Virtual Library

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In non-small cell lung cancer (NSCLC) chromosomal rearrangements involving the gene encoding for the receptor tyrosine kinase ROS1 have been first described in 2007 (1). These aberrations have been shown to trigger constitutive kinase activity and activation of downstream pathways like the MAPK pathway. ROS1 rearrangements can be found in about 2% of lung adenocarcinoma and are associated with female gender and never-smoking status (2). Different fusion partners have been described. In routine diagnostics ROS1 fusion genes can be reliably detected by fluorescence in situ hybridization (FISH; e.g. dual color break apart FISH), RT-PCR or next-generation sequencing (NGS). ROS1 fusions occur mutually exclusive of aberrations in EGFR, ALK and KRAS. However, using NGS, co-occuring mutations, preferentially in TP53, but also in other genes involved in oncogenic pathways, can be found in about 50% of these patients (3). ROS1 fusions also seem to be of prognostic relevance, since remarkable long survival times have been described in patients treated with chemotherapy only (3). The ALK/MET/ROS1 inhibitor crizotinib has been evaluated in a US-American cohort of 50 ROS1 positive patients with advanced, mostly pretreated lung adenocarcinoma and showed impressive activity (4). The overall response rate (ORR) was 72% (95% CI 58 to 84) with 3 complete responses. Median progression free survival (PFS) was 19.2 months (95% CI 14.4 to not reached). Treatment was well tolerated and the side effect profile resembled that observed in the treatment of ALK positive lung cancer with crizotinib. A similiar ORR of 80% was reported in a retrospectively analyzed European cohort (5). However, PFS was only 9.1 months in these patients. The EUCROSS trial, a collaborative study of the German Lung Cancer Group Cologne and the Spanish Lung Cancer Group, is a prospective European phase II trial which recruited 34 ROS1 positive patients between June 2014 and September 2015. ROS1 fusion genes were diagnosed using dual color break apart FISH and the results were confirmed by next-generation sequencing. With an ORR of 69% (95% CI, 49.1 to 84.3) similar efficacy has been reported (6). Based on its high activity and favorable toxicity profile, crizotinib is now approved for the treatment of ROS1-positive NSCLC by the FDA since March 2016 and by the EMA since August 2016. Treatment of ROS1-positive NSCLC with crizotinib thus has become standard first-line treatment in the leading international guidelines. Current challenges for the further development and improvement of targeted treatment of ROS1-positive patients are (I) implementation of ROS1 diagnostics in routine molecular diagnostics and (II) development of next-generation ROS1 inhibitors overcoming crizotinib resistance. The increasing number of actionable mutations in NSCLC including ROS1 requires implementation of molecular multiplex testing, since sequentially conducted single gene assays are no more feasible given the usually limited biopsy tissue specimens. However, conventional NGS technology is restricted to point mutations and does not cover copy number variations (CNV) and gene fusions. Thus, new NGS technologies have to be integrated in routine diagnostics like hybrid capture-based NGS, which does not require DNA amplification by PCR and thus allows to detect reliably CNV and gene fusions. While increasing knowledge of the molecular mechanisms underlying TKI resistance has led to the development of a series of highly potent next-generation inhibitors in ALK-positive NSCLC now, resistance of ROS1-positive patients to crizotinib is incompletely understood. In preclinical studies as well as in biopsy tissue, somatic mutations in the ROS1 kinase domain associated with acquired crizotinib resistance have been described (7). In functional studies these mutations were associated with different degrees of resistance. Alternatively, bypass activation of oncogenic signal transduction pathways has been described as mechanism underlying resistance. For instance, a cKIT activating mutation and EGFR pathway activation have been reported in single cases (8). In vitro, the multikinase inhibitors cabozantinib, foretinib and lorlatinib have been shown to overcome crizotinib reistance triggered by secondary mutations in ROS1. Response to cabozantinib has also been described in a ROS1-positive patient with a mutation confering resistance to crizotinib (10) and was also observed in a phase I trial of lorlatinib in the same clinical setting. In summary, ROS1 positivity characterizes a subgroup of patients with a major benefit from treatment with crizotinib. Consequently, crizotinib has become the current standard of care for these patients. ROS1 status thus should be available before decision on first-line treatment. Acquired resitance to crizotinib may be caused by mutations in the ROS1 kinase domain or by activation of bypass pathways. The multikinase inhibitor cabozantinib and the next-generation ALK/ROS1 inhibitor lorlatinib have shown promising efficacy in early clinical evaluation. (1) Rikova K et al. Global survey of phosphotyrosine sgnaling identifies oncogenic kinases in lung cancer. Cell 2007, 14; 131(6):1190-203. (2) Bergethon K et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012, 30(8):863-70. (3) Scheffler M et al. ROS1 rearrangements in lung adenocarcinoma: prgnostic impact, therapeutic options and genetic variability. Oncotarget 2015, 6(12):10577-84. (4) Shaw A et al. Crizotinib in ROS1-rearranged non-small cell lung cancer. NEJM 2014, 371(21): 1963-71. (5) Mazieres J et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol 2015, 33(8):867-76. (6) Michels e al. EUCROSS: a prospective European phase II trial to evaluate efficacy and safety of crizotinib in advanced adenocarcinoma of the lung harboring ROS1 translocations. WCLC 2016 (oral presentation). (7) Awas MM et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. NEJM 2013, 368(25):2395-401. (8) Dzadziuszko R et al. Activating KIT mutation induces crizotinib resistance in ROS1-positive lung cancer. J Thorac Oncol 2016, 11(8):1273-81. (9) Davies KD et al. Resistance to ROS1 inhibition mediated by EGFR pathway activation in non-small cell lung cancer. PLoS One 2013, 13 (8):e82236. (10) Drilon et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin Cancer Res 2016, 22 (10):2351-8.

