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Stephen Lam
Moderator of
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ES 07 - Recent Advances in Diagnostics and Interventional Bronchoscopy (ID 516)
- Event: WCLC 2017
- Type: Educational Session
- Track: Pulmonology/Endoscopy
- Presentations: 4
- Moderators:Stephen Lam, N. Kurimoto
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 503
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ES 07.01 - Endoscopic Staging of Lung Cancer (ID 7610)
11:00 - 12:30 | Presenting Author(s): Kazuhiro Yasufuku
- Abstract
- Presentation
Abstract:
Endoscopic Staging of Lung Cancer Kazuhiro Yasufuku During the management of patients with lung cancer, accurate lymph node staging is important not only to determine the prognosis but also to decide the most suitable treatment plan. Non-invasive staging such as computed tomography (CT) and positron emission tomography (PET) indicate size and metabolic activity, respectively. However imaging alone is inaccurate and therefore tissue sampling is the preferred and most reliable. Surgical staging by mediastinoscopy has been the gold standard for mediastinal lymph node staging but requires general anesthesia and complications cannot be ignored. Endoscopic ultrasound techniques provide a minimally invasive alternative for surgical staging and have become available for oncologists around the world. The current available endoscopic ultrasound techniques for mediastinal staging include transesophageal endoscopic ultrasound guided fine needle aspiration (EUS-FNA) and endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). Both procedures are performed in an outpatient setting under local anesthesia. EUS-FNA is a sensitive and safe method of evaluating the inferior mediastinal nodes (stations 7, 8, and 9) and some parts of the anterior mediastinal nodes if the lymph nodes are accessible from the esophagus. However, in spite of the strength of EUS-FNA for evaluating the inferior mediastinal nodes, its ability to evaluate lesions anterior to the trachea is limited. On the other hand, EBUS-TBNA has reach to the paratracheal and subcarinal (stations 2R, 2L, 4R, 4L, 7), as well as the N1 lymph nodes (stations 10, 11, 12). In experienced hands, EBUS can be used through the esophagus for a EUS-like approach to sample inferior mediastinal lymph nodes. With the transvascular approach, AP window lymph nodes (station 5) can be sampled by EUS-FNA and/or EBUS-TBNA. Specialized centers have reported the sampling of station 6 via EUS-FNA. Thus, EUS-FNA and EBUS-TBNA are complementary methods for lymph node staging in lung cancer and most of the mediastinum and the hilum can be evaluated with these endoscopic procedures beyond the reach of mediastinoscopy. Based on the current evidence, EBUS-TBNA and EUS-FNA presents a minimally invasive endoscopic procedure of choice for mediastinal staging of NSCLC with discrete N2 or N3 lymph node enlargement, provided negative results are confirmed by surgical staging. When combined the techniques offer safe and accurate assessment of mediastinum, with accuracy surpassing that of the pervious gold standard – cervical mediastinoscopy. EBUS-TBNA and/or EUS-FNA can also be repeated with ease and have been used for mediastinal restaging in patients who underwent neoadjuvant therapy in preparation for definitive surgical intervention. New size needles are now available for sampling of the lymph nodes during EBUS-TBNA including 25-gauge and 19-gauge needles. Smaller needles may provide greater reach with good quality samples, whereas larger 19-gauge needle may provide bigger tissue for histological evaluation of the lymph nodes samples. There are limitations of using cytological samples obtained during EBUS-TBNA or EUS-FNA for PD-L1 expression. The use of the 19-gauge needle may solve this problem.
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ES 07.02 - Guided Bronchoscopy for Peripheral Lung Nodules (ID 7611)
11:00 - 12:30 | Presenting Author(s): Takehiro Izumo
- Abstract
- Presentation
Abstract:
In the past several years, X-ray fluoroscopy had been commonly employed to determine the lung field during transbronchial biopsy (TBB); however, precise localization of a PPL has not always been possible leading to low diagnostic yield. For ground glass opacities (GGOs), the value of X-ray fluoroscopy even becomes less. The value of virtual X-ray fluoroscopy and CT fluoroscopy has potential but remains to be known. The advent of endobronchial ultrasound (EBUS) has dramatically increased precise bronchoscopic confirmation of the location of a PPL before sampling. In particular, the radial probe EBUS is used to indicate that a lesion has been reached. For solid peripheral pulmonary lesions (PPLs), Kurimoto et al have described three major types of echogenicities that might differentiate between benignity and malignancy. For GGOs, we have observed constant radial-EBUS patterns that we called blizzard and mixed blizzard signs. Currently, several acquired resistance mechanisms and rare driver oncogenes are identified in non-small cell lung cancer (NSCLC) relapses. Re-biopsy increases valuable information to guide treatment strategies, but the utility and feasibility of bronchoscopic re-biopsy especially endobronchial ultrasound (EBUS) guided re-biopsy has not been investigated. We recently reported the utility of bronchoscopic (EBUS-guided) re-biopsy for detecting the mutation in NSCLC. Re-biopsy by both EBUS-TBNA and EBUS-GS were useful and safe sampling procedures for mutation analysis of EGFR-TKI resistant NSCLC. Another alternative approach, specifically liquid biopsy, now present as a crucial point in the field. Liquid biopsy has grown in importance because the genetic profile of tumors can affect how well they respond to a certain treatment. A recent paper showed that the concordance between re-biopsy and liquid biopsy, including plasma DNA and circulating tumor cell, was 57–60%. The usefulness of monitoring T790M status in liquid biopsy was already reported. Although liquid biopsy has the potential to detect new mutations after chemotherapy, several reports have demonstrated some difficulties in detecting tumor-derived mutations in plasma. Therefore, liquid biopsy and re-biopsy may be considered to be complementary methods of mutation analysis. I would like to share our data and actual cases in this talk. Figure 1Figure 2
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ES 07.03 - Bronchoscopic Management of Central Airway Obstruction (ID 7612)
11:00 - 12:30 | Presenting Author(s): Hojoong Kim
- Abstract
- Presentation
