment with the proteasome inhibitor, MG132, restored BRCA1 expression in the absence of BAP1 indicating that BAP1 contributes to post-translational stabilization of BRCA1 protein and the stabilization of BRCA1 by BAP1 is independent of its de-ubiquitination activity. Knockdown of BAP1 induced SAC deficiency and vinorelbine resistance concurrent with reduced expression of BRCA1 and the SAC component, MAD2L1. We also identified a positive and significant correlation between BAP1 and BRCA1 expressionin patient samples.

      Conclusion

      Our data demonstrates that BAP1 regulates BRCA1 expression through regulating its protein stability. Our findings suggest that BAP1 inactivation dysregulates the spindle assembly checkpoint via BRCA1 dependent and independent mechanisms, conferring resistance to vinorelbine. As such BAP1 may have potential as a predictive biomarker for spindle poisons, to underpin chemotherapy stratification. A hypothesis that would be tested in a multicentre randomised phase II VIM trial.

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      MA23.04 - Discussant - MA23.01, MA23.02, MA23.03 (Now Available) (ID 3817)

      14:30 - 16:00  |  Presenting Author(s): Nobukazu Fujimoto

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA23.05 - A Phase II Trial of Nintedanib in Recurrent Malignant Pleural Mesothelioma (MPM) (Now Available) (ID 943)

      14:30 - 16:00  |  Presenting Author(s): Antoinette Josephine Wozniak  |  Author(s): Bryan J. Schneider, Gregory Kalemkerian, Robert Daly, Wei Chen, Jaclyn Ventimiglia, Misako Nagasaka, Marjorie Zauderer

      • Abstract
      • Presentation
      • Slides

      Background

      Background: Malignant pleural mesothelioma (MPM) is a disease that is resistant to chemotherapy and there remains an unmet need for better therapeutic options. Nintedanib (BIBF 1120) is an oral multikinase inhibitor impacting VEGF, FGF, PDGFR, and other kinase activity such as TGFß signaling pathways. VEGF, FGF, and TGFβ are commonly expressed in MPM. We conducted a phase II trial in patients with recurrent MPM after platinum-based chemotherapy.

      Method

      Methods: Patients (pts) with MPM previously treated with platinum-based chemotherapy, performance status (PS) 0-1, adequate organ function, and no contraindications to anti-angiogenic therapy were eligible for treatment. Nintedanib 200 mg twice per day was administered until disease progression or unacceptable toxicity. The primary endpoint was the 4-month progression-free survival (PFS). A two-stage design was used and >4 pts had to have a PFS of ≥4 months to proceed to the second stage.

      Result

      Results: Twenty pts. were enrolled. The median age was 70 yrs. (32-81), 90% were male, and 80% were PS=1. The histology was 70% epithelioidal, 5% sarcomatoid, 10% biphasic, and 15% unknown. 15% had prior bevacizumab. The median follow-up is 16.4 mo. A median of 2 treatment cycles (range 1-18) were delivered. There were no responses but 40% had stable disease. The median PFS was 1.8 mo. (95% CI: 1.68, 3.55) and the PFS rate at 4 mo. was 13%. The median OS was 4.2 mo. (95% CI: 2.53, 8.74) and the OS rate at 4 mo. was 55%. Toxicities were usually grade 1-2 and included diarrhea, fatigue, edema, transaminase elevation, anorexia, nausea, vomiting and dyspnea.

      Conclusion

      Conclusions: The activity of nintedanib in previously treated MPM pts. was modest. The trial did not meet the primary PFS endpoint. However, there was a small subset of pts. that had prolonged stable disease for >4 months thus potentially deriving some clinical benefit from treatment.

      Supported by Boehringer Ingelheim.

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      MA23.06 - Development of a Novel Genetically Engineered Mouse Model of Malignant Pleural Mesothelioma (Now Available) (ID 2506)

      14:30 - 16:00  |  Presenting Author(s): Katarina Gyuraszova  |  Author(s): Tiziana Monteverde, Tatyana Chernova, Rodger Duffin, Kevin Blyth, Anton Berns, Marion Macfarlane, Daniel J. Murphy

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive neoplasm strongly associated with inhalation of asbestos. MPM is difficult to diagnose and typically occurs after long latency period. Most of the studies are restricted to the end-stage disease and little is known about pre-malignant disease. Efforts to develop targeted therapeutic strategies based on cell culture have largely failed. Our aim was to develop a novel genetically engineered mouse model that combines deletion of the major tumour suppressors lost in human MPM with intra-pleural injection of asbestos. This model will allow us to investigate how mutagenesis combines with fibre-induced inflammation to drive disease evolution.

      Method

      We used genetic engineering to develop an accelerated mesothelioma mouse model combining pleural-restricted, CRE-mediated deletion of NF2, Tp53 (Tp53 is lost in c.10% of human MPM) and full-body knock-out of Cdkn2a with intra-pleural injection of asbestos recapitulating the disease-relevant inflammatory microenvironment. We used immunohistochemistry to analyse the tissue and the lesions.

      Result

      Intra-pleural injection of asbestos dramatically accelerates mesothelioma development in mice triple deleted for NF2, Cdkn2a and Tp53, with all such mice succumbing to malignant disease within 3-4 months (Figure 1). These mice develop malignant lesions in the mesothelial lining of the thoracic cavity accompanied with pleural effusion showing high similarity with human malignant mesothelioma. IHC analysis showes positive staining for mesothelioma markers, e.g. pancytokeratin, vimentin and WT-1. Positive macrophage staining (F4/80) strongly indicates involvement of inflamatory component.sc_pic.png

      Conclusion

      In our model, we combined conditional mouse genetics with dose-defined exposure to asbestos to mimic development of human MPM. Our system provides unique insights into the critical transition from pre-malignancy to MPM and will allow us to test emerging therapeutic interventions in the most physiologically relevant pre-clinical setting possible.

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      MA23.07 - Loss of Expression of BAP1 and/or MTAP Aids in the Diagnosis of Malignant Mesothelioma Metastatic to Lymph Nodes (Now Available) (ID 1121)

      14:30 - 16:00  |  Presenting Author(s): Anja C. Roden  |  Author(s): Tobias Peikert, Julie Vrana, Angela Hudson, Dennis Wigle, Marie Christine Aubry, Aaron S. Mansfield

      • Abstract
      • Presentation
      • Slides

      Background

      Stage and histology are the strongest prognostic parameters in malignant pleural mesothelioma and aid management of patients. However, the distinction between reactive intranodal mesothelial cells and metastatic malignant mesothelioma (MM) can be challenging. Loss of BRCA1 associated protein-1 (BAP1) and/or methylthioadenosine phosphorylase (MTAP) expression has been identified in a subset of MM but not in reactive mesothelial proliferation. We investigated the value of these markers in the distinction between reactive mesothelial cells and metastatic MM in lymph nodes.

