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A.F. Gazdar

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
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      ED07.01 - Adenocarcinomas and Squamous Cell Carcinomas (ID 6457)

      11:00 - 11:20  |  Author(s): W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ED07.02 - The 2015 WHO Classification of Neuroendocrine Tumors (ID 6458)

      11:20 - 11:40  |  Author(s): E. Brambilla

      • Abstract
      • Presentation
      • Slides

      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)

      11:40 - 12:00  |  Author(s): A. Marx

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    MA10 - Facing the Real World: New Staging System and Response Evaluation in Immunotherapy (ID 393)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Radiology/Staging/Screening
    • Presentations: 1
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      MA10.01 - Validations of the 8th AJCC/UICC Lung Cancer Staging System in a Large North America Cohort (ID 6094)

      14:20 - 14:26  |  Author(s): A.F. Gazdar

      • Abstract
      • Presentation
      • Slides

      Background:
      The new 8[th] AJCC/UICC lung cancer staging system was developed and validated using the International Association for the Study of Lung Cancer (IASLC) database, which contains 94,708 lung cancer patients worldwide, but only 5% of patients in this database came from North America. The goal of this study is to validate the prognostic performance of this new staging system, focusing on the upgraded "T" and “M” parameters, in North American lung cancer patients.

      Methods:
      We analyzed 1,163,465 non-small cell lung cancer (NSCLC) cases collected from 2004 to 2013 in the United States in the National Cancer Database (NCDB). After excluding patients with more than one malignant primary tumor or tumor size larger than 10 cm, 545,776 NSCLC patients were included in the final data analysis. We defined 8[th] T and M parameters according to the primary coding guidelines of the Collaborative Staging Manual and Coding Instructions for the new 8[th] AJCC/UICC lung cancer staging system. Kaplan-Meier survival curves and log-rank tests were used to compare survival difference among different stage groups, and Cox regression models were used for multivariate analysis adjusting for potential confounders.

      Results:
      We validated that the new staging system can provide better survival prognosis for NSCLC patients in the NCDB cohort than the existing 7[th] staging system. The median survival time for T1a is 58 months (N=15,860), for T1b is 47 months (N=78,379), and for T1c is 25 months (N=79,828) (p<2e-16). The median survival time for T2a is 19 months (N=111,925), for T2b is 12 months (N=54,601), for T3 is 10 months (N=105,234), and for T4 is 7 months (N=99,949) (p<2e-16). And the median survival time for M0 is 25 months (N=411,048), for M1a is 8 months (N=49,352), for M1b is 5months (N=42,224), and for M1c is 3 months (N=15,926 cases) (p<2e-16). Multivariate analysis showed that these staging parameters are significantly associated with survival when adjusting other factors.

      Conclusion:
      Both upgraded “T” and “M” parameters of the 8[th] AJCC/UICC lung cancer staging systems are significantly associated with NSCLC patient survival outcomes using data from the NCDB, indicating a good validation performance in patients from North America.

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    PL05 - Closing Plenary Session: A Life in Thoracic Oncology - Reflections from Giants on Milestones in the Treatment Advances in Lung Cancer (ID 433)

    • Event: WCLC 2016
    • Type: Plenary
    • Track:
    • Presentations: 1
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      PL05.01 - Pathology (ID 6914)