Abstract:
Introduction: Malignant airway obstruction can result from primary airway tumors, extension of adjacent primary tumors, or metastatic tumors. Partial or complete airway obstruction can deteriorate functional status of patients and result in impending respiratory failure. Malignant airway obstruction is considered to be one of the most distressing causes of morbidity and mortality in lung cancer patients. Bronchoscopic intervention can provide immediate relief from suffocation, improve general condition, and provide a bridge, allowing time for additional treatment such as surgery, radiation, or chemotherapy in patients suffering from malignant airway obstruction. Indication: Any patients who suffer from respiratory distress due to central airway obstruction are indicated for bronchoscopic intervention. However, patients should tolerate the morbidity of intervention, the length of the airway obstruction less than 4cm, and the duration of obstruction less than 2 month due to the technical limitation. Method: Due to it is safe from massive hemoptysis and respiratory failure, most experienced bronchoscopists prefer rigid bronchoscopy under general anesthesia, using intravenous propofol injection. After the induction of anesthesia, the patients are intubated with a rigid bronchoscope tube and a flexible bronchoscope is introduced through the rigid bronchoscope tube, and the narrowed central airway was evaluated. In every case, the obstructed airway is dilated gently using an 10 mm rigid bronchoscope tube initially and then progressively larger bronchoscope tubes until an adequate airway caliber was established. When indicated, a controlled radial expansion balloon is used to enlarge the airway sufficiently to allow bronchoscopic dilatation. Any intraluminal mass is removed mechanically using rigid bronchoscopic forceps or a snare. Frequently, a neodymium-yttrium aluminum garnet (Nd-YAG) or diode laser is used to ablate the residual endobronchial tumor or to cauterize the tumor bed after most of the tumor had been excised. After mechanical dilatation, the airway is maintained by inserting a silicone stent (Dumon-style stent) in patients whose airway is not maintained due to extrinsic compression or malacia. The silicone stents are inserted through the rigid bronchoscope using a standard Dumon technique. Outcome: In experienced center, the overall success rate is more than 90% after the emergency bronchoscopic intervention. A successful outcome is accompanied by subjective improvement in the symptoms and radiographic findings. After stabilizing the airway with the bronchoscopic treatment, favorable outcome is expected if additional definitive therapy can be applied, such as surgery, radiation, or chemotherapy. Nowadays, bronchoscopic intervention can achieve prolonged survival with sustained significant improvement of quality of life. Complications: Tracheal perforation, massive bleeding, respiratory failure and cardiac arrhythmia can develop after bronchoscopic intervention. However, the overall complication rate is not over 5% in experienced center. Conclusion: Bronchoscopic intervention in patients with malignant airway obstruction is helpful for the palliation the airway, allowing the multimodality therapeutic approach and prolonging the life of the patients. References 1. Jeon K, Kim H, Yu CM, et al. Rigid bronchoscopic intervention in patients with respiratory failure caused by malignant central airway obstruction. J Thorac Oncol 2006;1:319-323. 2. Cavaliere S, Venuta F, Foccoli P, et al. Endoscopic treatment of malignant airway obstructions in 2,008 patients. Chest 1996;110:1536-1542. 3. Han CC, Prasetyo D, Wright GM. Endobronchial palliation using Nd:YAG laser is associated with improved survival when combined with multimodal adjuvant treatments. J Thorac Oncol 2007;2:59-64. 4. Chhajed PN, Eberhardt R, Dienemann H, et al. Therapeutic bronchoscopy interventions before surgical resection of lung cancer. Ann Thorac Surg 2006;81:1839-1843. 5. Stratakos G, Gerovasili V, Dimitropoulos C, et al. J Cancer. 2016;25: 794-802.
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ES 07.04 - Endoscopic Options for Solitary Pulmonary Nodules (ID 7613)
11:00 - 12:30 | Presenting Author(s): Stephen Lam
- Abstract
- Presentation
Abstract:
World-wide, aside from men in France, Spain and the Netherlands, peripherally located adenocarcinomas have now overtaken squamous cell carcinoma as the predominant lung cancer cell type. With the implementation of lung cancer screening programs using low dose CT and increasing use of CT imaging for clinical investigations, a large number of people are found to have lung nodules. In contrast to symptomatic lung cancer, the size of screening CT detected or incidental lung nodules suspicious of malignancy is much smaller. Over 75% of screening CT detected lung cancers are ≤20 mm with 20% to 47% of the lung cancers found in the first screening CT and 33% to 62% of lung cancers found in annual repeat screening CT are ≤10 mm.[1-4] Because of the small size of these lesions, currently only 20% to 34% of screening CT detected lung cancers are diagnosed by endoscopy. The diagnostic yield of bronchoscopic biopsies is modest.[1,2] In the real world setting, even with advanced bronchoscopic methods such as navigation bronchoscopy and radial ultrasound, the diagnostic yield of peripheral lung lesions is less than 60%.[5,6] Several factors account for the suboptimal diagnostic yield. The diameter of the airways leading to the lesion may be smaller than the 1.4 mm diameter radial EBUS probe. The lesion may be eccentric rather than perpendicular to the biopsy forceps. Removable of the imaging probe from a guide sheath and re-insertion of biopsy forceps or needle may cause displacement or migration of the guide sheath to a different airway. To improve the diagnostic accuracy, other methods are being developed for endoscopic detection and biopsy of peripheral lung lesions ≤20 mm. Bronchoscopic transparenchymal approach to access peripheral lung nodules from more central airways and real time flouroscopic transbronchial guidance systems are under evaluation.[7,8] Flexible 21G peripheral needles are becoming commercially available for transbronchial aspiration or core biopsy. Small optical imaging probes < 0.5 mm that can be inserted within a 21G needle to confirm abnormal pathology in real time using optical frequency domain imaging[9,10] or diffuse reflectance spectroscopy before taking a biopsy. These newer endoscopic approaches hold promise to improve diagnostic accuracy while maintaining the advantage of lower complication rates such as pneumothorax and bleeding compares to CT guided transthoracic lung biopsy. References 1. National Lung Screening Research Team, Church TR, Black WC, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013 May 23;368(21):1980-91. 