Abstract:
"Lung adenocarcinoma" is a genetically heterogenous disease entity, characterized by a wide spectrum of different mutations. Some of these mutations lead to constitutive activation of receptor tyrosine kinases, which can be inhibited by small molecules (tyrosine kinase inhibitors, TKIs). EGFR mutations (2004) and ALK rearrangement (2007) were among the first actionable driver mutations identified in lung adenocarcinomas. Today, several drugs are approved for the treatment of advanced lung adenocarcinomas with EGFR mutations or ALK/ROS1 rearrangement. Combined, these molecular subgroups make up at least 20% of all lung adenocarcinomas or more, depending on the poplulation. Further actionable driver mutations include the genes BRAF, HER2, MET, and RET. These genes are less frequently mutated than EGFR/ALK, nevertheless, rare drivers are clinically relevant because of the availability of targeted therapies approved for other indications in oncology (ALK-lung, HER2-breast, RET-thyroid, and BRAF-melanoma). The discussant will summarize current knowledge about rare driver mutations, with a strong clinical focus. HER2 insertion 20, present in about 1% of lung adenocarcinomas, was initially proposed by Cappuzzo et al as a potential indication for trastuzumab-based therapy [1]. Prospective trials with HER2 targeting drugs are currently ongoing. BRAF V600E, present in about 3% of lung adenocarcinomas, was associated with high activity of combined therapy with dabrafenib and trametinib in a prospective phase II trial by Planchard et al [2]. Crizotinib, recently approved by the FDA for the treatment of ROS1-NSCLC, is also active in tumors harboring MET exon 14 mutations as demonstrated by Drilon et al [3]. Cabozantinib and vandetanib are active in tumors with RET rearrangement as shown by three recent phase II trials [4-6]. Entrectinib showed preliminary activity in tumors harboring TRK rearrangement in an early basket Trial [7]. These results will be discussed in detail, together with the results of international registries (EUHER2, EURAF, EUROS1 and GLORY [8]). Moreover, current treatment recommendations for patients with advanced lung adenocarcinomas and rare driver mutations will be summarized. References 1. Cappuzzo et al. N Engl J Med. 2006;354(24):2619-21. 2. Planchard et al. Lancet Oncol. 2016;17(7):984-93. 3. Drilon et al. J Clin Oncol 34, 2016 (suppl; abstr 108) 4. Drilon et al. Cancer Discov. 2013;3(6):630-5. 5. Seto et al. J Clin Oncol 2016;34(suppl; abstr 9012) 6. Lee et al. J Clin Oncol 2016;34(suppl; abstr 9013) 7. Drilon et al. AACR 2016 (abstract CT007) 8. Gautschi et al. WCLC 2016 (abstract 4325)

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Lung cancer is the leading cause of cancer death worldwide and cigarette smoking is a major causative environmental factor. Some unique biologic profiles are associated to tobacco-induced lung cancer, including clinical, pathological and genetic features. Lung cancer in never smokers (up to 20% of cases worldwide) has been suggested to represent a distinct disease, compared to tobacco-induced lung cancer. Cigarette smoke is a mixture of more than 5000 chemical compounds, among which more than 60 are recognized to have a specific carcinogenic potential. Carcinogens and their metabolites (i.e., N-nitrosamines and polycyclic aromatic hydrocarbons, among others) can activate multiple pathways, contributing to pulmonary cell transformation in different ways. Nicotine, originally thought to be responsible for tobacco addiction, only, is also involved in tumor promotion and progression with anti-apoptotic and indirect mitogenic properties (Tonini et al. Future Oncol 2013;9:649-55). Preclinical models were employed to define epigenomic alterations and gene expression profiles in respiratory epithelia exposed to cigarette smoke condensate. In a study, smoke condensate significantly repressed miR-487b, that directly targets several genes, including SUZ12, BMI1, WNT5A, MYC, and KRAS. Such repression correlated with overexpression of the above targets in lung cancer and coincided with DNA methylation within the miR-487b genomic locus, indicating this molecule as a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis. These findings may potentially pave the way for DNA demethylating agent treatment, in order to re-activate miR-487b in lung cancer therapy (Xi et al. JCI 2013; 123:1241-61). Among other effects of cigarette smoking, a synergy was described with the aryl hydrocarbon receptor (AHR), which is partially responsible for tobacco-induced carcinogenesis through incompletely understood mechanisms. It was reported that smoking induces AHR activating ligands, which in turn induced adrenomedullin both in vitro and in vivo, thus significantly