      16:10 - 16:25  |  Author(s): A.F. Gazdar

      • Abstract
      • Presentation
      • Slides

      Abstract:
      A life in Thoracic Oncology – Reflections from a pathologist. While many regard a pathologist as a physician involved in laboratory diagnosis, by definition Pathology is the science or the study of the origin, nature and course of diseases. This broader definition of pathology, which basically encompasses all of the study of medicine, is what first attracted me to the field. After my residency I joined the NCI as a research pathologist studying viral oncology in rodents. However a few years later John Minna gave me the opportunity to return to the study of human cancer when he was appointed the head of the NCI-VA Medical Oncology Branch in Washington, DC, with a focus on lung cancer therapy. Our branch was fortunate to have an outstanding lung pathologist, Mary Matthews who taught me most of what I know about lung pathology. Mary also had a profound effect on the understanding and treatment of lung cancer. In 1973 she established that small cell lung cancer (SCLC) was almost always metastatic at the time of diagnosis, and that surgery was unlikely to be curative.[1]These observations, plus the finding that SCLC showed initial responses to the therapy then currently available, helped establish the fundamental distinction of lung cancers into SCLC and NSCLC categories. The Mary Matthew award for Pathology and Translational Research is one of the distinguished awards of the IASLC and I was fortunate and honored to be the fourth recipient in 2003. John Minna assembled an outstanding group of physicians/scientist many of whom became pioneers in the field of lung cancer. Of interest, all three past and present Chief Executive Officers of the IASLC, Heine Hansen, Paul Bunn and Fred Hirsch, spent time at the NCI-VA Medical Oncology Branch. John preached that new approaches for the therapy of lung cancer were needed, that this would require understanding biology, and to understand biology we needed preclinical models. My job was to establish such models and help “translate” them into clinical care. By the early 1980s we had established and characterized large banks of SCLC cell lines and demonstrated that they expressed the entire neuroendocrine (NE) cell program.[2] The cell lines were widely distributed to the scientific community, and in the absence of reliable tumor tissue sources, became the major source of biologic and molecular knowledge of SCLC. Within that decade our group, largely from the use of cell lines, described chromosome 3p loss, MYC family amplification, RB1 and TP53 loss as being characteristics of SCLC and also discovered the MYCL oncogene. The NCI-VA Medical Oncology Branch later relocated to the Bethesda Naval Hospital, MD. In 1991, John Minna accepted a position at the University of Texas Southwestern Medical Center, Dallas, and I was his first recruitment. Thus, during my long career I have only had two employers! I believe this continuity has helped establish strong, long term collaborations and boosted overall productivity. One of the interests of Mary Matthews and me was the heterogeneity of SCLC. It became obvious to us that the so-called oat cell variant was an ischemic artifact. However we were intrigued by the plasticity of SCLC, with a substantial percentage of cases having abnormal (“variant”) morphologies or combined with NSCLC elements, especially after therapy.[3] The variant morphology and its relationship to NEUROD1 as the driver transcription factor (as opposed to ASCL1 as the driver in typical or “classic” SCLC) has recently been highlighted.[4] By the mid 1980s, advances in SCLC biology and therapy had hit a stonewall, and funding dried up. It was time to move onto NSCLC! We established a large collection of NSCLC cell lines and these also formed much of the basis of our understanding of this disease, although tumor tissues were much more readily available. While cell lines have their pluses and minuses, they are excellent for identifying driver mutations and testing targeted therapies. They contributed to the identification of the role of EGFR mutations in lung cancer.[5, 6] Soon after this discovery we used our international fellows and contacts to perform the first large multinational study of geographic and ethnic variations in mutation frequencies, and also demonstrated that mutations were largely absent in tumors other than NSCLC.[7] The advent of Precision Medicine has highlighted the crucial role of the pathologist. Instead of the image of a pathologist looking at microscope slides in isolation in a basement office, he or she plays a crucial role as an integral part of the diagnostic and therapeutic team involved in every aspect of patient management. The pathologist assumes further responsibilities such as tissue procurement and optimal utilization, triaging scant resources for clinical trial requirements, involvement in molecular testing, performing requested or required immunostaining, establishing tissue repositories etc. Previously clinical decision making required the pathologist only to make a diagnosis of SCLC or NSCLC. Precision Medicine has highlighted the importance of accurate classification of NSCLC. Classification is required for mutation testing, therapy selection (or exclusion) and entry onto histology dependent clinical trials. While the introduction of immunostains has greatly facilitated the classification of poorly differentiated NSCLC, the SEER database indicates that up to 14% of NSCLC may remain unclassified throughout the USA. For these reasons we developed a molecular classifier for NSCLC that can be applied to formalin fixed paraffin embedded (FFPE) materials and small core biopsies.[8] The assay is highly accurate and quantitative, and also provides information on grading and survival. While SCLC languished for three decades, its recent designation as a recalcitrant cancer by the US Congress has resulted in a dramatic resurrection of interest, funding and achievement.[9] This has highlighted the importance of preclinical models for SCLC.[10, 11] I feel very humbled and privileged to have lived through and contributed to the seminal advances in our understanding of the biology and therapy of lung cancer. This would not have been possible without the many wonderful and talented people I have worked with. I am reminded of the quote of Isaac Newton: “If I have seen further than others, it is because I have stood on the shoulders of giants”. References 1. Matthews MJ, Kanhouwa S, Pickren J, et al. Frequency of residual and metastatic tumor in patients undergoing curative surgical resection for lung cancer. Cancer chemotherapy reports Part 3 1973;4:63-67. 2. Gazdar AF, Carney DN, Russell EK, et al. Establishment of continuous, clonable cultures of small-cell carcinoma of lung which have amine precursor uptake and decarboxylation cell properties. Cancer Res 1980;40:3502-3507. 3. Gazdar AF, Carney DN, Nau MM, et al. Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties. Cancer Res 1985;45:2924-2930. 4. Borromeo MD, Savage TK, Kollipara RK, et al. ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs. Cell reports 2016;16:1259-1272. 5. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304:1497-1500. 6. Sharma SV, Bell DW, Settleman J, et al. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169-181. 7. Shigematsu S, Lin L, Takahashi T, et al. Clinical and biological features associated with Epidermal Growth Factor Receptor gene mutations in lung cancers. J Natl Cancer Inst 2005;97:339-346. 8. Girard L, Rodriguez-Canales J, Behrens C, et al. An Expression Signature as an Aid to the Histologic Classification of Non-Small Cell Lung Cancer. Clin Cancer Res 2016. 9. Gazdar AF, Minna JD. Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer. J Natl Cancer Inst 2016;108. 10. Gazdar AF, Hirsch FR, Minna JD. From Mice to Men and Back: An Assessment of Preclinical Model Systems for the Study of Lung Cancers. J Thorac Oncol 2016;11:287-299. 11. Gazdar AF, Savage TK, Johnson JE, et al. The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 2015;10:553-564.

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