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H. Popper
Moderator of
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ED07 - Classification and Druggable Targets of Thoracic Tumors (ID 272)
- Event: WCLC 2016
- Type: Education Session
- Track: Biology/Pathology
- Presentations: 3
- Moderators:A.F. Gazdar, H. Popper
- Coordinates: 12/06/2016, 11:00 - 12:30, Hall C1
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ED07.01 - Adenocarcinomas and Squamous Cell Carcinomas (ID 6457)
11:00 - 12:30 | Author(s): W.D. Travis
- Abstract
- Presentation
Abstract not provided
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ED07.02 - The 2015 WHO Classification of Neuroendocrine Tumors (ID 6458)
11:00 - 12:30 | Author(s): E. Brambilla
- Abstract
- Presentation
Abstract:
The 2015 WHO Classification of Neuroendocrine Tumors Elisabeth Brambilla, Professor of Pathology, Department of Pathology; CHU Grenoble INSERM U 1209; Institute of Advanced Biosciences; University Grenoble Alpes; France Neuroendocrine lung tumors were considered as separate entities in the previous WHO classification 2004: the carcinoid tumors, small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) were grouped separately. However, in the current WHO 2015 classification, they are grouped together [1]. They are listed in the order of their frequency with SCLC first as it is the most common. SCLC (15% of lung tumors) is a malignant epithelial tumor which consist of densely packed small cells with scant cytoplasm, finely dispersed granular chromatin and absent or inconspicuous nucleoli. In contrast LCNEC is made of large cells and should show both neuroendocrine morphology (rosettes, palisades) and immunohistochemical neuroendocrine markers (at least one). Both SCLC and LCNEC can be pure or combined with NSCLC components but keep their diagnostic priority (SCLC-or LCNEC- combined). Carcinoid tumors are neuroendocrine malignancies accounting for <1% of all lung cancer, divided in two categories with highly different frequencies, the typical and atypical carcinoid, the last being extremely rare. Typical carcinoids are carcinoid tumors with <2mm[2] and lacking necrosis. They measure ≥0.5 cm in size. Atypical carcinoids are carcinoid tumors with 2-10 mitoses per 2mm[2] and/or foci of necrosis. Despite the grouping of these tumors together, it is clear that the carcinoids have major clinical, epidemiologic, histologic and genetic differences compared to the high grade SCLC and LCNEC. Carcinoid patients are significantly younger, have a better prognosis and lack the strong association with smoking that applies for SCLC and LCNEC. Also compared to carcinoid tumors, SCLC and LCNEC have much higher mitotic rates (more than 11 per 2mm[2]), more necrosis and can show combinations with other lung cancer types including adenocarcinoma or squamous cell carcinoma, which testify of a common progenitor cell derivation, not shared by carcinoid which is never mixed with a non-neuroendocrine (NE) tumor type. Carcinoid tumors also have very few genetic abnormalities compared to SCLC and LCNEC which show the highest rate of mutations per megabase among all cancer[3,4,5] . While in many cases, SCLC and carcinoid tumors can be diagnosed on good quality tumor material with a high quality H&E stained section and in well preserved cytological samples, immunohistochemistry (IH)/neuroendocrine markers can be very helpful in diagnosing pulmonary NE tumors especially in small biopsies with crushed artefact. Endocrine morphology and neuroendocrine IH markers are both required for the diagnosis of LCNEC. The cases with one missing (endocrine morphology or NE markers) are considered as large cell carcinoma in the absence of other differentiation marker on resection specimens, and as non-small cell lung carcinoma on small samples (cytology or biopsy) Mitotic counts are still retained to differentiate typical carcinoids (less than 2 mitoses per mm[2]) from atypical carcinoids (2 to 10 per 2mm[2]) and from high grade NE tumors SCLC and LCNEC (more than 11 mitoses per 2 mm[2 ], for being more reproducible than KI-67 evaluation. The role of Ki-67 is mainly to separate the high grade SCLC (more than 50%) and LCNEC (more than 40%) from the carcinoid tumors (from 1 to 15%) especially in small biopsies with crushed and/or necrotic tumor cells. It is recommended to avoid the diagnosis of SCLC or LCNEC for tumors with less than 50% and 40% MIB1/KI67 index respectively. Data are conflicting regarding the use of KI-67 in separating typical from atypical carcinoid tumors, so it is not recommended in this setting. Careful counting of mitoses is essential as it is the most important histologic criteria for separating typical from atypical carcinoid and the carcinoids from the high grade SCLC and LCNEC. Due to recognition of the potential overlap in the morphology of LCNEC and basaloid squamous cell carcinoma, it can be helpful to confirm negative squamous markers (i.e. p40) in TTF-1 negative tumors that otherwise meet criteria for LCNEC. Many recent progress have been made on the comprehensive genomic profiles of SCLC [3,4 ], LCNEC [5] and carcinoids [6]. Although sharing NE features, these 3 tumors group show substantial and significant differences.Recent comprehensive genomic analyses have established the genomic profile of SCLC [3,6.] Their