Virtual Library

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    MINI 01 - Pathology (ID 93)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 14
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      MINI01.01 - Immunohistochemical Distinction between Primary Lung Squamous Cell Carcinoma and Pulmonary Metastasis of Head and Neck Squamous Cell Carcinoma (ID 1525)

      10:45 - 12:15  |  Author(s): J. Ichinose, A. Shinozaki-Ushiku, K. Nagayama, J. Nitadori, M. Anraku, M. Fukayama, J. Nakajima, D. Takai

      • Abstract
      • Presentation
      • Slides

      Background:
      It is extremely difficult to distinguish between primary lung squamous cell carcinoma (LUSq) and pulmonary metastasis of head and neck squamous cell carcinoma (HNSq) in patients with a past history of HNSq, even by histological examination of the resected specimen. This study aimed to establish an immunohistochemical scoring system for discrimination between LUSq and pulmonary metastasis of HNSq.

      Methods:
      We selected genes that were expressed in a markedly different manner in LUSq and HNSq using the results of expression microarrays and chose the antibodies for four proteins (CK19, MMP3, ZNF830, PI3) that had immunohistochemical results shown in the Human Protein Atlas (http://www.proteinatlas.org) that were distinguishable between LUSq and HNSq. We constructed the tissue microarrays using the resected specimens of 39 LUSqs and 48 HNSqs as the training set and evaluated the tendency of HNSq using the 16-grade system according to the positive staining of the four antibodies. Twenty-seven of the patients with pulmonary tumors that were resected and pathologically diagnosed as squamous cell carcinoma between 1999 and 2014 had a past history of HNSq. Their pulmonary tumors and primary HNSqs were analyzed immunohistochemically as the test set. We defined LU-associated recurrence as postoperative recurrence in the thoracic cavity, mediastinum, brain, bone, and liver and defined HN-associated recurrence as recurrence in the other sites. We compared the diagnosis of our immunohistochemical scoring system to the preoperative clinical diagnosis and the pathological diagnosis according to the predictive power of HN-associated recurrence.

      Results:
      The sensitivity, specificity, and accuracy of our immunohistochemical scoring system were 90%, 67%, and 79%, respectively in the training set, and our system correctly diagnosed 96% of HNSq specimens in the test set. Twenty-three out of 27 pulmonary tumors in the test set were diagnosed as pulmonary metastasis of HNSq, and four were diagnosed as LUSq. Eleven of 23 patients (48%) with pulmonary metastasis of HNSq developed HN-associated recurrence (3-year HN-associated recurrence-free probability was 46%), and 10 died because of HNSq, while none of the four patients with LUSq had HN-associated recurrence. Compared with the clinical diagnosis (five LUSq, 14 pulmonary metastasis of HNSq, eight uncertain) and the pathological diagnosis (two LUSq, 17 pulmonary metastasis of HNSq, eight uncertain), our immunohistochemical scoring system could predict the risk of HN-associated recurrence more accurately. Figure 1



      Conclusion:
      Immunohistochemical analysis of four proteins (CK19, MMP3, ZNF830, PI3) was clinically useful for discrimination between LUSq and pulmonary metastasis of HNSq.

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      MINI01.02 - Is It Possible to Distinguish between Second Primary vs Metastasis in Resectable Synchronous Nodules with the Same Histotype of Lung Cancer? (ID 2122)

      10:45 - 12:15  |  Author(s): G. Luciano, P. Viola, M. Al Sahaf, Z. Niwaz, H. Raubenheimer, M.E. Cufari, H. Chavan, C. Proli, M. Leung, V. Anikin, N. McGonigle, E. Beddow, G. Ladas, S. Jordan, M. Dusmet, A.G. Nicholson, E. Lim

      • Abstract
      • Presentation
      • Slides

      Background:
      The prognostic significance of additional lung nodules in the setting of lung cancer is important as the impact on survival is often considered for the justification of surgical selection in the management of patients with synchronous nodules. TNM 7 down staged the impact on T category but did not distinguish between second primary versus metastasis. Traditional distinctions such as the Martini criteria do not take the same histological type into account and classification continues to improve (e.g. IASLC classification of adenocarcinoma). The aim of our study is to determine if it is possible to distinguish between second primary versus metastases in patients with the same histological type and quantity any difference in survival.

      Methods:
      We retrospectively analysed data from a prospectively collated database at our institution. We collected all the records which included two resected nodules. The detailed pathology reports of these patients were retrieved and the histology, subtype and pTNM of tumours documented. Slides were re-reviewed to determine the histological subtypes according to the current IASLC adenocarcinoma classification. Survival was calculated using Kaplan Meier methods and adjusted survival compared using Cox regression on R (statistical software).

      Results:
      From April 1999 to February 2013, a total of 2925 lung cancer resection were performed. Of these, 379 (14%) operations fulfilled the inclusion criteria of multiple nodules with 316 having synchronous tumours (83.3%) and 63 having metachronous tumours (16.6%). The tumours were ipsilateral in 87.3% and the vast majority were in the same lobe (70.9%). For synchronous tumours, patients with the same histological type had a poorer 5-years survival rate compared to tumours with different histology (p=0.041). The pathologist’s designation between second primary versus intra-pulmonary metastasis distinguished between overall survival (p= 0.001) and this remained statistically significant in the tumours of the same cell type (p= 0.035). Figure 1. Survival outcomes between patients with multiple nodules classified as second primary versus intra-pulmonary metastasis Figure 1



      Conclusion:
      Our results suggest that distinction between second primary and intra-pulmonary metastasis remains important for staging as appreciable differences in survival were observed in patients with synchronous nodules. Survival was poorer in patients with multiple nodules of the same histologic type (compared to different histology) and within the same histological subtype it is possible for pathologists to distinguish between second primary and intra-pulmonary metastasis. As this is currently confirmed only on pathologic stage in the majority, it presently does not influence the selection for surgery.

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      MINI01.03 - Pathology-Imaging Agreement in Distinguishing Separate Primary Tumours and Intrapulmonary Metastasis in Staging of Multiple Lung Cancers (ID 2659)

      10:45 - 12:15  |  Author(s): P. Viola, A. Devaraj, E. Lim, G. Luciano, S. Popat, A.G. Nicholson

      • Abstract
      • Presentation
      • Slides

      Background:
      The 7[th] TNM staging system for lung cancer recommended staging for cases with multiple nodules viewed as intrapulmonary metastases (IM) as T3 (same lobe), T4 (ipsilateral different lobe) and M1a (contralateral lobe), whilst those classified as separate primary tumours (SPTs) as T(x)NM where “x” is the number of primary tumours, either as a number or “m” for multiple. With an increase in patients presenting with multiple nodules, we sought to develop a set of criteria for c-staging on imaging and to determine the agreement between clinical and pathological staging in a cohort of resected lung cancers who had multiple nodules.

      Methods:
      In 2013 and 2014, there were a total of 48 consecutive cases with available imaging resected with multiple tumours, ranging from 2 to 5 nodules. Of these, one case was excluded as it was a carcinoid with background DIPNECH. These cases were classified as SPT or IM based on previously published criteria (Girard et al. Am J Surg Pathol 2009;33:1752-64). Imaging criteria were generated based on clinical experience in similar fashion with indicators of SPT being 1) Lesions of equivalent size (one not more than 100% of the other) 2) Smaller lesion is spiculated , 3) At least one lesion is subsolid, 4) Presence of field change. (For signs 1 and 2, if the lesions were in different lungs, an absence of mediastinal disease on imaging was required). Cases with at least one positive sign were classified as SPTs. The interobserver agreement between radiologists and pathologist were then generated.

      Results:
      Of the 47 cases, the additional nodules were not identifiable on CT in 7 cases. In the remaining 40 cases, there was agreement in 28 cases, of which 16 were SPTs and 12 were IM. Of 12 cases where there was disagreement, only 3 were SPTS and the majority were cases classified on pathology as IM. There was 70% agreement, greater than that expected by chance (p = 0.002) with a kappa value of 0.41.

      Conclusion:
      Moderate agreement can be achieved in terms of clinical and pathological staging of lung cancers presenting with multiple nodules using imaging and pathologic criteria. Using pathology as the gold standard, there was greater agreement in categorisation of SPTs (84% (16/19)) than IM (57% (12/21)).

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      MINI01.04 - Discussant for MINI01.01, MINI01.02, MINI01.03 (ID 3296)

      10:45 - 12:15  |  Author(s): N. Rekhtman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI01.05 - Local Diagnostic Practices for Advanced Non-Small-Cell Lung Cancer in Europe and Japan: ASSESS Study (ID 2629)

      10:45 - 12:15  |  Author(s): N. Normanno, K. Hagiwara, B. Han, S. Tjulandin, C. Grohé, T. Yokoi, A. Morabito, S. Novello, E. Arriola, O. Molinier, R. McCormack, M. Ratcliffe, M. Reck

      • Abstract
      • Presentation
      • Slides

      Background:
      ASSESS (a large, multicentre, non-interventional, diagnostic study; NCT01785888) evaluated local diagnostic practices for patients with advanced non-small-cell lung cancer (aNSCLC) in Europe/Japan.

      Methods:
      Eligible patients: local/metastatic aNSCLC; chemotherapy-naïve, newly diagnosed/recurrent disease after resection; ineligible for curative treatment. We report diagnostic assessments and epidermal growth factor receptor (EGFR) mutation test turnaround times (secondary endpoints) associated with tissue/cytology samples from patients in Europe/Japan.

      Results:
      1311 patients enrolled (300 Japan). Immunohistochemistry (IHC) was used to confirm pathological diagnosis in 727/960 (76%) and 142/146 (97%) patients in Europe and Japan, respectively (where data were available); the following markers were assessed using IHC: TTF-1 (Europe 96% and Japan 79%); p65 (4% and 8%); and p40 (9% and 24%). EGFR mutation tests were not performed on samples from 110 patients and tested samples from 17 patients did not yield results. The most common reason for not testing was insufficient material provided (Europe 60% [47/78 responses]; Japan 56% [5/9 responses]). The percentages of neoplastic cells in samples (data available: Europe n=281; Japan n=20) were: <20% tumour cells: Europe 15% vs Japan 35%; 20–50% tumour cells: 23% vs 45%; >50% tumour cells: 61% vs 20%. Considering sampling methodologies, the most common sampling sites (data available: Europe n=996; Japan n=291) were the lung parenchyma (Europe 73%; Japan 79%) or lymph nodes (Europe 9%; Japan 9%); the most common sample collection method was bronchoscopy (Europe 39%; Japan 68%; Table 1). Median EGFR mutation test turnaround time was longer in Europe (11 days) versus Japan (8 days; Table 2). Mutation test success rates for Europe and Japan were 98.3% and 99.6%, respectively.

      Conclusion:
      Diagnostic assessments, sampling methodologies and EGFR mutation testing practices vary between and within Europe and Japan; further understanding of local practices will drive improvements and enable more patients to receive appropriate personalised treatment. Figure 1 Figure 2





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      MINI01.06 - Pathological Second-Predominant Component Predicts Recurrence in Lung Adenocarcinoma (ID 1070)

      10:45 - 12:15  |  Author(s): M. Ito, Y. Miyata, Y. Tsutani, T. Mimura, S. Murakami, H. Ito, H. Nakayama, M. Okada

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung adenocarcinoma is pathologically subdivided according to its predominant component. Approximately 50–70% of invasive adenocarcinomas are diagnosed as adenocarcinomas of either papillary or acinar predominant subtype. The prognostic difference between these subtypes has not been revealed, and these 2 similar subtypes may further be classified. This study aimed to investigate whether the pathological second-predominant component that follows the most predominant component predict recurrence in adenocarcinoma.

      Methods:
      We retrospectively reviewed 347 consecutive cN0 lung adenocarcinoma cases resected between April 2006 and December 2010 at Hiroshima University Hospital and Kanagawa Cancer Center. We further classified papillary and acinar predominant adenocarcinomas into either the papillary/acinar-lepidic type (Pap/Aci-Lep type) or the papillary/acinar-nonlepidic type (Pap/Aci-NonLep type). Tumor recurrence and the frequency of each invasion status such as lymphatic, vascular, and pleural invasion were compared between Pap/Aci-Lep type and Pap/Aci-NonLep type adenocarcinomas. In addition, we estimated the correlation between the radiological and pathological characteristics of these subtypes. Whole-tumor size, ground-glass opacity (GGO) ratio, solid size, and tumor disappearance ratio (TDR) on high-resolution computed tomography and maximum standardized uptake value (SUVmax) on positron emission tomography (CT) were measured as radiological parameters.

      Results:
      Papillary (n = 70) and acinar predominant adenocarcinomas (n = 61) were subdivided into the Pap/Aci-Lep type (n = 72) and Pp/Aci-NonLep type (n = 59). Compared with the Pap/Aci-NonLep type, the Pap/Aci-Lep type showed a significantly higher disease-free survival rate (5-year DFS: 89.4% vs 70.6%, p = 0.0374) and fewer cases of lymphatic invasion (15.3% vs 30.5%, p = 0.037), vascular invasion (15.3% vs 33.9%, p = 0.013), and pleural invasion (9.72% vs 25.4%, p = 0.031). Furthermore, radiological findings significantly differ between the Pap/Aci-Lep and Pap/Aci-NonLep types as follows: GGO ratio (μ ± 1 ´ SD: 34.4% ± 25.2% vs 3.81% ± 18.0%, p < 0.01), CT solid size (μ ± 1 ´ SD: 1.35 ± 0.65 cm vs 1.73 ± 0.55 cm, p = 0.015), TDR (μ ± 1 ´ SD: 41.8% ± 26.7% vs 17.5% ± 22.6%, p < 0.01), and SUVmax (μ ± 1 ´ SD: 2.37 ± 2.15 vs 3.96 ± 3.06, p < 0.01). Significant recurrence-free survival and prevalences of lymphatic and vascular invasion were observed between the lepidic predominant type (n = 109) and Pap/Aci-Lep type.

      Conclusion:
      The pathological second-predominant component allows for subclassification of papillary and acinar predominant adenocarcinomas with prognostic significance. Pathological features of these subtypes can be represented on clinical imaging. Not only the most predominant component but also the second-predominant component should be given clinical and pathological attention in order to predict malignant potential or decide indication for adjuvant therapy.

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      MINI01.07 - Comparison of Grading Systems Based on Histologic Patterns and Mitotic Activity to Predict Recurrence in Stage I Lung Adenocarcinoma (ADC) (ID 3030)

      10:45 - 12:15  |  Author(s): K.S. Tan, K. Kadota, A. Moreira, P.S. Adusumilli, W.D. Travis

      • Abstract
      • Presentation
      • Slides

      Background:
      An established grading system for lung adenocarcinoma does not exist but is greatly needed. The histologic classification proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) has been shown to define prognostically significant subgroups of lung adenocarcinoma (ADC). Since then, various grading systems based on histologic patterns have emerged as promising methods to further discriminate patient risk of clinical outcomes. The aim of this work is to quantitatively assess the discrimination properties of a set of grading systems proposed in recent years to identify the best grading scale(s) independent of other clinical factors to predict recurrence.

      Methods:
      We considered five grading systems: (1) single predominant pattern as six subtypes; (2) as three grades of low (lepidic), intermediate (acinar, papillary) and high (micropapillary, solid); (3) two most predominant grades; (4) predominant grade with mitotic grade; and (5) predominant grade with cribriform pattern and mitotic activity criteria. We evaluated the performance of each grading system with the concordance predictive estimate (CPE). The CPE represents the probability that for any pair of patients, the patient with the better predicted outcome from the Cox model had the longer survival time. CPE > 0.80 demonstrates strong performance. To compare the performance of the grading systems, we determined the significance of the differences between the CPEs. Five-year recurrence-free probability (RFP) was derived using the Kaplan-Meier method.

      Results:
      We applied the grading systems to a uniform large cohort of stage I lung ADC (N=909). The scale based on the single predominant pattern as five subtypes yielded a CPE of 0.63 (95% CI, 0.59-0.67), indicating moderate discrimination. Our analysis showed that grading systems (1), (2), and (3) were not significantly different from each other, suggesting that identifying finer subtypes and second predominant pattern may not improve discrimination. Grading system (4) [CPE, 0.67; 95% CI, 0.63-0.71] yielded a significantly higher CPE than (1), (2) and (3) [p<0.01]. Grading system (5) [CPE, 0.67; 95% CI, 0.63-0.71] was significantly better than (1), (2) and (3) but not (4) [p=0.776]. The lack of improvement in discrimination with the inclusion of cribriform between (4) and (5) can be attributed to the significant relationship between cribriform pattern and mitoses. As the proportion of cribriform pattern increased, the amount of mitotic activity also increased (p<0.001). Under (2), the 5-year RFP of the intermediate grade was 0.81. The addition of cribriform and mitotic counts further classified the intermediate (acinar, papillary) grade such that those with <10% cribriform and low mitotic count had 5-year RFP of 0.89, while the 5-year RFP for the other combinations are between 0.73-0.75.

      Conclusion:
      Grading systems based on histologic patterns and mitotic activity out-perform those with only histologic pattern. This comparison study suggests that proposed grading systems (4) or (5) provide valuable information in discriminating patients with different risks of disease-recurrence in patients with lung ADC.

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      MINI01.08 - Survival Differences of Adenocarcinoma Lung Tumors with Squamous Cell Carcinoma or Neuroendocrine Profiles by Gene Expression Subtyping (ID 384)

      10:45 - 12:15  |  Author(s): G. Mayhew, N. Hayes, C. Perou, M. Lai-Goldman, H. Faruki

      • Abstract
      • Presentation
      • Slides

      Background:
      Gene expression profiling can provide valuable information beyond the morphologic diagnosis. A previously validated 52-gene Lung Subtype Panel (LSP) for differentiating lung tumors into Adenocarcinoma (AD), Squamous Cell Carcinoma(SQ), and Neuroendocrine (NE) was explored in several publically available lung tumor datasets, including the TCGA RNAseq dataset.

      Methods:
      The LSP 3-class nearest centroid predictor developed in array data was applied to AD and SQ samples in TCGA (RNAseq, n=1,160), the Director’s Challenge (Affy array, n=442), and Tomida et al. (Agilent array, n=117) datasets. Each sample was predicted as AD, SQ, or NE. Kaplan Meier plots and log rank tests were used to assess and compare 5-year overall survival in two gene expression groups, AD predicted AD (AD-AD) and AD predicted SQ or NE (AD-notAD). Cox models were used to assess survival differences while controlling for T stage, N stage, and proliferation (as measured by the PAM50 score). The distribution of samples among the AD subtypes (Terminal Respiratory Unit(TRU), Proximal Proliferative(PP), and Proximal Inflammatory(PI)) was investigated.

      Results:
      The predictor confirmed AD in 80% of the AD samples. AD samples were called SQ and NE by the LSP in 8% and 12% of cases, respectively. The AD-notAD group (AD by histology and SQ or NE by gene expression LSP) had worse survival than the AD-AD group (AD by both histology and LSP) in each data set (logrank p-value in TCGA, Director’s Challenge, and Tomida were 1.17e-06, 0.0009, and 0.0001, respectively). Pooling the 3 data sets and using a stratified cox model that allowed for different baseline hazards in each study, the hazard ratio comparing AD-notAD to AD-AD was 2.14 (95% CI 1.70-2.70). When we fit the model adjusting for T stage, N stage, and proliferation score, the HR was 1.70 (95% CI 1.31-2.20). Adenosubtype profiling of AD-notAD samples indicated that tumors were overwhelmingly of the PP or PI gene expression subtypes (209/213).

      Conclusion:
      Gene expression tumor subtyping may provide valuable clinical information identifying a subset of AD samples with poor prognosis. Poor prognosis adenocarcinoma samples belong to the PI and PP expression subtypes, and demonstrate elevated proliferation scores. This subset of AD tumors may be less responsive to standard adenocarcinoma management.

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      MINI01.09 - Discussant for MINI01.05, MINI01.06, MINI01.07, MINI01.08 (ID 3297)

      10:45 - 12:15  |  Author(s): E. Thunnissen

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI01.10 - Analysis of the Status of Lymphocyte Infiltration in Patients with NSCLC (ID 2292)

      10:45 - 12:15  |  Author(s): E.A. Richardet, M.E. Richardet, P.A. Hernandez, E. Pets, M. Cortes, M. Molina, A.A. Riso, C. Di Tada, L.P. Acosta, P. Companys, M. Paradelo

      • Abstract
      • Presentation
      • Slides

      Background:
      Current evidence highlights the potential role of tumor-infiltrating lymphocytes (TILS) as a prognostic factor in many types of tumors; in non-small cell lung cancer (NSCLC), this relationship is not well determined. TILs are being studied with different methods such as immunohistochemistry and optical microscopy. The primary endpoint is to identify TILS in patients with NSCLC, classified as present or absent, and its relation to progression-free survival (PFS) and overall survival (OS). Our secondary endpoint is to establish the relationship between the TILS and treatment received.

      Methods:
      Retrospective and analytical case study of Instituto Oncológico de Córdoba, from 2004 to 2014. 166 patients with stage IIIB and IV NSCLC were analyzed. TILS are descriptively classified as present or absent. Survival curves were calculated using the Kaplan-Meier method.

      Results:
      59% of patients had adenocarcinoma and 41% squamous cell carcinoma. 70% were men. 82% were smokers. 58% of patients with squamous histology and 65% with adenocarcinoma, showed TILS. In relation to first-line chemotherapy, 63,8% of patients received carboplatin-paclitaxel (CP) and 36,2% gemcitabine-cisplatin (GC). Patients with adenocarcinom with TILS present had higher PFS and OS; 8.86 and 13.43 months respectively, compared to patients with absent, 3.78 and 7.9 months. These differences were statistically significant (PFS: p = 0.000002 and OS: p = 0.003). The patients with squamous cell carcinoma with TILS had 6.78 and 12 months PFS and OS respectively. Those who had infiltrated absent had a PFS of 3.96 months and OS of 6.37 months. These differences were also statistically significant (PFS: p = 0.003 OS p = 0.001).

      Conclusion:
      Our study shows that patients whose pathological samples presented inflammatory infiltrate had higher OS and PFS. The presence of TILS could be used as an important prognostic factor in this patient population.

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      MINI01.11 - Transcriptome Sequencing of Tumor vs. Surrounding Non-Malignant Lung Tissue in Non-Small Cell Lung Cancer (ID 1765)

      10:45 - 12:15  |  Author(s): K. Reynders, E. Wauters, J. Vansteenkiste, H. Decaluwé, P. De Leyn, K. Nackaerts, S. Peeters, C. Dooms, W. Janssens, D. Lambrechts, D. De Ruysscher

      • Abstract
      • Slides

      Background:
      Both the response and the therapeutic ratio of targeted agents in NSCLC may depend on the expression of the target molecules in the tumor and the surrounding non-malignant lung tissue. We therefore performed transcriptome analysis and investigated correlations with histology, gender, age, CRP level and smoking status as well as evaluated the differential pathway expression in primary resected NSCLC and the surrounding non-malignant lung of the same patient.

      Methods:
      Transcriptome sequencing was performed on the primary tumor and distant lung tissue of the same patient from resection specimens of NSCLC patients. Differential gene expression between different conditions was identified using the statistical algorithms Cufflinks, EdgeR and DeSeq. Differential expression with P-values <0.05 after Benjamini-Hochberg correction was considered significant. Pathway analysis for overall tumor versus distant lung tissue was performed with the PANTHER gene classification platform using the Cufflinks, DeSeq and EdgeR differentially expressed gene sets as input.

      Results:
      Twenty-five patients were studied, 19 males and 6 females, with a median age of 69 years. Ten were current smokers, 14 former smokers (>4 weeks before surgery) and 1 non-smoker. Eleven patients had squamous cell carcinoma, 14 adenocarcinoma. A heat map with the results for the most commonly targeted genes in NSCLC is represented in figure 1. When compared to distant lung tissue, PD-L1 was downregulated in tumor tissue of adenocarcinoma and active smokers, but not in squamous cell carcinoma or ex-smokers. Internal control of tumor tissue of squamous vs. adenocarcinoma and ex-smokers vs. active smokers shows an important trend towards a higher expression of PD-L1 in squamous cell carcinoma and ex-smokers in both Cufflinks and EdgeR algorithms. Additional pathway analysis revealed 188 differentially regulated pathways. The most notable were downregulation of VEGF signaling, angiogenesis and B and T cell activation in tumor tissue when compared to distant lung tissue. Figure 1



      Conclusion:
      Our first results show a higher expression of PD-L1 in squamous tumors than in adenocarcinoma and a higher expression in tumors of ex-smokers than in those of active smokers. This may have consequences for the therapeutic ratio with anti-PD-L1 treatment. Downregulation of VEGFR-genes in tumor tissue was observed across almost all conditions. We will make this data more complete by adding methylation data as well as immunohistochemistry for protein localization.