2. Aberle DR, DeMello S, Berg CD, et al. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 2013; 369(10):920-31. 3. McWilliams A, Tammemagi MC, Mayo et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910-9. 4. Horeweg N, van Rosmalen J, Heuvelmans MA, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol. 2014 Nov;15(12):1332-41. 5. Ost DE, Ernst A, Lei X, et al. AQuIRE Bronchoscopy Registry. Diagnostic yield and complications of bronchoscopy for peripheral lung lesions. Results of the AQuIRE Registry. Am J Respir Crit Care Med. 2016 Jan 1;193(1):68-77. 6. Ali MS, Trick W, Mba BI, et al. Radial endobronchial ultrasound for the diagnosis of peripheral pulmonary lesions: A systematic review and meta-analysis. Respirology. 2017; 22(3):443-453. 7. Herth FJ, Li S, Jiayuan Sun J, Nader D. Bronchoscopic TransParenchymal Nodule Access: Evaluation of safety and feasibility of Archimedes System. Am J Respir Crit Care Med 2017;195:A7597. 8. Stoy SP, Whitten PE, Al-Zubaidi A, Hogarth K. Bronchoscopic peripheral lung nodule navigation by a novel Live fluoroscopic overlay guidance technology. Am J Respir Crit Care Med 2017;195:A2865. 9. Tan KM, Shishkov M, Chee A, et al. Flexible transbronchial optical frequency domain imaging smart needle for biopsy guidance. Biomed Opt Express 2012; 3::1947-1954. 10. Pahlevaninezhad H, Lee AM, A. R, et al. Endoscopic Doppler optical coherence tomography and autofluorescence imaging of peripheral pulmonary nodules and vasculature. Biomedical Optics Express. 2015; 6(10):4191-9.
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Author of
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ES 07 - Recent Advances in Diagnostics and Interventional Bronchoscopy (ID 516)
- Event: WCLC 2017
- Type: Educational Session
- Track: Pulmonology/Endoscopy
- Presentations: 1
- Moderators:Stephen Lam, N. Kurimoto
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 503
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ES 07.04 - Endoscopic Options for Solitary Pulmonary Nodules (ID 7613)
11:00 - 12:30 | Presenting Author(s): Stephen Lam
- Abstract
- Presentation
Abstract:
World-wide, aside from men in France, Spain and the Netherlands, peripherally located adenocarcinomas have now overtaken squamous cell carcinoma as the predominant lung cancer cell type. With the implementation of lung cancer screening programs using low dose CT and increasing use of CT imaging for clinical investigations, a large number of people are found to have lung nodules. In contrast to symptomatic lung cancer, the size of screening CT detected or incidental lung nodules suspicious of malignancy is much smaller. Over 75% of screening CT detected lung cancers are ≤20 mm with 20% to 47% of the lung cancers found in the first screening CT and 33% to 62% of lung cancers found in annual repeat screening CT are ≤10 mm.[1-4] Because of the small size of these lesions, currently only 20% to 34% of screening CT detected lung cancers are diagnosed by endoscopy. The diagnostic yield of bronchoscopic biopsies is modest.[1,2] In the real world setting, even with advanced bronchoscopic methods such as navigation bronchoscopy and radial ultrasound, the diagnostic yield of peripheral lung lesions is less than 60%.[5,6] Several factors account for the suboptimal diagnostic yield. The diameter of the airways leading to the lesion may be smaller than the 1.4 mm diameter radial EBUS probe. The lesion may be eccentric rather than perpendicular to the biopsy forceps. Removable of the imaging probe from a guide sheath and re-insertion of biopsy forceps or needle may cause displacement or migration of the guide sheath to a different airway. To improve the diagnostic accuracy, other methods are being developed for endoscopic detection and biopsy of peripheral lung lesions ≤20 mm. Bronchoscopic transparenchymal approach to access peripheral lung nodules from more central airways and real time flouroscopic transbronchial guidance systems are under evaluation.[7,8] Flexible 21G peripheral needles are becoming commercially available for transbronchial aspiration or core biopsy. Small optical imaging probes < 0.5 mm that can be inserted within a 21G needle to confirm abnormal pathology in real time using optical frequency domain imaging[9,10] or diffuse reflectance spectroscopy before taking a biopsy. These newer endoscopic approaches hold promise to improve diagnostic accuracy while maintaining the advantage of lower complication rates such as pneumothorax and bleeding compares to CT guided transthoracic lung biopsy. References 1. National Lung Screening Research Team, Church TR, Black WC, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013 May 23;368(21):1980-91. 2. Aberle DR, DeMello S, Berg CD, et al. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med 2013; 369(10):920-31. 3. McWilliams A, Tammemagi MC, Mayo et al. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med 2013;369:910-9. 4. Horeweg N, van Rosmalen J, Heuvelmans MA, et al. Lung cancer probability in patients with CT-detected pulmonary nodules: a prespecified analysis of data from the NELSON trial of low-dose CT screening. Lancet Oncol. 2014 Nov;15(12):1332-41. 5. Ost DE, Ernst A, Lei X, et al. AQuIRE Bronchoscopy Registry. Diagnostic yield and complications of bronchoscopy for peripheral lung lesions. Results of the AQuIRE Registry. Am J Respir Crit Care Med. 2016 Jan 1;193(1):68-77. 6. Ali MS, Trick W, Mba BI, et al. Radial endobronchial ultrasound for the diagnosis of peripheral pulmonary lesions: A systematic review and meta-analysis. Respirology. 2017; 22(3):443-453. 7. Herth FJ, Li S, Jiayuan Sun J, Nader D. Bronchoscopic TransParenchymal Nodule Access: Evaluation of safety and feasibility of Archimedes System. Am J Respir Crit Care Med 2017;195:A7597. 8. Stoy SP, Whitten PE, Al-Zubaidi A, Hogarth K. Bronchoscopic peripheral lung nodule navigation by a novel Live fluoroscopic overlay guidance technology. Am J Respir Crit Care Med 2017;195:A2865. 9. Tan KM, Shishkov M, Chee A, et al. Flexible transbronchial optical frequency domain imaging smart needle for biopsy guidance. Biomed Opt Express 2012; 3::1947-1954. 10. Pahlevaninezhad H, Lee AM, A. R, et al. Endoscopic Doppler optical coherence tomography and autofluorescence imaging of peripheral pulmonary nodules and vasculature. Biomedical Optics Express. 2015; 6(10):4191-9.