      Method

      Surgical files of Mayo Clinic Rochester (1996-2018) were searched for metastatic MM in lymph nodes. All cases and if available corresponding primary MM were reviewed by a thoracic pathologist (ACR) to confirm the diagnosis. Primary MM and lymph nodes were stained with BAP1 (clone C-4) and MTAP (2G4). Absence of nuclear staining of BAP1 and absence of nuclear and cytoplasmic staining of MTAP in essentially all tumor cells was considered as loss of expression.

      Result

      Forty-four patients (25 males, 56.8%) had a median age of 64 years (range, 24-75) at time of surgery. Tissue was available from nodal metastases in all cases, either paired with the primary MM at time of nodal sampling (N=37) or at a different time (N=4) (time between tissue collections, range, 1day- 4 years, respectively), or without paired primary MM (N=3). Thirty-seven pleural, 6 peritoneal and 1 pericardial MM were of epithelioid (N=39) or biphasic (N=5) subtype. Patients underwent extrapleural pneumonectomy (N=17), pleurectomy (N=7), resection (N=9), debulking (N=2), biopsy (N=8), or autopsy (N=1). In nodal metastases, BAP1 and/or MTAP expression was lost in 29 (of 43, 67.4%) cases; specifically, BAP1 expression was lost in 28 (of 44, 63.6%), MTAP was lost in 14 (of 43, 32.6%), and both were lost in 12 (of 43, 27.9%) cases. Agreement in expression/loss of expression of BAP1 and/or MTAP in primary and metastatic MM occurred in all cases. During a median follow up of patients who underwent extrapleural pneumonectomy or pleurectomy (available in N=23) of 14.8 months (range, 1-119) 17 patients died within a median time of 16 months.

      Conclusion

      BAP1 and MTAP immunostains are helpful in the distinction between metastatic MM and reactive mesothelial cells in lymph nodes when one or both markers lost expression in the mesothelial cells. Expression of both markers does not exclude the possibility of metastatic MM.

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      MA23.08 - Discussant - MA23.05, MA23.06, MA23.07 (Now Available) (ID 3818)

      14:30 - 16:00  |  Presenting Author(s): Kemp Kernstine

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA23.09 - Fusion Genes Identified from Whole Genome and Whole Transcriptome Sequencing of Malignant Pleural Mesothelioma Tumours (Now Available) (ID 2014)

      14:30 - 16:00  |  Presenting Author(s): Tian Mun Chee  |  Author(s): Harald Oey, Kwun M Fong, Ian Yang, Lutz Krause, Rayleen Bowman

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is an asbestos-related cancer without curative treatment. Fusion genes result from structural chromosomal rearrangements such as translocation, inversion, amplification and deletions, leading to erroneous apposition of components of two or more genes. Consequences include abolition of gene functions that protect against tumourigenesis, or increased activation of genes that promote cell proliferation. To identify fusion genes in MPM genomes, we executed whole genome sequencing (WGS) on eight MPM tumours, and validated the expression of putative fusion genes identified from WGS by whole transcriptome analysis (RNA-Seq).

      Method

      Histology of eight MPM tumours was confirmed by two qualified anatomical pathologists, prior to extraction of genomic DNA and RNA. Whole genome and whole transcriptome sequencing were performed using Illumina HiSeq platforms. Following stringent data processing and filtration, putative fusion variants were called using an in-house bioinformatics pipeline. Fusion events with potential functional consequences were then validated by whole transcriptome analysis, and annotated using TCGA Fusion Gene Data Portal and The Gene Ontology Resource.

      Result

      A total of 592 and 321 putative fusion variants were called respectively from WGS data using Delly, and from RNA-Seq using STAR-Fusion computational tools. Expression of WGS putative fusion variants was confirmed in RNA-Seq data, resulting in twelve fusion genes being identified. Among 24 genes involved in fusion events, twenty-two were listed in TCGA Fusion Gene Data Portal with gene partners that were not identified in our cases. Two genes were novel to that database. Multiple functional processes that may lead to tumour development were attributable to these genes including protein polyubiquitination, protein deubiquitination, antioxidant activity, DNA repair, immune response, integrin-mediated signalling pathway, chromatin organization, transcription coactivator activity, angiogenesis, natural killer cell proliferation and DNA-binding transcription factor activity.

      Conclusion

      In combination, WGS and RNA-Seq data analysis revealed several fusion genes that warrant further investigation as possible drivers of malignant mesothelioma, and which may serve as diagnostic and therapeutic targets.

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      MA23.10 - Low Number of Mutations and Frequent Co-Deletions of CDKN2A and IFN Type I Characterize Malignant Pleural Mesothelioma (Now Available) (ID 1627)

      14:30 - 16:00  |  Presenting Author(s): Anca Mihaela Nastase  |  Author(s): Amit Mandal, Shir Kiong Lu, Spyridon Gennatas, Hima Anbunathan, Matthew Edwards, Deborah Morris-Rosendahl, Anthony Newman Taylor, Robert C Rintoul, Eric Lim, Sanjay Popat, Andrew G Nicholson, Mark Lathrop, Anne M Bowcock, Miriam F Moffatt, William O.C Cookson

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive tumour with dismal prognosis and overall survival.

      To expand our understanding of molecular background of MPM and to identify novel targetable aberrations we report an integrated genomic analysis of 121 tumour samples.

      Method

      Fresh-frozen tumour samples (obtained from Mesobank UK,the BLF funded Mick Knighton Mesothelioma Tissue Bank, Respiratory BRU Biobank Diagnostic Archive, Royal Brompton Hospital and an Imperial College London prospective study) were analysed by whole exome sequencing (WES, n=50), SNP genotyping (n=118) and targeted capture sequencing (n=119) for 57 genes.

      Sequencing libraries were prepared using Target Enrichment Systems for the Illumina Multiplexed Sequencing platform. Somatic mutations were called using VarScan after recalibration of alignments by Genome Analysis Toolkit (GATK). SNP genotyping was performed with the Human Infinium Omni-Express-Exome v1.3/1.4 Bead Chips arrays. Segmentation and copy number calling was performed using a combination of Allelic specific copy number analysis of tumour (ASCAT), DNACopy and GISTIC softwares.

      Result

      Analysis of WES paired samples revealed a median of 31 non-synonymous somatic mutations per tumour, lower than melanoma (315 somatic mutations) or lung cancer (187.5 for squamous and 158 for adenocarcinoma), two types of tumours linked to known carcinogen exposure.

      Investigation of copy number showed significant frequent deletion (q-value>0.05) of 9p21 locus where CDKN2A, MTAP and IFN type I genes are located. Deletion of CDKN2A was seen in 71/121 patients with homozygous deletion in 58/71 patients. Homozygous co-deletion of CDKN2A and IFN type I was seen in 38/58 patients, homozygous codeletion with MTAP in 49/58 patients while 37 patients showed all three as homozygous co-deleted.

      Patients with CDKN2A and IFN type I deletions had worse overall survival compared with the CDKN2A wild type and patients CDKN2A only deleted patients (median 8.3 months vs 13.1 months, p-value=0.016).