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      MINI01.12 - Implementation of a Molecular Tumor Board: The Impact on Treatment Decisions for NSCLC Patients Evaluated at Dartmouth-Hitchcock in One Year (ID 2719)

      10:45 - 12:15  |  Author(s): L.J. Tafe, I.P. Gorlov, F. De Abreu, J.A. Lefferts, X. Liu, J.R. Pettus, J.D. Marotti, K.J. Bloch, V.A. Memoli, A.A. Suriawinata, C.E. Fadul, G.N. Schwartz, C.R. Morgan, B.M. Holderness, J.D. Peterson, G.J. Tsongalis, T.W. Miller, M.D. Chamberlin, K.H. Dragnev

      • Abstract
      • Presentation
      • Slides

      Background:
      Genetic profiling of tumors is a powerful approach to predict drug sensitivity and resistance. Definitive interpretation of the clinical significance of somatic mutations is possible for only a few well studied mutations. For the majority, prediction of clinical significance is challenging. We established a Molecular Tumor Board (MTB) at our Cancer Center to interpret individual patients’ tumor genetic profiles and provide treatment recommendations.

      Methods:
      DNA from tumor specimens was sequenced in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory to identify coding mutations in a 50-gene panel. Cases were evaluated by a MTB composed of molecular and anatomic pathologists, medical oncologists, basic research scientists, and genetic counselors.

      Results:
      35 cases were evaluated in 1 year by the MTB including 8 metastatic NSCLC cases. The most common reason for MTB referral was for recommendations on targeted therapies (91.9%), and for potential germline mutations. Tumors exhibited genetic heterogeneity: 71 different mutations were found across 300 genes (for NSCLC 18 mutations across 10 genes). In 18/32 of advanced/metastatic cases, MTB recommended non-standard therapy with a specific targeted agent (11 clinical trials; 7 off-label use), 4 of the 18 patients were subsequently treated with a MTB-recommended targeted therapy. The remaining 14 patients continued on current therapy because disease was stable (n=4), were treated with non-MTB-recommended standard therapy (n=4), declined conventional therapy (n=5), or died prior to receiving further therapy (n=1). For 4 out of the 8 NSCLC cases MTB recommended a BRAF inhibitor (1), RET inhibitor (1), or MET inhibitor (2). One patient received a BRAF inhibitor, 6 continued on current standard of care therapy, one declined therapy.

      Conclusion:
      Case evaluation by a multidisciplinary group of individuals in the context of a MTB frequently shapes treatment options and decisions. Importantly, anticipated obstacles to capitalizing on the benefits of a MTB such as access to drugs were rarely encountered in the entire cohort and in the NSCLC patients. Instead, the most commonly encountered reasons that MTB-recommended therapy was not administered stemmed from patient preferences, and genetic profiling at a very late stage of disease.

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      MINI01.13 - Biologically Driven Sub-Classification of Early Lung Adenocarcinomas (ID 2418)

      10:45 - 12:15  |  Author(s): D.A. Moore, E. Al Dujaily, J. Le Quesne

      • Abstract
      • Presentation
      • Slides

      Background:
      Early lung adenocarcinomas have previously been successfully sub-classified by Noguchi et al on the basis of histopathological characteristics, in particular the pattern of growth exhibited by the tumour and the response of the adjacent stroma. A wholly in situ pattern of growth characterises preinvasive lung lesions, namely atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS). It is not uncommon for large areas of an invasive tumour to show this in situ pattern of growth. Metastases to the lung from other organs can also show areas of in situ spread, and this shows that truly invasive malignant clones of cells can grow along the alveolar surface. This study aimed to identify whether the characteristics of in situ growth in an individual tumour may give an indication of the underlying tumour biology, and be of prognostic value.

      Methods:
      We reviewed all small (sub 35 mm) lung adenocarcinomas resected with curative intent over a 4 year period from our thoracic surgical centre. Nodal metastasis data was also collected, which the reviewing pathologists were blinded to. All tumour sections were reviewed by 2 thoracic histopathologists, who separated these into 4 categories, based on the patterns of growth, stromal changes, cytological changes between in situ and invasive components and overall symmetry of the lepidic growth. On the basis of these appearances early lung adenocarcinomas were divided into 4 groups. Type 1 showed minimal stromal reaction analogous to Noguchi A/B tumours. Types 2 and 3 are subdivisions of mixed in situ/invasive adenocarcinomas (equivalent to the Noguchi C group). Type 2 showed marked stromal changes in the invasive component and a cytologically lower grade asymmetrical lepidic component. Type 3 showed a concentric rim of lepidic growth cytologically similar to the invasive disease. Type 4 were wholly invasive tumours. Tumour type was subsequently correlated to pathological lymph node staging.

      Results:
      156 tumours were included and sub-classified. Of these 12 were type 1, 30 were type 2, 46 were type 3 and 68 were type 4. The rate of nodal metastasis was increased across the tumour types from 1 to 4, at 0%, 7%, 24% and 29% respectively.

      Conclusion:
      We find that partly invasive lung adenocarcinomas fall into two histologically and biologically distinct groups with different potential toward nodal metastasis. We suggest the type 2 tumours represent the emergence of an invasive subclone in an in situ adenocarcinoma lacking this property. The type 3 tumours have a lepidic region at their edge which represents infiltration of normal structures by migratory malignant cells but may have no truly biologically ‘in situ’ disease. This group also shows more tendency toward metastasis. Type 4 lesions without any kind of lepidic growth have the highest rate of nodal involvement, and their destructive pattern of growth represents the most aggressive form of early tumours. Future molecular characterisation of these lesions and their various components may further inform our understanding of the pathways of tumorigenesis in lung adenocarcinoma.

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      MINI01.14 - Discussant for MINI01.10, MINI01.11, MINI01.12, MINI01.13 (ID 3298)

      10:45 - 12:15  |  Author(s): K. Politi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 04 - Clinical Care of Lung Cancer (ID 102)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 15
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      MINI04.01 - Years of Life Lost and Lifetime Earnings Lost in Metastatic Lung Cancer: Potential Societal Benefits of Improved Survival by Age and Histology (ID 774)

      16:45 - 18:15  |  Author(s): B. Korytowsky, K. Kulig, M. Halperin, M.D. Danese

      • Abstract
      • Presentation
      • Slides

      Background:
      “Years of life lost” (YLL) and “lifetime earnings lost” (LEL) are used to describe the population burden of cancer. Lung cancer (LC) is one of the most common cancers in the US. While it affects older patients, the younger subgroups of LC are large. Approximately 57% of LC cases are metastatic at diagnosis, with a 5-year survival rate of approximately 5%. Nivolumab, a recently-approved fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, demonstrated a mortality risk reduction of 41% compared to docetaxel in patients previously treated with platinum-based therapy for metastatic squamous, non-small cell LC (NSCLC) (hazard ratio [HR]: 0.59; 95% CI: 0.44, 0.79). This analysis quantifies YLL and LEL prior to the introduction of LC immunotherapy in order to benchmark potential population-level effects of improved long-term survival.

      Methods:
      A simulation model was developed using real-world US patients with LC diagnosed 1/1/2000–12/31/2011 in the Surveillance, Epidemiology, and End Results Program, with follow-up through 12/31/2012. Age-, sex-, and race-specific life expectancy were estimated using flexible parametric survival models. Comparable life expectancy was projected for the general US population using US vital statistics data. Life expectancy was combined with US Bureau of Labor Statistics income data to derive lifetime earnings in 2014 US dollars. Earnings reflect 18 possible income sources, including salary, investments, social security, and other retirement income. Mean YLL and LEL were estimated as the differences between patients with LC and the general US population. Results were stratified by age (<65; ≥65) and histology subtype (small cell, non-squamous NSCLC; squamous NSCLC).

      Results:
      An estimated 1,223,031 patients in the US were diagnosed with metastatic LC from 2000–2011. Estimated patient counts, expected survival, and expected lifetime earnings within each age and histology subtype are provided (Table). For patients aged <65, YLL per patient due to LC varied from 22.8–23.7 years by histology subtype, while for patients aged ≥65, YLL varied from 9.9–11.3 years. LEL per patient ranged from $862,000–$887,000 for patients aged <65, and from $274,000–$313,000 for patients aged ≥65. Figure 1



      Conclusion:
      YLL and LEL values across LC histologies are substantial in both older and, perhaps even more noticeably, younger populations. Improvements in survival reported with promising new LC therapies have the potential to substantially decrease the societal burden caused by YLL and LEL.

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      MINI04.02 - Value of Innovation in Systemic Therapy for US Patients with Advanced/Metastatic NSCLC (ID 783)

      16:45 - 18:15  |  Author(s): J. Nilsson, N. Justo, B. Korytowsky, N. Chehab, A. Stanford, A. McGuire

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer remains the leading cause of cancer death in the US. Over the past 40 years, treatment approaches have evolved and new systemic anti-cancer therapies have been introduced to the standard of care. With few exceptions, the impact of these agents for patients with advanced/metastatic non-small cell lung cancer (NSCLC) has been arguably minimal, with overall survival (OS) still less than 1 year for most patients. This study analyzed the association of available new systemic therapies with median OS, 1-year OS, and 1-year conditional survival (CS: adjusted probability of survival, specifically probability of living to year 2, given survival at 1-year) in patients with advanced/metastatic NSCLC.

      Methods:
      This study enrolled adult patients with advanced/metastatic NSCLC diagnosed between 1973 and 2011 in the US Surveillance, Epidemiology, and End Results (SEER-Research) Program of the American National Cancer Institute. We report the data from 1973 to 2008 for this analysis. Thirty-eight cohorts of patients were defined by year of diagnosis. Survivor functions were estimated using Kaplan-Meier analysis, with death as the failure event. Median OS, 1-year OS, and 1-year CS were derived for each year and analyzed graphically. The innovation index was defined as the sum of all systemic anti-cancer treatments available in the US market within a given year between 1973 and 2011 (Lichtenberg; Econ Hum Biol 2003;1:259–266).

      Results:
      Of 347,709 patients, a clear correlation was observed between the innovation index and survival measures (median OS, 1-year OS, and 1-year CS), with correlation coefficients of 77%, 92%, and 97%, respectively. Median OS, 1-year OS, 1-year CS, and the innovation index are plotted against time (Figure), enabling a comparison of survival measures between 1973 and 2008. Any change in the innovation index is reflected as a change in the survival curves, most notably in the 1-year CS, displaying a 1- or 2-year delay. From 1973 to 2008, median life expectancy of patients increased from 4 to 6 months; 1-year OS and 1-year CS improved by 71% and 31%, respectively. Figure 1



      Conclusion:
      The availability of systemic anti-cancer treatments for advanced/metastatic NSCLC has resulted in an incremental survival benefit, albeit modest, for US patients diagnosed between 1973 and 2008. Despite progress in treatment, outcomes for this patient population are very poor. Further research is needed to explore these treatment-survival relationships, including the resulting benefit for all patients with advanced/metastatic NSCLC and select patient subgroups.

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      MINI04.03 - Real-World Patterns of Access to Cancer Specialist Care Among Patients With Lung Cancer in the United States: A Claims Database Analysis (ID 1592)

      16:45 - 18:15  |  Author(s): A.K. Ganti, H. Borghaei, F.R. Hirsch, M. Wynes, A. Ravelo, R. Ionescu-Ittu, I. Pivneva, P. Lin, S.S. Ramalingam

      • Abstract
      • Presentation
      • Slides

      Background:
      Timely access to specialist care is an important first step in the care of patients with lung cancer (LC). This study describes real-world patterns of access to cancer specialist (CS) care in all LC patients and those with metastatic LC (mLC).

      Methods:
      Adult patients diagnosed with primary LC or mLC were identified in a US commercial claims database (01/01/2008 - 03/31/2014). Patients’ specialist visits were assessed before and after their first biopsy (index date). All patients had ≥3 months follow-up after index date. CS was defined as oncologists or hematologists. Patients were divided in four mutually exclusive groups based on the specialists seen in the 6 weeks pre-index period: patients seen by CS (± other specialists), pulmonologists (no CS, ± other specialists), internists or family physicians (no CS/pulmonologist, ± other specialists), and other. CS visits in the 8-weeks post-index were assessed for each group. Reversed Kaplan-Meier plots were used to describe time from index date to first CS visit.

      Results:
      The analysis included 75,163 LC and 25,191 mLC patients, with a median age of 67 [interquartile range (IQR): 59-76)] and 63 (IQR: 57-73) years and a median follow-up of 11 and 9 months, respectively. In the 8-week post-index period, over half of LC patients (54%) and nearly two-thirds of mLC patients (66%) had their first CS visit (Figure 1), while 38% of LC patients and 28% of mLC patients never saw a CS within 1-year of biopsy (Figure 1). In both samples, patients in the CS and pulmonologist pre-index groups were more likely to see a CS in follow-up (Figure 2; p<0.001 for all groups). Figure 1 Figure 1 Figure 2 Figure 2





      Conclusion:
      A substantial proportion of patients diagnosed with LC and mLC did not see any CS after biopsy, which may negatively affect access to optimal and timely treatment.

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      MINI04.04 - Economic Burden of Lung Cancer Patients Treated in Clinical Trials: Experience from a Comprehensive Cancer Center in Germany (ID 2841)

      16:45 - 18:15  |  Author(s): F. Kron, A. Kostenko, J.P. Glossmann, M. Hallek, I. Dohle, A. Hoss, M. Scheffler, T. Zander, J. Wolf

      • Abstract
      • Slides

      Background:
      Lung cancer leads to the highest costs among cancers in developed countries. Hospital inpatient care is the main cost driver. Comprehensive cancer centers (CCC) are designed to adopt innovative treatment methods within clinical trials. This analysis focuses on the economic burden of clinical trials for advanced lung cancer patients in a CCC in Germany.

      Methods:
      111 consecutive patients with advanced lung cancer treated in clinical trials (phase I - phase II) were analyzed. We integrated medical and economic data from a business perspective during patients’ in- and outpatient treatment. Different reimbursement systems and cost calculation models are linked with an internal budget system for lung cancer patients.

      Results:
      79 patients (71.2%) had at least one in-house stay with a total of 204 inpatient cases. 67 different diagnosis-related groups (DRGs) were coded for these cases. Grouping of the DRGs into 4 categories (i. Neoplasm, ii. Infection, iii. Radiotherapy and iv. Rest) reveals a statistically significant difference in the case mix index (p<0.001) and length of hospitalization (p<0.001). Cost type calculation demonstrated labor (46%) and infrastructure (31%) being the predominant cost factors. The average revenues of 1301 outpatient contacts (219 cases per quarter) of all patients are €144. Subgroup analysis of 44 cases with €117 revenues in average identified imaging procedures accounting for 74% of the costs.

      Conclusion:
      The medical development involves economic risks for the hospital that recommend a fully integrative cost- and sales controlling between the in- and outpatient treatment setting including standards care and clinical trials, which should be discussed with all stakeholder in the healthcare system.

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      MINI04.05 - Discussant for MINI04.01, MINI04.02, MINI04.03, MINI04.04 (ID 3308)

      16:45 - 18:15  |  Author(s): N. Leighl

      • Abstract
      • Presentation

      Abstract not provided

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      MINI04.06 - During-Treatment PET Metabolic Tumor Volume (MTV) Instead of FDG Activity Is Predictive of Survival in Patients with Non-Small Cell Lung Cancer (ID 3174)

      16:45 - 18:15  |  Author(s): F.(. Kong, J.L. Waller, L. Li, K. Frey, M. Piert, D. Owen, M. Stenmark, C. Huang, M. Matuszak, R.K. Ten Haken, T.S. Lawrence

      • Abstract
      • Presentation
      • Slides

      Background:
      We have previously reported that tumor reduces in activity and volume during the course of radiotherapy (RT), and such changes were correlated with post-treatment “tumor response”, known as a significant factor for overall survival in patients with non-small cell lung cancer (NSCLC). This study aimed to determine whether the metabolic activity or metabolic tumor volume (MTV) obtained from the during-treatment FDG-PET is predictive of overall survival in NSCLC.

      Methods:
      Patients with stage I-III NSCLC enrolled in prospective studies with during-treatment FDG-PET were eligible for this study. All patients were treated with a definitive course of RT + chemotherapy. FDG-PET/CT scans were acquired within 2 weeks before RT (pre-RT) and at about two thirds of the total dose delivered (during-RT). PET-MTVs were delineated by a tumor/aorta ratio of 1.5 autosegmentation combined with manual editing based on CT anatomy, as previously described (Mahasittiwat et al, 2013). FDG-activity was measured as maximum standard update value (SUVmax) and the average activity (SUVmean) of the defined MTV. Total lesion glycolysis (TLG) was computed as the product of MTV and SUVmean. CT gross tumor volume (CT-GTV) were also delineated in a consistent manner. Data are presented as mean (95% confident interval). P<0.05 is considered to be statistically significant.

      Results:
      A total of 129 patients with a minimum follow-up of 24 months (for surviving patients) were included in this study. The majority of subjects were male (73%), white (96%), current or former smokers (87%) with an average age of 67 years (range 45-92). Seventy-nine percent were treated with chemotherapy in combination with RT (dose range 45-90 Gy). Of the pre-RT PET parameters, neither SUVmax nor SUVmean was significant, while CT-GTV (P=0.03), PET-MTV (p=0.008), and PET-TLG (p=0.005) were all significant for overall survival. After 2/3 treatments were delivered, the mean SUVmax, SUVmean, CT-GTV, PET-MTV, and PET-TLG all decreased significantly (P<0.001) and remarkably (more than 30% reduction), with the PET-MTV showing the greatest extent of reduction. During-RT SUVmax or SUVmean were not significantly associated with overall survival, either as continuous variables or as binominal variables (split from median). While during-RT CT-GTV was a significant factor for survival (P=0.04), yet during-RT PET-MTV and PET-TLG as continuous variables were not. However, patients with during-RT PET-MTV values greater than the median had significantly shorter median survival (21 months, 95%CI: 12.1-32.0) than those of below the median (38 months, 95%CI: 29.0-89.9, p=0.01). The absolute reductions in SUVmax or SUVmean or CT-GTV were not, but changes of PET-MTV and PET-TLG during-RT were significantly associated with overall survival. Smaller reductions from Pre-RT to during-RT were associated with an increased risk of death for PET-MTV (HR=1.003, 95%CI: 1.001–1.006, P=0.01) and PET-TLG (HR=1.001, 95%CI: 1.000–1.001, P=0.02), respectively.

      Conclusion:
      MTV instead of SUV during the course of RT are significantly associated with overall survival in patients with NSCLC. Larger MTV during-RT may lead to worse survival. RTOG1106/ACRIN6697 is ongoing to adapt radiation therapy plan to give higher dose to residual PET-MTV during-RT to improve tumor control and overall survival.

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      MINI04.07 - Changes in Skeletal Muscle Index and Body Mass Are Prognostic Factors in First Line Stage IV Non-Small Cell Lung Cancer (NCSCL) Patients (ID 3091)

      16:45 - 18:15  |  Author(s): M.J. Fidler, S. Kerns, F.M. Esmail, M.D. Martin, S.M. Shors, N. Patel, R.R. Patel, S. Sayidine, S. Basu, R. Pithadia, M. Batus, J.A. Borgia, P. Bonomi, P.N. Shah

      • Abstract
      • Presentation
      • Slides

      Background:
      Cancer cachexia is a complex metabolic syndrome affecting 60-80% of patients with non-small cell lung cancer (NSCLC). The characteristic involuntary weight loss observed in cachexia is associated with poor outcomes in advanced NSCLC; however, reduced muscle mass may be a more reliable prognostic indicator. In this study, we examine the impact of changes in weight and skeletal muscle index (SMI) in the first 12-weeks of therapy on clinical outcome parameters for front line stage IV NSCLC patients.

      Methods:
      Cancer cachexia is a complex metabolic syndrome affecting 60-80% of patients with non-small cell lung cancer (NSCLC). The characteristic involuntary weight loss observed in cachexia is associated with poor outcomes in advanced NSCLC; however, reduced muscle mass may be a more reliable prognostic indicator. In this study, we examine the impact of changes in weight and skeletal muscle index (SMI) in the first 12-weeks of therapy on clinical outcome parameters for front line stage IV NSCLC patients.

      Results:
      119 patients had serial weights available and were included for analysis: 49% were male, median age of males was 71, and females were 63 years; 82% had smoking history. Histology was predominantly adenocarcinoma and squamous (62% and 22%). Median PFS was 159 days, and medial OS was 314 days. Median weights for males at baseline, 6 weeks, and 12 weeks were 77.3, 76.9, and 77.3 kilograms respectively. Median weights for females at baseline, 6 weeks, and 12 weeks were 67.1, 66.7, 65.8 kilograms respectively. Baseline weights were less for women than men (p<0.0007) but the change in weight with time was not significantly different at measured time points. Weight loss of greater than 10.39 pounds in the first six weeks of treatment was strongly associated with inferior outcomes (PFS 2.35 vs. 6.44 months, p=2.02 x 10[-7]; OS 3.96 vs. 15.48 months, p=8.71 x 10[-9]). Persistent weight loss at 12 weeks was also associated with worse outcomes (PFS p=1.72x10[-7 ], OS p= 0.00286). Within this cohort, 41 patients had baseline SMI measured from their CT scans, 27 patients had additional CT-derived SMI available at 6- and 12- weeks. Patients with SMI decrease at 12 weeks of at least 2.6 units (n=9, 33%) had an inferior median PFS compared with those not meeting this threshold (2.79 months vs. 9.75 months p<0.05). In a multivariate analysis, this loss, when adjusted by gender, remained significantly associated with PFS (HR=2.37, p < 0.05).

      Conclusion:
      This study shows the prognostic value of weight loss for progression on first line chemotherapy as early as six weeks following therapy initiation. This analysis confirms the significant association between weight loss on serial measurements and inferior survival in stage IV NSCLC pts. Additionally, this is the first report of decreasing CT-derived SMI correlating with inferior progression free survival on front line platinum doublet therapy for NSCLC.

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      MINI04.08 - Malignant Pleural Effusions Are Predictive of Peritoneal Carcinomatosis in Patients with Advanced EGFR Positive Non-Small Cell Lung Cancer (ID 3191)

      16:45 - 18:15  |  Author(s): T. Patil, D.L. Aisner, S.A. Noonan, P.A. Bunn, Jr, E.M. Berge, W.T. Purcell, R. Camidge, L.L. Carr, R.C. Doebele

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the most frequent cause of cancer death and metastatic disease at the time of initial diagnosis is common. Peritoneal carcinomatosis (PC) from lung cancer is a rare clinical event with a reported incidence of 1.2% (Satoh et al. 2001). However, there are limited data on what factors predict peritoneal progression in lung cancer. Over the last decade, molecular analysis of NSCLC has provided more detailed classification of patterns of metastatic spread. It has also been shown that oncogene-addicted subsets of NSCLC have different patterns of metastatic spread (Doebele et al. 2012). We investigated whether certain baseline patterns of metastatic spread in patients with advanced EGFR mutation positive (EGFR+) NSCLC can predict subsequent PC.

      Methods:
      We identified 156 patients with EGFR+ (Exon 19 or L858R) mutations from 2009 - 2014, of which 139 had metastatic NSCLC. 11 patients developed PC. This was defined as the presence of biopsy-proven adenocarcinoma from peritoneal fluid or radiographic patterns consistent with omental metastases. We identified areas of metastatic disease in predefined sites (brain, liver, lung, adrenal, soft tissue and pleura) at the time of diagnosis or metastatic recurrence. We noted if patients developed T790M, a resistance mutation to targeted therapy, in EGFR+ patients. A Fisher-Exact test was used to determine statistical significance between metastatic site and subsequent PC.

      Results:

      Table 1 - Sites of metastasis and presence of T790M mutation in patients with PC and without PC
      Metastatic site / mutation PC No PC P value
      Lung 9.1% 38.6% P = 0.06
      Liver 18.2% 15.8% P = 0.689
      Bone 36.4% 46.8% P = 0.549
      Brain 0% 23.7% P = 0.3570
      Adrenal 0% 6.4% P = 0.123
      Soft tissue 9.1% 2.2% P = 0.265
      Pleural effusion 100% 26.6% P = 0.0001
      T790M mutation 81.1% 34.5% P = 0.0001
      The presence of a pleural effusion was universal in all 11 EGFR+ patients who subsequently developed PC and this finding was statistically significant (P = 0.0001). 9 out of 11 patients with PC were identified to have a T790M mutation, a finding that was statistically significant (P = 0.0001). Except one patient, all EGFR+ patients developed PC following targeted tyrosine kinase therapy.