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MA 05 - Immuno-Oncology: Novel Biomarker Candidates (ID 658)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:Yoichi Nakanishi, P. Mitchell
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 303 + 304
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MA 05.12 - Oncogenic Drivers Induce Production of CCL5 to Recruit Regulatory T-Cells Early in Lung Cancer Progression (ID 10289)
15:45 - 17:30 | Author(s): Stephen Lam
- Abstract
- Presentation
Background:
Lung cancer development is driven by the expression of mutant oncogenes, with EGFR and KRAS the most frequent in lung adenocarcinoma. However, these mutations alone are not sufficient for tumorigenesis suggesting additional factors influence tumour development and progression, including the balance of anti-tumour immune effector cells and pro-tumorigenic immune suppressor cells. Tumour cells can evade immune surveillance by producing cytokines to recruit immune modulatory cells that promote an immune suppressive environment, such as regulatory T cells (Tregs). We hypothesized that oncogene signaling regulates the production of cytokines by tumour cells in order to recruit immune suppressive cells and promote lung tumour development.
Method:
We used CIBERSORT to quantify 22 immune cell types in over 300 human lung adenocarcinoma and 100 matched normal lung tissues, and validated findings with immunohistochemistry. Cells expressing doxycycline inducible EGFR[L858R] and KRAS[G12V]were analyzed for cytokine production using a multiplex assay (LUMINEX). EGFR (Afatinib) and MEK (Trametinib) inhibitors were used in lung cancer cell lines harbouring EGFR or KRAS mutations and cytokine production was quantified using ELISA. Conditioned media from EGFR[L858R] and KRAS[G12V] expressing cells were used in a trans-well assay to determine if secreted cytokines could induce Treg migration. Transgenic mouse models of lung adenocarcinoma and bronchoalveolar lavage (BAL) from patients with and without lung cancer were used to assess CCL5 and Tregs in vivo.
Result:
Treg cells were significantly enriched in lung tumours and not normal tissue. CCL5 production is increased rapidly upon oncogene induction and subsequent transformation of normal cells and is dependent on sustained ERK signaling for continued expression. Conditioned medium from EGFR[L858R] expressing cells increased Treg migration, which was mitigated by an anti-CCL5 antibody. Transgenic mice expressing EGFR[L858R ]or KRAS[G12D] in the lung epithelium recruited Tregs to the lung upon tumor induction. Assessment of CCL5 in BAL from patients with and without lung cancer is currently in progress.
Conclusion:
Oncogene driven ERK signaling may regulate expression of CCL5 from lung tumour cells, and oncogene induced CCL5 production stimulates Treg migration ex vivo. These data suggest CCL5-mediated Treg recruitment to lung tumours may occur in early stages of lung tumour development and that targeted inhibition of CCL5 or ERK signaling may represent therapeutic strategies to block recruitment of immunosuppressive Tregs by lung tumours.
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MA 14 - Diagnostic Radiology, Staging and Screening for Lung Cancer I (ID 672)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:H. Kondo, Hong Kwan Kim
- Coordinates: 10/17/2017, 15:45 - 17:30, F205 + F206 (Annex Hall)
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MA 14.11 - Malignancy Risk Prediction of Pulmonary Nodule in Lung Cancer Screening – Diameter Or Volumetric Measurement (ID 9113)
15:45 - 17:30 | Author(s): Stephen Lam
- Abstract
- Presentation
Background:
Nodule size is an important parameter to determine malignancy risk. Semi-automated size measurements have the potential to replace manual measurements due to their higher accuracy and reproducibility, and less inter/intra-user variation. However, controversy exists regarding the relative accuracy of 2D diameter versus 3D volumetric measurement to predict malignancy risk. The objective of this study is to compare nodule malignancy prediction models based on 2D mean diameter versus volumetric measurement, both generated by a CAD Software.
Method:
We analyzed baseline LDCT reconstructed using high spatial frequency algorithm from 1746 participants (47% women, 53% men, age: 62.5 ± 5.8 yrs) in the Pan-Canadian Early Detection of Lung Cancer Study (PanCan), who had ≥1 non-calcified nodules ≥3mm in diameter. CAD software (CIRRUS Lung Screening, Radboud University Medical Center, Nijmegen, the Netherlands) performed an automatic nodule segmentation, which could be optimised manually, measurement of mean diameter and volume was generated. Malignant or benign nodule status was confirmed by pathology or prolonged follow-up (median follow-up 5.5 years). Logistic regression models predicting cancer were prepared with one including mean diameter and the other including volume. The discrimination, the ability to classify cancer versus benign nodules correctly, was evaluated by the area under the receiver operator characteristic cure (AUC). The calibration - do predicted probabilities match observed probabilities, was assessed using Spiegelhalter’s z-test and graphically by plotting the observed and predicted mean probabilities of cancer by deciles of model risk.
Result:
There were in total 5878 nodules, including 119 cancers in 115 individuals. Both models gave similar predictive performances. AUC was 0.947 (95% CI 0.922-0.964) in the mean diameter model and 0.946 (95% CI 0.921-0.966) in the volumetric model (p=0.83). The calibrations were similar between the two models (figure). Figure 1
Conclusion:
The predictive performances of nodule malignancy prediction models using mean 2D nodule diameter and 3D volumetric data were indistinguishable.