unique and remarkable characteristic is the universal bi-allelic alteration of both TP53 and RB1 gene (100% for P53 and 93% for RB1) by different alterations of each of the 4 alleles: non synonymous mutations, damaging mutations by complex genomic rearrangements. Locally clustered mutations, indicative of functional selection, occurred on CREBBP (15%) and EP300 (13%) genes, inactivating their histone acetylase functions. Notch family genes inactivating their protein functions occurred in 25% of SCLC [4]. Notch is considered as a master regulator of NE differentiation. LCNEC genomics share characteristic features with SCLC for a part of LCNEC (SCLC-like LCNEC) or with AD /SQC for another part (about 25%). Mutations pattern and frequency of combined cases imply a considerable plasticity of theses tumours which might represent an evolutionary trunk branching SCLC to NSCLC. Carcinoid is a unique example of a tumor driven entirely by chromatin modifiers and remodeling genes, which are not mutant in SCLC. In summary, 51% of carcinoid carried mutations in chromatin remodeling genes. In addition, the eukaryotic translation initiation factor (EIF1AX) was mutated in 9% of cases, genes of the E3 ubiquitin ligases system were mutated or rearranged in 18%. Altogether 73% of carcinoids have driver genes that are candidates for targeted therapy [6.] New evidence is provided that carcinoid is not an early progenitor of high grade NE tumors SCLC and LCNEC. References: 1. Travis WD, Brambilla E, Burke A, Marx A, Nicholson A. WHO Classification of the Tumours of the Lung, Pleura, Thymus and Heart. 4th Edition. Lyon: IARC Press; 2015. 2. Clinical Lung Cancer Genome Project (CLCGP), Network Genomic Medicine (NGM). A genomics-based classification of human lung tumors. Sci Transl Med. 2013;5(209):209ra153. doi:10.1126/scitranslmed.3006802. 3. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44(10):1104-1110. doi:10.1038/ng.2396. 4. George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47-53. doi:10.1038/nature14664. 5. Fernandez-Cuesta L, Peifer M, George J, et al. Genomic Characterization of Large-Cell Neuroendocrine Lung Tumors. J Thorac Oncol. 2015;10(9 - WCLC 2015 Abstracts: PDF Only):S185. doi:10.1097/01.JTO.0000473439.77589.a7. 6. Fernandez-Cuesta L, Peifer M, Lu X, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014;5:3518. doi:10.1038/ncomms4518.
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ED07.04 - The WHO Classification of Thymomas and Thymic Carcinomas (ID 6460)
11:00 - 12:30 | Author(s): A. Marx
- Abstract
- Presentation
Abstract not provided
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Author of
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IA01 - Multidisciplinary Diagnosis of Lung Cancer in the Era of Molecular Medicine (ID 284)
- Event: WCLC 2016
- Type: Interactive Session
- Track: Biology/Pathology
- Presentations: 1
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IA01.01 - The Role Pathology for Diagnosis and Treatment of Lung Cancer (ID 6514)
11:00 - 12:30 | Author(s): H. Popper
- Abstract
- Presentation
Abstract not provided
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MTE03 - Basics of Molecular Biology for the Clinician (Ticketed Session) (ID 297)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 07:30 - 08:30, Schubert 4
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MTE03.01 - Basics of Molecular Biology for the Clinician (ID 6542)
07:30 - 08:30 | Author(s): H. Popper
- Abstract
Abstract:
The rapid development of molecular biology in recent years has allowed us to understand the main molecular steps involved in the development and progression of lung cancer. The identification of molecular alterations in specific tumor genes that function as key drivers for neoplastic growth has laid the foundations for new therapeutic approaches with targeted agents. An accurate detection of target mutation is mandatory for an efficient treatment. The main limitation of targeted therapies is the occurrence of acquired resistance that makes cancer unresponsive to treatment. In many cases, through the acquisition of additional (secondary) mutations the tumor is able to acquire the heterogeneity which may enable it to adapt to various conditions of the microenvironment, including those determined by the effect of treatment with specific drugs. New generation drugs are constantly under development to overcome tumor resistance and increase survival of lung cancer patients. In this process, a constant monitoring of the mutational status of the tumor is required. Different types of genetic alterations are involved in tumor development, progression, and induction of resistance, including single nucleotide variants, indels, amplifications, fusions etc. Mutation detection before first line treatment is usually performed on tissue or cytological samples. Resected tumor samples, biopsies and cytological specimens are available in about 25%, 35% and 40% of NSCLC patients, respectively. At progression, a re-byopsy should be obtained to detect the emergence of resistance-inducing mutations. Transbronchial tissue biopsy is the most common sampling method used for re-biopsy. However, several factors limit the success rate of re-biopsy, such as the performance status of the patient, the difficulty of accessing some tumor sites, and the