contributing to the carcinogenicity of tobacco-activated AHR. These effects were not reproduced in fibroblasts and mice lacking the aryl hydrocarbon receptor (Portal-Nuñez et al. Cancer Res 2012; 72:5790-800). Genetic factors involved in tobacco-induced lung cancers have been widely investigated to determine the genetic susceptibility to lung cancer, including epigenomic alterations (Fujimoto et al. PlosOne 2010;5:e11847. Liu et al. Oncogene 2010;29:3650-64). In addition, tobacco-induced lung cancer is characterized by a deregulated inflammatory microenvironment (Spitz et al. Cancer Epidemiol Biomark Prev 2012; 21:1213-21). Therefore variants in inflammation pathway associated genes, as well as a number of genetic polymorphisms have been identified as putative candidates predisposing to lung cancer development. The effects of single polymorphisms on lung cancer development risk have been investigated, with inconsistent results. Most currently identified polymorphisms involve genes encoding proteins associated with the metabolic processing of tobacco smoke carcinogens and the repair of mutations induced by those carcinogens. Polymorphisms on chromosomes 5p15.33, 6p21, and 15q24-25.1 were identified, being the former specifically associated to a higher risk for adenocarcinoma (Yokota et al. Adv Cancer Res 2010;109:51-72). Regarding inflammation genes, analyzing a comprehensive panel of over 11,000 inflammation pathway single-nucleotide polymorphisms (SNP), six SNPs were significantly (p < 0.05) associated to a higher risk of lung cancer development, including two SNP variants in former smokers (BCL2L14) and in current smokers (IL2RB) (Spitz et al. Cancer Epidemiol Biomark Prev 2012; 21:1213-21). The above genetic alterations are observed in all histological subtypes of lung cancer with several differences, especially between small cell lung carcinoma (and the other neuroendocrine tumors) and non-small cell lung cancers. Though all lung cancers are generally tobacco related, changes of incidence of different histological types (with an increase of adenocarcinoma in both sexes) are well known, reflecting modifications of smoking habits, cigarette types, filter types and content of tar, among others. Wide sequencing of single cancer histotypes has provided a relatively complete map of most common alterations in each tumor. In adenocarcinoma, a mean exonic somatic mutation rate of 12.0 events/megabase was identified, which included most previously reported genes in adenocarcinoma as significantly mutated, as well as recurrent mutations in U2AF1, RBM10 and ARID1A genes, and structural rearrangements within EGFR and SIK2 kinases (Imielinski et al. Cell 2012; 150, 1107–1120). Regarding squamous cell carcinoma, the Cancer Genome Atlas Network profiled 178 tumors and found complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor. Recurrent mutations were found in 11 genes, with TP53 mutations occurring in nearly all specimens and novel alterations affecting a proportion of cases, including HLA-A class I major histocompatibility gene, NFE2L2, KEAP1, phosphatidylinositol-3-OH-kinase pathway genes, CDKN2A, RB1 and specific squamous differentiation genes (Cancer Genome Atlas Res Network. Nature 2012;489:519-525). As far as small cell lung cancer is concerned, high mutation rates (up to 8.6 non-synonymous mutations per million base pairs) were identified. Of these, up to 28% were found to be C:G>A:T transversions, a type of alteration associated to heavy smoking, although the smoking history was not correlated with the type and number of mutations. Other genes exhibiting mutations and inactivating translocations included the histone acetyltransferase genes CREBBP and EP300, genes with functional roles in the centrosome (ASPM, ALMS1 and PDE4DIP), in the RNA-regulating gene XRN1 and the tetraspanin gene PTGFRN. Damaged genes were commonly found, including the known TP53, RB1, but also TP73, CREBBP and COL22A1, as well as FMN2 and NOTCH family genes (mostly inactivation in the latter) (George et al. Nature 2015; 524: 47–53). Whether the identified genetic signatures and peculiar biological features will produce a corresponding reproducible therapeutic “signature” is still not the case, but the way is paved for stratifying patient groups based on their unique pathological and genetic tumor characteristics, among different histotypes and also within individual neoplastic variants. The future challenge will be to define the biological profile of immunocheckpoint molecule expression in tobacco related lung cancers, in order to identify a reliable predictive marker of response to treatments targeting PD1 or PDL1, in relationship with the different mutational burden and immunological status of individual cases.