      Conclusion:
      The presence of a malignant effusion is highly predictive of developing PC in patients with EGFR+ NSCLC. Although the underlying mechanism of PC is not entirely clear, it may be related to serosal communication with subsequent micrometastatic seeding of the peritoneal cavity. The T790M mutation, the most common acquired resistance mechanism to EGFR kinase inhibitors, was significantly more prevalent in the group that developed PC, although it remains unclear whether this mutation has any causative effect on spread to the peritoneum.

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      MINI04.09 - The Impact of Next-Generation Sequencing on Clinical Decisions in Lung Cancer (ID 2978)

      16:45 - 18:15  |  Author(s): A. Belilovski Rozenblum, M. Ilouze, E. Dudnik, D. Flex, L. Soussan-Gutman, A. Dvir, N. Peled

      • Abstract
      • Presentation
      • Slides

      Background:
      In the last decade, important advances have been made in understanding genetic and molecular mechanisms of Non-Small Cell Lung Cancer (NSCLC) tumor development. This has led to the creation of innovative, targeted drugs that significantly prolong survival in advanced patients. Recent data shows that 63% of NSCLC tumors harbor at least one activating driver mutation, including treatable mutations such as RET, HER2 and ROS1 gene mutations, besides the regularly screened ALK and EGFR genes that account for 23% of the patients. Clinical cancer genomic profiling tests based on Next Generation Sequencing (NGS) technologies are capable to reveal clinically actionable genetic alterations in up to three times the number of actionable alterations detected by current diagnostic tests. However, there is no data regarding the true impact of these tests on clinical decisions in lung cancer. In this study, our objective is to evaluate the impact of NGS-based genetic profiling tests on treatment strategy in NSCLC patients in the real life setting, considering the additional diagnostic tests performed. Based on clinical experience from Israel, NGS-based tests actively change treatment plans, but the effect size is unknown and merits further investigation.

      Methods:
      In this retrospective study, data is collected from patient files at the Thoracic Cancer Unit of Davidoff Cancer Center, Rabin Medical Center, Israel. The current study population is 78 NSCLC patients who performed NGS-based genetic profiling tests.

      Results:
      Out of 78 patients, 58 patient files have already been reviewed and 6 were excluded. Treatment decision change rate after NGS testing was 33% (17 out of 52 patients were treated with a targeted therapy - 24% of the current study population). Interestingly, 9 patients became EGFR and ALK positive by NGS after the previous standard local molecular testing was negative. Based on the RECIST criteria of response evaluation, 41% of the patients had a partial response after switching to targeted therapy, 23% had a complete response, 18% experienced progressive disease and 18% were not evaluated yet. Survival rates will be calculated further in the study based on data availability.

      Conclusion:
      The use of NGS for tumor classification and treatment planning holds a great potential for improving patient life quality and survival. In this study, we aimed to determine its clinical impact in the real life setting in the treatment of lung cancer. Our partial results show that in addition to performing standard molecular testing for NSCLC, almost a quarter of the patients can be identified having an actionable driver mutation and switched to targeted therapy. Most of these patients showed a positive response to treatment. Although this topic needs to be further assessed in large randomized controlled trials, these positive results emphasize the importance of upfront multiplex testing or suggest such technology as a reflex test in places where the primary kits are done first in sake of cost-benefit.

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      MINI04.10 - Discussant for MINI04.06, MINI04.07, MINI04.08, MINI04.09 (ID 3309)

      16:45 - 18:15  |  Author(s): K. Reckamp

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI04.11 - Incidence of Brain Metastasis in Non-Small Cell Lung Cancer Over Eleven Years at a Single Canadian Institution (ID 1585)

      16:45 - 18:15  |  Author(s): A. D'Silva, H. Li, S. Otsuka, D. Morris, J. Wu, G. Bebb

      • Abstract
      • Presentation
      • Slides

      Background:
      The highest percentage of metastasis to the brain exists among non-small cell lung cancer (NSCLC) patients. The exact incidence of brain metastasis (BM) in NSCLC is unknown, but current literature suggests that incidence for this cohort is increasing as cancer patients live longer. To date, only a single Canadian study reporting BM occurrence in lung cancer patients is available. A key limitation to this study is the method of incidence reporting, as number of cases, rather than number of cases as a percentage among lung cancer population. Reliable estimates of BM in NSCLC patients are necessary to further improve patient care and resource allocation.

      Methods:
      The Alberta Cancer Registry dataset was used to identify all NSCLC patients living in southern Alberta who are consulted at the Tom Baker Cancer Centre, Calgary, Alberta, Canada between 1999 and 2010. These patients were registered and their charts were reviewed for an institutional lung cancer database (Glans-Look Database). NSCLC patients were categorized into two groups: (i) having BM at diagnosis or (ii) developing BM between diagnosis and death. Patient characteristics were compared to the database NSCLC cohort and all metastatic cases. The number of BM cases was reported for each group per year. Incidence was calculated as a percentage of the NSCLC and metastatic disease cases, where applicable. Linear trend testing was performed.

      Results:
      A total of 5297 NSCLC patients were consulted. The percentage of BM at diagnosis in the cohort was 11% in 1999 and 8% in 2010 (linear trend test p-value=0.010). These numbers were 26% in 1999 and 15% in 2010 (p=0.010) in the metastatic cohort. The percentage of BM developed by death in the NSCLC cohort was 20% in 1999 and 13% in 2010 (p=0.010). These numbers were 44% in 1999 and 26% in 2010 (p=0.009) in the metastatic cohort (Figure 1). Out of 2501 non-metastatic NSCLC patients, 46% developed BM by death in 1999 compared to 62% in 2010 (p=0.14).

      Conclusion:
      Although the absolute number of NSCLC patients with BM at diagnosis has increased between 1999 and 2010, the incidence, reported as a percentage of the all NSCLC cases, is decreasing. Similar trends were not observed for non-metastatic patients. As a future step, a pre-specified multivariable analyses will be conducted to examine effects of age, gender, histology, smoking, and treatment on rates of BM in NSCLC.Figure 1



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      MINI04.12 - Systematic Review of Brain Metastases in Non-Small Cell Lung Cancer (NSCLC) in the United States, European Union, and Japan (ID 1591)

      16:45 - 18:15  |  Author(s): D.C. Fenske, G.L. Price, A.W. Nyhuis, L.M. Hess

      • Abstract
      • Presentation
      • Slides

      Background:
      Prevalence of brain metastases (BRM) is increasing due to better detection methods and patients living longer with their disease, presenting an unmet need. Importantly, BRM are more common in NSCLC than most other cancers. Published literature offers incomplete data on prevalence, treatment, costs, and outcomes associated with BRM in NSCLC. This study was designed to better understand the epidemiology, treatment patterns, costs, and overall survival (OS) of NSCLC patients with BRM in the US, EU, and Japan.

      Methods:
      A systematic review was conducted by searching PubMed, Ovid, and Embase from January 2003 to December 2013 according to PRISMA guidelines. Keywords, MeSH, and Emtree terminology were used to define the search strategy. Eligible studies were observational, published in English, and peer-reviewed research of patients with NSCLC and BRM. Demographic, clinical, and outcomes data were extracted into Excel. Descriptive statistics were generated with SAS version 9.2. Demographics were summarized and treatment patterns and median OS were assessed by country.

      Results:
      The literature search identified 8,257 articles and 243 studies were eligible. There were 46,422 NSCLC cases included. Patient characteristics are summarized in Table 1. Treatment patterns for BRM from NSCLC were reported across the US, EU, and Japan. Median OS of NSCLC patients from the time of BRM diagnosis ranged from 5.0 to 13.1 months by country (Figure 1). The rate, by country, of radiation therapy among NSCLC patients with BRM ranged from 32.9% to 90.1%, systemic therapy ranged from 5.8% to 39.7%, and surgery was used in 2.2% to 31.6% of studies. Figure 1 Figure 2





      Conclusion:
      Reported median OS and treatment patterns were highly variable. Exposure to risk factors associated with BRM may help explain some of the geographic variability in survival. The lack of published cost data underscores the need to quantify the economic burden of BRM on patients and society.

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      MINI04.13 - Survival Analysis of 51 Leptomeningeal Metastatic Non Small Cell Lung Cancer Patients Treated with Whole Brain Radiotherapy (ID 2625)

      16:45 - 18:15  |  Author(s): E. Topkan, B. Akkus Yildirim, O.C. Guler, Y. Ozdemir

      • Abstract

      Background:
      Although leptomeningeal carcinomatosis (LC)in Non small cell lung cancer is less frequently seen in radiotherapy (RT) clinics, it is an important cause of mortality and morbidity. As the median survival is limited to 2-4 months, the role of RT in treatment is controversial. In this Study, we try to analyze the survival rates and associated factors of 51 leptomeningeal brain metastatic NSCLC patients treated with whole brain radiotherapy (WBRT).

      Methods:
      Between January 2007 to August 2014, during follow up with the diagnosis of NSCLC, 51 patientswho develop LC and treated with WBRT in our clinic had included this study. Patients were treated with 20-30 Gy (3-4 Gy/fr) WBRT. Kaplan-Meier method was used for survival analysis. Bonnefoni correction was performed for survival analysis of groups more than two before statistical analysis.

      Results:
      Median age of patients were 64 (37-83) and 34(67.7%) of them are male. Patient number with ECOG performance status of 0-1, 2 and 3 were23 (%45.1), 15 (%29.4) and 13 (%25.5) respectively.%58.8 of patients had squamous cell cancer and %41.2 of them were adenocancer. The dose of WBRT in 31 patients was 20 Gy (4 Gy/fr; BED~10~=28 Gy) and 30 Gy (3Gy/fr; BED~10~=39 Gy) in the other 20 patients. At the time of performing these analyses all the patients had died.Median survival was 3.9 ay (%95 CI: 3.3- 4.5). On univaryan analyses, age (≤50 vs. >50; p=0.46), gender (p=0.37),histological subtype (squamous cell vs. adenocancer; p= 0.74) and BED~10~value (39 vs. 28 Gy; p=0.26) did not show any statistically difference but ECOG performance status (0-1 vs. 2-3; p<0.001) was associated with overall survival. Median survival duration times for ECOG 0-1 and 2-3 groups were 5.7 and 3.7 respectively.

      Conclusion:
      Median survival of 3.9 months of our study is similar with literature but it is also querying the necessity of RT in this group of patients especially with poor performance status. However, the survival benefit of 5.8 months in ECOG performance 0-1 group may lead us to think that WBRT is useful. Although there has been no survival benefit between two RT dose schemes, 20 Gy (4 Gy/fr) may be the treatment of choice because of the shorter duration.

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      MINI04.14 - Comparative Survival in Patients with Brain Metastases from Non-Small Cell Lung Cancer Treated before and after Implementation of Radiosurgery (ID 2862)

      16:45 - 18:15  |  Author(s): A. Swaminath, J. Broomfield, G.R. Pond, S. Caetano, P.M. Ellis, J. Greenspoon

      • Abstract
      • Presentation
      • Slides

      Background:
      Survival after a diagnosis of brain metastases (BM) in non-small cell lung cancer (NSCLC) is generally considered poor. We previously reported median survival of approximately 4 months in a cohort of patients treated with whole brain radiotherapy (WBRT), the standard of care in many centres. Since that time, we implemented a program of stereotactic radiosurgery (SRS), based on randomized trials and large prospective series, supporting WBRT + SRS or SRS alone in selected patients. The current study examined survival and prognostic factors in a consecutive cohort of NSCLC BM patients after the introduction of an SRS program.

      Methods:
      A retrospective review of 167 NSCLC patients referred with BM to a tertiary cancer centre from 2010-2012 (NEW cohort) was undertaken. These data were compared to a prior cohort of 91 patients treated between 2005 and 2007 (OLD cohort). Summary statistics were used to describe the patient characteristics as well as outcomes. The Kaplan-Meier method was used to calculate time-to-event outcomes for overall survival (OS), from the time of BM diagnosis. Cox proportional hazards regression was used to investigate factors prognostic for outcomes. An optimal model was constructed using forward stepwise selection, and tests were two-sided with a p-value <0.05 deemed statistically significant.

      Results:
      Overall survival from diagnosis of BM (median 4.3 months NEW vs 3.9 months OLD p=0.74) was not significantly different between cohorts. A univariate analysis of the NEW cohort demonstrated significant differences in OS between treatment groups (SRS, WBRT + SRS, WBRT or no treatment), in terms of female gender (p=0.034), lack of neurological symptoms (p=0.001), number of BM (p<0.001), GPA (p=0.001), and ECOG status at BM (p=0.009). Treatment regimen with SRS or WBRT + SRS was significant as a prognostic factor for OS as well (p<0.001). Results were similar if one excluded the no treatment group. As some factors were not collected in the OLD cohort, a separate model was constructed including only data available from both cohorts. After adjusting for factors included in the optimal model, cohort was not statistically significant for OS (hazard ratio=1.03, 95% CI 0.90-1.59; p =0.88). There was a trend towards improved OS in the NEW vs OLD cohorts in patients <50 years of age (median 11.8 vs 7.5 months, p=0.39) and 50-59 years of age (median 7.8 vs 3.7 months, p=0.052); this trend reversed to favour the OLD vs NEW cohort in patients >70 (4.3 vs 2.8 months, p=0.01). This was coincident with increased uptake of chemotherapy (p<0.001) and better ECOG status (p=0.007) in younger age groups in the NEW versus OLD cohort.

      Conclusion:
      There has been no improvement in survival of NSCLC patients with BM, following the implementation of SRS. Selected patients (younger age, female gender, good fitness, fewer brain metastases) appear to demonstrate improved OS with SRS. However, this may also reflect a better natural history of the disease, or a greater tendency to offer them systemic therapy, in addition to receipt of SRS.

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      MINI04.15 - Discussant for MINI04.11, MINI04.12, MINI04.13, MINI04.14 (ID 3310)

      16:45 - 18:15  |  Author(s): S.S. Yom

      • Abstract
      • Presentation

      Abstract not provided

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    MINI 14 - Pre-Clinical Therapy (ID 119)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 15
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      MINI14.01 - EGFR-Mutated PDX in NSCLC: Molecular Fidelity and Correlation of PDX and Patient Response to EGFR Inhibition (ID 2191)

      10:45 - 12:15  |  Author(s): J.W. Riess, D.R. Gandara, R.A. Tsai, M. Cheng, W.S. Holland, K.D. Crawford, H. Yang, T. Li, P. Lara Jr., K. Kelly, S. Airhart, J. Graber, C. Bult, J.G. Keck, P.C. Mack

      • Abstract
      • Presentation
      • Slides

      Background:
      Inevitable emergence of resistance to tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated NSCLC warrants development of pro-active therapeutic strategies to delay or circumvent this evolution. To model such approaches, we are employing a clinically and genomically annotated patient derived xenotransplant (PDX) resource designed to duplicate relevant known mechanisms of resistance to TKI therapy. This analysis examines molecular fidelity and correlates response between patient and PDX in EGFR-mutant NSCLC.

      Methods:
      Six EGFR-mutated NSCLC, 1 EGFR-TKI naïve and 5 after progressive disease on erlotinib, were implanted subcutaneously into the flank of NOD.Cg-Prkdc[scid] Il2rg[tm1Wjl]/SzJ (NSG) mice as previously described (DR Gandara, Clin Lung Cancer 2015). Models were considered established when PDX growth was confirmed in passage 1 (P1); tumor growth studies were conducted in P3-P5. The donor patient tumor (PT) and the resultant PDX were analyzed for driver mutations (Response Genetics Inc., and Illumina TSCAP), copy number variants (CNV) and global RNA expression (Affymetrix arrays). Informed consent was obtained from all patients. EGFR-mutant PDX treatments included: erlotinib, afatinib, cetuximab, and afatinib+cetuximab. Patient response was graded by RECIST 1.1 and measured in PDX by tumor shrinkage from pre-treatment baseline. In select models, pharmacodynamic studies (kinase arrays; immunoblotting) were also performed.

      Results:
      The EGFR mutation subtypes identified in the donor PT were preserved in all PDX models (4 EGFR E19del and 2 EGFR L858R). Corresponding putative mechanisms of resistance were identical in both PT and PDX in 3 cases: EGFR T790M (2 of 5) and MET amplification (1 of 5). Of 5 post-erlotinib progression PDX models, 3 had progressive disease (PD) and 2 had transient tumor shrinkage to erlotinib. The PDX derived from an erlotinib-naïve patient (EGFR E19del) demonstrated sustained tumor shrinkage to erlotinib. Patient-PDX treatment correlations were possible in 3 post erlotinib-progression models. Two of these patients received afatinib-cetuximab: 1 with partial response (PR) and 1 with PD. The two models corresponding to these patients, when treated with afatinib-cetuximab, underwent complete regression of tumor (CR) and PD, respectively. Pharmacodynamic assessment of the responding model at 24h showed near complete diminishment of pEGFR following afatinib-cetuximab, concomitant with decreased pHer2, pERK, pAKT and p38. Erlotinib showed transient inhibition on signaling in this model at 6h, returning to baseline by 24h. In contrast, the non-responding model showed minimal effects on target inhibition and signal transduction following treatment with any EGFR inhibitor.

      Conclusion:
      Genomic fidelity was preserved in EGFR-mutant PDX, including putative mechanisms of resistance in the post-erlotinib progression models. The majority (3/5) of the EGFR-mutant PDXs created after erlotinib resistance demonstrated PD. In the other post-erlotinib progression models transient tumor shrinkage was noted, which may reflect PDX passaging in the absence of selective pressure of EGFR-inhibition or pharmacokinetic considerations. Overall, the PDX response to treatment reflected the corresponding patient’s clinical course. Pharmacodynamic studies of select models informed PDX response to treatment.

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      MINI14.02 - TAE226, a Bis-Anilino Pyrimidine Compound, Shows Anti-Tumor Effect on EGFR-Mutant Non-Small Cell Lung Cancer Cells including T790M Mutant (ID 1646)

      10:45 - 12:15  |  Author(s): H. Yamamoto, H. Otani, M. Takaoka, M. Sakaguchi, J. Soh, M. Jida, T. Ueno, T. Kubo, H. Asano, K. Tsukuda, K. Kiura, S. Hatakeyama, E. Kawahara, Y. Naomoto, S. Miyoshi, S. Toyooka

      • Abstract
      • Presentation
      • Slides

      Background:
      TAE226, a bis-anilino pyrimidine compound, has been developed as an inhibitor of focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR). These tyrosine kinases are known to be overexpressed in many malignant tumors including some NSCLCs and to play an oncogenic role in cancer cells.

      Methods:
      We investigated the effect of TAE226 on non-small-cell lung cancer (NSCLC), especially focusing on the EGFR mutational status. Drug sensitivity of TAE226 to various NSCLC cell lines was determined by MTS assay. Interaction of TAE226 and variant EGFR proteins was evaluated by in vitro binding assay, and kinetic interaction analysis to calculate K~d~ value. Finally, the effect of TAE226 on NSCLC was investigated using a xenograft mouse model.

      Results:
      TAE226 was more effective against cells with mutant EGFR, including the T790M mutant, than against cells with wild-type one. TAE226 preferentially inhibited phospho-EGFR and its downstream signaling mediators in the cells with mutant EGFR than in those with wild-type one. Phosphorylation of FAK and IGF-IR was not inhibited at the concentration at which the proliferation of EGFR-mutant cells was inhibited. Results of the in vitro binding assay indicated significant differences in the affinity for TAE226 between the wild-type and L858R (or delE746_A750) mutant, and the reduced affinity of ATP to the L858R (or delE746_A750) mutant resulted in good responsiveness of the L858R (or delE746_A750) mutant cells to TAE226. Of interest, the L858R/T790M or delE746_A750/T790M mutant enhanced the binding affinity for TAE226 compared with the L858R or delE746_A750 mutant, resulting in the effectiveness of TAE226 against T790M mutant cells despite the T790M mutation restoring the ATP affinity for the mutant EGFR close to that for the wild-type. TAE226 also showed higher affinity of about 15-fold for the L858R/T790M mutant than for the wild-type one by kinetic interaction analysis. The anti-tumor effect against EGFR-mutant tumors including T790M mutation was confirmed in mouse models without any significant toxicity.

      Conclusion:
      We showed that TAE226 inhibited the activation of mutant EGFR and exhibited anti-proliferative activity against NSCLCs carrying EGFR mutations, including T790M mutation. Our results showed that the EGFR L858R/T790M (or delE746_A750/T790M) mutant retains the binding affinity to TAE226 comparable to that of the L858R (or delE746_A750) mutant, suggesting that TAE226, or its relatives, is promising to overcome acquired TKI resistance mediated by EGFR T790M mutation.

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      MINI14.03 - New Monoclonal Antibody Targeting on Basic Fibroblast Growth Factor against Lung Cancer In Vitro and In Vivo (ID 3136)

      10:45 - 12:15  |  Author(s): M. Xu, P. Hu, F. Zhao, J. Xiang

      • Abstract
      • Slides

      Background:
      basic fibroblast growth factor (bFGF) is an important molecule that involved with proliferation, angiogenesis, invasion and metastasis in malignant tumors. bFGF in lung adenocarcinoma,squamous cell carcinoma, breast cancer, colon cancer, malignant melanoma cells was highly expressed in the cytoplasm and cytoplasm. bFGF expression was closely related with tumor poor prognosis. FGF pathway activation is a potent driver of lung cancer. Autocrine activation of FGF signaling in NSCLC may contribute to EGFR inhibitor insensitivity. We have developed new monoclonal antibody targeting bFGF (anti-bFGF mAb) which neutralizes bFGF, blocking its ability to activate FGFR1 in treating solid tumors. The antitumor, antiangiogenesis, antimetastatic and reversal multidrug resistance (MDR) activities of anti-bFGF mAb could be investigated.

      Methods:
      The effect of anti-bFGF mAb on the proliferation of cancer cells was detected by CCK-8 method. Cellular apoptosis, cell cycle distribution and the expression of associated protein were analyzed by flow cytometry. The expressions of associated protein with apoptosis, metastasis, multidrug resistance, anti-bFGF mAb in suppressing cancer cells growth through the PI3K/AKT/mTOR pathway were examined by real-time fluorescence quantitative PCR and Western blotting. Preclinical pharmacokinetics of anti-bFGF mAb was measured in mice.

      Results:
      Anti-bFGF mAb significantly could inhibit the proliferation and induce apoptosis of lung cancer and show obvious inhibitory effects on the migration of cancer cells and the tube formation of HUVECs in vitro. Treatment of transplanted cancer with anti-bFGF mAb in vivo resulted in significant reduction in tumor size and prolonged survival time of mice. The expression of caspase-3,caspase-9, PARP, and BAX in combination group was higher than those from either agent alone. Anti-bFGF mAb suppressed the PI3K/AKT/mTOR pathway. The radiotherapy sensitization enhancement ratio of the combined treatment group increased 2.37 times by anti-bFGF mAb. bFGF, VEGF expression and MVD were significantly decreased by anti-bFGF mAb. Anti-bFGF mAb could induce down-regulated P-glycoprotein and MDR1. The main pharmacokinetic parameters of anti-bFGF mab were as follows: T1/2α 0.2 h,T1/2β 1.84h and T1/2γ 90.3h. Lung tissue was major organ for deposition of anti-bFGF mAb.

      Conclusion:
      Anti-bFGF mAbs display remarkable antitumor and antiangiogenic effects in vitro and in vivo. Anti-bFGF mAb is potential therapeutic candidates for lung cancer by effectively suppressing the tumor growth through inhibition of angiogenesis, proliferation, induction of apoptosis and autophagy, reversal of MDR. Further preclinical and systematical investigation on anti-bFGF mAb may help to increase efficacy and safety of molecular target treatment in lung cancer.

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      MINI14.04 - In Vitro and in Vivo Evaluation of the Kinase Inhibitor, MGCD516, in TRK and RET Fusion Cancer Cells (ID 2756)

      10:45 - 12:15  |  Author(s): A.T. Le, A. Estrada-Bernal, S. Nelson, J. Christensen, R.C. Doebele

      • Abstract
      • Presentation
      • Slides

      Background:
      The paradigm of treating oncogene-selected patients with non-small cell lung cancer (NSCLC) and other malignancies using targeted kinase inhibitors has significant improved patient outcomes, specifically for patients harboring ALK, ROS1, and EGFR oncogenes. Additional oncogene targets that may benefit from this therapeutic strategy are therefore of immense interest. NTRK1 (TRKA) and RET gene fusions are recently identified oncogenes in NSCLC (and other malignancies) without approved kinase inhibitors. MGCD516 is a spectrum-selective tyrosine kinase inhibitor with activity against TRKA, RET, MET, VEGFR, PDGFR, AXL, and Eph family of receptors. In this report, we evaluated MGCD516 in vitro activity in cell lines with an NTRK1, NTRK3, or RET gene rearrangements. Additionally, we used a mouse xenograft model to assess the in vivo effects of MGCD516 on tumors harboring TRKA and RET fusions.