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MA 20 - Recent Advances in Pulmonology/Endoscopy (ID 685)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Pulmonology/Endoscopy
- Presentations: 1
- Moderators:C. Lee, S. Sasada
- Coordinates: 10/18/2017, 14:30 - 16:15, F205 + F206 (Annex Hall)
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MA 20.11 - Chronic Obstructive Pulmonary Disease Prevalence in a Lung Cancer Screening Population (ID 9588)
14:30 - 16:15 | Author(s): Stephen Lam
- Abstract
- Presentation
Background:
Chronic obstructive pulmonary disease (COPD) and lung cancer are associated through tobacco use. COPD is underdiagnosed in both the primary care and lung cancer populations. Diagnosis of COPD should lead to improved care and quality of life. Screening programs could provide an opportunity to capture undiagnosed COPD. We analyzed the Pan-Canadian Early Detection of Lung Cancer Study (PanCan Study) to evaluate the prevalence of COPD in a screening population.
Method:
The PanCan Study was a single arm lung cancer screening trial which recruited individuals to low dose CT scan, autofluorescence bronchoscopy, and biomarker screening. Eligible individuals were 50-75 years of age, had smoked within 15 years, and had a minimum six-year risk of lung cancer ≥ 2% based on a risk prediction model derived from PLCO study data, which included COPD as a risk factor. Consenting subjects completed a questionnaire including background medical conditions, high-risk work exposures, and smoking history. Baseline spirometry was performed, and COPD was defined by GOLD criteria. For individuals not receiving post-bronchodilator spirometry, COPD was defined as ‘probable’ if GOLD criteria were met pre-bronchodilator and there was no prior diagnosis of asthma. Individuals with definite or probable COPD were defined as having COPD.
Result:
Of 2537 individuals recruited, 2514 had available spirometry data. Mean age was 62.3 years, 55.3% were male, median pack-years smoked was 50, 62.3% were active smokers, 45.1% had symptoms of dyspnea, 52.4% cough, and 37.5% wheeze. 35.2% had worked in a high-risk occupation. Overall, 1136 (45.2%) met spirometry criteria for COPD. Of 1987 individuals without a prior history of COPD, 41.9% met spirometry criteria for COPD, of which 53.7% had moderate to severe disease. Of 527 individuals (21%) reporting a diagnosis of COPD at baseline, 57.5% met spirometry criteria for COPD, 32.2% did not, and 10.3% had a prior diagnosis of asthma. In a multivariate model for risk of COPD, age (odds ratio (OR)~per year~ 1.06), dyspnea (OR 1.42), being a current smoker (OR 1.43), and pack-years (log transformed OR 1.42) were significant (all p < 0.001) as were high-risk occupation (OR 1.24, p=0.013) and wheeze (OR 1.24, p = 0.024).
Conclusion:
A diagnosis of COPD by spirometry is common in a lung cancer screening trial population. Individuals with a pre-existing self-reported diagnosis of COPD often fail to meet spirometry criteria for their diagnosis. Testing a lung cancer screening population for COPD could significantly improve COPD diagnosis and treatment.
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OA 07 - Biomarker for Lung Cancer (ID 659)
- Event: WCLC 2017
- Type: Oral
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Philip Christopher Mack, Shinichi Toyooka
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 503
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OA 07.07 - Inhibition of the Novel Oncogene ELF3 Abolishes Lung Adenocarcinoma Growth (ID 8408)
15:45 - 17:30 | Author(s): Stephen Lam
- Abstract
- Presentation
Background:
Oncogenic reactivation of transcription factors involved in fetal lung development is integral to lung adenocarcinoma (LUAD) biology, as observed with TITF1/NKX2-1 and the ETS transcription factors ETV4 and ETV5. ELF3 is an uncharacterized ETS family member implicated in fetal lung development encoded at 1q32.1. Interestingly, chromosome 1q is a region of frequent gain in LUAD that lacks a bona fide oncogene. We hypothesize that ELF3 is a novel oncogene and putative therapeutic target in LUAD.
Method:
Multiple independent datasets encompassing 1,685 clinical samples of LUAD, lung squamous cell carcinoma (LUSC), small cell lung cancer, and non-malignant lung tissues were analyzed to establish the frequency of ELF3 overexpression and underlying genetic mechanisms of selection. Protein-protein interaction (PPI) networks were constructed around ELF3, and integrated pathway analysis was performed to decipher the signaling network disruptions resulting from ELF3 overexpression. Isogenic cell lines were established to assess the ability of ELF3 to regulate oncogenic phenotypes. The effect of ELF3 loss on tumour growth was assessed in xenograft mouse models.
Result:
Strong ELF3 overexpression was frequently observed in LUAD (>2-fold: TCGA 40% p=1.5E-07; BCCA 73% p=1.6E-21), but was not observed in other lung cancer subtypes. Similarly, high ELF3 expression was significantly associated with poor overall survival of LUAD patients (all Stages p<0.0001, Stage I p<0.0001), but not LUSC patients (p>0.05). These clinical associations prompted further examination of ELF3 in the LUAD subtype of lung cancer. While mutations in ELF3 were rare, up to 80% of LUAD patients harboured focal amplification, DNA gain, and/or promoter hypomethylation at the ELF3 locus, which resulted in transcript overexpression. ELF3 overexpression induces remodeling of 23 direct PPI networks, resulting in loss of interaction with proteins such as MYC and GLI2, while forming new interactions with NKX2-1, HOXA5 and CDK8, among others. This reprogramming of PPI networks affects multiple oncogenic pathways including MAPK, TGF-beta and WNT. ELF3 knockdown in LUAD cell lines resulted in significantly reduced proliferation, viability, and anchorage-independent growth, demonstrating ELF3 has oncogenic properties. Loss of ELF3 abolished the ability of LUAD cells to establish tumours in xenograft mouse models, demonstrating the requirement of ELF3 expression for tumour growth.
Conclusion:
ELF3 is a novel LUAD oncogene encoded on chromosome 1q, activated in up to 73% of patients, and strongly associated with poor overall survival. As ELF3 inhibition abolished tumour growth, therapeutic targeting of ELF3 could benefit LUAD patient outcome.