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There are many important changes in the 2015 WHO classification of lung tumours, reflecting the numerous advances in tumour genetics and therapy over the past decade.[1] Many have been in the field of adenocarcinoma, with discontinuation of the term bronchioloalveolar carcinoma and the concept of stepwise progression accepted for adenocarcinoma.[1] Adenocarcinoma in situ (AIS) is a small (less than 3 cm in diameter), pure lepidic adenocarcinoma; minimally invasive adenocarcinoma (MIA) is also a small lepidic adenocarcinoma but has small invasive areas less than 5 mm across. As both entities have a very favorable outcome, with an expected 5-year survival rate of 100%, AIS and MIA are targets for reduction surgery, and are frequently detected by low-dose CT screening. High-resolution (HR)-CT demonstrates these tumours as a pure ground glass nodule (GGN) or a part-solid nodule (PSN), being closely correlated with their pathological features.[2] Therefore, AIS and MIA can be assessed by HR-CT. However, the size of the solid component in HR-CT images does not necessarily correspond to the extent of histological invasion, since features such as alveolar collapse and fibrosis are also included in the solid part demonstrated by HR-CT.[1] Although the new WHO classification defines the histological criteria for MIA invasion, the degree of inter-observer agreement regarding the histological definition of invasion in MIA has still not been fully studied, and a consensus trial will be needed in the near future. More advanced adenocarcinoma is subdivided into five categories: lepidic, papillary, acinar, solid and micropapillary. These subtypes are diagnosed according to the predominant component and the group comprising lepidic, papillary and acinar adenocarcinomas shows a better prognosis than those with solid and micropapillary patterns. Therefore the presence of solid and/or micropapillary adenocarcinoma should be reported, even if the predominant component is lepidic, papillary or acinar adenocarcinoma. These patterns also predict response to adjuvant chemotherapy,[3] and the above changes overall have also led new proposals for both clinical and pathologic staging in the 8[th] TNM revision in terms of multiple primary tumours and measurement of tumour invasive size.[4,5] For the other three major tumour types (large cell carcinoma (LCC), squamous cell carcinoma (SQCC) and neuroendocrine (NE) tumours), the classification has evolved from mainly morphological to a more biologically based system, which allows more appropriate decisions in relation to adjuvant therapy and better defined subgroups for studies into molecular characterisation and the search for potentially treatable targets. LCC is now restricted to resected tumours that lack clear morphologic and immunohistochemical differentiation, with reclassification of those that do to solid adenocarcinoma (TTF-1 positive) and non-keratinising SQCC (P40 and/or CK5/6 positive). This has already been shown to correlate with molecular data.[6] For SQCC, classification is simplified to keratinizing, nonkeratinizing and basaloid subtypes, with the non-keratinizing tumours ideally requiring immunohistochemical confirmation. Criteria for diagnosing NE tumours remain essentially unchanged but these tumours are now grouped in one category, with further subdivision into carcinoids, and large cell neuroendocrine carcinoma and small cell carcinoma. Molecular studies based on these definitions are already identifying interesting subgroups.[7] In relation to rarer entities, the definition of pleomorphic carcinomas is also being shown to have clinical relevance in terms of correlating with potential therapies, both in relation to specific molecular abnormalities (exon 14 skipping mutations)[8] and immunoodulatory therapy with high levels of PD-L1 expression.[9] Molecular characterisation is also increasingly important in the accurate diagnosis and potential treatment of other rare tumours, such as NUT-carcinoma and inflammatory myofibroblastic tumours (ALK and ROS1/RET gene rearrangements).[10] A classification system for small biopsies and cytology is provided for the first time, with emphasis on integration of molecular testing and usage of a limited panel of immunohistochemistry when needed (table 1). The presence of such a system for the first time provides a system for consistent classification of the majority (unresectable) of lung cancer cases, both in terms of clinical management, assignment to pathways for molecular and immunomodulatory characterisations, and for assessment of the results of clinical trials that have sometimes been confounded by inaccurate subgrouping. The book also emphasises how to obtain the greatest value from small sample via efficient usage and avoidance of inappropriate testing.[1] Table 1: Classification of non-small cell lung carcinoma in small biopsies and cytology specimens when there is no morphologic evidence of differentiation

2015 WHO Small Biopsy/Cytology Terminology	Morphology/Stains	2015 WHO Classification in resection specimens
Non-small cell carcinoma, favour adenocarcinoma using IHC	Morphologic adenocarcinoma patterns (lepidic, acinar, papillary, micropapillary) not present, but supported by special stains (+TTF-1)	Adenocarcinoma, solid pattern (may only be a component)
Non-small cell carcinoma, favour squamous cell carcinoma using IHC	Morphologic squamoid features (keratinization and/or clear intercellular bridging) not present, but supported by stains ( +p40)	Squamous cell carcinoma, (non-keratinizing pattern may be just one component)
Non-small cell carcinoma, not otherwise specified NSCLC-NOS using IHC	No clear adenocarcinoma, squamous or neuroendocrine morphology or staining pattern (IHC or mucin stains).	Large cell carcinoma

REFERENCES 1. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyons, France.: International Agency for Research on Cancer (IARC); 2015. 2. Kakinuma R, Noguchi M, Ashizawa K, et al. Natural History of Pulmonary Subsolid Nodules: A Prospective Multicenter Study. J Thorac Oncol. Jul 2016;11(7):1012-1028. 3. Tsao MS, Marguet S, Le Teuff G, et al. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol. Oct 20 2015;33(30):3439-3446. 4. Detterbeck FC, Nicholson AG, Franklin WA, et al. The IASLC Lung Cancer Staging Project: Summary of Proposals for Revisions of the Classification of Lung Cancers with Multiple Pulmonary Sites of Involvement in the Forthcoming Eighth Edition of the TNM Classification. J Thorac Oncol. Feb 29 2016. 5. Travis WD, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol. Aug 2016;11(8):1204-1223. 6. Clinical Lung Cancer Genome P, Network Genomic M. A genomics-based classification of human lung tumors. Sci Transl Med. Oct 30 2013;5(209):209ra153. 7. Rekhtman N, Pietanza MC, Hellmann MD, et al. Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets. Clin Cancer Res. Jul 15 2016;22(14):3618-3629. 8. Schrock AB, Frampton GM, Suh J, et al. Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations. J Thorac Oncol. Sep 2016;11(9):1493-1502. 9. Chang YL, Yang CY, Lin MW, Wu CT, Yang PC. High co-expression of PD-L1 and HIF-1alpha correlates with tumour necrosis in pulmonary pleomorphic carcinoma. Eur J Cancer. Jun 2016;60:125-135. 10. Antonescu CR, Suurmeijer AJ, Zhang L, et al. Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am J Surg Pathol. Jul 2015;39(7):957-967.