      Methods:
      Gene fusion positive cell lines, KM12 (TPM3-NTRK1), CUTO-3 (MPRIP-NTRK1), MO-91 (ETV6-NTRK3) and LC-2/Ad (CCDC6-RET) were used for the in vitro evaluation of MGCD516 inhibitory activity against these oncogenic fusion kinases. Cell lines were assessed for cell viability (MTS-base proliferation assay) and downstream signaling pathways (immunoblot analysis) upon treatment with MGCD516. For in vivo studies, xenograft models of TRKA fusion tumors (CUTO-3 and KM12) and RET fusion tumors (LC-2/Ad and a tumor biopsy from a KIF5B-RET patient) were generated in athymic nude mice. Once tumors reached ~200cm[3], a single daily dose of 5mg/kg, 10mg/kg or 20mg/kg of MGCD516 was given to mice by oral gavage. Mice in the control arm of the study were gavaged with vehicle at similar volume. Tumor size and weight measurement of mice were assessed 3 times per week.

      Results:
      MGCD516 had notable in vitro effects on the proliferation of cell lines with either RET fusion (LC-2/Ad), TRKA fusion (KM12 and CUTO-3) or TRKC fusion (MO-91) with low nanomolar IC~50~. Western blot analyses showed specific loss of phosphorylated CCDC6-RET or TRKA/C fusion protein and decreased activation of the AKT and MAPK signaling pathways when cells were treated with MGCD516. In mouse xenograft studies, tumors with TRKA fusion displayed dose-dependent growth inhibition at 5mg/kg and 10mg/kg daily doses of MGCD516 compared to controls. Notably, we observed tumor regression in the mice originally assigned to the vehicle control arm once we enrolled the mice on a 10mg/kg or 20mg/kg daily regimen of MGCD516. Comparable to the TRKA fusion xenografts studies, RET fusion tumors were growth inhibited with a 20mg/kg daily dose of MGCD516.

      Conclusion:
      The spectrum-selective tyrosine kinase inhibitor, MGCD516, demonstrates potent in vitro activity in multiple TRKA/C and RET fusion cancer cell line models and in vivo activity against TRKA and RET fusion kinase in murine xenograft models. A phase I clinical trial of MGCD516 is ongoing and the inclusion of patients with TRK and RET fusion is planned.

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      MINI14.05 - Discussant for MINI14.01, MINI14.02, MINI14.03, MINI14.04 (ID 3341)

      10:45 - 12:15  |  Author(s): J.V. DeGregori

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MINI14.06 - High-Affinity α3β1 Integrin Ligand LXY30 for the Screening, Imaging and Targeted Drug Delivery in Non-Small Cell Lung Cancer (NSCLC) (ID 1758)

      10:45 - 12:15  |  Author(s): W. Xiao, R. Liu, A. Ma, K. Zhou, A. Nguyen, J. Lee, K.Y. Yoneda, K.S. Lam, Y. Li, T. Li

      • Abstract
      • Presentation
      • Slides

      Background:
      High-affinity peptidomimetic or small-molecule ligands against cancer cell surface receptors have attracted wide interest as cancer-targeting agents to enhance cancer diagnosis and treatment. We have previously identified and characterized several peptide ligands specific for different integrins, such as a3b1, a4b1 and avb3, on live tumor cells using our invented high throughput one-bead one-compound (OBOC) random combinatorial libraries and “on-bead” whole-cell binding assay. The objective of this study was to select the best integrin ligand for the screening, imaging and targeted drug delivery studies in NSCLC.

      Methods:
      High-affinity integrin ligands coated on the surface of TentaGel resin beads were screened for the binding to a panel of NSCLC cell lines, malignant pleural effusion and peripheral blood mononuclear cells (PBMCs) from lung cancer patients using the established whole-cell binding assay. The binding affinity was determined in selected NSCLC tumors by flow cytometry using the biotinylated integrin ligands and Streptavidin-Phycoerythrin (PE). For in vivo biodistribution, mice bearing subcutaneous and intracranial NSCLC xenograft tumors were injected with LXY30-biotin-streptavidin-Cy5.5 conjugate for 6 hrs before being subjected to in vivo and ex vivo optical imaging.

      Results:
      Among the available integrin ligands, LXY30, a recently optimized cyclic peptide targeting α3β1integrin, bound to the majority of NSCLC cell lines tested within one hour of incubation. We further demonstrated that LXY30 bound to α3β1 integrin on the surface of lung cancer cells with high specificity by flow cytometry and entered into the cells via endocytosis by fluorescence microscopy imaging. Flow cytometry confirmed the high specificity binding of LXY30 to NSCLC cells. While sparing the PBMCs isolated from lung cancer patients, LXY30 strongly bound to tumor cells in the pleural effusion from several NSCLC patients and could capture the tumor cells spiked into PBMCs in 1: 5,000 dilution after a 2-hour incubation. Furthermore, several EGFR-mutant lung cancer cell lines have high level expression of α3β1 integrin on their surface. In nude mice bearing two representative, EGFR-mutant lung cancer H3255 (EGFR L858R) and H1975 (EGFR 858R/T790M) xenograft tumors, optical images have shown the preferential updates of LXY30-biotin-streptavidin-Cy5.5 conjugate in the subcutaneous and intracranial xenograft tumors.

      Conclusion:
      The rapid, sensitive and high specificity binding of LXY30 makes it an ideal candidate for screening and isolating NSCLC tumor cells in the pleural effusion and whole blood. LXY30 can be used as a cancer-targeting agent to guide in vivo delivery of imaging dye and cancer drugs to the simulated extracranial and metastatic brain tumors.

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      MINI14.07 - Bavituximab Activates CD8+ TILs in a 3D Ex Vivo System of Lung Cancer Patients Derived Tumors With Negative PD-L1 Expression (ID 2162)

      10:45 - 12:15  |  Author(s): S. Altiok, M. Mediavilla Valera, J. Kreahling, N.L. Kallinteris, D. Noyes, T.N. Razabdouski, J. Shan, J. Hutchins, K. Menander, S.J. Antonia

      • Abstract
      • Presentation
      • Slides

      Background:
      Bavituximab is a chimeric monoclonal antibody that targets the membrane phospholipid phosphatidylserine (PS) exposed on endothelial cells and cancer cells in solid tumors. Bavituximab blocks PS-mediated immune suppression and activates cytotoxic T lymphocyte anti-tumor responses.

      Methods:
      Tissues from consented patients with adenocarcinoma of the lung were extracted at the time of surgical resection and disaggregated to characterize expression of immune checkpoint proteins such as PD-1, CTLA-4, LAG3, TIM3, BTLA and adenosine A2A receptor on both CD4+ and CD8+ tumor infiltrating cells by flow cytometry (FACS) and stained for PD-L1, CD68, and CD163 via immunohistochemistry (IHC). 3D tumor microspheres were prepared and treated ex vivo with an IgG control, F(ab)’2 version of bavituximab, bavituximab, docetaxel, anti-PD-1 or PD-L1 and combinations of bavituximab, anti-PD-1 or PD-L1 and docetaxel for 36 hours within an intact tumor microenvironment. A multiplex human cytokine assay was used to simultaneously analyze the differential secretion of cytokines. Additionally, a NanoString platform containing probes to quantitate 770 immune function genes was used to determine potential positive or negative associations between expression of immune function genes and TIL activation by treatment. In a few cases, the expanded TILs were tested in PDX models using the consented patient’s tumor.

      Results:
      Bavituximab induces activation of TILs in 3D ex vivo tumor microsphere models of lung cancer, as demonstrated by a significant increase in IFN-ɣ, TNF-a, and GM-CSF secretion. FACS, IHC, and NanoString gene function analysis read out assays revealed that this effect was associated with low PD-1 expression on CD8+ cells, negative PD-L1 expression in the stating biopsy tissue, and a conversion of the M2 to M1 macrophage phenotype.

      Conclusion:
      These data support the use of bavituximab as an immunomodulatory treatment in adenocarcinoma of the lung by enhancing the activation of CD8+ TIL derived from patients' tumors with negative PD-L1 expression; correlating with increased cytokine production by lymphoid cells and repolarization of myeloid cells from an immunosuppressive to an immune active state.

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      MINI14.08 - HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells and Inhibits Lung Cancer Stem Cells (ID 2789)

      10:45 - 12:15  |  Author(s): R. Gomez-Casal, C. Bhattacharya, P. Basse, M. Epperly, H. Wang, D. Proia, J. Greenberger, M.A. Socinski, V. Levina

      • Abstract
      • Presentation
      • Slides

      Background:
      Ionizing radiation (IR) therapy is an integral component of treatment for NSCLC, however, the majority of patients succumb to this disease as the disease tends to relapse and metastasize. The failure of the therapies is associated with hypermalignant cancer-initiating cells (CICs). CICs are radiation-resistant; therefore, targeting CICs represent an important therapeutic strategy for improving the outcome of IR treatment. Ganetespib, a novel heat shock protein 90 (HSP90) inhibitor, reduces expression of multiple HSP90-dependent client oncoproteins. We evaluated both the in vitro and in vivo antitumor effects of ganetespib, in combination with IR, in human lung adenocarcinoma (AC) cells.

      Methods:
      The radiosentisizing activity of ganetespib, HSP90 inhibitor, was evaluated in human lung AC cells established from surgical tumor samples.

      Results:
      Ganetespib inhibits growth of bulk AC cells, as well as lung CICs, growing as tumor spheres. The cytotoxic effects of ganetespib G2/M cell cycle DNA repair, apoptosis, and senescence. All of these antitumor effects were both concentration- and time-dependent. At the molecular level, ganetespib inhibited pro-survival signaling in adenocarcinoma cells through decreased p-AKT expression, the downregulation of RAD51 and the upregulation of p21. Ganetespib, at low nanomolar concentrations sensitizes AC to IR treatment. Importantly, both pretreatment and post –radiation treatment (24h after IR) with ganetespib (3nM) could dramatically augment the antitumor effects of IR decreasing the survival rate of IR-treated cells. Our study suggests that ganetespib may impart radiosensitization through multiple mechanisms: such as the down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and the promotion of cellular senescence. In vivo, ganetespib was effective in reducing the tumor growth of primary T2821 tumor xenografts in mice and sensitized tumors to IR.

      Conclusion:
      The HSP90 inhibitor, ganetespib, potentiates the effect of IR in NSCLC and eliminates CICs. The radiosensitizing effect of ganetespib is mediated by the combinatorial inhibition of cell growth and survival pathways. Ganetespib is the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validated in a clinically relevant in vivo model. The use of ganetespib as a therapeutic warrants a further investigation in the clinical setting.

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      MINI14.09 - Discussant for MINI14.06, MINI14.07, MINI14.08 (ID 3342)

      10:45 - 12:15  |  Author(s): R. Dziadziuszko

      • Abstract
      • Presentation

      Abstract not provided

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      MINI14.10 - CAY10603, a Novel Inhibitor of HDAC6, Suppresses Non-Small Cell Lung Cancer Cell Growth via Modulating Both Autophagy and Apoptosis Pathways (ID 1305)

      10:45 - 12:15  |  Author(s): Z. Wang, F. Tang, S. Sun, C. Yang, C. Xie

      • Abstract
      • Slides

      Background:
      Histone deacetylase 6 (HDAC6) is a key regulator of many signaling pathways linked to cancer. But unlike other HDACs, inhibition of HDAC6 is believed not to be associated with severe toxicity, making HDAC6 a possible cancer treatment target. Overexpression of HDAC6 has been observed in many types of cancer including NSCLC. Knockdown of HDAC6 sensitizes NSCLC cell lines to chemotherapy induced cell apoptosis. Apoptosis and autophagy are the 2 cellular processes likely to alter efficacy of a therapeutic agent. Autophagy confers resistance to chemotherapy by inhibiting apoptosis. HDAC6 controls autophagosome maturation and is essential for autophagy. CAY10603 is a potent and selective inhibitor of HDAC6. Therefore, inhibition of HDAC6 by CAY10603 could be a promising strategy to treat NSCLC by targeting both apoptosis and autophagy pathways.

      Methods:
      We evaluated the effect of CAY10603 alone or in combination with autophagy inhibition on cell proliferation, apoptosis and autophagy in two human NSCLC cell lines, A549 and H460. Pharmacological (chloroquine or bafilomycin-A1) or genetic (knockdown of ATG5 or Beclin1 with shRNA) approaches were utilized to block autophagy. Cell proliferation of untreated or drug-treated cells was measured by CCK8 assay. Percentage of apoptotic cells was measured using PE-conjugated Annexin V with a flow cytometer. Autophagy was determined by conversion of LC3I to LC3II and p62 degradation using Western blot.

      Results:
      CAY10603 inhibits NSCLC cell proliferation and induces apoptosis. CAY10603 also inhibits HDAC6 dependent basal autophagy and activates the PI3K-Akt-mTOR pathway. Meanwhile, HDAC6 independent autophagy exists in NSCLC cells and confers resistance to CAY10603. Cotreatment with chloroquine or bafilomycin-A1 promotes the autophagy inhibition, cell growth suppression and apoptosis induction of NSCLC cells compared to CAY10603 alone. Knockdown of ATG5 or Beclin1 by shRNA also increased CAY10603-induced cytotoxicity in above NSCLC cells.

      Conclusion:
      Our results indicate that CAY10603 may be a promising agent for the treatment of NSCLC by modulating autophagy and apoptosis pathways. Furthermore, the combination of CAY10603 with classical autophagy inhibitors represents a promising therapeutic strategy that warrants further clinical evaluation in NSCLC.

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      MINI14.11 - Establishment of a Lung Cancer Patient-Derived Xenografts Panel (ID 2607)

      10:45 - 12:15  |  Author(s): M. Boeri, M. Moro, G. Leone, M. Tortoreto, R. Caserini, P. Gasparini, G. Bertolini, R.M. Moresco, S. Valtorta, A. Fabbri, L. Roz, G. Pelosi, U. Pastorino, G. Sozzi

      • Abstract
      • Presentation
      • Slides

      Background:
      Studies based on cell lines were found to be poor predictors of clinical effects and therefore in many cases translation of the results into the clinics failed. A major determinant for the poor performance of cell lines is the observation that cell lines do not reflect the whole complexity and heterogeneity of primary tumors. A growing body of work suggests that Patient-Derived Xenografts (PDX) represent a more informative cancer model, providing a faithful representation of the patient’s original tumor.

      Methods:
      PDX were obtained by direct implants of small tumor fragments (30mm[3]) in previously anesthetized SCID mice, and were subsequently passaged as tissue explants. PDX metabolic in vivo imaging was performed using weekly [18F]FDG-PET and coronal and 3D-reconstruction at different days. Analysis of mutations and copy number alterations of PDX and human constitutive and tumoural DNA was performed by SALSA MLPA® probe mix X050-A1 Lung Cancer (MRC Holland).

      Results:
      Tumor samples from 95 lung cancer patients (66 AC, 16 SCC and 13 other lung cancer histotypes (OL)) have been implanted in the flanks of SCID mice. Overall, 36 samples (37,9%) successfully grafted and were propagated for at least 3 passages in immunocompromised mice. Take rate was 34,8 % (23/66) in AC, 43,8% (7/16) in SCC and 46.1% (6/13) in OL (2 large cell carcinomas, 1 sarcomatoid carcinoma and 3 small cell carcinomas). A detailed immunohistochemical analysis of 27 PDX, at different passage in mice, confirmed that tumor histology, expression of specific markers (TTF-1, p40, Vimentin, Ki64 and Synaptophysin) and the amount of specific tumor cell subpopulations (i.e. CD133[+] Cancer Initiating Cells) were generally maintained in PDX. In vivo animal PET imaging showed that also metabolic activity of PDX was strictly correlated with parental tumor’s features, especially for tumours with a SUV~max~ level higher than 8 (R[2]=0.67, p<0.05). Mutation and copy number analyses, performed on 29 biological samples belonging to 11 different engrafted models, showed that genetic changes were maintained in PDX that well recapitulated the frequency of the major changes involved in lung cancer development (66.7% TP53; 60% CDKN2A, 40% LKB1, 40% KEAP1, 38.4% KRAS, 20% SWI/SNF, 20% PTEN, 8% ERBB2). Furthermore, we developed a freeze/thawing procedure on samples derived from PDXs that allows for 100% successfully thawing and established a large collection of more than 200 frozen PDX samples for future preclinical studies.

      Conclusion:
      The deep characterization of our established PDX panel confirmed that these mouse models recapitulate the parental primary tumors in terms of tumor histology, cellular and mutation pattern, metabolic activity and expression of specific markers for several passages in mice. All these data support the use of these “human in mouse” models for functional studies, highlighting the relevance of our PDX panel as a valuable platform for preclinical studies.

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      MINI14.12 - Genomic Profiling of Patient-Derived Xenografts Identify Passenger Aberrations Associated with Better Prognosis in Non-Small Cell Lung Cancer (ID 1735)

      10:45 - 12:15  |  Author(s): N. Pham, D. Wang, S. Sakashita, G. Allo, L. Kim, N. Yanagawa, C. Zhu, M. Li, E. Kaufman, N. Moghal, G. Liu, M. Pintilie, I. Jurisica, F. Shepherd, J.D. McPherson, M.S. Tsao

      • Abstract
      • Slides

      Background:
      Patient-derived tumor xenografts (PDXs) increasingly are being used as preclinical models to study human cancers, test novel therapeutics, and identify potential biomarkers, as they more accurately model human cancers than established tumor cell line cultures. However, uncertainty remains as to how well the genomic characteristics of patient non-small cell lung cancer (NSCLC) are recapitulated in these PDX models.

      Methods:
      PDXs were established by implantation of surgically resected NSCLC patient tumors into the subcutaneous or sub-renal capsule of non-obese diabetic severe combined immune deficient (NOD-SCID mice. Comprehensive genomic profiling including exome, gene copy number, DNA methylation and mRNA expression were conducted on 36 independent PDX models, their matched patient tumors and normal lung tissue. Publicly available cell line and TCGA data were used for comparison. Integrative analysis was performed to identify genomic alterations in PDXs that are associated with significant clinical outcomes in patients.

      Results:
      From 441 resected NSCLC tumors, 127 serially transplantable and stable PDX models were established. Among 264 NSCLC patients with at least 3-years follow-up, patients whose tumor formed stable PDXs (versus those who did not) showed significantly worse disease free (HR=3.12, 95% CI =2.02-4.83, P<0.0001) and overall survival (HR=4.08, 95% CI =2.16-7.73, P<0.0001), after multivariable adjustment for clinical pathological factors. Genomic and transcriptomic profiling of 36 PDXs showed greater similarity in somatic alterations between PDX and primary tumors than with published cell line data. In addition to known mutations, we found at least 16 non-synonymous somatic mutations in known oncogenes and tumor suppressors that have never been reported. All these mutations had higher observed variant allele frequency in PDXs compared to their matched patient tumors, suggesting that these were tumor sub-clones selected or enriched for growth in the PDXs. Tumor models characterized by a higher number of somatic alterations among 865 frequently altered genes were associated with better overall patient survival (HR=0.15, p=0.00015) compared to patients with corresponding PDXs characterized by higher alteration number; this was validated in the TCGA lung cancer dataset patients (HR=0.28, p=0.000022). These 865 genes were enriched for those encoding for proteins involved in cell adhesion and interactions with the extracellular matrix, and a quarter of the genomic alterations would putatively form neo-antigens implicating a potential role of immune response in the observed improved patient survival.

      Conclusion:
      PDXs are close preclinical models of patient tumors. Further investigations of passenger mutations may clarify their clinical impact on interactions between tumor cells, stroma, immune microenvironment and patient prognosis.

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      MINI14.13 - Small Molecule Demonstrates Potent Tumor Suppression by Inhibiting the PI3K/AKT Pathway in Non-Small Cell Lung Cancer (ID 721)

      10:45 - 12:15  |  Author(s): G.A. Woodard, J. Crockard, C. Peto, B. Tolani, B. He, D. Jablons

      • Abstract
      • Presentation
      • Slides

      Background:
      The phosphoinositide 3-kinase (PI3K) / protein kinase B (AKT) / mammalian target of rapamycin (mTOR) pathway is frequently activated in many malignancies including non-small cell lung cancer (NSCLC). Dysregulation of this pathway leads drives oncogenic genes and imparts resistance to conventional chemotherapy. We identified a small molecule AKT pathway inhibitor as a potential lead compound.

      Methods:
      The AKT pathway inhibitor was tested in vitro on a panel of NSCLC cell lines A427, A549, NCI-H1703, NCI-H2170, NCI-H1650, and NCI-H1975. Cell viability was determined by MTS assay after 72 hours of drug treatment. Activation kinases in the PI3K/AKT/mTOR pathway was determined by western blot analysis.

      Results:
      Treatment with the PI3K/AKT pathway inhibitor caused potent concentration-dependent inhibition of cell proliferation with a half maximal inhibitory concentration (IC~50~) in the nanomolar range. Kirsten rat sarcoma (KRAS) mutant cell lines were the most sensitivity to the PI3K/AKT pathway inhibitor while epidermal growth factor receptor (EGFR) mutant cell lines were more resistant. Western blot analysis showed inhibition of AKT and mTOR phosphorylation at nanomolar concentrations.

      Conclusion:
      A novel small molecule AKT inhibitor inhibits growth of NSCLC cells in vitro, is potent against KRAS mutants, and shows promise as a small molecule targeted chemotherapy drug for NSCLC.

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      MINI14.14 - Suppression of Lung Cancer Growth by CD26/DPP4 Inhibitor (ID 1546)

      10:45 - 12:15  |  Author(s): J. Jang, F. Janker, S. Arni, Y. Yamada, I. Gil-Bazo, I.D. Meester, W. Weder, W. Jungraithmayr

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the most prominent cause of death among cancers, accounting for 1.38 million deaths worldwide annually. In spite of improved treatment in surgery, chemo- and radiation therapy, the five year survival is poor, being 69% for stage Ia and <5% for stage IV. The cure rates of current therapies are disappointing and did not significantly prolong long term survival. Surfactant protein (SP) in lung determines not only function of the organ, but also inflammatory reaction in an infectious condition. Recently Nishioka et al. showed that stimulated SP production in the orthotopic models of human lung cancer recruits inflammatory, type I macrophages in the tumor which decreased the size of the tumor. Also, Stephan et al. found increased productions of SPs in rat by CD26/DPP4 inhibitor treatment or CD26-/- animal. In our previous work, we found the activity of CD26/DPP4 of lung cancer from patients was four times higher than normal lung tissue from same patients (n=38). Therefore, we tested if pharmacological CD26/DPP4 inhibitor (Vildagliptin) inhibits lung cancer growth in various animal models.

      Methods:
      Mouse lung cancer cell line (Lewis Lung Carcinoma (LLC)) and human lung adenocarcinoma cell line, H460, were used to develop syngeneic (C57BL6: n=8) or xenogeneic (CD1-nude: n=20) tumor models by sc. injection. Tumor growth was represented by wet weight of tumor mass at harvest (4 weeks). BALB/c mouse strain (n=12) was used to induce lung cancer by Urethane (1g/kg) ip. Urethane injected mice were harvested 5 months after ip. Vildagliptin treatment was given in drinking water (0.2 mg/ml: 50mg/kg day) during the experimental course. Tumor nodules were counted macroscopically under surgical microscope. For histological assessment, HE, TUNEL, immunohistochemistry (IHC) of CD31, Ki67, CD3, Nkp46, and F4/80 were performed. The expression of surfactant protein C (SP-C) was detected by western blotting.

      Results:
      Vildagliptin treatment significantly reduced the size of tumor developed by lung cancer cell line injection (p<0.05 for both). Tumor induced by Urethane ip. in BALB/c mice was less incident by Vildagliptin treatment (40%: 2/5 mice) than control (100%: 7/7) group. The number of tumor nodule per mouse was also significantly reduced by Vildagliptin compared to control (p<0.05). Beside tumor weight, there was no difference in HE, TUNEL stain, and IHCs of CD31, Ki-67, CD3, and Nkp46. However we found significantly increased numbers of macrophages (F4/80) in the tumors induced by lung cancer cell line injection (p<0.05 for both) along with increased expression of SP-C in lung cancer cell lines in vitro.