invasiveness of sampling methods. When the amount and/or quality of the biological material is insufficient for molecular analysis, circulating free DNA (cfDNA) can represent a valid alternative in selected patients. Liquid biopsies have several advantages over tissue or cells: they are less invasive, can be repeated over time, and have a more rapid turnaround time. However, there are some critical issues that must be considered: 1) the possibility to detect a mutation in cfDNA is dependent on several clinicopathological parameters, including tumor type, tumor burden, and particularly tumor stage (a locally advanced tumor has a significantly lower probability to spread mutant DNA in the blood than a metastatic tumor); 2) a large amount of wild-type DNA circulates in the plasma with only trace amounts of the mutant allele; therefore, the analysis of genetic aberrations in cfDNA is challenging, requiring well standardized pre-analytical/analytical protocols and dedicated techniques with high sensitivity and specificity. Different technologies/protocols are required for the detection of these genetic aberrations. Robust and sensitive molecular biology techniques are nowadays available to detect mutations in driver genes before initiating a targeted treatment or to identify the emergence of secondary mutations at disease progression. The use of multimarker assays, and in particular next generation sequencing, is progressively becoming popular, allowing on one hand to reduce the working time, costs per single assay, and the amount of nucleic acids required for testing and increasing, in the other hand, throughput and overall quality. Recently, semi-quantitative or quantitative detection methods for the assessment of genetic aberrations in cfDNA have been developed with a number of potential clinical implications. An accurate quantification of mutated alleles in cfDNA during the first days of treatment could: a) complement or replace more expensive and invasive methods to assess response in treated patients; b) represent a new way to compare the effectiveness of different drug; c) be an additional tool to evaluate the best treatment regimen for patients. In addition, a periodic quantification of the mutation burden during all the treatment time could allow an early detection of resistance-inducing mutations for possible changes to therapy.
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OA20 - Immunotherapy and Markers (ID 401)
- Event: WCLC 2016
- Type: Oral Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:M. Früh, C.S. Baldotto
- Coordinates: 12/07/2016, 11:00 - 12:30, Stolz 2
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OA20.08 - Discussant for OA20.05, OA20.06, OA20.07 (ID 7099)
11:00 - 12:30 | Author(s): H. Popper
- Abstract
- Presentation
Abstract not provided
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-036 - Eukaryotic Translation Initiation Factors impact Non Small Cell Lung Cancer (ID 3923)
14:30 - 15:45 | Author(s): H. Popper
- Abstract
Background:
Non small cell lung cancer (NSCLC) belongs to the most frequently diagnosed cancer entities and is one of the leading causes of cancer related death worldwide. Deregulation of protein synthesis has received considerable attention as a major step in cancer development and progression. Protein synthesis is regulated at multiple stages, including translation of mRNA into proteins. Studies suggest that ribosomal protein synthesis plays a direct role during tumor-initiation. Crucial for this translation process are eukaryotic initiation factors (eIFs), which ensure the correct 80S ribosome assembly. eIFs are linked to the MAPK and the mTOR signalling pathways, which have become major targets in cancer therapy. Mutations or deregulated expression of eIFs influence cell growth and proliferation, and contribute to carcinogenesis. We hypothesized that eIFs represent crossroads for carcinogenesis in lung cancer and might serve as potential biomarker.
Methods:
Expression profiling of paired NSCLC and non-neoplastic lung tissue (NNLT) from 1.000 individuals were studied by immunohistochemistry on tissue micro arrays (TMAs) with antibodies against the eIF subunits 2α; 3C; 3H; 3M; 4E and 6. eIF expression was evaluated with respect to the staining intensity (intensity score 0-3; 0: no staining, 1: weak, 2: moderate and 3: strong) and percentage of positive tumor cells (proportion score; 0-100%). In addition, the protein and mRNA expression levels of eIFs and mTOR pathway members were determined in 25 patients by Western Blot analysis and qRT-PCR. For the statistical analysis α was set to 5%.
Results:
Western Blot analysis of NSCLC revealed a significant up-regulation of mTOR and the eIF subunits p2α, 2α, 1A, 4A, and eIF6 compared to NNLT (p< 0,05). The mRNA levels of NSCLC also displayed a significant upregulation of the eIF subunits 2α, 4A, and eIF6 compared to NNLT. Immunohistochemistry highlighted a stronger staining in neoplastic cells for eIF2α, eIF4E, eIF3H and eIF6.
Conclusion:
Our data indicated that eIFs are significantly upregulated in NSCLC, suggesting an important contribution of eIFs and mTOR signalling to the development and progression of lung carcinomas. A better understanding of the molecular mechanisms in pulmonary carcinogenesis is necessary for the development of novel treatment strategies.