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Up to a decade ago, the main non-surgical treatment modalities in oncology have been cytotoxic chemotherapy and/or radiation therapy. These therapies are aimed at inducing DNA damage, thus selectively killing the highly proliferative cancer cells. More recently, new therapies are targeting signaling pathways that are critical to support cancer cell proliferation and/or survival, including micro-environmental factors that sustain tumor. The first part of our presentation will review pathways operating mainly in the tumor cells, and how they constitute targets for lung cancer therapies. The second part will focus on the vascularization mechanisms in primary and metastatic lung tumors, antivascular drugs, potential biomarkers and on mechanisms through which tumors can become resistant to antivascular drugs. DNA Repair Pathway: Genomic DNA encodes all biochemical processes that drive cellular function and biology. Extensive damage to DNA encoding proteins/enzymes involved in cell proliferation will result in cell cycle arrest and cell death. DNA damage may also induce replicative errors and mutations, which leads to constitutive activation of oncogenes, or inactivation of tumor suppressor genes. DNA repair mechanisms are crucial for mitigating catastrophic chromosomal damage during DNA synthesis and replication, thus allowing tumor cells to survive chemotherapy or radiotherapy. New targeted anti-cancer agents being developed include those that inhibit the activity of critical molecules involved in DNA repair, or inhibit cell cycle checkpoint proteins that allow DNA repair mechanisms to occur. EGFR and downstream pathways: The proliferation of epithelial cells depends on growth stimuli arising from either factors produced by the tumor cells themselves (autocrine), factors produced by cells from distant organs (endocrine), or factors from neighboring tumor or non-tumor cells in the tumor microenvironment (paracrine). For lung epithelial cells, a major growth stimulating pathway involve the epidermal growth factor receptor (EGFR) family members. EGFR (HER1) is highly expressed in >90% of squamous cell carcinoma and in 60-80% of adenocarcinoma. EGFR has many ligands, including EGF, TGF-a, amphiregulin, HB-EGF, etc. Binding of the ligands to the EGFR induces homo or hetero dimerization of EGFR and its family members, activates the cytoplasmic tyrosine kinase of the receptor, and promotes auto-phosphorylation. This sequentially leads to binding of SOS1, activation of downstream RAS, RAF, MEK and ERK/MAPK. Targeting EGFR by monoclonal antibodies and small molecule kinase inhibitors have demonstrated clinical efficacy in subpopulation of NSCLC patients. Targeted agents against KRAS, BRAF and MEK are in clinical trials. MET, ALK, and ROS1 pathways: Other tyrosine kinase receptors (RTKs) that may play important role in lung cancers include hepatocyte growth factor (HGF) receptor MET and fibroblast growth factor receptor (FGFR) family members. In contrast to EGFR, the ligands for MET and FGFRs appear to be produced by the tumor stromal fibroblasts. While attempts to inhibit MET signaling pathway by neutralizing antibody have not been successful, more recent data suggest that MET kinase inhibitors may be highly effective in patients with MET exon 14 splice site mutations. Such mutations cause the loss of exon 14, which encode the Cbl binding site of the receptor, a crucial domain required for the degradation of MET receptor. The RTKs with close homology to MET are ALK and ROS1. Constitutive activation of ALK and ROS1 occurs by formation of new chimeric protein through translocation involving these genes. Inhibitors to ALK and ROS1 are now clinically approved for treatment of lung cancers that express fusion proteins resulting from the rearrangement of the ALK and ROS1 genes. PI3K/AKT/mTOR pathway: Aside from activating the MAPK pathway, tyrosine kinase receptors may also activate the PI3K/AKT/mTOR pathway, which plays a crucial role in the survival of lung cancer cells. This pathway is commonly activated in NSCLC through amplification or activating mutation of the PIK3CA gene, or inactivation of PTEN by gene deletion, mutation or methylation. While there is intense research to develop targeted therapies that inhibit this important survival pathway, the efforts have so far met little success, revealing the complexity of this pathway. There is also evidence that alternative RTK and PI3K signaling play an important role as bypass mechanisms for the development of resistance to kinase inhibitor therapies. Angiogenesis pathways: Because an adequate blood supply is regarded as essential for tumor development, there had been overwhelming optimism initially that blocking angiogenic pathways would represent an effective treatment strategy in solid malignancies, including primary and metastatic lung tumors. However, clinical trials investigating antivascular drugs have been both encouraging and disappointing. Success with