      Conclusion:
      Inhibition of CD26/DPP4 by Vildagliptin decreased lung cancer growth in the models of mouse and human lung cancer cell lines and increased infiltrating macrophages within tumors. Furthermore, there was increased expression of SP-C by Vildagliptin treatment found in lung cancer cell lines. This finding suggests that surfactant production in lung cancer is induced and potentially activates macrophages against lung cancer by CD26/DPP4 inhibitor, Vildagliptin.

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      MINI14.15 - Discussant for MINI14.10, MINI14.11, MINI14.12, MINI14.13, MINI14.14 (ID 3343)

      10:45 - 12:15  |  Author(s): F. Cappuzzo

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MINI 35 - Biology (ID 161)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 14
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      MINI35.01 - Genetic Alterations in the Fanconi Anemia Pathway in Lung Cancers (ID 2325)

      18:30 - 20:00  |  Author(s): W. Duan, L. Gao, K. Dotts, A. Kalvala, B. Aguila, G. Otterson, M. Villalona

      • Abstract
      • Presentation
      • Slides

      Background:
      The FA pathway contains 17 complementation groups, referred to as FA subtypes A, B, C, D1/BRCA2, D2, E, F, G, I, J, L, M, N, O, P, Q and S. Cells with FA deficiency are hypersensitive to DNA damaging agents such as cisplatin and mitomycin C (MMC). Disruptions of the FA pathway may involve epigenetic silencing of the FA-core complex, mutations or deletion of one or several FA genes. Recently we developed a FA triple-staining immunofluorescence (FATSI) method to detect FANCD2 foci formation using formalin fixed paraffin embedded (FFPE) tumor samples. We screened 139 non-small cell lung cancer (NSCL) FFPE tumors for FANCD2 foci formation by FATSI analysis. Based on the FATSI analysis, 104 of 139 tumor samples were evaluable (lack of Ki67 was defined as non-evaluable samples) for FANCD2 foci status. Among 104 evaluable tumors, 23 (22%) were FANCD2 foci negative. However, further investigation and confirmation of the genetic and epigenetic alterations involved in the FANCD2 foci defective tumors is critical for supporting application of this selection process to justify subsequent clinical treatment strategies for cancer patients.

      Methods:
      The aim of the study is to investigate the genetic alterations in the FANCD2 foci defective lung tumors and matching non-tumors. The FANCD2 foci defective tumors were identified with the FATSI method. DNA samples isolated from frozen tumor and matching non-tumor tissues were analyzed with whole exome sequencing. All 17 genes involved in the FA pathway were analyzed.

      Results:
      To investigate the gene involved in disrupting the FA pathway in patient tumors, we applied exome sequencing to 18-paired DNA samples (15 paired foci-negative non-small cell lung tumor and non-tumor frozen tissues, and 3 paired foci-positive non-small cell lung tumor and non-tumor frozen tissues). Among the 15 foci negative tumors, 7 tumors contain 9 somatic mutations including FANCA, FANCC, FANCD2, FANCM, FANCM, FANCP/ SLX4 and FANCS/BRCA1. There was no mutation detected among the three foci positive tumors. Loss of heterozygosity (LOH) events were detected in nine tumors, including one foci positive and eight foci negative tumors. The LOHs occurred in FANCA, FANCD1, FANCD2, FANCM, FANCI, FANCP/SLX4, FANCQ/ERCC4. LOHs on FANCA gene were found in three tumors and LOHs on FANCD2 gene were detected in four tumors including one foci positive tumor.

      Conclusion:
      Based on our preliminary study, 7 of the 15 FANCD2 foci negative lung tumors contained somatic mutation and 8 of the 15 foci negative tumors contained LOHs in the FA genes. A higher frequency of somatic mutation (2 of 7 tumors) and LOHs (3 of 9 tumors) was detected in FANCA gene. In addition, 4 of 9 tumors contained LOHs on FANCD2 indicating the importance of this gene in maintaining FA foci formation. However, we are uncertain if these alterations are functional. Given that FA pathway disruptions may also involve epigenetic silencing of the FA-core complex, plus its collaboration with other proteins, it is necessary to investigate the genetic alteration in the FA associated proteins and promoter methylation status of these genes.

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      MINI35.02 - Inhibitor of Differentiation 1 (Id-1) Gene Silencing Reduces Liver Metastases Formation in a NSCLC Animal Model (ID 2995)

      18:30 - 20:00  |  Author(s): E. Castanon, I. Lopez, M. Ponz-Sarvise, M. Collantes, M. Ecay, I. Gil-Aldea, C. Rolfo, A. Calvo, I. Gil-Bazo

      • Abstract
      • Presentation
      • Slides

      Background:
      Around 30% of non-small cell lung cancer (NSCLC) patients present LM during the disease course causing a negative clinical impact on survival and quality of life. The expression of certain genes in cancer cells might be crucial for allowing tumor cells to spread to the liver. According to this hypothesis Id1 and Id3 genes, part of the signature that facilitates breast cancer cells to disseminate to the lungs, might be determinant for NSCLC LM development.

      Methods:
      Three cohorts including totally 80 mice were compared; Id1 wild-type C57BL/6 (WT) female mice (n = 40) vs. Id1 knock out (IDKO) female animals (n = 28) vs Id1/Id3 knock out mice (Id1Id3KO) (n = 12). In both groups of mice 500,000 Lewis Lung Carcinoma cells (LLC) Id1 WT (Id1+/+) Id3 WT (Id3+/+), or Id1 homozygously deficient (Id1-/-) and Id3 WT (Id3+/+) or Id1-/- and Id3 heterozygously deficient (Id3+/-) were generated through gene silencing, and intrasplenically injected. Thereafter, both groups of mice were weekly monitored with FDG-micro-positron emission tomography (mPET) scans for LM formation. Animals were sacrificed (and tissues microscopically analyzed) by the time LM were developed and clinical deterioration was evident.

      Results:
      Expression of Id1 in both the host and the tumor cell line injected were independent predictive factors for the presence of LM. In fact, silencing Id1 expression in tumor cells (OR = 0.04; CI 95% 0.2 (0.04-0.9) or knocking down Id1 in the host tissues (OR: 0.2; CI 95% 0.06-0.7), impaired LM presentation. Silencing Id3 seemed not to diminish the risk of LM presentation.

      Conclusion:
      Absence of Id1 expression in the host partially impairs LM presentation. Silencing Id1 in tumor cells diminish the odds of presenting LM. Knocking down Id1 in the host or targeting Id1 in the tumor cell may represent a new approach to prevent LM presentation, and thus, improving the outcome in NSCLC patients.

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      MINI35.03 - N-Myc Downstream Regulated Gene 1(NDRG1) Promotes the Stem-Like Properties of Lung Cancer Cells Through Stabilized C-Myc (ID 996)

      18:30 - 20:00  |  Author(s): Y. Wang, K. Wang

      • Abstract
      • Presentation
      • Slides

      Background:
      Tumor-initiating cells (TIC) which were defined their ability to generate tumor play a critical role in tumorigenesis and development of lung cancer. However, the mechanism underlying how TICs keep self-renewal needs to be clarified. We investigated the biological function and clinical significance of N-myc downstream regulated gene 1 (NDRG1) in lung TICs.

      Methods:
      Recombinant NDRG1 shRNA lentivirus or NDRG1-overexpressed lentivirus was employed to knock down or reinforce NDRG1 expression respectively. Biological functions of NDRG1 silenced and overexpressed cells were investigated using in vitro and in vivo methods.

      Results:
      NDRG1 was much highly expressed in lung tumor-initiating cells compared with parental lung cancer cells in both human NSCLC cell lines and primary NSCLC cells. Immunohistochemical on the lung cancer tissues showed that NDRG1 was highly expressed. The GSEA analysis showed that patients with increased expression of NDRG1 had a worse survival and prognosis in the analysis of 226 cases of lung cancer specimens. Enhanced expression of NDRG1 promoted stem-like properties of NSCLC cells in A549 and H1975 cells while the knockdown of NDRG1 decreased the expression of iPS factors (OCT4、SOX2、KLF4、C-MYC), the spheres-forming ability in vitro and tumorigenecity and mass of lung cancer H1299 and HCC827 cells in vivo. Furthermore, we revealed that c-Myc was a key molecule of which NDRG1 involved in the self-renewal of TICs. NDRG1 was positively correlated with c-Myc expression. NDRG1 inhibited the ubiquitylation degradation of c-Myc to promote self-renewal of lung TICs through interaction with Skp2. The Interaction between NDRG1 and Skp2 was enforced in lung TICs. Moreover, the distribution of NDRG1 was generally in cellular membrane, cytoplasm and nucleus of lung cancer cells and its nuclear localization was positively regulated by the 79th tyrosine phosphorylation of NDRG1. Phosphorylated NDRG1 at Y79 which was positively regulated by PI3K-AKT pathway increased the expression of c-Myc.

      Conclusion:
      NDRG1 promotes the self-renewal of lung TICs through stabilizing c-Myc by interaction with Skp2. Our study indicates that NDRG1 is one of potential targets for eradication of lung TICs.

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      MINI35.04 - Degradation of FGFR1/Akt/Src/C-Raf/Erk by Arsenic Trioxide and FGFR Inhibitor in Squamous Cell Lung Cancer (ID 747)

      18:30 - 20:00  |  Author(s): S.K. Lam, J.C.M. Ho

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is one of the top cancer killers. Squamous cell lung carcinoma (SCC) represents the second most common histologic subtype of lung cancer. Arsenic trioxide (ATO) inhibits tumor growth and initiates apoptosis in lung adenocarcinoma and acute promyelocytic leukemia. Fibroblast growth factor receptor (FGFR) amplification has been shown in some SCC. FGFR inhibitor (e.g. PD173074) has been developed to inhibit FGFR.

      Methods:
      The combination effect of ATO and PD173074 (PD) was studied using a SCC cell line (SK-MES-1) with FGFR1 amplification. The effect of ATO and/or PD on cell viability and protein expression was studied by MTT assay and Western blot respectively. Cell cycle analysis, phosphatidylserine externalization and mitochondrial membrane depolarization were monitored by flow cytometry. Proteasome inhibitor (MG-132) was used to study the degradation mechanism. The in vivo effect of ATO and/or PD was investigated with a nude mice xenograft model.

      Results:
      Combination of ATO and PD reduced cell viability along with increased sub-G1 population, phosphatidylserine externalization and mitochondrial membrane depolarization, more significantly than single agents alone. Downregulation of FGFR1, p-Akt, Akt, p-Src, Src, p-c-Raf, c-Raf, Erk and survivin as well as upregulation of cleaved PARP were observed upon ATO and/or PD treatment. MG-132 partially reversed the degradation of Akt, Src, c-Raf and Erk induced by ATO/PD, suggesting the involvement of proteasome degradation system (Fig 1). Nonetheless, the mechanism of FGFR1 downregulation remained unknown. Downregulation of FGFR1, Akt, Src, c-Raf and Erk as well as cleaved PARP elevation induced by ATO and/or PD were confirmed in vivo (Fig 2). Figure 1 Figure 2





      Conclusion:
      Massive protein degradation (FGFR1, Akt, Src, c-Raf and Erk) was induced by ATO and/or PD treatment mainly via proteasomal degradation in a SCC cell line (SK-MES-1) in vitro and in vivo. Potential role of combined ATO with FGFR inhibitor in SCC warrants further exploration.

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      MINI35.05 - Discussant for MINI35.01, MINI35.02, MINI35.03, MINI35.04 (ID 3436)

      18:30 - 20:00  |  Author(s): M.G. Kris

      • Abstract
      • Presentation

      Abstract not provided

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      MINI35.07 - ATM Mutations in Cancer Cell Lines Predict Higher Mutation Rates and Genetic Instability (ID 1704)

      18:30 - 20:00  |  Author(s): L.F. Petersen, Y. Shen, A. Fox, J. Laskin, D..G. Bebb

      • Abstract
      • Presentation
      • Slides

      Background:
      Ataxia telangiectasia-mutated (ATM) is a critical first responder in the cell to DNA damage. Individuals lacking ATM are extremely sensitive to DNA-damaging ionizing radiation, and are predisposed to develop cancers. The mechanism for ATM dysfunction in A-T patients, or cancer patients that are ATM-deficient, is unknown. ATM has been sequenced in lung cancer patient samples, but no specific mutation hotspots have been linked with disease development, despite ATM being one of the most mutated genes in lung cancer. Our own quantitative analysis of ATM protein levels in patient samples suggests that expression is lost in 20-25% of cases and that this loss correlates with poor overall survival and increased response to adjuvant chemotherapy treatments. We believe that this may be the result of increased genomic instability within the cancer cells caused by a lack of adequate DNA repair. Given that ATM-deficient cancer cells may have higher genetic instability, and that ATM is so highly mutated in lung cancer, we sought to quantify the relationship between ATM mutations and genomic instability, as measured by total somatic mutations.

      Methods:
      Using data available from the Broad Institute’s Cancer Cell Line Encyclopedia (CCLE), we correlated mutations in ATM and other genes involved with the DNA repair response with the total number of mutations annotated in ~900 cancer cell lines. We also analyzed total mutations per cell line against the functional impact score of single nucleotide variations (SNVs) within ATM. To determine the clinical relevance of the cancer cell line observations, we partnered with the BC Genome Sciences Centre (BCGSC) to perform similar analyses on ~100 whole-genome-sequenced patient samples.

      Results:
      We show that in cell lines across all cancer types, mutations in ATM correlate with a significantly higher number of total mutations. When analyzed by site of origin, the greatest differences in total mutations were found in lung, breast, intestinal, and esophageal cancer cells. We examined additional genes associated with the DNA-repair response, including direct response genes (i.e. ATR, BRCA1&2) and downstream targets (i.e. p53). Only mutations in the direct response genes appeared to associate with total mutations, whereas p53 – while more commonly mutated – did not correlate with higher mutations. In 10 lung cancer patients, one had a truncating mutation and had the second highest number of somatic mutations, and highest among non-smokers.

      Conclusion:
      We have identified a potential relationship between ATM mutation and total somatic mutations in cancer cell lines and patient tumour genomes, which may be indicative of overall genetic instability in these samples. Analysis of the ATM mutations in cell lines and patient samples clearly shows that there are no specific hotspots for mutation in ATM that correlate with increased total mutations. Thus screening for ATM mutations alone may not be sufficient to indicate loss of function or instability. However, this data may prove useful in developing panels of targets to screen as mutation hotspots of instability, and ultimately to help identify patients that may benefit from targeted or modified therapy options based on ATM-deficiency or higher genetic instability.

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      MINI35.08 - Functional Role of Cancer Associated Fibroblasts in Non-Small Cell Lung Cancer Patients (ID 3134)

      18:30 - 20:00  |  Author(s): R. Navab, J. Hao, M. Pintilier, T. Wang, I. Jurisica, M.S. Tsao

      • Abstract
      • Slides

      Background:
      Cancer-associated fibroblasts (CAFs) are well known to strongly influence tumor development, progression and metastasis. Their characteristics and prognostic role in non-small cell lung cancer (NSCLC) patients have been recognized. However, the functional heterogeneity of CAFs between patients and their genetic basis are less understood.

      Methods:
      Primary cultures of CAFs and noncancer fibroblasts were established from 28 independent resected non-small cell lung cancers and their corresponding non-neoplastic lung parenchyma. Collagen gel contraction, xCELLigence Real-Time Cell Analysis of proliferation and in vivo tumorigenicity were studied to assess the CAF activity. Percent area of desmoplasia among total tumor stroma was used to define high desmoplasia (HD) versus low desmoplasia (LD). Gene expression data on RNA extracted from contracted gels following 8 hours incubation was obtained using Illumina Human HT-12v4 Bead Chips array and was preprocessed and normalized using RMA and values were log2 transformed. Two-fold change cutoff was applied to identify differentially expressed genes in CAF-HD versus CAF-LD.

      Results:
      High desmoplasia correlates with higher ability to contract collagen gel, increased cell proliferation and tumor growth. Microarray gene expression analysis of the 24 CAF cell lines identified 23 genes that were differentially expressed between 12 CAF-HD versus 12 CAF-LD lines and were correlated significantly (p ≤ 0.05) with the gel contraction. 23 differentially gene expression were evaluated in gene expression microarray data (Affymetrix HG-U133 Plus 2 Array) from 181 NSCLC patients. We found 7 out of 23 differential gene expression to be significantly in concordant with the cohort of 181 NSCLC patients. Taking 7 prioritized genes, we have generated physical protein-protein interaction network by quering I2D ver. 3 and visualizing it in NAViGaTOR ver 2.3 (http://ophid.utoronto.ca/navigator). To study the degree of desmoplasia and outcome, we used the cohort of 181 NSCLC patients data set. We observed that desmoplasia appears to be associated with the time to relapse in univariable analysis. The association was far stronger in the adenocarcioma group with significance for both univariable and multivariable analysis.

      Conclusion:
      We provide evidence for a functional heterogeneity of CAFs in NSCLC patients based on the level of desmoplasia in tumor stroma. Furthermore, we develop desmoplasia-specific gene signature that could subgroup CAFs and contribute to their functional heterogeneity.

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      MINI35.09 - Sonic Hedgehog Is Required for Tumor Progression in a Mouse Model of Small Cell Lung Cancer (ID 1103)

      18:30 - 20:00  |  Author(s): A. Szczepny, S. Jayasekara, A. Mudiyanselage, D.N. Watkins

      • Abstract
      • Slides

      Background:
      Activation of the Hedgehog (Hh) signaling pathway is well documented in many cancers including Small Cell Lung Cancer (SCLC). Whilst it has been shown that Smoothened, the central Hh pathway mediator, is required for the initiation and progression of SCLC in a mouse model, it is unclear what drives activation of this pathway in these tumors. As these tumors commonly express the Sonic Hedgehog (Shh) ligand and lack pathway activating mutations, it was hypothesized that production of the Shh ligand by SCLC cells could be causing cell-autonomous pathway activation and thereby driving tumorigenesis.

      Methods:
      To address this question, we used a well-characterized conditional genetic mouse model of SCLC in which inhalation of recombinant adenovirus expressing Cre can trigger recombination at loxP sites in the airway epithelium. When the virus is administered to mice double homozygous for the conditional p53 and Rb knockout alleles (p53[lox/lox];Rb[lox/lox]), mice develop multiple tumors over 9 months. To define the role of the Shh ligand in the initiation and progression of SCLC in this tumor model, p53[lox/lox];Rb[lox/lox] animals were further crossed with a conditional Shh-overexpressing transgenic mouse (ShhTg). Reciprocally, genetic deletion of Shh was achieved by crossing p53[lox/lox];Rb[lox/lox ]mice with a conditional Shh knockout mouse (Shh[lox]).

      Results:
      Aged cohorts of AdenoCre-infected p53[lox/lox];Rb[lox/lox];ShhTg mice developed more frequent and significantly larger tumors compared to their p53[lox/lox];Rb[lox/lox ]littermate controls, with tumors exhibiting a highly malignant and proliferative phenotype. Conversely, genetic deletion of Shh resulted in a dramatic reduction in tumor size in p53[lox/lox];Rb[lox/lox];Shh[lox/lox] mice compared to littermate controls.

      Conclusion:
      Together, these findings demonstrate that Shh plays a crucial role in driving the progression of SCLC, suggesting that Shh may be a potentially useful therapeutic target.

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      MINI35.10 - Discussant for MINI35.07, MINI35.08, MINI35.09 (ID 3554)

      18:30 - 20:00  |  Author(s): B.E. Johnson

      • Abstract
      • Presentation

      Abstract not provided

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      MINI35.11 - Mutant ARAF Drives Lung Carcinogenesis Through a Distinct Oncogenic Mechanism (ID 1016)

      18:30 - 20:00  |  Author(s): L.H. Araujo, J.M. Amann, M. Imielinski, H. Greulich, M. Meyerson, D.P. Carbone

      • Abstract
      • Presentation
      • Slides

      Background:
      We recently identified a novel somatic mutation in ARAF in a lung adenocarcinoma from a patient that demonstrated a remarkable response to sorafenib. The S214C lies in a negative regulatory domain of ARAF, distinct from the catalytic domain mutations commonly found in BRAF. The aim herein was to characterize the biochemical and functional aspects of ARAF S214C.

      Methods:
      ARAF constructs were generated and ectopically expressed in an immortalized bronchial epithelial cell line (BEAS-2B). We evaluated the acquisition of anchorage independence, MEK activation, and cell morphology. COS7 cells were used for co-immunoprecipitation (IP) and kinase assays.

      Results:
      Cells expressing ARAF S214C substantially increased soft agar colony formation relative to vector, wild-type, kinase-dead (D429A), and double-mutant (S214C+D429A) variants. Accordingly, ARAF S214C cells exhibited increased phospho-MEK levels, suggesting that the transforming potential is dependent on its kinase activity. Interestingly, ARAF S214C cells acquired an elongated, fibroblast-like shape, characteristic of MEK-active cells, whereas none of other variants presented this morphology. We also demonstrated that cells expressing ARAF S214C with an additional RAS-binding domain mutation (R52L) or dimerization interface mutation (R362H) lacked MEK activation, showing that RAS binding and RAF-RAF dimerization are essential for activity. To elucidate the role of BRAF and RAF1 as dimerization partners of ARAF S214C, we performed knockdowns of BRAF, RAF1, or both. ARAF S214C-induced MEK activation was not reversed by the BRAF knockdown, however both RAF1 and double knockdowns (BRAF and RAF1) led to loss of MEK activation, suggesting that RAF1 is required. Subsequently, COS7 cells were co-transfected with tagged constructs of ARAF and either BRAF or RAF1, followed by co-IP. We showed that mutant ARAF presents a higher rate of dimerization than wild-type ARAF in the presence of sorafenib. Importantly, sorafenib-induced heterodimers lacked kinase activity, compatible with the clinical response reported.

      Conclusion:
      ARAF S214C demonstrates the in vitro features of a driver oncogene, and also a distinct mechanism of action. This oncogenic process can be successfully suppressed by RAF inhibitors like sorafenib, and could represent a new target for personalized therapy in advanced lung adenocarcinoma. Figure 1 Figure: Summary of the ARAF S214C oncogenic mechanism.



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      MINI35.12 - Stratifin Accelerates Progression of Lung Adenocarcinoma at an Early Stage (ID 506)

      18:30 - 20:00  |  Author(s): A. Shiba, Y. Kim, M. Noguchi

      • Abstract
      • Presentation
      • Slides

      Background:
      Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation (Aya Shiba-Ishii, IJC. 2011). We also found that SFN expression was totally suppressed in normal lung tissue, whereas demethylation of its promoter triggered aberrant SFN overexpression in eIAs in a p53-independent manner (Aya Shiba-Ishii, AJP. 2012). SFN has been linked to cancer most directly, possibly having tissue-specific functions and regulating progression of the cell cycle. Here, we performed an in vivo study to clarify the role of SFN in progression of lung adenocarcinoma.

      Methods:
      We induced stable knockdown of SFN using two individual shRNAs (shSFN). To evaluate the oncogenic activity of SFN, we injected A549-shSFN intrabronchially or intravenously into SCID mice. Additionally, we generated SFN-transgenic mice (Tg-SPC-SFN[+/-]) showing lung-specific expression of human SFN (hSFN) under the control of a tissue-specific enhancer, the SPC promoter. In order to observe the tumorigenic activity of SFN, Tg-SPC-SFN[+/-] and WT ICR mice were intraperitoneally administered 4 mg 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, a pulmonary carcinogen) or saline as a control, and tumorigenicity was assessed for 20 weeks. Lungs of representative mice were periodically examined using animal CT.

      Results:
      Although control A549 cells formed advanced tumors in the lungs of SCID mice after intrabronchial and/or intravenous injection, we also found pleural dissemination in the control group (in 75% after intravenous injection and in 25% after intrabronchial injection). However, A549-shSFN did not form any tumors. Next, we confirmed the lung-specific expression hSFN in Tg-SPC-SFN[+/-] using RT-PCR and IHC. In a chemical carcinogenesis experiment, animal CT revealed several pulmonary tumors in some Tg-SPC-SFN[+/-] from 15 weeks after NNK administration, and at 20 weeks 47.8% of Tg-SPC-SFN[+/-] (11/23) had developed lung tumors, whereas only 11.1% of WT ICR (3/27) had done so (statistically significant). Surprisingly, two of seven Tg-SPC-SFN[+/-] mice (28.6%) developed tumors even though they were not administered NNK. All of the tumors that developed in Tg-SPC-SFN[+/-] lung expressed hSFN abundantly.