      Deletion of 3p21.1 locus and mutations in BAP1 were detected in 54.5% of the patients, making BAP1 the second most commonly altered gene. RB1 (13q14.2) was commonly altered mainly by deletion in 25.6% of the patients. NF2 and TP53 were affected by mutations in 19.8% and 7.4% of the patients, repectively. Patients with mutations in TP53 had worse overall survival compared with TP53 wild type patients (p-value=0.0005).

      Conclusion

      Co-deletion of CDKN2A, MTAP and IFN type I genes could have therapeutic implications for the patients. Deletion of IFN type I may have direct implications for patient responses to immunotherapy. In the contex of multiple vulnerabilities, the presence of both CDKN2A and RB1 loss might define an important group of patients susceptible to CDK4/6i targeted therapies.

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      MA23.11 - Analysis of Immune Phenotype Composition in Malignant Pleural Mesothelioma (MPM) Using Bulk RNA Sequencing (Now Available) (ID 2326)

      14:30 - 16:00  |  Presenting Author(s): Amit Mandal  |  Author(s): Anca Mihaela Nastase, Shir Kiong Lu, Spyridon Gennatas, Hima Anbunathan, Matthew Edwards, Deborah Morris-Rosendahl, Anthony Newman Taylor, Robert C Rintoul, Eric Lim, Sanjay Popat, Andrew G Nicholson, Anne M Bowcock, Mark Lathrop, Miriam F Moffatt, William O.C Cookson

      • Abstract
      • Presentation
      • Slides

      Background

      Exploiting the immune status of the tumour microenvironment (TME) is increasingly being adopted for many cancer types. Investigation into immune phenotype composition of the TME is at present lacking for malignant pleural mesothelioma (MPM) but critically important in light of the cancer’s overall poor prognosis and lack of targeted therapy as clinical standard of care. In this study, CD8+ve tumour infiltrating lymphocyte (TIL) level has been used as a starting point to compare differences in mutational patterns, histology and survival in MPM.

      Method

      Bulk RNA sequencing of tumour tissue from 35 MPM patients (in-house cohort) was performed. Sequencing read alignment and gene count estimation were performed using STAR (v.2.5.2b). To increase the sample size, raw data from Bueno et al. (n=211 subjects) was accessed and gene count estimations performed. In addition, the TCGA-MESO cohort (n=86 subjects) count data was included from the GDC (Genomic Data Commons) website. All count data were normalized cohort-wise using the ‘voom’ method implemented in limma package. Deconvolution of constituent immune phenotypes in the TME from the bulk RNA-sequencing data was performed by applying CIBERSORT (v.1.04) on normalized count data sets. For assessing the genetic context of observed immune phenotypes, somatic mutations were profiled using targeted sequencing of a custom gene panel for the in-house cohort. For the Bueno et al. and the TCGA-MESO cohorts, somatic mutations were either available from an overlap of whole-exome sequencing (WES) and targeted gene panel, or from WES only.

      Result

      A total of 27 samples (3 of 35 (8.6%), 21 of 211 (9.9%) and 3 of 86 (3.5%) from the in-house, Bueno et al. and TCGA-MESO cohorts respectively) were identified with immune phenotype enriched for CD8+ve TIL. Histological subtype distribution in the CD8+ve enriched samples was seen to be almost equivalently split between Epithelioid and Biphasic subtypes (51.85% and 48.15% respectively). Interestingly, BAP1 mutation was found to be present in only 7.7% of the samples. Considering in addition the genes NF2, SETD2, SETD6, SETDB1, TP53 and LATS1/2, mutations were only found to be present in 57.7% of the samples in total. As such >40% of samples with CD8+ve TIL do not have any mutations detected in known hotspot genes for MPM. Histological subtype is not significantly different between these ‘wild-type’ and hotspot gene(s) mutated samples. Median survival for the groups was found to be 1.85 and 0.73 years respectively.

      Conclusion

      In the present study, approximately 3-10% of MPM samples were found to have enrichment for CD8+ve TIL. Nonetheless on closer examination of the genetic context, mutation patterns emerge that warrant further investigation. For samples that have TP53 (n=3) mutation or mutations in multiple hotspot genes (BAP1, NF2, SETD2, LATS2; n=1), survival understandably is lowest (0.27 years average). This raises a number of further questions including what sustains a tumour despite high CD8+ve TIL population? And more importantly with lack of tumour mutational burden what other TME signals draw effector immune cells? Further investigations, by comparing additional immune markers with copy number changes that might be present in hotspot genes, are therefore required.

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      MA23.12 - Discussant - MA23.09, MA23.10, MA23.11 (Now Available) (ID 3819)

      14:30 - 16:00  |  Presenting Author(s): Kenneth John O’Byrne

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS09 - Immunotherapy in Small Cell Lung Cancer (ID 72)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 3
    • Now Available
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      MS09.01 - Immune Checkpoint Blockade for SCLC: State of the Art (Now Available) (ID 3487)

      14:00 - 15:30  |  Presenting Author(s): Scott J. Antonia

      • Abstract
      • Presentation
      • Slides

      Abstract

      It is clear that small cell lung cancer can be an immunotherapeuticly responsive disease. Single agent anti-PD1 and anti-PD-L1 can produce tumor regressions. Anti-PD-L1 given in combination with chemotherapy produces a survival benefit when given as first-line therapy for extensive stage disease. Anti-PD1 is also an option in third line. Although responses are produced in the second line setting neither anti-PD1 nor anti-PD-L1 has proven to produce a survival benefit in unselected patients. The proper application of relevant biomarkers such as TMB has the potential to identify patients who are likely to benefit. Given the fact that small cell lung cancer tumors have a paucity of tumor infiltrating lymphocytes, it is not surprising that immunotherapeutics solely directed at the immune suppressed tumor microenvironment have limited clinical activity. It is likely that combination immunotherapy, with a component of the combination influencing the lymphoid compartment to increase the number of tumor reactive T cells will be necessary to significantly increase the clinical activity of immune-based therapies. There are several potential ways that this could be accomplished. Anti-CTLA.4 can have an impact on regulatory T cells in the tumor microenvironment, however at least in melanoma it has been shown to be operational within the lymphoid compartment as well to increase circulating tumor reactive T cells. Anti-CTLA.4 has been combined with both anti-PD1 and anti-PD-L1. Response rates of the combination have been higher than what can be produced with anti-PD 1 monotherapy. The combination has not yet been shown to produce a survival advantage. Another approach to increasing tumor reactive T cells is to utilize radiation which can release tumor antigens and immunogenic fashion. Trials are ongoing combining radiation with anti-PD1 and anti-CTLA.4. Vaccines offer another potential means to accomplish expansion of tumor reactive T cells. An autologous dendritic cell based vaccine with p53 as the tumor antigen has been shown to produce clinical responses in small cell lung cancer as monotherapy, and is now being combined with anti-PD1 and anti-CTLA.4. An alternative approach is to redirect peripheral T cells through ex vivo transduction with tumor protein-specific antigen binding molecules. An example of this is a chimeric antigen receptor specific for DLL 3. These sorts of combinations have the potential to advance the efficacy of immunotherapy for small cell lung cancer.