antivascular strategies therefore requires a deeper knowledge of the clinical significance of the different angiogenic machineries that control lung tumors. VEGF (vascular endothelial growth factor) is the key molecular regulator of new tumor blood capillary formation (i.e. angiogenesis) and its high expression is associated with poorer survival in NSCLC. Bevacizumab, a humanized monoclonal anti-VEGF antibody, is currently approved for the first-line treatment of advanced stage non-squamous NSCLC in combination with chemotherapy. Ramucirumab (a fully human monoclonal antibody against VEGFR2) has been approved for use in combination with docetaxel for the treatment of metastatic NSCLC patients who progressed after platinum-based chemotherapy. Nintedanib (an oral RTK inhibitor against VEGFRs, platelet-derived growth factor receptors (PDGFR) and FGFRs in combination with chemotherapy has been approved by the EMEA in NSCLC patients with locally advanced, metastatic or locally recurrent lung adenocarcinoma after first-line chemotherapy. Additional anti-vascular strategies including vascular disrupting agents (VDAs) to destroy the established tumor vasculature and other investigational antiangiogenic antibodies and small molecule RTK inhibitors are also under clinical testing for NSCLC therapy, though enthusiasm is tempered by short disease control and modest overall survival benefit. Angiogenesis Resistance Mechanisms and Biomarkers: Unfortunately, resistance against antivascular therapies is poorly understood. The possible resistance mechanisms include increased intratumoral hypoxia, the activation of compensatory angiogenic machineries, the release of myeloid or endothelial progenitor cell populations, the downregulation of target receptors in endothelial and/or tumor cells, limited tumor tissue drug penetration, and also a switch to an alternative vascularization mechanism such as intussusceptive angiogenesis or vessel-cooption. Reliable biomarkers for the prediction of response to antivascular drugs are also yet to be identified and clinically validated.

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Lung cancer remains the number one cause of cancer-related death worldwide. Cancer immunotherapy nowadays has become not only a growing field but also a fascinating area as recent clinical trials have improved both PFS and OS in first line and second line treatment for patients with advanced NSCLC. The idea of immunotherapy in cancer is to modify the host immune system, so cytotoxic T-cells (CTCs) can recognize tumor-associated antigens (TAAs) as abnormal and be destroyed by an immune response. For many decades, we have tried unsuccessfully many vaccines against different lung cancer antigens. It was thought at one point that lung cancer was a non immunogenic tumor very different from melanoma and kidney cancers. Whole-cell vaccines (e.g. belagenpumatucel-L) and antigen-specific vaccines (e.g., CIMAvax, MAGE-A3, L-BPL25) showed just promising results in clinical trials, but failed to significantly improve clinical outcomes [1-4]. The major reason why vaccines failed in lung cancer was due to tumor escape mechanisms from host immune surveillance [5, 6]. One of this mechanisms was recently elucidated, checkpoint pathway. Lung cancer has been found to have high levels of CTLA-4 expression, programmed death-1 (PD-1), PD ligand 1 (PD-L1), B7-H3 and B7-H4 expression on tumor-infiltrating lymphocytes (TILs), and regulatory CD4+ T-cells (Tregs) suggesting that lung cancer is immunogenic. For many years, cancer immunology was centered on the adaptive immune system and T-cell activation. Stimulation of the T-cell response involves antigen presenting cells (APCs), or dendritic cells (DCs), expressing tumor antigens from the tumor microenvironment, which then bind to the T-cell receptor (TCR) on CD4+ or CD8+ T-cells. Meanwhile, B7-1/CD80, or B7-2/CD86 on the APC, bind to CD28 on the T-cell in a costimulatory fashion to stimulate tumor-antigen specific T-cells to proliferate. However, cross talk between APCs and T-cells at the immunological synapse is regulated very closely and can be attenuated. One of this attenuation signal is mediated by CTLA-4, which is also stimulated by CD80 and CD86. Although CTLA-4 and CD28 have the same ligands, CTLA-4 has a much higher affinity for them; hence, T-cell proliferation occurs despite the effects of CTLA-4 because of the intracellular location, short half-life and quick degradation of CTLA-4 [7, 8]. Another example of a tumor immune checkpoint is PD-1 which binds B7-H1/PD-L1 and B7-DC/PD-L2 [9]. By using PD-1 inhibitors, we are able to remove the interaction between PD-1 receptor located in the T-cells and its ligand expressed in the tumor cells which causes inhibitory signaling over the T-cells. Hence, an immune response cannot be mounted. CTLA-4 has been studied in lung cancer in combination with platinum-based doublet (carboplatin/paclitaxel). Outcomes from that study were not enough to grant approval from regulatory