      Conclusion:
      Here, we showed that suppression of SFN expression in lung adenocarcinoma A549 cells was significantly reduced in terms of not only lung tumor formation but also metastatic potential. Additionally, it was found that Tg-SPC-SFN[+/-] mice developed lung tumors at a significantly higher rate than control mice after NNK administration. Interestingly, several Tg-SPC-SFN[+/-] mice developed lung tumors without carcinogen. Because these tumors showed high hSFN expression, SFN was thought to facilitate not only tumor progression but also tumor initiation, and to work as an oncogene. Soda et al. found that 100% of Tg-EML4-ALK mice developed hundreds of adenocarcinoma nodules in both lungs within a few weeks after birth (Nature 2007). Although the oncogenic activity of SFN is weaker than that of EML4-ALK fusion kinase, SFN might also have the potential to initiate peripheral-type lung adenocarcinoma.

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      MINI35.13 - Targeting Cancer Stem Cell Factor BMI1 to Sensitize Non-Small Cell Lung Cancer to Chemotherapy and Radiation Therapy (ID 502)

      18:30 - 20:00  |  Author(s): K.R. Chaudhary, B. Halmos, H. Cheng, J.M. Silva, T.K. Hei, S.K. Cheng

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is known to be the most frequent disease and the leading cause of cancer-related death in men and women worldwide. Despite treatment advances, patient outcomes remain dismal and overall survival at 5 years is only 15%. The resistance mechanisms for concurrent chemoradiation therapy are poorly studied. Cancer stem cells have been proposed to be the driver for many cancers including lung cancer and may be also responsible for therapy resistance.

      Methods:
      We sought therefore to identify therapy resistance pathways in lung cancer by using genome-wide RNAi high-throughput screen via a shRNA viral library pool containing approx. 60,000 individual shRNAs targeting alomost 80% of human genome on a human lung adenocarcinoma cell line (PC9) treated with cisplatin alone, radiation alone and combined radiation and cisplatin.

      Results:
      From the cisplatin and radiation screen, analysis of top 100 potential hits interestingly showed several cancer stem cells markers including Sox, Lrg6, and members of the Hedgehog signaling pathway Patched and Bmi1. FACS analysis showed increased stem cell markers CD133, ABCG2 and CXCR4 expression on PC9 cells treated multiple times with cisplatin and radiation compared to non-treated cells, pointing towards acquired stemness of lung cancer cells after treatmentent and subsequently resistanve to treatment. Further FACS and real time PCR analysis revealed evlevated EMT marker such as CD44 and SNAIL and decreased expression of E-Cadherin and Vementin in treated cells compared to non-treated cells. Cells treated with cisplatin and radiation in combination with PTC-209 showed increased cleaved-PARP staining compared to cells treated with combined chemoradiation. We further determined the effects of Bmi1 on therapy resistance with survival assays by treating PC9 cells with Bmi1 inhibitor PTC-09. MTT cell survival and colonogenic assays was performed by treating PC9 cells with PTC-09 in triplicate and then treated with increasing dosage of cisplatin (0.1, 1 and 10 µM) or X-ray radiation (2, 4 and 6 Gy). Significantly decreased cell survival was observed in PTC-09 treated PC9 cells treated with cisplatin or radiation compared to control and cisplatin or radiation alone treated cells. Further colonogenic assay of PC9 cells treated with 2Gy+1 um cisplatin and increasing dosage of PTC-09 showed significant decrease in the ability of cells to form colonies compared to control.

      Conclusion:
      By performing an unbiased genome wide RNAi screen for therapeutic resistance, we have successfully identified and validated a molecular regulator of cancer stem cell pathway which enabled us to successfully test the revelance of the cancer stem cell model in lung cancer. Our study provides evidence for the concept that targeting cancer stem cells can be therapeutically beneficial. We are further evaluating effect of Bmi1 using CRISPR knock out model and downstream target.

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      MINI35.14 - Microthrombosis Enhances Extravasation via Myeloid Hypoxia-Inducible Factors (ID 94)

      18:30 - 20:00  |  Author(s): C.E. Evans, A. Prodger, C. Branco-Price, A. Palazon, P. Tyrakis, J. Sim, H. Rundqvist, P. Bendahl, M. Belting, R.S. Johnson

      • Abstract
      • Presentation
      • Slides

      Background:
      Mechanisms that regulate the positive association between thrombosis and pulmonary metastasis are incompletely understood. It was hypothesised that thrombus formation stimulates a hypoxic response, which in turn promotes extravasation. The primary aim was to determine whether thrombosis of the pulmonary microvasculature (T~pm~) increases extravasation via myeloid (neutrophil and macrophage) hypoxia-inducible factor (HIF).

      Methods:
      Pulmonary microthrombosis was induced in wildtype and conditional HIFα knockout mice by administration of intravenous polystyrene microbeads (n=15/group). Murine lung cancer cell extravasation was quantified, and both murine pulmonary and human breast tumors (n=221) were characterised by immunostaining and image analysis.

      Results:
      T~pm~ was induced in wild type mice via tail vein administration of polystyrene microbeads (15μm diameter, 1000/mouse). T~pm~ led to chronological increases in pulmonary HIF1α expression (P=0.01), HIF2α expression (P<0.01), neutrophil infiltration (P<0.05), and macrophage infiltration (P<0.05; 1-5days post-T~pm~ vs. non-thrombosed vehicle controls, n=8/group/time point); these increases were comparable with changes observed following vena cava thrombosis (assessed via image analysis of immunostained tissue throughout). In wild type mice with circulating Lewis lung cancer cells (LLCs, 1million/mouse i/v), T~pm~ led to increases in pulmonary fibrin deposition (P<0.0001), HIF1α expression (P<0.05), HIF2α expression (P<0.05), and LLC extravasation (P<0.0001; 14days post-LLCs vs. non-thrombosed controls, n=15/group). Using conditional HIFα knockout mice (vs. wild type littermates), it was shown that T~pm~-induced increases in pulmonary fibrin deposition and LLC extravasation were dependent upon HIF1α or HIF2α in neutrophils and macrophages; myeloid HIFs were also responsible for T~pm~-induced increases in pulmonary tumour proliferation and vascularisation (n=15/group). In human tumour samples (n=221), fibrin deposition was positively correlated with HIF2α expression (RS=0.22, P<0.001), while increases in HIF2α were associated with reductions in metastasis-free survival (P<0.05).

      Conclusion:
      Thrombus formation in mouse pulmonary microvasculature enhances cancer cell extravasation via neutrophil- and macrophage-specific HIF1α or HIF2α. In human tumours, HIF2α is associated with increased fibrin deposition, and reduced survival. Pulmonary microvascular thrombosis can enhance cancer cell dissemination via myeloid cell-specific HIFs.

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      MINI35.15 - Discussant for MINI35.11, MINI35.12, MINI35.13, MINI35.14 (ID 3555)

      18:30 - 20:00  |  Author(s): J.W. Goldman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS 10 - Management of Screening Detected Lung Cancer (ID 28)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 7
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      MS10.01 - Epidemiology of Lung Cancer and Smoking (ID 1889)

      14:15 - 15:45  |  Author(s): P. Yang

      • Abstract
      • Presentation
      • Slides

      Abstract:
      As of 2014, use of low-dose computed tomography (LDCT) screening for lung cancer was recommended by the U.S. Preventive Services Task Force (USPSTF), i.e., to annually screen people aged 55-80 years of age who have smoked 30 or more pack-years of cigarettes and are either current smokers or have quit within 15 years recommend. From the perspective of epidemiology of lung cancer and smoking, the USPSTF criteria target precisely on the population at the highest risk: peak age range and the heaviest cumulative exposure to cigarette smoking. On the other hand, through closely following the dynamic trends of tobacco smoking and lung cancer incidence and mortality, updating and improving the eligibility criteria for lung cancer screening should be a continuing effort. Reported in 2015 from the Global Adult Tobacco Survey (GATS), current tobacco use prevalence ranges from 43% in Bangladesh to 6% in Panama and Nigeria. Based on a WHO 2015 report, lung cancer remains as the most common cancer in men worldwide with the highest estimated age-standardized incidence rates in Central and Eastern Europe and Eastern Asia (>50.4 per 100,000); in women, the highest estimated rates are in Northern America (33.8) and Northern Europe (23.7). In United States, during 2005-2012, the proportion of heavy smokers who smoked ≥30 cigarettes per day declined significantly, from 12.6% to 7.0%. With the declining percentage of the population who smoke, lung cancer incidence and mortality have been decreasing among men in the past three decades, and only recently, has shown decrease among women. A similar trend has been observed in Olmsted County population, Minnesota (Figure). Meanwhile, former cigarette smokers remain at a high risk for lung cancer although at lower risk than they would have been had they continued smoking. As a consequence, more people with lung cancers are now identified in former smokers rather than in current smokers. Specifically, less than 18% of United States adults are current smokers and more than 30% are former smokers. Intriguingly, our recent report showed that approximately two thirds of newly diagnosed lung cancer patients would not have met the current USPSTF high-risk criteria for LDCT screening. Particularly, we found a 24% offal in screening-eligibility (from 57% in 1984-1990 to 43% in 2005-2011) which exceeded the 17% decline in incidence in lung cancer (from 53 to 44/1000000) over the same time intervals. We have conducted further investigations to delineate the high-risk subpopulations based on evidence from two prospective lung cancer patient cohorts and a retrospective community cohort. Our goal was to improve the identification of individuals at high-risk for lung cancer by (1) demonstrating the chronological patterns of patients who would have been the beneficiaries or missed-outs under USPSTF criteria for lung cancer screening in two contrasting cohorts, and (2) provide strong evidence of a new subpopulation that should be added to the definition of high risk and the public health impact of this subgroup on smoking cessation effort. Two prospective cohorts are primary lung cancer patients diagnosed between 1997-2011 from referral patients (Hospital) and defined-community residents (Community); the retrospective cohort is the Olmsted County population (Minnesota, USA) followed for 28 years (1984-2011). Hospital and Community cohorts include 5988 and 850 patients, respectively; the Olmsted County population is approximately 140,000. Between 1997 and 2011, former smokers with 15-30 quit-years age 55-80 formed the largest subgroup not meeting current USPSTF screening criteria. This subgroup constituted 12% of the hospital cohort and 17% of community cohort of patients with lung cancer. Between 1984 and 2011, using current screening criteria, the age- and sex-adjusted lung cancer incidence rates in Olmsted County decreased significantly from 1.5/1000 to 0.6/1000 person-years; when adding former smoker cases with 15-30 quit-years to the high risk group, the incidence rate was doubled by 2011. Evidence from both Community and Hospital cohorts in this study suggest that former smokers with 30+ pack-years and 15-30 quit-years of cigarettes remain at high risk and should be considered as eligible for lung cancer screening. These individuals may perceive the USPSTF’s requirement to stop screening after 15 years as an indication they are no longer at high risk for lung cancer or as a pass not to quit smoking. These results may impact smoking cessation and optimize the effectiveness of screening program, and demand more effective criteria to define high-risk for lung cancer. Individuals who are under 81 years, had 30 or more pack-year smoking history, and had quit for 15-30 years should also be considered as eligible for lung cancer screening. Figure 1 References: 1. Moyer VA, US Preventive Services Task Force. Screening for Lung Cancer: USPSTF Recommendation Statement. Ann Intern Med. Mar 4 2014;160(5):330-338. 2. The GATS Atlas. Global Adult Tobacco Survey. Global Tobacco Surveillance System. Published by CDC 2015. 3. GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance. July 23, 2015 4. Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System Prevalence and Trends Data, 2013. Atlanta: U.S. DHHS, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2013 [accessed January 2015]. 5. Lung Cancer Incidence Trends in U.S.A. SEER Program: http://surveillance.cancer.gov/. April 2015. 6. St Sauver JL, Grossardt BR, Yawn BP, et al. Data resource profile: the Rochester Epidemiology Project medical records-linkage system. Int J Epidemiol. Dec 2012;41(6):1614-1624. 7. Wang Y, Midthun DE, Wampfler JA, Deng B, Stoddard SM, Zhang S, Yang P. Trends in the proportion of patients with lung cancer meeting screening criteria. JAMA. 2015; 313(8):853-5. 8. Yang P, Allen MS, Aubry MC, et al. Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest. Jul 2005;128(1):452-462.



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      MS10.02 - Positive Lung Cancer Screens - Which Ones are Lung Cancer? (ID 1890)

      14:15 - 15:45  |  Author(s): M. Tammemägi

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      Abstract not provided

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      MS10.03 - What Is the Ideal Method of Diagnosis for Screening Detected Lung Nodules? (ID 1891)

      14:15 - 15:45  |  Author(s): D. Minnich

      • Abstract

      Abstract not provided

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      MS10.04 - When to Intervene on Screening Detected Lung Nodules (ID 1892)

      14:15 - 15:45  |  Author(s): G. Veronesi

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The National Lung Screening Trial (1) largely resolved the dispute as to whether low-dose computed tomography (LDCT) screening can reduce lung cancer mortality. However the trial was characterized by a high recall rate and high rate of benign disease at surgery, probably because a diagnostic and management protocol for indeterminate nodules was not in place. Screening has improved the stage distribution of lung cancer at diagnosis and greatly increased the cure rate (2). It has also increased numbers of overdiagnosed cancers and of potentially harmful diagnostic procedures carried out for benign disease. It is therefore critical to establish quality criteria for screening programs to reduce the risks of these occurrences. Recommendations from the surgeon team at the 2011 WCLC workshop, Amsterdam (3) were that: (i) A formal diagnostic and surgical management protocol should be part of any screening program; surgeons should be involved drawing up protocols along with other members of the multidisciplinary team. (ii) A false positive rate of less than 15% should be aimed at. (iii) Screening should only be performed at centres with access to a full minimally invasive surgical program (VATS or robotic anatomical resection). (iv) For pure ground-glass or partially-solid LDCT-detected lung cancers below 2 cm, anatomical segmentectomy is adequate treatment provided intraoperative frozen section examination shows that lymph nodes at hilar and mediastinal stations are negative. The diagnostic algorithm of COSMOS (4) was non-invasive, with no routine CT-guided transthoracic biopsy, and indication for surgery based on nodule size, volume doubling time (VDT), and SUV on PET-CT. After 5 years, only 14% of surgical biopsies were for benign disease, one of the lowest in the literature. Around half the biopsied benign nodules had a VDT generally considered to indicate malignancy, and the other half were PET positive. Thus addition always of reducing false positives are needed and molecular markers appear promising in this respect. The false negative rate is a good indicator of screening program quality. In COSMOS we defined false negatives as stage II-IV cancers present on a previous annual scan but not considered to merit further workup: 16 of the 190 cancers (8%) were false negatives, similar to the I-ELCAP figure of 9%. Most false negatives were centrally located, rapidly-growing nodules, but a few were misinterpreted by radiologists. The role of PET-CT in the workup algorithm was investigated on 378 COSMOS volunteers with indeterminate nodules (5). PET-CT was found highly sensitive for nodules detected at baseline, nodules ≥15 mm, and solid nodules. Sensitivity was lower for partially solid and nonsolid nodules, and those discovered after baseline, for which other methods, e.g. VDT, should be used. The Danish Lung Cancer Screening Trial investigated both PET-CT and VDT, finding that the best predictor of malignant nodules was PET-CT and VDT combined (6). NELSON trial investigators were the first to introduce VDT as main the component of the diagnostic algorithm (7). As regards overdiagnosis, in a retrospective analysis of 175 COSMOS patients VDT was suggested as a marker of aggressiveness that could be used to estimate overdiagnosis and tailor treatment [8]. We divided nodules into: fast-growing (VDT <400 days) days), slow-growing (VDT 400-599 days), and indolent (VDT >600 days). Median VDT was significantly faster in new cancers than slow-growing and indolent cancers (52, 223 and 545 days, respectively). Median VDT (303 days) was significantly longer in adenocarcinomas than squamous cell carcinomas (77 days) and small cell cancers (70 days). The authors concluded that slow-growing nonsolid nodules, many of which are likely to be overdiagnosed, could be safely treated with minimally invasive (sublobar) surgery. If centrally located, stereotactic ablative body radiotherapy (SABR) should be considered and discussed with the patient. The recent paper of Yankelevitz et al. (9) focused on the frequency, treatment and prognosis of nonsolid nodules encountered the large I-ELCAP screening cohort. Nonsolid nodules were rare, being identified in 2392 (4.2%) of 57,496 baseline screenings, with new nonsolid nodules identified in 485 (0.7%) of 64,677 repeat screenings. All 84 lung cancers identified were stage I adenocarcinomas and survival was 100% a median of 78 months (IQR, 45–122). after diagnosis. The authors concluded that nonsolid nodules of any size could be safely followed at 12-month intervals and that transition to part-solid should prompt a pathologic diagnosis. The authors suggested the nonsolid nodules should be renamed ‘indolent lesions of epithelial origin,’ in part to counter the fear that the word cancer evokes; in part because they behave much like benign lesions. In the COSMOS study, nonsolid lesions constituted 17% of all cancers detected, probably more than in I-ELCAP (although an updated breakdown is not available). This may be because COSMOS investigators removed these nodules if they increased in size or were PET-CT positive. As regards the question of lymph node dissection for early lung cancers, 193 consecutive patients with non-screening detected clinically N0 lung cancers, were studied (10). It emerged that 42/43 cases had negative PET-CT (usually SUVmax <2.0) or nodule ≤10 mm were pN0, suggesting that, for cancers with these characteristics, node dissection can be avoided because the risk of nodal involvement is minimal. To conclude, the results of the National Lung Screening Trial (1) shifted the debate from whether to how screening should be performed. Various diagnostic algorithms have been proposed, most with good results in terms of safety and number of resections for benign disease, however there is still room for improvement. The role of molecular markers, alone or in combination with VDT and PET positivity (FDG uptake), is under evaluation. Nonsolid nodules can be safely monitored at yearly intervals until the appearance of a solid component. Large scale implementation of screening in Europe is now a priority: although many investigators still have reservations, LDCT screening, with an appropriate diagnostic and surgical management protocol, is now good enough to save many lives with limited risks. References 1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. doi: 10.1056/NEJMoa1102873. 2. Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006; 355: 1763–1771. 3. Field JK, Smith RA, Aberle DR, et al. IASLC CT Screening Workshop 2011 Participants. International Association for the Study of Lung Cancer. Computed Tomography Screening Workshop 2011 report. J Thorac Oncol. 2012;7(1):10-9. doi: 10.1097/JTO.0b013e31823c58ab. 4. Veronesi G, Maisonneuve P, Spaggiari L, et al. Diagnostic performance of low-dose computed tomography screening for lung cancer over five years. J Thorac Oncol. 2014;9(7):935-9. doi: 10.1097/JTO.0000000000000200. 5. Veronesi G, Travaini LL, Maisonneuve P, et al. Positron emission tomography in the diagnostic work-up of screening-detected lung nodules. Eur Respir J. 2015;45(2):501-10. doi: 10.1183/09031936.00066514. 6. Ashraf H, Dirksen A, Loft A, et al. Combined use of positron emission tomography and volume doubling time in lung cancer screening with low-dose CT scanning. Thorax. 2011;66(4):315-9. doi: 10.1136/thx.2010.136747. 7. Horeweg N, van der Aalst CM, Vliegenthart R, et al. Volumetric computer tomography screening for lung cancer: three rounds of the NELSON trial. Eur Respir J 2013; 42: 1659–1667. 8. Veronesi G, Maisonneuve P, Bellomi M, et al. Estimating overdiagnosis in low-dose computed tomography screening for lung cancer: a cohort study. Ann Intern Med 2012; 157: 776–784 9. Yankelevitz DF, Yip R, Smith JP, et al. As the Writing Committee for The International Early Lung Cancer Action Program Investigators Group. CT Screening for lung cancer: nonsolid nodules in baseline and annual repeat rounds. Radiology. 2015:142554. 10. Veronesi G, Maisonneuve P, Pelosi G, et al. Screening-detected lung cancers: is systematic nodal dissection always essential? J Thorac Oncol. 2011;6(3):525-30. doi: 10.1097/JTO.0b013e318206dbcc.

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      MS10.05 - Rationale for Sublobar Resection for Early Cancer (ID 1893)

      14:15 - 15:45  |  Author(s): H. Asamura

      • Abstract
      • Presentation
      • Slides

      Abstract:
      THE oncological appropriateness of the limited, sublobar resection (segmentectomy or wide wedge resection) for lung cancer has been again discussed in the thoracic surgical community, although the previous randomized trial definitively showed the prognostic advantage of the lobectomy over sublobar, limited resection. Generally, the operative modes used for pulmonary parenchymal resection have been classified into pneumonectomy, bi-lobectomy, lobectomy, segmentectomy, and wedge resection according to the volume of the resected lung parenchyma. From a technical viewpoint, these can be divided into non-anatomic (wedge resection) and anatomic (all the others) resections. In anatomic resections, all vessels and bronchi are divided at the hilum to ensure the resection of the whole lung area related to the divided bronchus. The term, “limited resection”, is also used as opposed to “standard resection”, which is essentially at least lobectomy with hilar and mediastinal lymph node sampling/dissection as of now. Therefore, the present-day “limited” resection inevitably indicates “sublobar” resections. There are several important landmark articles in the surgical evolution for lung cancer. In 1930s, Churchill and Belsey originally introduced segmentectomy for the treatment of bronchiectasis of the lingular segment, and it was termed as “segmental pneumonectomy” [1]. In 1970’s, Jensik reported a 5-year survival rate at 56% and local recurrence rate at 10% after segmentectomy for T1 lung cancer. He suggested that anatomic segmentectomy could be effectively applied to small primary lung cancers when the surgical margins were sufficient [2]. After these, many non-randomized, case series came out, and suggested the prognostic equivalence between lobectomy and segmentectomy for T1 lung cancer. To definitively answer the question regarding the prognoses after lobectomy and limited resection, a prospective, randomized trial was conducted by the North American Lung Cancer Study Group (LCSG) [3]. Segmentectomy and wide wedge resection were compared with lobectomy for stage IA lung cancer with regard to the postoperative prognosis and pulmonary function. A three-fold increase in local recurrence rate and 30% increase in overall death rate were shown for limited resection, and therefore, this study solidified lobectomy as the procedure of choice for the treatment of T1N0 lung cancer. This is still the only completed, randomized trial that directly compared limited resection with lobectomy, and therefore, the gold standard for lung cancer still remains as lobectomy as of now. However, there has been a surge of the interest in the sublobar resection among thoracic surgeons recently, since many earlier, smaller cases are being found owing to the improved technology in CT image and the introduction of the CT screening programs. [4] Among the lesions that are specifically found in this context, the non-solid lesion that is referred to as ground glass opacity (GGO) is a newly established clinical entity that may be a candidate for limited pulmonary resection. The understandings of pathobiological nature of such earlier lesions have progressed [5]. New proposal for the classification of adenocarcinoma was also promulgated, in which the earlier forms of adenocarcinoma were newly defined as AIS (adenocarcinoma in situ) or MIA (minimally invasive adenocarcinoma) [6]. In the face of this situation, it is not surprising that questions have arisen as to whether it might be possible to manage smaller, earlier lung cancers by sublobar resections. Moreover, it has been more than 20 years since the LCSG randomized clinical trial was conducted in the 1980s. Given this situation, randomized clinical trials with peripheral lung cancers no more than 2 cm in diameter as the target lesions were begun in the United States (CALGB 140503) and Japan (JCOG 0802) at almost the same time [7]. JCOG0802/WJOG4607L trial is a prospective, randomized, multi-institutional study which intends to compare the prognosis and postoperative pulmonary function between patients with non-small lung cancer 2 cm or less in diameter undergoing either lobectomy or segmentectomy. The target number of patient accrual is 1,100, and as of the end of June, 2015, accrual is over in full and the data maturation is awaited. The important fact is that the candidate lesions of this trial are supposed to be invasive adenocarcinomas pathologically with solid part in ground glass opacity (GGO) on the CT images. As a selection criterion, a consolidation/tumor ratio has been employed as 25 to 100% to define invasive adenocarcinomas preoperatively. This study is coupled with JCOG0804/WJOG4507L trial, which deals with the non-invasive or minimally invasive adenocarcinomas (adenocarcinoma in situ, AIS/minimally invasive adenocarcinoma, MIA) with CT images as pure GGO with/without minimal solid part. They are treated with limited, sublobar resection (segmentectomy or wide wedge resection). This study is a prospective, but non-randomized, single-arm study because no death is expected for these tumors despite surgical modes. Target accrual is 330, and the registration was already closed, waiting for data maturation. The present-day selection of the surgical mode for lung cancer should be based upon the solid data which demonstrate the overt advantage over the standard mode of resection (lobectomy). We need another some years until getting the definitive conclusion as to the appropriateness of sublobar resection for early stage lung cancer. Until then, surgeons should be prudent in performing a sublobar resection as a radical resection for lung cancer.[8] Figure 1 SEGMENTECTOMY OF THE ANTERIOR SEGMENT OF THE RIGHT UPPER LOBE (from "Asamura's Operative Thoracic Surgery") [References] 1. Churchill ED, Belsey R. Segmental pneumonectomy in bronchiectasis: the lingular segment of the left of the left upper lobe. Ann Surg 1939;109:481-99 2. Jensik RJ. Faber LP, Milloy FJ, Monson DO. Segmental resection for lung cancer. A fifteen-year experience. J Thorac Cardiovasc Surg 1973;66:563-72 3. Lung Cancer Study Group, Ginsberg RJ, Rubinstein LV. Randomized trial of lobectomy versus limited resection for T1N0 non-small cell lung cancer. Ann Thorac Surg 1995;60:615-23 4. El-Sherif A, Gooding WE, Santos R, et al. Outcome of sublobar resection versus lobectomy for stage I non-small cell lung cancer: a 13-year analysis. Ann Thorac Surg 2006;82:408-16 5. Asamura H, Hishida T, Suzuki K, et al. Japan Clinical Oncology Group Lung Cancer Surgical Study Group. Radiographically determined noninvasive adenocarcinoma of the lung: Survival outcomes of Japan Clinical Oncology Group 0201. J Thorac Cardiovasc Surg 2013;146:24-30 6. Travis WD, Brambilla E, Noguchi M, et al. International association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-85 7. Nakamura K, Saji H, Nakajima R, et al.. A phase III randomized trial of lobectomy versus limited resection for small-sized peripheral non-small cell lung cancer (JCOG0802/WJOG4607L). Jpn J Clin Oncol 2010;40:271-4 8. Asamura H. Role of limited sublobar resection for early-stage lung cancer: steady progress. J Clin Oncol. 2014;32(23):2403-4.