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      MS09.02 - Clincal and Molecular Biomarkers for Selection of Sclc Patients Candidate to Immunecheckpoint Blockade (Now Available) (ID 3489)

      14:00 - 15:30  |  Presenting Author(s): Lauren Averett Byers

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immunotherapy has dramatically altered the treatment options available to patients with lung cancer. In the past year, small cell lung cancer (SCLC) fully joined the immunotherapy era with approvals by the US Federal Drug Administration (FDA) for three separate immune checkpoint inhibitors – atezolizumab for frontline therapy in patients with extensive stage SCLC (ES-SCLC) (in combination with platinum-etoposide chemotherapy) and nivolumab and pembrolizumab (each as monotherapy) for relapsed SCLC. The combination of nivolumab plus ipilimumab also demonstrated durable activity in a subset of patients treated on the Phase 1/2 CheckMate032 trial, with an overall response rate of 22% and a 2 year overall survival rate of 26%.1 The addition of atezolizumab to carboplatin and etoposide as a new standard of care was based on results from the Phase 3 IMpower133 trial.2 In that randomized trial, the addition of atezolizumab to carboplatin-etoposide, followed by atezolizumab maintenance, led to improvements in both progression free survival (PFS) (4.3 months in the placebo control arm versus 5.2 months in patients receiving atezolizumab) and overall survival (OS) (10.3 months with placebo versus 12.3 months with atezolizumab). Additional randomized trials testing other immune checkpoint inhibitors in combination with standard platinum-etoposide chemotherapy are ongoing, with clinical findings expected in the next several months. This includes the phase 3 trial of durvalumab plus platinum-etoposide (CASPIAN), which has now been reported to show improved overall survival (OS) with the addition of durvalumab at a planned interim analysis (press release).

      Despite these landmark approvals for immune checkpoint inhibitors in ES-SCLC, a large number of patients with SCLC do not appear to receive clinic benefit with the currently available inhibitors of PD-1/PD-L1 and/or CTLA-4. Furthermore, there are not yet established biomarkers for identifying those patients with SCLC who are likely to respond. As with non-small cell lung cancer, immunohistochemistry (IHC) for PD-L1 levels and tumor mutation burden (TMB) are both candidate biomarkers.3,4 However, neither of these have been prospectively validated to date in SCLC and there may be important differences in their performance depending on how testing is done (e.g., variation between antibodies, scoring methods/cutoffs, or technical differences between molecular platforms).

      Recently, new combinations of targeted therapies together with immune checkpoint inhibitors (such as inhibitors of DNA damage response (DDR) such as PARP1 or Chk1 to enhance STING pathway activation) have demonstrated promise in preclinical studies of SCLC and are being translated into the clinic for further investigation.5 In addition, other new immunotherapeutic approaches are being tested in ongoing trials. Examples of these include studies of chimeric antigen receptor T-cells (CAR-T) and bi-specific T-cell engagers (BiTE molecules) targeting the notch inhibitor ligand DLL3 for patients with relapsed SCLC. In this context, additional biomarkers related to specific combinations of targeted and immune-therapies and/or new classes of immunotherapy (e.g., SLFN11 levels for PARP inhibitors; cMyc status for Chk1 inhibitors; markers of STING pathway activation; or DLL3 expression levels) may emerge as additional biomarkers relevant to immune responses. Finally, a better understanding of tumor and immune environment heterogeneity between patients – as well as intra-tumoral heterogeneity – will lead to more effective strategies for matching patients to specific immunotherapies and overcoming immunotherapy resistance.

      REFERENCES

      1. Della Corte CM, Gay CM, Byers LA. Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era. Cancer 2019;125:496-8.

      2. Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 2018;379:2220-9.

      3. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-95.

      4. Hellmann MD, Callahan MK, Awad MM, et al. Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell 2018;33:853-61 e4.

      5. Sen T, Rodriguez BL, Chen L, et al. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov 2019;9:646-61.

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      MS09.03 - Small Cell Lung Cancer: The Immune Microenvironment (Now Available) (ID 3490)

      14:00 - 15:30  |  Presenting Author(s): Stephen V. Liu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Based in part on the relatively high tumor mutational burden (TMB) and the strong link to tobacco use, there was a relative optimism regarding the prospects of success with immunotherapy in small cell lung cancer (SCLC). Over the past few years, while we have seen promising activity with checkpoint inhibitors in SCLC, the gains have been somewhat modest. As in other immune-responsive tumors, durable responses and long-term survival are possible. Nivolumab and pembrolizumab monotherapy have both demonstrated impressive durations of response, circling 18 months in the third line setting (Ready, JTO 2018; Chung, AACR 2019). Landmark survival rates far exceed historic controls in this setting. Meaningful benefit, though, is limited to a subset of patients, with response rates of only 12-19%. Both agents received accelerated approval by the FDA as third-line therapy for SCLC, but given the high attrition rate in SCLC, the impact of these approvals will be limited. Second-line and maintenance trials have failed to improve upon historic standards (Reck, ESMO 2018; Owonikoko, ELCC 2019). Fortunately, the addition of the PD-L1 inhibitor atezolizumab to first line carboplatin and etoposide improved both progression-free survival and overall survival (Horn, NEJM 2018). While the long-overdue improvement in survival was important and led to the FDA approval of atezolizumab in March 2019, there is significant room for improvement.

      The current use of checkpoint inhibitors in SCLC is empiric, though it is glaringly obvious that the true, durable benefit is limited to a subset of patients. Biomarkers are needed to identify those patients – to ensure they receive the appropriate therapy but also to help direct other patients to novel strategies. Predictive biomarkers can also provide valuable insight into the underlying biology of immune responses. Biomarker studies are challenging in SCLC; tissue samples are often scant, and the aggressive nature of the disease often precludes in depth study. Early data, though, speak to particular importance of the immune microenvironment in SCLC.