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OA 15 - Diagnostic Radiology, Staging and Screening for Lung Cancer II (ID 684)
- Event: WCLC 2017
- Type: Oral
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:Y. Satoh, Jin Mo Goo
- Coordinates: 10/18/2017, 14:30 - 16:15, Room 303 + 304
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OA 15.01 - Lung Cancer Screening: Participant Selection by Risk Model – the Pan-Canadian Study (ID 8466)
14:30 - 16:15 | Presenting Author(s): Stephen Lam
- Abstract
- Presentation
Background:
Retrospective studies indicate that selecting individuals for low dose computed tomography (LDCT) lung cancer screening based on a highly predictive risk model is superior to applying National Lung Screening Trial (NLST)-like criteria, which use only categorized age, pack-year and smoking quit-time information. The Pan-Canadian Early Detection of Lung Cancer Study (PanCan Study) was designed to prospectively evaluate whether individuals at high risk for lung cancer could be identified for screening using a risk prediction model. This paper describes the study design and results.
Method:
2537 individuals were recruited through 8 centers across Canada based on a ≥2% of lung cancer risk estimated by the PanCan model, a precursor to the validated PLCOm2012 model. Individuals were screened at baseline and 1 and 4 years post-baseline.
Result:
At a median 5.5 years of follow-up, 164 individuals (6.5%) were diagnosed with 172 lung cancers. This was a significantly greater percentage of persons diagnosed with lung cancers than was observed in the NLST(4.0%)(p<0·001). Compared to 57% observed in the NLST, 77% of lung cancers in the PanCan Study were early stage (I or II) (p<0.001) and to 25% in a comparable population, age 50-75 during 2007-2009 in Ontario, Canada’s largest province, (p<0·001).
Conclusion:
Enrolling high-risk individuals into a LDCT screening study or program using a highly predictive risk model, is efficient in identifying individuals who will be diagnosed with lung cancer and is compatible with a strong stage shift – identifying a high proportion at early, potentially curable stage. Funding This study was funded by the Terry Fox Research Institute and Canadian Partnership Against Cancer. ClinicalTrials.gov number, NCT00751660
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P1.04 - Clinical Design, Statistics and Clinical Trials (ID 690)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.04-003 - The International Lung Screen Trial: A Multi-Centre Study to Evaluate LDCT Screening Selection Criteria and Nodule Management (ID 8141)
09:30 - 16:00 | Author(s): Stephen Lam
- Abstract
Background:
There remain important knowledge gaps surrounding the optimal selection criteria of high-risk individuals for low-dose CT (LDCT) screening for lung cancer and the optimal management of screening-detected pulmonary nodules. The International Lung Screen Trial (ILST) is an international, multi-centre prospective cohort study with recruitment sites in Canada and Australia. The rationale and design for the study are presented here. The PLCO~m2012~ risk prediction model[1] may have higher sensitivity and positive predictive value in identifying individuals who develop lung cancer compared to the United States Preventive Services Task Force (USPSTF) criteria. The PanCan model[2] calculates malignancy probability in screen-detected nodules and provides a risk-based approach to managing pulmonary nodules. Both models will be prospectively tested in this study. Primary aims: (a) to define the optimal selection criteria for LDCT screening, (b) to evaluate pulmonary nodule management using the PanCan nodule risk calculator.
Method:
We aim to recruit 4,000 high-risk individuals with 5 years follow up. Eligible participants are current or former smokers, aged 55-80 years, with a PLCO~m2012~ lung cancer risk of ≥1.51% over 6 years or USPSTF criteria (age as above, plus ≥30 pack year history of smoking and smoking cessation <15 years ago). Exclusion criteria include: symptoms suspicious of lung cancer, severe co-morbidity, previous lung cancer and chest CT within the last 2 years. Baseline assessment includes interview, smoking status assessment and pulmonary function testing. Eligible individuals are offered a baseline screening LDCT and subsequent interval surveillance LDCTs dependent on the PanCan risk score. Participants with no nodules or nodule risk score of <1.5% will have biennial LDCT screening. Participants with nodule malignancy risk score ≥10%, or significant growth in subsequent scan will be considered suspicious for lung cancer and undergo clinical review for further investigation. The primary outcome is the proportion of lung cancers detected by either selection criteria. Secondary outcomes include: number needed to screen, cancer detection rate, lung cancer mortality, cancer stage distribution, resection rate, number of interval cancers, recall rate, invasive procedure rate, benign biopsy/surgery rate, screening-related adverse events and comprehensive healthcare economic evaluation.
Result:
This study is currently in its recruitment phase. Results will be reported in future conferences and peer-reviewed publications.
Conclusion:
The ILST trial will provide a clearer understanding on the optimum selection criteria for LDCT screening for lung cancer and prospective validation of the PanCan model. ClinicalTrials.gov number: NCT02871856 References: Tammemägi MC et al (2013). NEJM; 368:728-736. McWilliams A et al (2013). NEJM; 369:910-919.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-017 - Aberrant Expression of Long Non-Coding RNAs from Pseudogene Loci Highlights Alternative Mechanisms of Cancer Gene Regulation (ID 10231)
09:30 - 16:00 | Author(s): Stephen Lam
- Abstract
Background:
Less than half of lung adenocarcinoma (LUAD) patients harbour clinically actionable driver genes, emphasizing the need to explore alternative mechanisms of cancer gene deregulation. Long non-coding RNAs (lncRNAs) have emerged as important players in cell biology, and can be exploited by tumours to drive the hallmarks of cancer. Pseudogenes are DNA sequences that are defunct relatives of their functional protein-coding parent genes but retain high sequence homology. Interestingly, several lncRNAs expressed from pseudogene loci have been shown to regulate the protein-coding parent genes of these pseudogenes in trans due to sequence complementarity. We hypothesize that this phenomenon occurs more broadly than previously realized, and that these events provide an alternative mechanism of cancer gene deregulation in LUAD tumourigenesis that has clinical implications.