entities. However, investigators found better response to CTLA-4 inhibition in patients with squamous cell histology; this population has higher percentage of TILs than their non-squamous counterparts. Why the combined therapy (chemotherapy plus ipilimumab) had limited effect remains unclear. Conversely, studies using PD-1 inhibitors pembrolizumab and nivolumab have shown OS advantage over docetaxel in second line therapy, and more recently, OS and PFS advantage in first line against chemotherapy when tumor cells expressed > 50% of PD-L1 [10]. We also understand that PD-L1 is not the perfect predictive biomarkers so efforts are directed to discover more specific markers which can help us to tailor checkpoint inhibitors in lung cancer. The approval of nivolumab in NSCLC came from two phase III trials CheckMate 017 and CheckMate 057 which studied nivolumab vs docetaxel in second-line for squamous and non-squamous advanced NSCLC, respectively. The CheckMate 017 reached the “trifecta” proving that nivolumab was statistically superior to docetaxel for OS, PFS and response rate (RR). Interestingly, OS benefit was independent of PD-L1 expression. The CheckMate 057 showed OS and RR in favor of nivolumab. There was no difference in PFS between nivolumab and docetaxel in non-squamous NSCLC patients. In this study, PD-L1 expression levels at different cut-off matter for OS. For those patients who had ≥1%, ≥ 5%, and 10%, the hazard ratio (HR) for OS were 0.59 (p < 0.06), 0.43 (p < 0.001), and 0.40 (p < 0.001), respectively. In both studies, nivolumab was well tolerated and had better treatment-related adverse event profile. In case of pembrolizumab, it was KEYNOTE-010 study which proved OS advantage over docetaxel in second line therapy. Herein, pembrolizumab at a dose of 10 mg/kg and 2 mg/kg shown an OS of 12.7 months (HR 0.61; p < 0.001) and 10.4 months (HR 0.71; p < 0.001); OS for docetaxel was 8.5 months. Noteworthy, OS was better in patients whose tumors expressed PD-L1 ≥50%; these patients had an OS of 17.3 and 14.9 months when received pembrolizumab at 10 mg/kg and 2 mg/kg, respectively. Again, grade 3-5 treatment-related AEs were less common for both pembrolizumab doses than for docetaxel. Recently, press release on KEYNOTE-024 phase III study, reported OS in favor of pembrolizumab over platinum-based doublet in first-line therapy for advanced NSCLC patients with PD-L1 expression. The clinical results from KEYNOTE-024 may change the landscape of lung cancer treatment at first-line for advanced NSCLC. Also in development are the PD-L1 inhibitors which affect the interaction between PD-L1 and B7.1 and PD-1 receptor and PD-L2; the later interactions are not affected by PD-1 inhibitors. Atezolizumab and darvulumab have several phase III trials ongoing in first line for advanced NSCLC. Phase II trials for both compounds have shown promising results. The role of PD-L1 as predictive biomarker is still not well defined. PD-L1 expression is a dynamic process and it also varies as part of an adaptive immune resistance exerted by the tumor. There are other possible predictive biomarkers such as higher nonsynonymous mutation burden, molecular smoking signature, higher neo-antigenic burden, DNA repair pathway mutations, high levels of PD-L1 expression, T-helper type 1 gene expression, and others. There is no question that we must continue looking for a better predictive biomarker which can help us to determine the therapeutic benefit of PD-1/PD-L1 inhibitors. References. 1. Nemunaitis J, Dillman RO, Schwarzenberger PO, et al. Phase II study of belagenpumatucel-L, a transforming growth factor beta-2 antisense gene-modified allogeneic tumor cell vaccine in non-small-cell lung cancer. J Clin Oncol. 24, 4721–30 (2006). 2. González G, Crombet T, Neninger E, Viada C, Lage A. Therapeutic vaccination with epidermal growth factor (EGF) in advanced lung cancer: analysis of pooled data from three clinical trials. Hum Vaccin. 3(1), 8-13 (2007). 3. Vansteenkiste J, Zielinski H, Linder A, et al. Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of MAGE-A3 immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC). J Clin Oncol. 25(18S), 7554 (2007). 4. Palmer M, Parker J, Modi S, et al. Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer. Clin Lung Cancer. 3(1), 49-57 (2001). 5. Gross S, Walden P. Immunosuppressive mechanisms in human tumors: why we still cannot cure cancer. Immunology Letters. 116(1), 7–14 (2008). 6. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 3, 991–8 (2002). 7. Egen JG, Kuhns MS, Allison JP. CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat immunol 3(7):611-618, 2002. 8. Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res 13(18):5271-5279, 2007. 9. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. CancerI Immunol Immunother 56(5):739-745, 2007. 10. http://www.businesswire.com/news/home/20160616005393/en/Merck%E2%80%99s-KEYTRUDA%C2%AE%C2%A0-pembrolizumab-Demonstrates-Superior-Progression-Free-Survival. Access online September 20, 2016.