      Expression of PD-L1 by immunohistochemistry holds predictive value in non-small cell lung cancer (NSCLC). Its role in SCLC is evolving. In the CheckMate-032 study, nivolumab alone or in combination with the anti-CTLA-4 antibody ipilimumab, was explored in patients with previously treated SCLC (Hellmann, ASCO 2017). Using the 28-8 PD-L1 clone and a cutoff of 1%, only 18% of evaluable samples expressed PD-L1. Surprisingly, responses were more frequent in the PD-L1 negative tumors. With nivolumab alone, the response rate was 9% in PD-L1 positive tumors compared to 14% in PD-L1 negative tumors. With the combination of nivolumab and ipilimumab, the difference was even greater with a 10% response rate in PD-L1 positive tumors compared to 32% in PD-L1 negative. Some parallels are seen with pembrolizumab, but our understanding of PD-L1 as a biomarker is evolving. In a single arm study of maintenance pembrolizumab for SCLC (Gadgeel, JTO 2018), only 3 out of 30 patients had tumors with PD-L1 expression using the 22C3 clone (tumor proportion score, TPS). While the median PFS for the entire population was only 1.4 months, the 3 patients with TPS PD-L1 positive tumors all had a PFS over 10 months. Expression of PD-L1 at the stromal interface was also explored (combined proportion score, CPS). More patients had PD-L1 positive tumors using the CPS approach (8/20, 40%) and outcomes were superior in the CPS PD-L1 positive population: response rate was 37.5% vs. 8.3%, median PFS was 6.5 months vs. 1.3 months, and median overall survival was 12.8 months compared to 7.6 months. Similar results were seen in the salvage setting. In KEYNOTE-158, patients with previously treated SCLC received pembrolizumab monotherapy (Chung, ASCO 2018). Using the CPS approach, 39% of patients were PD-L1 positive, 47% were negative and 14% were non-evaluable. Again, outcomes favored the CPS PD-L1 positive subset including response rate (35.7% vs. 6%) and overall survival (14.9 months vs. 5.9 months). A separate retrospective analysis of a 95-sample cohort noted tumor expression of PD-L1 in 18% of samples but PD-L1 expression on tumor infiltrating lymphocytes (TILs) was seen in 67% of samples (Rivalland, ASCO 2017). There was no difference in survival based on tumoral expression of PD-L1, but median survival was longer in patients with PD-L1 positive TILs compared to PD-L1 negative TILs (17.2 months vs. 7.9 months, HR 0.36; 95% CI 0.22-0.60). The importance of the immune microenvironment in facilitating an immune response is becoming increasingly clear but it extends beyond expression of PD-L1. The presence and the specific location of tumor-infiltrating T-cells also holds value. Specific immunophenotypes are present and have been described as immune-desert (with few or no CD8+ T cells), immune-excluded (with CD8+ T cells present but limited to the adjacent stroma), and immune-inflamed (with CD8+ T cells in contact with tumor cells). A study of olaparib and durvalumab examined these phenotypes in patients with advanced SCLC (Thomas, JTO 2019) and found 14% with an immune-desert phenotype, 64% of samples with an immune-excluded phenotype and 21% with an immune-inflamed phenotype. PD-L1 expression was noted in all patients who achieved a response but was also noted in non-responders. In contrast, all of the patients with an immune-inflamed phenotype achieved a response.

      Much more work is needed to fully understand how the immune microenvironment facilitates (or precludes) immune responses. It is not yet clear whether these characteristics can be used as a predictive marker for use of checkpoint inhibitors. It is also not clear whether strategies to alter the microenvironment (with radiation therapy or other immune modulators) will induce effective immune responses. What is clear is that empiric therapy can only take us so far in the management of this exceptionally lethal disease. The path forward will require insight into the complexities orchestrating immune responses and a personalization of therapy for specific subsets of SCLC, subsets that certainly exist but, to date, evade proper detection. We have made tremendous strides in recent years to improve outcomes in SCLC but there remains much work to do.

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    MS10 - Lung Cancer Screening, Opportunistic Evaluation of Findings (ID 73)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Screening and Early Detection
    • Presentations: 7
    • Now Available
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      MS10.01 - COPD/Emphysema (Now Available) (ID 3492)

      15:45 - 17:15  |  Presenting Author(s): Javier Zulueta

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer and COPD are now the second and third most frequent causes of death in the US. Mortality from COPD has increased by 86% in the last 25 years (1), but remains a greatly underdiagnosed disease. Furthermore, COPD, and in particular emphysema, has been shown to signficantly increase the risk of having, and dying from, lung cancer (2-4). In spite of these facts, the USPSTF continues to recommend against screening for COPD mainly because there is no evidence showing that any treatment or intervention can have an impact on the outcome of COPD. In this presentation we will review the latest data showing that lung cancer screeing may be an opportunity to uncover a large proportion of patients with underdiagnosed COPD, and that screening for lung cancer may have an impact on long term outcome of COPD. In addtition, the presence of COPD and/or specific subtypes of emphysema may be key in improving the selection of optimal candidates for lung cancer screening. Questions regarding the potential harms involved in screening for lung cancer in individuals with COPD/emphysema will be addressed.

      1. Mulshine. AJPH 2018; 108:1294-5

      2. de Torres et al. Chest 2007;132:1932-8

      3. Zulueta et al. Chest. 2012;141(5):1216-23

      4. Wilson et al. Am J Respir Crit Care Med. 2008;178:738

      5. Gonzalez et al. PLoS One 2019; in press.

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      MS10.02 - Coronary Artery Diseases (Now Available) (ID 3493)

      15:45 - 17:15  |  Presenting Author(s): Joseph Shemesh

      • Abstract
      • Presentation
      • Slides

      Abstract

      Coronary artery calcification (CAC) on low dose chest CT for lung screening

      J. Shemesh MD

      Professor emeritus of cardiology

      Sheba Medical Center

      Introduction:

      CT-based Coronary artery calcification (CAC) Agatston score on Lung cancer screening has an unequivocal prognostic contribution to future cardiovascular (CV) events and mortality.

      Aim: To provide the radiologists with helpful information regarding on how to diagnose, quantify and routinely report on CAC while reading low dose chest CT (LDCT) performed for lung cancer screening.

      Current understandings: CAC can be easily detected and its extent can be quantify or semi-quantify while reading the chest CT without extra radiation, efforts or cost. Most of the target subjects for lung screening are at the same time at high risk to develop cardiovascular (CV) events and mortality (1) . Reporting on CAC enhances the lung screening benefit by providing the clinicians with an additive powerful risk stratification tool that can improve the management of primary prevention of CV events particularly the need for statin . Recently the Society of Cardiovascular Computed Tomography (SCCT) and the Society of Thoracic Radiology (STR) have jointly published guidelines for coronary artery calcium scoring derived from non contrast noncardiac chest CT scans (2). The experts of this guideline , recommend reporting on CAC as Class I indication.

      It has been shown that the absence , presence and severity of CAC identify those who are most likely to benefit from statin therapy for primary prevention (3) Comparing those with and without statin exposure, statin therapy was associated with reduced risk of MACE in patients with CAC but not in patients without CAC . They further found that the effect of statin use on MACE was significantly related to the severity of CAC , with the number needed to treat to prevent 1 initial MACE outcome over 10 years ranging from 100 (CAC 1 to 100) to 12 (CAC >100).

      The most recent guidelines recognize the CAC score as disease score that can individualize the CVD risk and recommended its use to refine the risk estimation in order to better allocate asymptomatic subjects to statin treatment,intensification or avoidance, for primary prevention of CVD (4). The Multi-Ethnic Study of Atherosclerosis (MESA) score is a new score that incorporates the Agatston CAC score in addition to traditional risk factors to estimate the 10 years cardiac risk (5)

      In summary: CAC is the most prevalent incidental finding on LDCT. It can be easily detected measured and reported on lung screening CT without extra radiation, efforts or cost. CAC score helps to avoid or recommend life time statin or aspirin treatment .