Method:
Illumina HiSeq reads were processed and aligned to the ENSEMBL annotation file in order to derive the most complete set of both protein-coding and non-coding genes. Two datasets were selected due to their paired nature, complete with both LUAD and non-malignant lung profiles (TCGA n=108, BCCA n=72). LncRNAs were filtered based on positional overlap within pseudogene loci, and a Wilcoxon sign-rank test was run to identify lncRNAs with significantly altered expression between paired tumour and normal tissues (FDR p<0.05). To identify lncRNAs that likely regulate protein-coding parent gene expression in trans, tumours were ranked by lncRNA expression, and protein-coding parent gene expression of top and bottom ranked tertiles was compared by Mann Whitney U-test (p<0.05). Survival analysis was performed using a Cox proportional hazard model.
Result:
Our analysis has identified 129 lncRNAs expressed from pseudogene loci that were significantly deregulated in LUAD in both datasets. Remarkably, many of these deregulated lncRNAs (i) were expressed from the loci of pseudogenes related to known cancer genes, (ii) had expression that significantly correlated with protein-coding parent gene expression, and (iii) protein-coding parent gene expression was significantly associated with survival. For example, RP11-182J1.1 is a lncRNA expressed from a pseudogene to EGLN1, a previously described cancer gene involved in regulation of tumour hypoxia. RP11-182J1.1 was underexpressed in LUAD and significantly positively correlated with EGLN1 expression. In addition, EGLN1 was significantly associated with patient survival (p=1.2e-08) emphasizing the clinical potential of these lncRNAs.
Conclusion:
This work uncovers evidence to suggest the lncRNA-pseudogene-protein-coding gene axis is a prominent mechanism of cancer gene regulation. Further characterization of this understudied gene regulatory mechanism could lead to novel therapies that silence oncogenes or reactivate tumour suppressor genes.
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P2.02-038 - Imaging Platform for the Quantification of Cell-Cell Spatial Organization within the Tumour-Immune Microenvironment (ID 9605)
09:30 - 16:00 | Author(s): Stephen Lam
- Abstract
Background:
The contribution of the tumour-immune microenvironment to tumour progression and patient outcome has become increasingly evident. Newly developed genomic tools have enabled the study of immune cell composition from bulk tumour data. However, such tools (e.g. CIBERSORT) do not provide the key spatial information that is crucial to understand tumour-immune cell interactions. To this end, we have developed a multispectral imaging platform that improves upon traditional analysis methods of cell segmentation and cell density calculations by further quantifying nearest-neighbour interactions (cell-cell spatial relationships). We apply this technology to investigate tumour-immune cell spatial relationships and their clinical significance to discover novel biological insights.
Method:
Whole tissue sections from 20 lung adenocarcinomas were stained for CD3, CD8, and CD79a and counterstained with haematoxylin. Multispectral images were acquired for five fields of view and analyzed to quantify cell types. Regions of Interest (ROIs) were then identified for the characterization of intra-tumoural and dense inflammatory regions. Image files including ROIs were analyzed in order to quantify cell-cell spatial relationships. Non-random patterns of immune cell distributions were identified using the Monte Carlo re-sampling method (500 iterations). Immune cell counts, densities, spatial relationships, and significant immune cell distributions were associated with clinical features by two-group comparison (Kruskal-Wallis p<0.001).
Result:
Our analysis generated 234 image files for analysis, including ROIs. Each field of view contained an average of 16,400 cells. The densities of intra-tumoural CD3+CD8+ and CD3+ T cells were significantly lower in recurrent cases, agreeing with literature reports. Following Monte Carlo analysis, non-random cell-cell spatial proximities emerged that were not observed at a cell density level. For example, an increased proximity of CD3+ T cells and B cells was observed in never smokers, while a decreased proximity was observed in ever smokers.
Conclusion:
While immune cell densities are of clinical prognostic importance, their spatial organization within the tumour architecture is of functional importance (e.g. the inhibition of cytotoxic T cell activity by adjacent PD-L1 expressing cells). In addition to cell densities, our platform is capable of quantifying cell-cell spatial relationships, thereby providing further information for clinical associations and for the identification of novel prognostic interactions. This automated quantification could be used to complement visual diagnostics and improve prognostic interpretation of histology specimens.
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P2.13 - Radiology/Staging/Screening (ID 714)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.13-011 - Optimal Selection Criteria for LDCT Lung Cancer Screening (ID 9628)
09:30 - 16:00 | Author(s): Stephen Lam
- Abstract
Background:
Lung cancer screening programs with low dose computed tomography (LDCT) could be economically viable if they targeted high-risk people. The optimal selection criteria have not been defined in prospective clinical trials. The goal of this prospective study is to test the hypothesis that lung cancer screening based on a highly predictive risk model: The Prostate, Lung, Colon, Ovarian (PLCO~m2012~) is superior to applying National Lung Screening Trial (NLST)-like criteria.
Method:
Participants were enrolled through three screening studies, two in Canada (Vancouver and Alberta) and one in London, UK. Eligibility included a PLCOm2012 6-year lung cancer risk ≥1.5% or NLST-like criteria (≥30 pack-years smoking history and quit ≤15 years with some variation in age limits – 55 to 80 years in BC, 55 to 74 in Alberta and 60 to 75 in UCL). The proportion of participants who have been found to have lung cancer or high risk lung nodules, requiring repeat imaging studies or biopsy prior to the next scheduled annual screening were compared between the two selection methods.