Abstract not provided

Abstract not provided

Abstract:
LYMPH NODE MAPPING IN LUNG CANCER Kenji Suzuki (Japan), David Waller (UK) The How and Why ? The Aim will be to outline the various methods to map the extent of lymph node metastasis from a primary NSCLC and to assess the clinical application and implications of each intervention. The Aim will also be to highlight the following areas of clinical debate and controversial issues 1.Preoperative Non-invasive – Lymph node mapping may start with simple Ultrasound guided cervical node aspiration cytology [1] . Can this be all that is needed in some advanced cases? c Can computed tomography/ positron emission tomography (CTPET) be relied upon to obviate the need for invasive nodal mapping ? Can newer techniques including CT lymphography [2] improve the accuracy of mapping ? Does magnetic resonance imaging (MRI) have a role in preoperative lymph node mapping. Invasive – We will consider in detail the debate between endobronchial and endoluminal ultrasound (EBUS/EUS) and surgical lymph node mapping. What role, if any, does cervical mediastinoscopy have in addition to EBUS/EUS [3] ? Does the increased sensitivity of more invasive surgical mediastinal procedures like VAMLA [4] and TEMLA contribute significantly to preoperative mapping ? We will discuss why these investigations should influence primary therapy and which patients should undergo induction therapy and which should have primary resection. Evidence from the latest TNM revision suggest that mediastinal nodal disease needs more accurate mapping than previously appreciated. We will consider how many of these stages of mapping are required before making a decision to operate and will propose a controversial algorithm for surgical treatment of N2 disease [5]. 2.Intraoperative We will discuss the arguments surrounding the necessary extent of intraoperative lymph node dissection. We will consider the relative merits of the methods for intraoperative sentinel node identification including Near Infrared thoracoscopy and radiolabelling [6,7]. We will ask whether the investment in technology and time is beneficial for the patient. Is the added information about metastases of clinical value ? We will evaluate the argument between nodal sampling vs systematic nodal dissection [8] and attempt to formulate an intraoperative mapping algorithm. Intraoperative nodal mapping has been proposed as a prerequisite to direct the extent of lung resection. We will examine how the findings of nodal disease have been used to discriminate between lobectomy vs pneumonectomy or between lobectomy vs segmentectomy. We will consider the argument that nodal metastatic disease is not a justification for more extensive sacrifice of functioning lung tissue. Is there any role for intraoperative nodal analysis in determining the extent of resection? How reliable is this method of nodal mapping. 3.Postoperative Once the pathologist has the resected lymph nodes we will attempt to rationalize how they should be analysed, asking the question : “ What are the minimum sampling requirements ?”. We will also analyse whether the more detailed nodal mapping of micrometastatic disease by immunohistochemistry significantly influences patient management or outcome [10] ? Finally we will discuss how these pathological results could influence the use of adjuvant chemotherapy/ radiotherapy or more interestingly targeted therapies. We intend the session to be interactive between presenters and delegates with a free exchange of ideas and experience. We hope to stimulate delegates to re-evaluate their own approach to lung cancer staging. References 1. Chang DB, Yang PC, Yu CJ, Kuo SH, Lee YC, Luh KT.Ultrasonography and ultrasonographically guided fine-needle aspiration biopsy of impalpable cervical lymph nodes in patients with non-small cell lung cancer.Cancer. 1992 Sep 1;70(5):1111-4 2. Suga K, Yuan Y, Ueda K, Kaneda Y, Kawakami Y, Zaki M, Matsunaga N Computed tomography lymphography with intrapulmonary injection of iopamidol for sentinel lymph node localization. Invest Radiol. 2004 Jun;39(6):313-24. 3. Annema JT, van Meerbeeck JP, Rintoul RC, Dooms C, Deschepper E, Dekkers OM, De Leyn P, Braun J, Carroll NR, Praet M, de Ryck F, Vansteenkiste J, Vermassen F, Versteegh MI, Veseliç M, Nicholson AG, Rabe KF, Tournoy KG. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial .JAMA. 2010 Nov 24;304(20):2245-52 4. Witte B, Hürtgen M.Video-assisted mediastinoscopic lymphadenectomy (VAMLA).J Thorac Oncol. 2007 Apr;2(4):367-9 5. De Leyn P, Dooms C, Kuzdzal J, Lardinois D, Passlick B, Rami-Porta R, Turna A, Van Schil P, Venuta F, Waller D, Weder W, Zielinski M. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014 May;45(5):787-98 6. Hachey KJ, Colson YL. Current innovations in sentinel lymph node mapping for the staging and treatment of resectable lung cancer. Semin Thorac Cardiovasc Surg. 2014 Autumn;26(3):201-9 7. Tomoshige K, Tsuchiya T, Otsubo R, Oikawa M, Yamasaki N, Matsumoto K, Miyazaki T, Hayashi T, Kinoshita N, Nanashima A, Nagayasu T.Intraoperative diagnosis of lymph node metastasis in non-small-cell lung cancer by a semi-dry dot-blot method.Eur J Cardiothorac Surg. 2016 Feb;49(2):617-22 8. Darling GE, Allen MS, Decker PA, Ballman K, Malthaner RA, Inculet RI, Jones DR, McKenna RJ, Landreneau RJ, Rusch VW, Putnam JB Jr. Randomized trial of mediastinal lymph node sampling versus complete lymphadenectomy during pulmonary resection in the patient with N0 or N1 (less than hilar) non-small cell carcinoma: results of the American College of Surgery Oncology Group Z0030 Trial . J Thorac Cardiovasc Surg. 2011 Mar;141(3):662-70 9. Nomori H, Cong Y, Sugimura H. Utility and pitfalls of sentinel node identification using indocyanine green during segmentectomy for cT1N0M0 non-small cell lung cancer. Surg Today. 2016 Aug;46(8):908-13 10. Deng XF, Jiang L, Liu QX, Zhou D, Hou B, Cui K, Min JX, Dai JG Lymph node micrometastases are associated with disease recurrence and poor survival for early-stage non-small cell lung cancer patients: a meta-analysis. J Cardiothorac Surg. 2016 Feb 16;11:28.