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K. Yasufuku
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MA11 - Novel Approaches in SCLC and Neuroendocrine Tumors (ID 391)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:P. Lara, A. Mohn-Staudner
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 3
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MA11.03 - INSM1 is a Novel Biomarker and a Crucial Regulator of the Neuroendocrine Differentiation Pathway in Neuroendocrine Tumours of the Lung (ID 5205)
14:20 - 15:50 | Author(s): K. Yasufuku
- Abstract
- Presentation
Background:
Insulinoma-associated protein 1 (INSM1) is expressed predominantly in embryonic developing neuroendocrine (NE) tissues, and the expression is significantly reduced/restricted in adult tissues. We previously revealed that INSM1 is expressed exclusively in small cell lung cancer (SCLC) compared to non-small cell lung cancer (NSCLC). The significance of the expression of INSM1 in lung cancer has been largely unknown. We investigated the utility of INSM1 as a novel immunohistochemical marker and researched the biological significance in lung cancer cell lines.
Methods:
We compared INSM1 as an immunohistochemical marker for NE tumours of the lung to conventional markers (chromogranin A (CGA), synaptophysin (SYP), and CD56). To elucidate the biological function of INSM1 in the NE differentiation pathway, we conducted INSM1 gene knockdown/overexpression experiments using human lung cancer cell lines.
Results:
INSM1 was expressed in 100% of SCLCs (44/44), Large cell neuroendocrine cell carcinomas (7/7), and Carcinoids (11/11), but was not expressed in NSCLCs (90 adenocarcinomas and 47 squamous cell carcinomas). This novel immnohistochemical marker showed high sensitivity and specificity when compared to conventional NE markers. We demonstrated that knockdown of INSM1 expression resulted in significant reduction of NE molecules in SCLC cell lines, and overexpression of INSM1 induced NE differentiation in NSCLC cell lines.
Conclusion:
INSM1 was a superior NE immunohistochemical marker when compared to conventional markers. Furthermore, our biological molecular experiments revealed that INSM1 is a critical upstream regulator of the NE differentiation pathway in SCLC cell lines. The elucidation of the significance of INSM1 expression in lung cancer strongly supports the diagnosis of NE tumours of the lung and promotes the understanding of the molecular biology of these tumours.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-077 - EGFR/ALK+ Patient-Derived Xenografts from Advanced NSCLC for TKI Drug Selection & Resistance Development: The REAL-PDX Study (ID 6081)
14:30 - 15:45 | Author(s): K. Yasufuku
- Abstract
Background:
Lung cancer patient-derived xenografts (PDX) have shown to be representative models for individual patient tumors. Theoretically, such models could inform the choice of subsequent lines of therapy, since PDX development, TKI resistance induction, and subsequent drug-screening can be completed before TKI resistance develops in the patient. The goal of Resistance modeling in EGFR and ALK Lung cancer (REAL)-PDX is to develop PDX models for real-time treatment selection of subsequent lines of therapy in advanced-stage NSCLC patients.
Methods:
Since August 2015, Princess Margaret Cancer Centre patients with EGFR/ALK+, as well as lifetime never-smoking lung cancer patients with unknown mutation status, were consented to have additional tumor sampling for PDX development during routine- or trial-related biopsies. Tumor sufficiency was confirmed prior to implantation into non-obese severe combined immunodeficient (NOD-SCID) mice, with successful engraftment defined as propagation beyond first passage; unsuccessful implantations had no palpable tumor after 6 months.
Results:
72/82 (88%) approached patients consented; 49/72 (68%) had adequate tumor tissue for implantation (71% stage III/IV): 46 adenocarcinomas, 2 squamous cell carcinoma, 1 LCNEC. 36/49 (73%) were lifetime never smokers. Patients received adjuvant chemotherapy (3), TKI therapy (15), both (5), or no treatment (26) prior to sampling. Tumor samples were taken from surgically resected lung (18), metastatic adrenal (1) and brain (2), CT-guided lung biopsies (5), endoscopic ultrasound-guided (EBUS) biopsies (6), and thoracentesis pleural fluid (17) specimens. Twenty-eight implanted tumors were EGFR+ (12 exon19 deletions, 2 exon19 deletion/T790M, 1 exon19 del/exon18 mutation, 12 L858R, and 1 L858R/T790M); 7 had ALK-rearrangements, and 1 had ROS1-rearrangement. Engraftment rates of 31 assessable implanted tumors were as follows: lung resections 12/12 (100%), metastatic resections 2/3 (67%), CT- or EBUS-guided biopsies 1/5 (20%), and pleural fluid 2/11 (18%); Engraftment rate was associated with no prior treatment (14/17 no treatment vs 3/14 any treatment, p=0.001). Of 17 assessable tumors with EGFR activating mutations, 9 engrafted (53%). Of 3 assessable tumors with ALK-rearrangement, 1 was successful (33%).
Conclusion:
PDX development of EGFR/ALK+ models for testing with novel therapeutics from various tumor biopsy sites is feasible and will provide valuable real-time information for subsequent treatment decisions in advanced NSCLC patients. Updated engraftment and drug screening data will be presented.
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SC19 - Interventional Pulmonology in Diagnosis and Treatment of Thoracic Malignancies (ID 343)
- Event: WCLC 2016
- Type: Science Session
- Track: Pulmonology
- Presentations: 1
- Moderators:Y. Nakanishi, R. Ulmeanu
- Coordinates: 12/06/2016, 16:00 - 17:30, Lehar 3-4
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SC19.02 - Invasive Staging of Lung Cancer: EBUS, EUS and Beyond (ID 6678)
16:00 - 17:30 | Author(s): K. Yasufuku
- Abstract
- Presentation
Abstract:
Despite the advances in surgical treatment and multimodality treatment, lung cancer is still the leading cause of death from malignant disease worldwide. Accurate staging is important not only to determine the prognosis but also to decide the most suitable treatment plan. During the staging process of non-small cell lung cancer (NSCLC), mediastinal lymph node staging is one of the most important factors that affect the patient outcome. 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. 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 can be 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 the inferior mediastinal lymph nodes. 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. Aortic nodes (stations 5 and 6) are exceptions and must be evaluated by surgical methods (anterior mediastinotomy, VATS, thoracotomy). Based on the current evidence, EBUS-TBNA and EUS-FNA presents a minimally invasive endoscopic procedure as an alternative to mediastinoscopy for mediastinal staging of NSCLC with discrete N2 or N3 lymph node enlargement, provided negative results are confirmed by surgical staging. EBUS-TBNA can access all lymph nodes accessible by mediastinoscopy as well as hilar (N1) lymph nodes. EUS-FNA has access to the inferior mediastinal lymph nodes not accessible by mediastinoscopy. EBUS-TBNA and/or EUS-FNA have in fact replaced mediastinoscopy in many patients with diffuse mediastinal adenopathy, where a simple tissue diagnosis is required to determine treatment. 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. Ultrasound image analysis of lymph nodes may assist bronchoscopists during EBUS-TBNA or EUS-FNA. Standard sonographic classification of lymph nodes can help characterize mediastinal and hilar lymph nodes as benign or malignant, which may guide the decision on which lymph nodes to sample. Newer imaging technology such as elastography can potentially enhance US guided image analysis of the lymph nodes.
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