      10 Take home messages

      Most of the target subjects for lung screening are at the same time at high risk to develop cardiovascular (CV) events and mortality.

      CAC is the most prevalent incidental finding on LDCT

      CAC is the best biologic prognostic marker for the prediction of CV events and mortality.

      The measure of CAC is now accepted as common practice for primary prevention of CV events.

      CAC can and should be measured and reported on chest CT done for lung cancer screening.

      CAC is associated strongly and in a graded fashion with 10-year risk of incident ASCVD as it is for CHD, independent of standard risk factors, and similarly by age, gender, and ethnicity. While those with zero CAC are almost exclusively below 5% 10 years risk (statin is not indicated), those with CAC ≥ 100 were consistently above 7.5% (statin is indicated).

      In a large-scale cohort without baseline ASCVD, the presence and severity of CAC identified patients most likely to benefit from statins for the primary prevention of CVDs:

      There was no benefit of statins in those with no CAC and low or intermediate baseline risk.

      Patients with a CAC >100 had a 64-71% reduction in MACE even with low (<5%) or intermediate risk (5-20%).

      Reporting on CAC enhances the lung screening benefit by providing the clinicians with an additive powerful risk stratification tool that can improve the management of primary prevention of CV events particularly for the initiation / withhold / intensification / avoidance of statin treatment.

      CAC can be estimated as none, mild, moderate or severe but it is recommended to perform the Agatston CAC score.

      CAC score can recategorize up to half of those who underwent chest CT into a higher or lower CV risk category.

      REFERENCES

      Hecht HS, Henschke CI, Yankelevitz D et al. Combined detection of coronary artery disease and lung cancer. Eur Heart J. 2014;35:2792–6

      Harvey S. Hecht, Paul Cronin Michael J. Blaha et al 2016 SCCT/STR guidelines for coronary artery calcium scoring of noncontrast noncardiac chest CT scans: A report of the Society of Cardiovascular Computed Tomography and Society of Thoracic Radiology. Journal of Cardiovascular Computed Tomography 2017, Volume 11, Issue 1, Pages 74–84

      Mitchell JD, Fergestrm N, Gage BF, et al. Impact of statins cardiovascular outcomes following coronary artery calcium scoring. J Am Coll Cardiol 2018:72:3233-3244

      2018AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Grundy SM et al. J Am Coll Cardiol. (2018)

      McClelland RL, Jorgensen NW, Budoff M, et al. 10-Year Coronary Heart Disease Risk Prediction Using Coronary Artery Calcium and Traditional Risk Factors: Derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) With Validation in the HNR (Heinz Nixdorf Recall) Study and the DHS (Dallas Heart Study). J Am Coll Cardiol. 2015;66:1643–53

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      MS10.03 - Aortic Valve Calcifications (Now Available) (ID 3494)

      15:45 - 17:15  |  Presenting Author(s): Yeqing Zhu  |  Author(s): Yong Wang, William Gioia, Rowena Yip, Artit Jirapatnakul, Micheal Chung, David Yankelevitz, Claudia I Henschke

      • Abstract
      • Presentation
      • Slides

      Abstract

      INTRODUTION: Smoking is a major risk factor for both cardiovascular disease and lung cancer. Low-dose computed tomography (LDCT) screening for lung cancer provides an opportunity to identify both diseases in asymptomatic smokers (1). The extent of aortic valve calcification (AVC) is the predominant driver of degenerative aortic valve stenosis (AS) (2), which is an underdiagnosed and undertreated disease. Cardiovascular morbidity and mortality is higher for people with moderate/severe AVC as compared to those with none or mild AVC as demonstrated on echocardiography (3). Our study aimed to assess sensitivity and reliability of visual AVC scoring on LDCT for predicting AS in older smokers. In addition, we aimed to determine the frequency of any AVC and its significant predictors in a program of LDCT screening for lung cancer, separately on baseline and annual repeat screenings.

      MOTHODS: We reviewed 1225 consecutive participants in annual LDCT screening for lung cancer at the Mount Sinai Hospital before July 2018, who had at least two LDCTs without aortic valve replacement (AVR) before enrolled. The baseline LDCT was the first scan obtained at the time of enrollment and the most recent LDCT was the last LDCT obtained before July 2018, unless the participant had either AVR or had died before July 2018; for these cases, the last LDCT scan before surgery or death was used. Sensitivity and specificity of moderate/severe visual AVC score on LDCT to identify AS on echocardiogram was calculated for 126 participants who had both tests within 12 months. Using regression analyses, risk factors for AVC at baseline, for progression, and for new AVC on annual rounds of screening were identified. Reliability of AVC assessment on LDCT was assessed by comparing AVC visual scores with 1) standard-dose, electrocardiography (ECG)-gated CT for 31 participants who had both tests within 12 months, 2) with Agatston scores of 1225 participants on the most recent follow-up LDCT, and 3) by determining the intra-reader agreement on baseline LDCTs and separately for the most recent LDCTs of all participants.

      RESULTS: Among these 126 participants who had LDCT and echocardiography within 12 months, 7 (5.6%) were diagnosed with moderate/severe AS, 3 (2.4%) were diagnosed with mild AS, 37 (29.4%) with aortic sclerosis, and 79 (62.7%) with no sclerosis or AS (Table 1). Of the 3 diagnosed as severe AS on echocardiography, all 3 had severe (grade 3) AVC on LDCT and of the 4 diagnosed as moderate AS on echocardiography, all 4 had moderate (grade 2) AVC on LDCT. Visual AVC scores on LDCT had substantial agreement with the severity of AS on echocardiography (weighted kappa=0.68, 95% CI: 0.56, 0.80). In addition, correlation was significant between the AVC visual scores on LDCT and both the echocardiographically determined mean pressure gradient (p = 0.02) and aortic valve area (p = 0.02) in these 10 participants with AS. Sensitivity and specificity of moderate/severe visual AVC scores for moderate/severe AS on echocardiogram was 100% and 94%, respectively.

      There is substantial inter- (total weighted kappa of 0.73) and excellent intra-observer agreement (Baseline LDCT: weighted Kappa=0.91, 95% CI: 0.88-0.95; The most recent LDCT: weighted Kappa=0.90, 95% CI: 0.88-0.92).

      Of the 1225 participants, no AVC was identified on the baseline LDCT in 1081 (88.2%), while 116 had mild AVC (grade 1), 26 moderate AVC (grade 2), and 2 severe AVC (grade 3). On the most recent LDCT, median follow-up time from baseline LDCT was 10.9 years (IQR: 4.2 to 15.1 yrs.), 865 (70.6%) had no AVC, 262 (21.4%) mild AVC, 80 (6.5%) moderate AVC, and 18 (1.5%) severe AVC. Multivariable logistic regression analysis showed significant predictors for baseline AVC were male sex (OR=3.39), age (OR=1.11) and CAC score (OR=1.28), for AVC progression after baseline, was pack-years of smoking (HR=1.01), and for new AVC on annual LDCT, were male sex (HR=1.65), age (HR=1.06), and BMI (HR=1.06).