Result:
The demographics of participants are shown in Table 1. To date, 1,533 received a LDCT, of these, 341 met the PLCOm2012 criteria alone, 169 met NLST-like criteria and 1023 met both criteria. Twenty-seven participants have been found to have lung cancers. All 27 met the PLCOm2012 selection criteria alone while 62% met NLST- like criteria. No lung cancer was found in participants who met NLST-like criteria alone. There are 129 participants with suspicious lung nodules under close surveillance or scheduled for biopsy. Among these, 97% met the PLCOm2012 criteria and 74% met NLST-like criteria.Table 1. Clinical and Demographic Features of Study Cohorts
Study Site British Columbia Alberta London Total No. Contacted 802 1661 1990 4453 No. Eligible 364 741 812 1917 No. Screened 241 688 604 1533 Age (yrs) 65+/- 6.3 63.5 +/- 4.2 66+/-4.2 64.8+/- 5.7 Sex (female/Male) 91F:150M 342F:346M 273F:331M 706M;827M Current:Former Smoker 103CS:138Ex 341CS:347Ex 443CS:161Ex 887CS:646Ex Pack Years (Mean +/-SD) 47.3+/-22 42.4+/-15.8 47.7+/-22.3 45.3+/-19.8 Median Follow-up(months) 7.5 9.7 9.7 No. of lung Cancers 3 7 17 27 Participants with suspicios nodules 21 41 67 129
Conclusion:
Our preliminary results show that fewer people are eligible for screening using NLST-like criteria compare to a highly predictive risk model such as PLCOm2012. Thirty-seven percent more participants with lung cancer are identified by PLCOm2012.
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P2.13-012 - Recruitment for Lung Cancer Screening (ID 9673)
09:30 - 16:00 | Author(s): Stephen Lam
- Abstract
Background:
The efficiency of a lung cancer screening program with low dose computed tomography (LDCT) is influenced by the screening uptake. The most efficient method to improve participation rate of individuals in the general population who are eligible for screening has not been determined. We evaluated different methods of recruitment on the participation rate.
Method:
The BC lung screening trial is part of the International Lung Screen Trial (ILST) in Canada, Australia, the UK and Hong Kong. ILST aims at defining the optimal selection criteria for LDCT by comparing the relative sensitivity of the US Preventative Services Task Force criteria versus the PLCOm2012 prediction model with 6-year lung cancer risk>=1.5%. Individuals with a chest CT within 2 years are excluded from the screening study. Different methods [social media, radio, newspaper, QuitNow smoking cessation program, BC Lung Association and referrals by general practitioners (GP)] to recruit eligible individuals are compared.
Result:
Of the 802 participants referred or self-referred to the study, 364 (41% female, 59% males, 53% ex-smokers and 47% current smokers) were eligible. The largest draw was radio which reached 64% of respondents, however only 29% of these were eligible. General practitioners (GP) reached only 24% but of these 70 % were eligible. 13% had a CT scan within 2 years, and but only 40% would have been eligible via risk criteria (Table 1). Table1. Figure 1
Conclusion:
The largest number of eligible participants were referred by their GPs. Media (radio) reached a larger number of participants but many were ineligible. A combined approach of media publicity and GP referrals may be the best way to reach the target the population. Ad hoc screening is likely occurring in the absence of a publicly funded screening program inappropriately exposing participants outside of the criteria.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-091 - Concurrent Aberrations in G2/M-Phase Transcriptional Programs and Genomic Gatekeepers Highlight Lung Cancer Predisposition in COPD Patients (ID 8485)
09:30 - 16:00 | Author(s): Stephen Lam
- Abstract
Background:
Patients with chronic obstructive pulmonary disease (COPD) have a 7-fold increased risk of developing lung cancer. COPD is defined by clinical symptoms and reduced lung function measurements. It is characterized by chronic inflammation, small airway remodelling and loss as well as destruction of alveoli (emphysema). While this disease is an important lung cancer risk factor independent of smoking, the molecular progression from COPD to lung cancer tumourigenesis is relatively understudied.
Method:
In order to examine the molecular overlap between these two diseases, we first analyzed small airway epithelial gene expression profiles obtained from bronchial brushings from 127 COPD and 140 non-COPD ever-smoker patients. We performed weighted gene correlation network analysis (WGCNA) on these gene expression profiles to discover deregulated gene modules (‘metagenes’) associated with reduced lung function (Forced Expiratory Volume at 1 second, FEV~1~)—a clinical measure of COPD severity most robustly negatively correlated with lung cancer risk. We then assessed the preservation of these modules in two non-small cell lung cancer (NSCLC) tumour/normal data sets (lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC), n= 887 tumors total). Airway and tumor patient cohorts were matched for age, gender, tumour stage, and smoking status.
Result:
We discovered 10 distinct small airway gene expression modules, two of which were significantly negatively correlated (p < 0.05) with patient FEV~1~. One of these FEV~1~ modules was the top overall module preserved in both NSCLC subtypes. This lung cancer-FEV~1~ module contained 31 genes solely enriched for two related mitotic functions— G2/M phase transition (BH-p = 0.02) and mitotic roles of polo-like kinase (BH-p = 0.001, n=31). Of these, 28 genes were significantly overexpressed in both LUAD and LUSC, and mapped to a highly-clustered sub-network of 23 proteins with 465 known and in silico-predicted protein-protein interactions. When tumours enriched for this lung-cancer-FEV~1 ~gene signature were further examined, we observed a significant co-occurrence of DNA-level alterations in DNA damage associated checkpoints, specifically mutated TP53.
Conclusion:
Coordinated gene expression changes associated with COPD severity measures in small airways and preserved in NSCLC tumors are enriched for G2/M phase transition genes. These genes are further disrupted in tumors, where co-occurring mutations to gatekeeper genes are present. Progression of mitosis during abnormal aneuploidy in lung tissues of COPD patients may confer increased risk of oncogenic transformation in this population, and may underlie the molecular progression from COPD to lung cancer.
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WS 02 - IASLC Symposium on the Advances in Lung Cancer CT Screening (Ticketed Session SOLD OUT) (ID 631)
- Event: WCLC 2017
- Type: Symposium
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/14/2017, 09:00 - 18:15, F201 + F202 (Annex Hall)
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WS 02.09 - Lung Cancer Guidelines (ID 10624)
09:00 - 18:15 | Presenting Author(s): Stephen Lam
- Abstract
- Presentation
Abstract not provided
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