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      MS10.06 - Is There a Role for SBRT in Screening Detected Non-Diagnosed Lung Nodules? (ID 1894)

      14:15 - 15:45  |  Author(s): D.A. Palma

      • Abstract
      • Presentation
      • Slides

      Abstract:
      With the results of the National Lung Screening Trial (NLST) demonstrating improved overall survival with low-dose CT screening in high-risk patients,[1] the management of screen-detected lung nodules has taken on increased clinical importance. In the NLST, low-dose CT scans showing any non-calcified mass or nodule were classified as ‘positive’, but with this definition, fewer than 4% of ‘positive’ results were ultimately shown to be lung cancer. Ongoing randomized trials of lung cancer screening use alternative definitions of a positive result, which may improve the specificity of CT screening. However, despite this high rate of false-positives, validated models are available to allow for accurate prediction of malignancy risk. One such model, developed from the Pan-Canadian Early Detection of Lung Cancer Study and validated, achieved excellent discrimination and calibration, with AUC values in excess of 0.90.[2 ]The availability of such tools should substantially reduce the risk of patients undergoing unnecessary investigations or treatments for benign disease. For patients with a high probability of malignancy, surgical resection has been the historic treatment of choice. Surgical interventions provide a pathologic diagnosis and also allow for lymph node sampling, but can be associated with significant morbidity and mortality. Although surgical morbidity in the NLST was low,[1] such results from specialized centers may not be widely generalizable. Population data have shown higher rates of complications than data from specialized centers, both in terms of complications for CT-guided biopsies, and also for surgical morbidity and mortality.[3,4] Stereotactic ablative radiotherapy (SABR), also called stereotactic body radiation therapy (SBRT), is a non-invasive treatment often delivered in 1-8 fractions on an outpatient basis. For T1-T2N0 NSCLC, SABR achieves high-rates of local control, and with results comparable to surgery in many well-controlled studies. Randomized data, not specific to screen-detected lesions, suggests that SABR may achieve better overall survival than surgical resection.[5] A major advantage of SABR appears to be a reduced risk of serious toxicity in high-risk patients: for example, a systematic review of outcomes for patients with T1-T2 NSCLC and severe COPD (GOLD III/IV) indicated a 30-day mortality rate of 10% with surgical resection and 0% with SABR.[6] Modeling studies comparing surgical resection and SABR suggest that as operative mortality rises, SABR is preferred. This presentation will discuss the relative merits and limitations in the use of SABR for screen-detected lung nodules, including evidence-based thresholds for treating without a definite pathologic diagnosis, issues pertaining to treatment delivery for small targets, toxicity of SABR for small lesions, and ongoing follow-up after SABR. References 1. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5):395-409. 2. McWilliams A, Tammemagi MC, Mayo JR, Roberts H, Liu G, Soghrati K, Yasufuku K, Martel S, Laberge F, Gingras M, Atkar-Khattra S, Berg CD, Evans K, Finley R, Yee J, English J, Nasute P, Goffin J, Puksa S, Stewart L, Tsai S, Johnston MR, Manos D, Nicholas G, Goss GD, Seely JM, Amjadi K, Tremblay A, Burrowes P, MacEachern P, Bhatia R, Tsao MS, Lam S. Probability of cancer in pulmonary nodules detected on first screening CT. N Engl J Med. 2013 Sep 5 3. RS Wiener, LM Schwartz, S Woloshin, HG Welch. Population-based risk for complications after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records. Ann Intern Med, 155 (2011), pp. 137–144 4. D LaPar, C Bhamidipati, C Lau, D Jones, B Kozower. The Society of Thoracic Surgeons General Thoracic Surgery Database: establishing generalisability to national lung cancer resection outcomes. Ann Thorac Surg, 94 (2012), pp. 216–221 5. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, Groen HJ, McRae SE, Widder J, Feng L, van den Borne BE, Munsell MF, Hurkmans C, Berry DA, van Werkhoven E, Kresl JJ, Dingemans AM, Dawood O, Haasbeek CJ, Carpenter LS, De Jaeger K, Komaki R, Slotman BJ, Smit EF, Roth JA. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015 Jun;16(6):630-7. 6. Palma D, Lagerwaard F, Rodrigues G, Haasbeek C, Senan S. Curative treatment of Stage I non-small-cell lung cancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review. Int J Radiat Oncol Biol Phys. 2012 Mar 1;82(3):1149-56. 7. Louie AV, Rodrigues G, Hannouf M, Zaric GS, Palma DA, Cao JQ, Yaremko BP, Malthaner R, Mocanu JD. Stereotactic body radiotherapy versus surgery for medically operable Stage I non-small-cell lung cancer: a Markov model-based decision analysis. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):964-73

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      MS10.07 - Biomarkers: Current Status and Future Direction (ID 1895)

      14:15 - 15:45  |  Author(s): R. Young

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The need for biomarkers Yearly low-dose computed tomography (CT) screening for lung cancer is now widely recommended in the United States.[1] Published articles reviewing the benefits versus harms of lung cancer screening have highlighted the potential harms from radiation exposure, unnecessary invasive workup and overdiagnosis.[2] While cost-effectiveness analysis has suggested that CT screening for lung cancer is comparable to other existing cancer screening programs, this analysis makes a number of assumptions based on the NLST findings which may not translate to the wider community. These issues highlight the need for identifying biomarkers that may improve patient selection, maximise lung cancer detection, minimizing overdiagnosis and the treatment of indolent disease.[2] The eligibility criteria for the NLST were specifically designed to maximize the number of cancers that could be identified during screening within a relatively high risk group. However, it has been shown that age and pack years alone have only limited utility in identifying those smokers at greatest risk.[3-5] It was never intended that screening eligibility should be based solely on the NLST criteria. The first problem is the NLST screening criteria include low risk individuals for whom the risk of screening far outweighs the benefit.[3-5] The second problem is that between 40-60% of lung cancer cases are currently ineligible for lung cancer screening due to restrictions on age and smoking history.[6,7] The former group is estimated to represent about 30-40% of those currently eligible for screening based on the NLST and can be identified using multivariate risk models incorporating several clinical risk variables such as age, detailed smoking history, past diagnosis of COPD, BMI, occupation and ethnicity.[4] Lung Function and related tests of COPD There have been several studies that show lung function testing adds considerable predictive utility to clinical multivariate models. This approach stratifies smokers with normal lung function (no airflow limitation and/or DLCO reduction) into a low risk group, where it has been shown their lung cancer incidence is only a quarter of that observed in those with COPD.[8] Emphysema identified on CT has also been shown to identify high risk smokers for lung cancer where airflow limitation is absent.[9] These studies confirm past epidemiology identifying that co-existing COPD, characterized by reductions in forced expiratory volume (and its ratio with forced vital capacity) are significant risk factors for lung cancer. Genetic Markers A limited number of studies have found that genetic markers, primarily single nucleotide polymorphic (SNP) variants, add to the predictive utility of clinically-based risk tests.[10 ]These SNP markers reside in genes encoding several important proteins, including epithelial based receptors, involved in mediating smoking-related inflammation in the lungs.[10 ]The value of identifying these genetic markers lies in their predictive utility to recognize high risk individuals long before the clinical manifestations of smoking damage (airflow limitation or emphysema) are clinically evident. The addition of SNP modestly increases the sensitivity and specificity of the risk models which use clinical variables alone. More importantly, the addition of these markers improves the correct assignment of risk in up to 25-30% of people participating in lung cancer screening trials. Other Molecular Biomarkers Other molecular markers for lung cancer currently under investigation are protein markers, antibody assays and expression (RNA) profiles.[11-14] These types of assay are potentially subject to biological interference from smoking status (eg. current vs ex-smokers) or co-existing COPD, where drug therapies (eg. inhaled corticosteroids or antibiotics) and bacterial colonisation of the lung (eg. effects from the lung microbiome) are present. The “noise” from these co-existing conditions may cause confounding or mediating effects that reduce the predictive utility of the assay of interest. One of the more promising of these biological assays involves the analysis of exhaled volatile compounds from the lung which can now be measured with more accurate devices.[14] These molecular assays are currently being validated in large prospective clinical trials. Biomarkers in CT screening – risk assessment While the utility of these assays in the context of CT screening remains to be established, they all have the potential to improve the current risk-benefit ratio of CT screening. First, this might involve identifying low risk individuals currently eligible for screening based on the age and pack year criteria (“NLST approach”) but who gain little benefit from screening. Alternatively, wider risk assessment would help identify those smokers who are at high risk despite not meeting the NLST criteria (“NCCN approach”). In this setting, markers related to a predisposition to COPD, such as airflow limitation based on spirometry, reduced DLCO (as a marker of emphysema and interstitial lung disease) or CT-based emphysema, are particularly relevant. Genetic (SNP) markers associated with an increased predisposition to COPD or lung cancer may also help in this regard.[10] Second, expression-based markers may be helpful in distinguishing benign from malignant nodules. With time, greater refinement of these techniques for identifying and validating novel biomarkers will provide greater confidence in their use in conjunction with serial CT screening. This approach might augment existing risk models based on clinical parameters. However, these biomarkers are competing with serial CT -based volumetric analyses which appears on initial studies to considerably reduce the false positive rate (discriminate benign from malignant based on growth rate). These novel biomarkers would be combined with multivariate risk models to reduce the treatment of indolent nodules, reducing overdiagnosis and minimize harm. In a recent post-hoc analysis of the NLST-ACRIN data, we found that airflow limitation based on pre-bronchodilator spirometry is associated with little if any overdiagnosis. This finding is consistent with the results of others showing COPD to be associated with more aggressive lung cancer. Other biomarkers may have a similar utility. Biomarkers in CT screening – smoking cessation Smoking cessation is the only proven lifestyle modification that reduces the risk of lung cancer. Little thought is given to the use of biomarkers in smoking cessation. In a limited number of studies it has been shown that risk assessment tools have some contribution to make to smoking cessation.[15] Inconsistency of findings with respect to the effects of lung function testing and CT nodule identification on quit rates means there is more work to be done here. The basic psychology of smoking suggests that challenging some smokers with personal biodata enhances their perception of smoking-related risks. In particular, showing a smoker they are at greater risk than the average smoker based on personal data increases their interest in quitting.[15] This is believed to occur because personal biodata increases motivational tension and undermines the smoker’s denial which maintains their smoking habit. This aspect of CT screening programmes is not one that has received as much attention as it warrants. However CT screening programmes, with routine use of personalised risk appraisal, are uniquely positioned to reinforce existing public health strategies aimed at reducing smoking rates. Summary While there remains much to do to confirm the utility of biomarkers in the CT screening process , existing data suggests that significant gains may be made by their use in improving risk-benefit appraisal of screening participants, better management of nodules and perhaps significant gains in reducing smoking rates among high risk smokers. References 1. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, et al. Benefits and harms of CT screening for lung cancer: A systematic review. JAMA 2012; 307(22):2418-29. 2. Humphrey LL, Deffebach M, Pappas M, Baumann C, Artis K, Mitchell JP, et al. Screening for lung cancer with low-dose computed tomography: a systematic review to update the US Preventive Services Task Force recommendation. Ann Int Med 2013; 159(6):411-20. 3. Bach PB, Gould MK. When the average applies to no one: personalized decision making about potential benefits of lung cancer screening. Ann Int Med 2012, August 14. 4. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung cancer death. N Eng J Med 2013; 369: 245-254 5. Young RP, Hopkins RJ, MidthunDE. Benefits and harms of CT screening for lung cancer: A systematic review – Letter. JAMA 2012; 308: 1320-1321. 6. Young RP, Hopkins RJ. Lung cancer risk prediction to select smokers for screening. Cancer Prev Res 2012; 5: 697-698. 7. Wang Y, MidthunDE, Wampfler JA, et al. Trends in the proportion of patients with lung cancer meeting screening criteria. JAMA 2015; 313: 853-855. 8. Young RP, Hopkins RJ. Diagnosing COPD and targeting lung cancer screening. Eur Respir J 2012; 140: 1063-1064. 9. Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med 2008; 178: 738-744. 10. Young RP, Hopkins RJ, Whittington CF, Hay BA, Epton MJ, Gamble GD. Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD. Plos One 2011; 6: e16476. 11. Silvetsri GA, Vachani A, Whitney, D, et al. A bronchial genomic classifier for the diagnostic evaluation of lung cancer. N Eng J Med 2015; May 17. 12. Hassanein M, Rahman JSM, Chaurand P, Massion P. Advances in proteomic strategies towards the early detection of lung cancer. Proc Am Thorac Soc 2011; 8: 183-188. 13. Healey GF, Lam S, Boyle P, et al. Signal stratification of autoantibody levels in serum samples and its applications to the early detection of lung cancer. J Thorac Dis 2013; 5: 618-625. 14. Dent AG, Sutedja, Zimmerman PV. Exhaled breath analysis for lung cancer. J Thorac Dis 2013; 5: S540-S550. 15. Young RP, Hopkins RJ. Genetic susceptibility testing to lung cancer and outcomes in smokers. Tob Control 2012; 21: 347-354.

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    MS 12 - NSCLC Stems Cells: Are They a Real Target? (ID 30)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 4
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      MS12.01 - Biology of Cancer Stem Cells (ID 1900)

      14:15 - 15:45  |  Author(s): N. Watkins

      • Abstract
      • Presentation

      Abstract:
      There is general agreement amongst biomedical researchers that stem cells exist in multicellular organisms. The most well characterized model of adult somatic stem cells is the bone marrow, in which serial transplantation in both immunocompetent and immunodeficient mice have clearly identified the hematopoietic stem cell (HSC). Using the same models, it is now generally accepted, even amongst cancer stem cell (CSC) sceptics, that most forms of myeloid leukemia are maintained by a self-renewing, transplantable HSC-like cell, even though the initial transformation event may have occurred in a committed progenitor. Given that nature tends to conserve processes across evolution, it is logical to hypothesize that a similar functional hierarchy exists in solid tumors. Over two decades, numerous papers have reported the presence of a functionally distinct, rare population of cells within solid tumors with stem-like properties based on the same criteria used to define the HSC and leukemic CSC. However, the idea that CSCs exist solid tumors remains controversial at best. The difficulties in reproducing results in highly complex models systems, and questions over the validity of CSC surface markers in solid tumors, have clearly contributed to these, often heated, arguments. If we assume for a moment that CSCs do not exist in solid tumors, they would constitute the only multicellular entity in nature without a hierarchical organisation based on self-renewal and differentiation. If this were true, then solid tumors would behave like colonies of bacteria or yeast, in which all cells were identical, where the capacity to self-renew in the face of an environmental challenge would be entirely determined by random genetic variants. In the setting of acquired resistance to targeted therapies, there is convincing evidence for such a “rare clone” hypothesis. For example, the source of acquired resistance to tyrosine kinase inhibitor (TKI) therapy in EGRF-mutant adenocarcinoma seems to be pre-existing clones that already possess a point mutation that confers resistance. But, can this genetic model explain other stemness phenotypes in non-small cell lung cancer (NSCLC)? In clinical terms, a pressing question is whether random genetic events can explain the rapid regeneration of NSCLC tumors after a long period of dormancy following curative surgery. Equally, can the “rare clone” hypothesis explain innate the innate chemoresistance of quiescent CSC-like NSCLC cells that have a greatly enhanced capacity for self-renewal. If the answer to either of questions is “not always”, then targeting CSCs based on function rather than genome remains a potential avenue for improving outcomes in NSCLC patients. The characterization of NSCLC CSCs is made difficult by the phenotypic and genomic heterogeneity of the disease, problems identifying robust surface markers, and in defining what experimental endpoints constitute CSC function. In addition, there is no general agreement on which markers are associated with CSC in NSCLC, although several studies suggest that the surface markers CD44 and CD133 can prospectively identify such cells. In therapeutic terms, elimination of CSCs in NSCLC would require such markers be reproducible and robust, but can also be therapeutically targeted in humans. An alternative approach is to target embryonic signaling pathways known to regulate self-renewal in development. This idea is the driving force behind clinical trials of Notch and Hedgehog inhibitors in several cancer types. Unfortunately, most of these clinical trials add the experimental agent along side standard-of-care chemotherapy rather than delivering the experimental agent following treatment in order to determine whether stem-cell targeting can “burn out” quiescent, undifferentiated residual disease. One promising candidate marker in NSCLC is ALDH1. In most published studies, expression of ALDH1 or ALDH1A correlates with reduced overall survival, consistent with the presence of enhanced regenerative capacity and innate chemoresistance in NSCLC. Moreover, experimental evidence supports the notion that expression of the ALDH1 protein, and its enzymatic activity, is associated with enhanced CSC functions in vitro and in vivo. Since secondary prevention studies in advanced NSCLC are impractical, it may be possible strengthen the case for targeting NSCLC, using ALDH1 as an example, using more practical preclinical and clinical approaches. Such an approach might be: 1. Concentrate on one subgroup of NSCLC- for example KRAS mutant lung adenocarcinoma. 2. Show that rare, single ALDH1+ cells give rise to tumors with the same ratio of ALDH1+ to ALDH1- cells as was seen in the parent tumor. 3. Using single cell genomics, determine whether ALDH1+ and ALDH1- cells share the same genotype. 4. In lung cancer patients treated with neoadjuvant chemotherapy, show that the percentage of ALDH1+ cells increases in the residual tumor removed at surgery. 5. In lung cancer patients with recurrent disease following surgery, show that the recurrent tumor contains the same ratio of ALDH1+ to ALDH1- cells as was seen in the parent tumor. References: Jordan CT. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell, 2009; 4:203-5. Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN. Cancer stem cells in lung cancer: Evidence and controversies. Respirology, 2013; 18:757-764 Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, Schuster K, Shao C, Larsen JE, Sullivan LA, Honorio S, Xie Y, Scaglioni PP, DiMaio JM, Gazdar AF, Shay J, Wistuba II, Minna JD. Aldehyde Dehydrogenase Activity Selects for Lung Adenocarcinoma Stem Cells Dependent on Notch Signaling. Cancer Res, 2010; 70:9937-48. Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, Behrens C, Shay JW, Wistuba II, Minna JD. Essential Role of Aldehyde Dehydrogenase 1A3 for the Maintenance of Non–Small Cell Lung Cancer Stem Cells Is Associated with the STAT3 Pathway. Clin Cancer Res; 2014; 20:4154–66. Alamgeer M, Ganju V, Szczepny A, Russell PA, Prodanovic Z, Kumar B, Wainer Z, Brown T, Schneider-Kosky M, Conron M, Wright G, Watkins DN. The prognostic significance of ALDEHYDE DEHYDROGENASE 1A1 (ALDH1A1) and CD133 expression in early-stage non-small cell lung cancer. Thorax, 2013; 68(12):1095-104. Alamgeer M, Ganju V, Kumar B, Fox J, Hart S, White M, Harris M, Stuckey J, Prodanovic Z, Schneider M, Watkins DN. Changes in ALDEHYDE DEHYDROGENASE-1 (ALDH1) expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer. Breast Cancer Res, 2014; 16:R44.

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      MS12.02 - Current Therapeutic Targets and Ongoing Trials (ID 1901)

      14:15 - 15:45  |  Author(s): M. Diehn

      • Abstract
      • Presentation

      Abstract not provided

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      MS12.03 - Where to Go from Here? (ID 1902)

      14:15 - 15:45  |  Author(s): R. Rosell, J. Codony, I. Chaib, C. Codony, S. Pilotto, A. Verlicchi, J.L. Ramírez-Serrano, N. Karachaliou, M.A. Molina-Vila, T. Bivona, P.C. Ma

      • Abstract
      • Slides

      Abstract:
      Lung cancer is a dismal disease, however, anticipated selective responses are observed in a subgroup of non-small cell lung cancer (NSCLC) patients where the disease is driven by epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 15 – 40% of lung adenocarcinomas, according to gender, smoking history and geographical region. Two types of EGFR mutations account for 90% of all lung adenocarcinoma-associated EGFR mutations and are related to sensitivity to treatment with oral tyrosine kinase inhibitors (TKIs), such as gefitinib, afatinib or AZD9291: (i) small in-frame deletions in exon 19 that lead to elimination of an LREA motif in the protein (DEL) and (ii) a point mutation in exon 21 that substitutes an arginine for a leucine at position 858 in the protein (L858R). Lung cancer patients bearing EGFR mutations show radiographic responses to TKIs in 60 – 70% of cases. Although the majority of patients achieve a significant therapeutic benefit, almost all invariably progress in less than 1 year. Therefore there is an unmet medical need for novel therapies in order to avoid resistance to treatment. We have employed a wide array of approaches (MTT, western blot analysis, PCR, Aldefluor assay and mouse models) to demonstrate that the combination of gefitinib, afatinib or AZD9291 with compounds targeting signal transducer and activator of transcription 3 (STAT3) can suppress the mechanisms of early adaptive resistance. STAT3 is a member of a family of proteins responsible for transmission of peptide hormone signals from the extracellular surface of the cells to the nucleus. STAT3 is a master regulator of several key hallmarks and enablers of cancer cells, including cell proliferation, resistance to apoptosis, metastasis, immune evasion, tumor angiogenesis, epithelial-mesenchymal transition, response to DNA damage and the Warburg effect. In addition STAT3 promotes an increase in the cell renewal of tumor-initiating cells or cancer stem cell subpopulation, mainly aldehyde dehydrogenase (ALDH). EGFR mutations cause receptor oligomerization and activation of intrinsic or receptor-associated tyrosine kinases, respectively. These activated kinases phosphorylate receptor tyrosine residues creating docking sites for recruitment of cytoplasmic STAT3. STAT3 docks to receptor phosphotyrosyl (pY) peptide sites through its Src-homology (SH2) domain which leads to its phosphorylation on Y705 followed by STAT3 tail-to-tail homodimerization (SH2 domain of each monomer binds to the pY peptide domain of each partner). STAT3 homodimers accommodate in the nucleus, where they bind to specific STAT3 response elements in the promotor of target genes and regulate their transcription. EGFR mutations and tyrosine kinase-associated receptor interleukin-6 (IL-6) lead to the activation of STAT3 that is not obliterated by EGFR TKIs. Even more, 2 hours after starting gefitinib treatment there is an increase in STAT3 activation in EGFR mutant cell lines (P. Ma, Cancer Research, 2011). Moreover, following erlotinib treatment there is an enrichment of ALDH+ stem-like cells through EGFR-dependent activation of Notch3. We have tested several small molecules that target STAT3. The combination inhibits cell viability in several human EGFR mutant cells and blocks STAT3 activation. However, neither the combination of EGFR TKIs with TPCA1 (repurposed as a STAT3 inhibitor), nor the combination of gefitinib with AZD0530 (a Src inhibitor) prevent the increment in the ALDH + cancer stem cell subpopulation. Therefore, we are exploring more in depth the crosstalk between EGFR and IL-6. As a whole, human EGFR mutant cell lines have increased levels of IL-6 which leads to STAT3 hyper-activation. Nevertheless, recent evidence indicates that IL-6-Src can induce YAP activation and NOTCH signaling. The downstream effectors of YAP and NOTCH ligands CTGF and HES1, respectively, are being examined in clinical tumor samples. We have examined the combination of Src, YAP and NOTCH inhibitors in addition to the use of STAT3 inhibitors. The triple combination of gefitinib plus TPCA1 plus AZD0530 had great synergism with a very low combination index and also eliminated the ALDH+ population (Figure). Furthermore, the overexpression of ALDH1A1 was decreased with the triple combination, however with only gefitinib plus TPCA1 or gefitinib plus AZD0530, ALDH1A1 mRNA was substantially increased in comparison with gefitinib alone (Figure). The western blot for the triple combination shows the inhibition of STAT3 Y705 phosphorylation as well as the phosphorylation of YAP (Ser397) and also from BMI1. We plan to confirm some of the data in clinical tumor samples to understand the contribution of IL6 and well established effectors-the SHP2-ERK, PI(3)K-Akt-mTORC1 and JAK-STAT3 modules and the interaction with YAP. Figure 1



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      MS12.04 - Tumor-Propagating Cells in Non-Small Cell Lung Cancers (ID 1903)

      14:15 - 15:45  |  Author(s): C. Kim

      • Abstract
      • Presentation

      Abstract:
      Our long-term goal is to elucidate the role of stem cells in lung homeostasis as a prerequisite to the development of therapeutic strategies that can be used to prevent or attenuate lung disease and lung cancer. Our previous experience isolating the first stem cell population from the adult murine lung, termedbronchioalveolar stem cells (BASCs), and our demonstration of a role for these cells in lung cancer serves as a platform to address these questions. We have recently developed three-dimensional co-culture and subcutaneous co-injection assays that allow us to quantitatively assess the identity and the differentiation potential of lung stem cells. This approach led us to uncover a cross-talk between lung endothelial cells and lung stem cells via a novel signaling axis involving Bmp4, NFATc1 and Tsp1;this pathway drives BASCs to differentiate into the alveolar epithelial cell lineage. Our work in the intersection of stem cell biology and lung disease has expanded into new insights for understanding metastasis and non-small cell lung cancer (NSCLC). We previously showed the adenocarcinoma Kras/p53 mutant mouse model contains Sca1+ tumor-propagating cells (TPCs), the cells that recapitulate the tumor by transplantation. We recently showed multiple lung tumor sub-populations can give rise to metastatic disease, and that the Sca1+ CD24+ TPCs have the highest metastatic potential. We also showed the Hippo pathway mediators Yap/Taz are necessary andsufficient for lung cancer progression. Finally, in a new mouse model of lung squamous cancer, the second most common type of NSCLC, we identified a TPC population defined by the markers Sca1 and NGFR. These studies illustrate the utility of stem cell biology approaches to provide new avenues for lung cancer therapeutic targeting.