      CONCLUSIONS: Our results suggest that moderate to severe AVC scores could be reliably obtained on LDCT, should also be reported on screening LDCTs and further workup by echocardiography should be recommended as finding moderate or severe AVC on LDCT was associated with a high probability of AS in asymptomatic smokers.

      References:

      1. Lu MT, Onuma OK, Massaro JM, D'Agostino RB, Sr., O'Donnell CJ, Hoffmann U. Lung Cancer Screening Eligibility in the Community: Cardiovascular Risk Factors, Coronary Artery Calcification, and Cardiovascular Events. Circulation. 2016;134(12):897-9.

      2. Nguyen V, Cimadevilla C, Estellat C, et al. Haemodynamic and anatomic progression of aortic stenosis. Heart. 2015;101(12):943-7.

      3. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. The New England journal of medicine. 1999;341(3):142-7.

      TABLE 1. Agreement of AVC Score on LDCT by Extent of Aortic Stenosis on Echocardiogram Among Those Who Had Both Tests Within 12 Months.

      Aortic stenosis categories based on Echocardiography*

      No Aortic Stenosis

      Aortic Stenosis

      Total

      None

      Aortic sclerosis

      Mild

      Moderate

      Severe

      Visual AVC scores

      None (0)

      72

      14

      0

      0

      0

      86

      Mild (1)

      7

      18

      1

      0

      0

      26

      Moderate (2)

      0

      5

      2

      4

      0

      11

      Severe (3)

      0

      0

      0

      0

      3

      3

      Total

      79

      37

      3

      4

      3

      126

      Weighted Kappa=0.68 (95% CI: 0.56, 0.80).

      FIGURE 1. Visual and Agatston AVC Scoring.

      figure 1.jpg

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      MS10.04 - Liver - Pulmonary Disease (Now Available) (ID 3495)

      15:45 - 17:15  |  Presenting Author(s): Andrea D Branch

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      Abstract

      Evidence of an Association between Pulmonary Dysfunction and Fatty Liver Disease

      Background: There is an epidemiological association between pulmonary dysfunction and fatty liver disease.

      Aim: To investigate the association between pulmonary dysfunction and liver steatosis in members of the World Trade Center General Responder Cohort and other populations.

      Methods: FIB-4 scores were calculated from the most recent data in electronic health records; fibrosis was defined as a FIB-4 score ≥ 2.67, which is associated with a 43-fold increased risk of liver-related mortality. Fatty liver was determined by automated analysis of non-contrast chest CT scans; attenuation < 40 Hounsfeld Units (HU) indicated moderate-to-severe steatosis, which means that ≥ 30% of hepatocytes contain excessive lipid. Primary liver cancer was identified by filtering on international classification of diseases (ICD9/10) codes 155/C22, and verifying the diagnosis by chart review. Multivariable logistic (MVL) regression was used to identify factors independently associated with liver fibrosis and steatosis. All reported findings are significant at p < 0.05.

      Results: Among 18,231 responders, 414 (2.3%) had liver fibrosis, which was associated with lower body mass index (BMI), obstructive pulmonary disease, male sex, smoking history, alcohol history, and less education. Among 7227 responders who denied smoking and/or heavy alcohol consumption, 112 (1.5%) had liver fibrosis, which was again associated with lower BMI, reduced pulmonary function, male sex, and less education. Among 1248 responders with CT scans available for analysis of liver status, 184 (15%) had moderate-to-severe steatosis. Fatty liver was associated with arrival at the WTC site on 9/11 and higher values of ALT, AST, bilirubin, neutrophils, and BMI. Among the responders with fatty liver, 38 (21%) were not obese (BMI < 30 kg/m2). The non-obese responders had higher values of ALT, AST, and bilirubin, and lower values of platelets, indicating that they had more advanced liver disease. Thirty-three responders had primary liver cancer.

      Conclusions: Among WTC responders, liver fibrosis was associated with pulmonary dysfunction and lower BMI; excessive weight and metabolic disease were not the primary drivers. Among responders with liver fat, those with lower BMI had more extensive liver damage, as often occurs in toxicant-associated steatohepatitis (FAMRI, NIOSHU01OH011489).

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      MS10.05 - Osteoporosis (Now Available) (ID 3496)

      15:45 - 17:15  |  Presenting Author(s): Jessica Gonzalez-Gutierrez

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      Abstract not provided

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      MS10.06 - Interstitial Lung Diseases (Now Available) (ID 3497)

      15:45 - 17:15  |  Presenting Author(s): Mary Salvatore

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      Abstract

      Lung Cancer in patients with Lung Fibrosis

      Mary M. Salvatore MD, MBA

      Patients with a history of smoking are enriched population for studying pulmonary fibrosis and as patients are living longer with fibrosis, they are becoming an enriched population for studying lung cancer (1). Usual interstitial Pneumonitis is the most frequent pattern of pulmonary fibrosis in the United States. There are 48,000 new patients with IPF each year in the US and 40,000 die (2). Ozawa found that the cumulative incidence of lung cancer is 3.3%, 15.4%, and 54.7% at 1, 5, and 10 years of IPF (3). Adenocarcinoma is most common lung cancer in the general population. Kawasaki found that of 53 patients with IPF and lung cancer, there was no predominant histology. There are similarities between lung cancer and fibrosis, which include invasion of normal tissue, lack of monoclonality, mutation of tumor suppressor genes and epithelial mesenchymal transformation (4). The tumor microenvironment often causes cancers in fibrosis to have shorter doubling times. The survival of patients with lung fibrosis and cancer is poor with up to 93% 5-year mortality (5). Screening for lung cancer in patients with fibrosis is different from screening in non-fibrotic patients because of the potential rapid growth of some cancers.

      Lung cancer occurring in a patient with fibrosis are different from lung cancer occurring in a patient with emphysema. The patients are often not candidates for surgery. If they have surgery, it should be as limited as possible to decrease the risk of exacerbation (6). Chemotherapy increase risk of an exacerbation as does immunotherapy (7). Radiation has an increased risk of exacerbation as well; perhaps proton therapy may have better outcomes (8). In summary as patients are living longer with fibrosis the incidence of lung cancer is increasing however the treatments for early cancer in patients with lung cancer increase the risk of fibrosis exacerbation and further study is necessary in this area to make recommendations for best practices.

      References:

      1. Salvatore M, Henschke CI, Yip R, Jacobi A, Eber C, Padilla M, Knoll A, Yankelevitz D. JOURNAL CLUB: Evidence of Interstitial Lung Disease on Low-Dose Chest CT Images: Prevalence, Patterns, and Progression. AJR Am J Roentgenol 2016 Mar; 206(3):487-94.

      2. G. Raghu, S.Y. Chen, Q. Hou, W.S. Yeh, H.R. Collard, Incidence and prevalence of idiopathic pulmonary fibrosis in US adults 18-64 years old, Eur. Respir. J.48 (1) (2016).

      3. Ozawa Y, Suda T, Naito T, Enomoto N, Hashimoto D, Fujisawa T, Nakamura Y, Inui N, Nakamura H, Chida K.: Cumulative incidence of and predictive factors for lung cancer in IPF. Respirol. Carlt. Vic., 14 (5) (2009), pp. 723-728.

      4. H. Kawasaki, K. Nagai, T. Yokose, J. Yoshida, M. Nishimura, K. Takahashi Clinicopathological characteristics of surgically resected lung cancer associated with idiopathic pulmonary fibrosis. J. Surg. Oncol., 76 (1) (2001), pp. 53-57.

      5. Teixeira MR, Heim S. Cytogenetic analysis of tumor clonality. Adv Cancer Res. 2011; 112: 127–149.

      6. Joo S, Kim DK, Sim HJ, Lee GD, Hwang SK, Choi S, Kim HR, Kim YH, Park SI. Clinical results of sublobar resection versus lobectomy or more extensive resection for lung cancer patients with idiopathic pulmonary fibrosis. J Thorac Dis. 2016; 8(5): 977–984.

      7. E Watanabe N, Taniguchi H, Kondoh Y, Kimura T, Kataoka K, Nishiyama O, Kondo M, Hasegawa Y. Efficacy of chemotherapy for advanced non-small cell lung cancer with idiopathic pulmonary fibrosis. Respiration 2013; 85(4): 326–331.

      8. Hakyoung Kim, Hongryull Pyo, Jae Myoung Noh, Woojin Lee, Byoungsuk Park, Hye Yun Park and Hongseok Yoo. Preliminary result of definitive radiotherapy in patients with non-small cell lung cancer who have underlying idiopathic pulmonary fibrosis: comparison between X-ray and proton therapy. Radiat Oncol. 2019 Jan 28; 14(1):19.

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      MS10.07 - Breast Evaluation (Now Available) (ID 3498)

      15:45 - 17:15  |  Presenting Author(s): Laurie Margolies

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      Abstract

      for spain abstract dejnsity.jpgfor spain abstract 2.jpg

      Opportunistic Evaluation of the Breast on Cross Sectional Imaging

      Breast tissue is visualized on Chest CT, Chest MRI and to a limited extent on cross sectional imaging of the abdomen; much information about the breasts can be obtained. While cross sectional imaging does not substitute for mammography, for those women who have not had recent mammograms it may be the only opportunity for the breasts to be evaluated. Additionally, there are portions of the medial and posterior breast which can sometimes be seen to better advantage on cross sectional imaging.

      Breast Density is a known risk factor for breast cancer development and can mask tumors on mammography. Traditionally, it has been taught that breast density can only be determined by mammography, but it can be reliably determined by evaluating the breasts on CT.[i] (figure shows a Chest CT of a woman with heterogenously dense breasts and corresponding cranio-caudal mammogram image) Reporting of breast density on Chest CT can better inform the patient of her risk and possible imaging strategies.

      Masses and some calcifications can be seen on CT. Some are known and require no further evaluation, others are classically benign and also require no further evaluation, but some appear new or changed and do require dedicated breast imaging. By using a breast assessment and recommendatin score (BARCS) system to evaluate and report breast CT findings one can communicate to referring physicians what the next steps if any might be. This is similar to the BI-RADS system used for reporting mammography A BARCS score of 1 or 2 is analogous to the commonly used BI-RADS 1 or 2 and indicates that the findings are negative or benign and no special evaluation is needed. A CT-BI-RADS 2 might be used, for example, in the setting of a classic fibroadenoma. A mass that does not exhibit classic benign features, however, might be given a BARCS 0 and the patient referred for dedicated breast imaging (or review and correlation with prior breast imaging) as the imaging evaluation is incomplete. [ii] Some of these findings will be breast cancer (figure 2 shows a mass in the medial right breast that is easier to see on Chest CT than on mammogram where there is only a developing asymmetry - arrows). The opportunity to fully include and evaluate the breasts on cross sectional imaging should not be missed.[iii] Breast masses can also be an incidental MRI finding.[iv]

      Dedicated breast imaging also has the opportunity to detect lung and other disease. Breast MRI, for example, typically includes portions of the lung and abdomen where osseous, lung, liver and renal lesions can be seen.[v] Mammography can detect lymphoma, metastatic melanoma and other systemic diseases such as congestive heart failure [vi] or even be the first indication of re-activation of Tuberculosis.[vii]Cardiovascular disease can manifest itself with breast arterial calcification evident on mammography; this often correlates with coronary artery calcification despite the differences in the pathogenesis of the calcifications. [viii]

      Patients[ix] and providers[x] want interpreting radiologists to report on all the imaging findings; chest imagers have the opportunity to detect breast disease and promote appropriate evaluation of findings as well as to assist in personalizing breast cancer screening algorithms.

      [i] Salvatore M, Margolies L, Kale M, et al. Breast Density: Comparison of Chest CT with Mammography. Radiology 2014 270:1, 67-73.

      [ii] Margolies, LR, Salvatore M, Yip R, et al. The chest radiologist's role in invasive breast cancer detection. Clinical Imaging 2018, Volume 50, 13 - 19.

      [iii] Salvatore M, Margolies, L, Bertolini, A, et al. The need to be all inclusive: Chest CT scans should include imaged breast parenchyma. Clinical Imaging 2018 Volume 50, 243-245.

      [iv] Bignotti B, Succio G, Nosenzo F, et al. Breast findings incidentally detected on body MRI. Springerplus. 2016;5(1):781.

      [v] Gao Y, Ibidapo O, Toth HK and Moy L. Delineating Extramammary Findings at Breast MR Imaging. Radiographics. 2017; 37:10–31.

      [vi] Cao MM, Hoyt AC, Bassett LW. Mammographic Signs of Systemic Disease. RadioGraphics 2011 31:4, 1085-1100

      [vii] Hwang E, Szabo J, Federman A and Margolies LR. Reactivation tuberculosis presenting with unilateral axillary lymphadenopathy. Radiology Case Reports. 2018: 13(6): 1188-1191.

      [viii] Margolies L, Salvatore M, Hecht HS, et al. Digital Mammography and Screening for Coronary Artery Disease. JACC Cardiovasc Imaging. 2016 Apr;9(4):350-60.

      [ix] Margolies LR, Yip R. Hwang E, et al. Breast Arterial Calcification in the Mammogram Report: The Patient Perspective. AJR Am J Roentgenol. 2019 Jan;212(1):209-214.

      [x] Nasir K and McEvoy JW. Recognizing Breast Arterial Calcification as Atherosclerotic CVD Risk Equivalent. JACC: Cardiovascular Imaging Apr 2016, 9 (4) 361-363.

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