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    MS 26 - Genomic Alterations and Drug Targets in Small Cell Lung Cancer (ID 44)

    • Event: WCLC 2015
    • Type: Mini Symposium
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 5
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      MS26.01 - Genomic Alterations (ID 1963)

      14:15 - 15:45  |  Author(s): J.C. Yang

      • Abstract
      • Presentation

      Abstract:
      Genomic Alterations and Drug Targets in Small Cell Lung Cancer Over the past 15 years, we have made a lot of advances in the treatment of non small cell lung cancer (NSCLC). However, the treatment paradigm for small cell lung cancer (SCLC) remains the same as 30 years ago, e.g., concurrent chemoradiotherapy for limited stage SCLC and chemotherapy for extensive stage SCLC. The successful introduction of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of lung cancer patients has helped us understand the underlying genomic alterations in responding patients and the biology of tumor cells harboring EGFR mutations. In contrast to the successful story of EGFR TKIs in NSCLC treatment leading to the discovery of EGFR mutations in responding patients, the discovery of EML4-ALK fusion in NSCLC has led to the successful treatment of crizotinib in patients harboring this mutation. Crizotinib was designed to inhibit cMET but was developed successfully as an ALK inhibitor for those patients. Further genomic analysis of lung adenocarcinoma patients disclosed that some specific recurrent mutations in EGFR, HER2, KRAS, NRAS, BRAF, cMET, EML4-ALK, ROS1, RET fusions etc. were found in patients. However, each patient only harbored one mutation. Specific inhibitors are very effective in the treatment of lung adenocarcinoma patients harboring corresponding targeted mutations. Thus, driver mutation or oncogene addiction hypothesis was built through genomic analysis of lung adenocarcinoma patients and clinical observations of successful targeted therapy treatment. Several targeted therapies have been tested in a small scale of advanced stage SCLC patients. None of the studies showed any signal of anticancer activity in years. Thus, radiotherapy and chemotherapy remain the effective treatment for SCLC. Current technique allowed us to examine cancer genome in detail. The information can be used to predict clinical usage of certain targeted therapy. Genomic analysis of SCLC may open a door for us to understand the basic differences between NSCLC and SCLC and ponder the ineffectiveness of targeted therapy in SCLC. Genomic alterations of SCLC cells were first described in 1980s by observation of chromosome aberrations. Frequent deletion of 3p was first observed by Peng-Whang J et al. The most frequent reported genetic alterations in SCLC cells were inactivting mutations of TP53, RB1, PTEN, mutations in PIK3CA, EGFR and KRAS, amplification of myc family, EGFR and BCL2 as well as loss of RASSF1A, PTEN and FHIT. Those genomic alterations were examined through small series of samples and target gene examinations. Systemic approach to explore the multitude and magnitude of genomic alterations in SCLC was only possible with recent next generation sequencing technology and the application of bioinformatics to analyze the vast amount of data generated from the samples. Rudin et al. have collected 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines and examined the exome, transcriptome and copy number alterations. In 4 primary tumors and 23 SCLC cell lines, the authors identified 22 significant mutated genes. In the exome of 42 SCLC tumor normal tissue pairs, they identified 26406 somatic mutations. 30% of them resulted in protein alterations. An average of 175 protein-altering single nucleotide variants was calculated per patient. G-to-T transversions were the predominant mutation, followed by G-to-A and A-to-G transition mutations signify that these mutations were related to tobacco smoke carcinogens. In the whole genome analysis of one patient, 286 protein-altering changes were found. Frequent altered genes included genes encoding for kinases, G-protein-coupled receptors and chromatin-modifying proteins. The authors found that SOX2 mutation or amplification was frequently found in its series. SOX2 expression may play some crucial roles in SCLC cells, such as maintenance of pluripotency of stem cells property. In addition, the authors also discovered several non-recurrent fusion genes from RNA-seq data. The roles of these fusion proteins in SCLC are less well understood. But some of those fusion proteins seem to result in activating kinases. Peifer M et al. sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes. They discovered inactivation of TP53, RB1 and recurrent mutations in CREBBP, EP300 and MLL genes. Additional findings included mutations in PTEN, SLIT2, EPHA7 and FGFR1 amplification. They concluded that histone modification is a major feature of SCLC. Both comprehensive genomic studies disclosed similar gene alterations such as TP53 and RB1 are the important signatures of SCLC genomic alterations. However, an individual analysis pointed out at different angles, for example, SOX2 or histone modification. The different results of two series reflected that only a limited number of samples were tested, interpatient heterogeneity may be huge and more genomic studies should be performed in the future. When major genomic alterations were compared among lung adenocarcinoma, squamous cell carcinoma and SCLC, alterations of TP53, CDKN2A, PIK3CA and PTEN were commonly found in all three types of lung cancer. FGFR1 and SOX2 alterations were found in SCLC and squamous cell carcinoma, whereas KEAP1 alterations was detected in both squamous cell carcinoma and adenocarcinoma. Recently, transformation from adenocarcinoma to SCLC was detected in a minority of patients with EGFR mutations who have received EGFR TKIs and developed resistance. Typical EGFR mutations can be found in untreated SCLC patients, especially in east Asian ethnic patients. Occasionally mixed SCLC and adenocarcinoma were described under light microscopy. Some of those patients harbor EGFR mutations. Unfortunately, EGFR TKI was usually not effective in the treatment of such patients, it suggested that alterations of the transcriptional factors contributed SCLC phenotype being more dominant and only chemotherapy was effective to control the progression of the disease. The heterogeneous nature of genomic alterations in SCLC suggested that targeted therapy may be difficult to be successful in SCLC treatment. None of the altered genes seems to be the dominant driver. On the other hand, RB1 and myc, genes altered easily that are not the good targets for current targeted therapy. Thus, genomic analysis of SCLC further indicated that the combination of targeted therapy may not be useful. It may have to combine targeted therapy and chemotherapy to obtain better anti-cancer activity. However, patient selection may be needed according to the genomic findings and pathway predictions. The hyper mutational genomic background was a good predictor for immune checkpoint inhibitor therapy. However, in a recent report in American Society of Clinical Oncology Meeting suggested that only a low response rate was noted in SCLC treated with immune checkpoint inhibitors. More genomic, immune studies and clinical trials are needed to advance the treatment of SCLC in the future.

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      MS26.02 - The MYC/MAX and the SWI/SNF Networks: Biological Understanding and Therapeutic Applications (ID 1964)

      14:15 - 15:45  |  Author(s): M. Sanchez-cespedes

      • Abstract
      • Presentation

      Abstract:
      The SWI/SNF chromatin-remodeling complex modifies the structure of the chromatin by the ATP-dependent disruption of DNA–histone interactions at the nucleosomes to activate or repress gene expression. The widespread occurrence of alterations at genes encoding different components of the SWI/SNF complex reveals an important new feature that sustains cancer development and offers novel potential strategies for cancer therapeutics. We discovered that in lung cancer the SWI/SNF component, BRG1 (also called SMARCA4), is genetically inactivated in about thirty per cent of non-small cell lung cancers (NSCLC), and that its inactivation occurs in a background of wild type MYC (either C, L or N). Here, we also report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in about ten percent of small cell lung cancers (SCLC). This is mutually exclusive with alterations at MYC and BRG1. We also demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to up-regulate MYC-targets, such as glycolytic-related genes. Finally, we observed genetic inactivation of the MAX dimerization protein, MGA, in lung cancers with wild type components of the SWI/SNF or MYC pathways. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development. Altogether, the genetic observations coupled with the functional evidence demonstrate that an aberrant SWI/SNF-MYC network is essential for lung cancer development, and opens novel therapeutic possibilities for the treatment of SCLC patients with MAX-deficient tumors. In healthy adults and during embryonic development, the complex is involved in the control of cell differentiation and in the specification of different tissues. The effect of the SWI/SNF complex on some of these processes is, at least in part, related to its involvement in regulating hormone-responsive promoters. Components of the SWI/SNF complex bind to various nuclear receptors, such as those of estrogen, progesterone, androgen, glucocorticoids and retinoic acid, thereby adapting the gene expression programs to the demands of the cell environmental requirements. Retinoic acid (RA) and glucorticoids (GC) are well known modulators of cell differentiation, embryonic development and morphogenesis. Their role in promoting cell differentiation makes it possible to use GC and RA therapeutically to treat some types of cancers. GC are part of the curative treatment of acute lymphoblastic leukemia while RA is the therapeutic agent for some neuroblastomas and acute promyelocytic leukemia, which both carry the PML–RARa gene fusion. GC are also used as a co-medication in the therapy of solid tumors, because of their effectiveness in treating the malignancy, or due to their less severe side effects in cancer treatment, such as electrolyte imbalance, nausea and emesis. However, most solid tumors, including lung cancers, are refractory to GC- and RA-based therapies. Underlying some cases of refractoriness to GC and RA is a dysfunctional SWI/SNF complex, for example due to alterations at BRG1. On the other hand, compounds that modulate the structure of the chromatin are currently used to treat cancer. These include histone deacetylase (HDAC) inhibitors, in hematological malignancies and cutaneous T-cell lymphomas, and inhibitors of DNA methylation such as azacytidine for myelodysplasic syndrome. HDACs and DNA methylation inhibitors promote gene transcription by increasing DNA accessibility through the inhibition of histone deacetylation and DNA methylation, respectively. These drugs have been tested in lung cancer patients in two studies, in which they showed no major responses. However, in a phase I/II trial, the combination of the two inhibitors produced a median survival of the entire cohort that was significantly longer than those of the existing therapeutic options. Here, we aimed to determine whether there could be a therapeutic use for GC plus RA (GC/RA) in combination with the epigenetic drugs azacytidine and SAHA (A/S) for treating lung cancers carrying BRG1 inactivation or MYC amplification. We found that in vitro, GC/RA treatment reduced growth, triggered pro-differentiation gene expression signatures and downregulated MYC, in MYC-amplified but not in most BRG1-mutant lung cancer cells. The co-administration of A/S enhanced all these effects, accompanied by sustained reductions in genome-wide DNA methylation. In vivo, treatments with GC/RA improved overall survival of mice implanted with MYC-amplified cells and reduced tumor-cell viability and cell proliferation. Thus, we propose that the combination of retinoids, corticoids and epigenetic treatments of lung tumors with MYC amplification constitute a strategy for therapeutic intervention in this otherwise incurable disease. REFERENCES Collins SJ. The role of retinoids and retinoic acid receptors in normal hematopoiesis. Leukemia 2002; 16, 1896–905. Liu SV, Fabbri M, Gitlitz BJ, Laird-Offringa IA. Epigenetic therapy in lung cancer. Front Oncol 2013; 3, 135. Medina PP et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mut 2008; 29, 617-22a. Pottier N et al. The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia. J Natl Cancer Inst 2008; 100, 1792-803. Rodriguez-Nieto S et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mut 2011; 32, E1999-2017. Romero OA et al. The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med 2012; 4, 603-16. Romero OA et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov 2014; 4, 292-303. Romero OA, Sanchez-Cespedes M. The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases. Oncogene 2014; 33, 2681-9. Rutz HP. Effects of corticosteroid use on treatment of solid tumours. Lancet 2002; 360, 1969–70. Wilson GB,Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11, 481-92.

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      MS26.03 - Targeting ASCL1 in Neuroendocrine Lung Cancers via a MAPK-Regulated Double-Negative Feedback Loop (ID 1965)

      14:15 - 15:45  |  Author(s): J. Minna, A. Augustyn, S. Earnest, P. Dospoy, J. Johnson, M. Cobb

      • Abstract
      • Presentation

      Abstract:
      ASCL1 is a lineage-specific transcription factor responsible during development for the formation of pulmonary neuroendocrine cells. ASCL1 is highly expressed in the majority of neuroendocrine lung tumors including small cell lung cancer (SCLC) and non-small cell lung cancer with neuroendocrine features (NSCLC-NE). Others have shown that SCLC survival depends on continued ASCL1 expression while we showed that ASCL1 is also required for the survival of NSCLC-NEs; that ASCL1 down-stream targets predict for poor survival in NSCLC patients; and that BCL2 is a therapeutically actionable ASCL1 target gene (PNAS 2014;111(41):14788-93). Thus, we are trying to target ASCL1 and its “druggable” downstream genes by developing ASCL1 based ChIP-Seq datasets in SCLC and NSCLC-NE tumors. We have now discovered a way to reliably regulate ASCL1 protein expression through “upstream” targeting. Phorbol 12-myristate 13-acetate (PMA) is an agonist of the MAPK pathway via specific activation of Protein Kinase C. Treatment of ASCL1(+) HCC1833 cells for 24 hours with nM quantities of PMA resulted in a robust down-regulation of ASCL1 mRNA and protein. Tumor cell death was apparent and apoptosis confirmed via induction of cleaved PARP. ASCL1 down-regulation was associated with activation of the MAPK pathway, measured by increased protein levels of phosphorylated ERK (pERK), and decreased ASCL1 mRNA expression was found to be at least partly due to mRNA degradation. These data indicate that activation of the MAPK pathway in high-grade neuroendocrine tumors has potential for therapeutic intervention and also provides a reason for the previously unexplained low levels of MAPK activation (pERK) in SCLC. Unexpectedly, we also found that siRNA mediated knockdown of ASCL1 resulted in activation of the MAPK pathway. In addition, pERK was significantly induced with ASCL1 knockdown even when we also knocked down MEK1 (MEK1 knockdown by itself completely eliminated pERK expression). The MAPK pathway depends on active phosphorylation/dephosphorylation and this is regulated in part by dual-specificity phosphatases (DUSPs). Using our ASCL1 ChIP-Seq data, we identified a conserved ASCL1 binding site in the promoter region of DUSP6. DUSP6 mRNA was found to be dramatically elevated in ASCL1(+) lines HCC1833 and H889, while by contrast there was little or no DUSP6 expression in ASCL1(-) SCLC lines H82 and H526, and knockdown of ASCL1 resulted in a decrease of DUSP6 protein suggesting transcriptional regulation. This led us to try a DUSP6 allosteric inhibitor (E/Z-BCI, Sigma-Aldrich) which induced pERK, decreased ASCL1 protein expression, and inhibited soft agar colony forming ability of H889 SCLC cells. In conclusion: Our data indicate that the MAPK pathway regulates ASCL1 expression, where activation of pERK signaling is correlated with decreased ASCL1 mRNA and protein. In addition, ASCL1 in turn, actively down-regulates the MAPK pathway. Our hypothesis is that high-grade neuroendocrine lung cancers down-regulate the MAPK pathway in order to maintain ASCL1 expression, which promotes cell survival and maintenance of the neuroendocrine lineage. This points to a double-negative feedback loop involving the MAPK pathway, ASCL1, and at least one DUSP. Targeting components of the MAPK pathway regulating ASCL1 expression is thus a new therapeutic avenue for high-grade neuroendocrine lung cancers. (Lung Cancer SPORE P50CA70907, NIH 1F30CA168264, CPRIT).

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      MS26.04 - FGFR1 Co-Activation Networks in Lung Cancer (ID 1966)

      14:15 - 15:45  |  Author(s): L. Heasley

      • Abstract
      • Presentation
      • Slides

      Abstract:
      FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of FGFR-specific and selective tyrosine kinase inhibitors (TKIs) are underway. Our recent studies have demonstrated a role for unmutated FGFR1 as a driver in lung cancer cell lines of all histologies including small cell lung cancers (SCLCs), head and neck squamous cell carcinomas (HNSCCs) and mesotheliomas. Although potent in vitro growth suppression of lung cancer cell lines is observed in response to multikinase inhibitors such as ponatinib as well as FGFR-specific TKIs (AZD4547, BGJ398), the in vivo inhibitory effects of these drugs on xenografts propagated in immune deficient mice are more modest and short-lived in our hands. Thus, while treatment with single FGFR TKIs represents a logical entry point to personalized therapy of cancers bearing over-expressed FGFR1, we hypothesize that intrinsic mechanisms involving rapid kinome reprogramming events limit the therapeutic efficacy of these TKIs. In fact, ample precedent exists to support the signaling of receptor tyrosine kinases (RTKs) within "co-activation networks" where multiple RTKs engage multiple signal pathways to bring about robust and flexible activation of signal cascades. We deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and HNSCC cells to ponatinib, a multi-kinase FGFR-active inhibitor. Mammalian Target of Rapamycin (MTOR) was identified and validated as a synthetic lethal kinase with ponatinib in H157 and H1299 cells. In other FGFR1-expressing cell lines (Colo699, H520 and H1703), MTOR was an essential protein kinase as evidenced by high sensitivity to MTOR-targeting shRNAs and pharmacological inhibitors. Despite wide ranging MTOR dependencies observed among the FGFR1-dependent cell lines, synergistic in vitro growth inhibition was a general observation when FGFR inhibitors where combined with pharmacological inhibitors of MTOR or AKT. At the molecular levels, FGFR inhibitors potently inhibited MEK/ERK activity while MTOR inhibitors reduced the activity of TORC1 (p70S6K, S6) and TORC2 (AKT Ser473)-specific targets. In combination, FGFR TKIs and MTOR inhibitors simultaneously eliminated MEK/ERK and MTOR signaling. Xenografts generated from the FGFR1-dependent lung cancer cell lines, Colo699 and H1581, exhibited only modest sensitivity to monotherapy with the FGFR-specific TKI, AZD4547. However, consistent with the in vitro findings, combination treatment with AZD4547 and the MTOR inhibitor, AZD2014, afforded significantly greater tumor growth inhibition and prolonged survival. The data support the existence of a signaling network wherein unmutated FGFR1 drives the ERK pathway and distinct receptors under investigation activate the MTOR/AKT pathway to induce full transformation. Combining MTOR inhibitors with FGFR-specific TKIs may yield greater clinical efficacy in FGFR1-driven lung cancers.

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      MS26.05 - Drug Screening Targets (ID 1967)

      14:15 - 15:45  |  Author(s): C. Lee Hann

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 30 - Community Practice (ID 141)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Community Practice
    • Presentations: 8
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      ORAL30.01 - Evolution in the Surgical Care of Non-Small Cell Lung Cancer (NSCLC) Patients in the Mid-South Quality of Surgical Resection (MS-QSR) Cohort (ID 2980)

      16:45 - 18:15  |  Author(s): X. Yu, E.T. Robbins, N. Faris, R.S. Signore, L. McHugh, R. Eke, M.P. Smeltzer, G. Relyea, C. Fehnel, N. Chakraborty, C. Houston-Harris, F. Lu, B. Wolf, C. Mutrie, L. Deese, E. Crocker, L. Wiggins, P. Levy, R.U. Osarogiagbon

      • Abstract
      • Presentation
      • Slides

      Background:
      Surgical resection is the most important curative modality for NSCLC. However, gaps in the quality of surgery adversely affect patients’ survival. In the Mid-South region, at the center of the US lung cancer mortality belt, we began a project in 2009 to improve the quality of surgery and pathology examination across all hospitals. We report the evolution of surgical quality in this region from 2004-2013.

      Methods:
      The MS-QSR database includes patient-level details from all NSCLC resections in 11 institutions in 5 Dartmouth Hospital Referral Regions in Eastern Arkansas, North Mississippi, and Western Tennessee. Data span the care delivery process from initial radiographic detection, through diagnostic and staging tests, to surgical treatment and post-operative outcomes. We performed trend analysis and comparisons among institutions.

      Results:
      There were 2,410 curative-intent NSCLC resections. Patient demographics, rates of non-invasive staging tests and pre-operative adjuvant therapy did not change. 92% of patients had a pre-operative CT, 80% had a PET-CT scan. The use of invasive staging tests (endobronchial ultrasound, mediastinoscopy, etc.) increased from 11.3% in 2009 to 22.3% in 2013 (p<0.001). The pneumonectomy rate decreased from 12% in 2004 to 6.2% in 2013 (p=0.05). The margin positivity rate remained stable at 5.8%. Stage distributions remained unchanged, with 63% stage I, 18% stage II, and 19% stage III or above. The total number of lymph nodes retrieved during resection remained unchanged until 2010 (median 4-5 from 2004 to 2010), after which, it increased significantly (median 7 in 2011, 9.5 in 2012, and 10 in 2013) (p<0.001) (figure 1). The mediastinal lymph node (MLN) examination rate increased from 53% in 2004 to 82% in 2013 (p<0.001). However, the rate of non-examination of lymph nodes (pNX) remained stable at 10%. Although the proportion of patients with N1 disease remained stable (17.6%), the proportion with N2 disease increased during a pilot testing phase with a MLN specimen collection kit implementation (10.8% in 2010 and 2011, and 7-8% in all other years). Finally, the re-hospitalization rate was 13.3%; the 60-day mortality rate was 6.4%. Figure 1



      Conclusion:
      In this population-based cohort, pre-operative and intraoperative nodal staging practice improved significantly. However, other quality measures (margin positivity and pNX rates) need further improvement. This early analysis suggests that a regional quality improvement project can improve overall patient survival in this high lung cancer mortality zone of the US.

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      ORAL30.02 - Treatment of Non-Small Cell Lung Cancer in Patients with a High Comorbidity Index (ID 496)

      16:45 - 18:15  |  Author(s): J. Rios, B. Huang, T. Tucker, J. Nee, M. Oechsli, C. Pinkston, G.H. Kloecker

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer has the highest cancer mortality. The life expectancy of untreated NSCLC is dismal, while treatment for NSCLC improves survival. However, the perceived outcome of NSCLC therapy in general is less favorable compared to other types of solid tumors. The presence of comorbidities is thought to play a significant role on the decision to treat or not-to-treat a given patient. We aimed to evaluate the impact of comorbidities on the survival of patients treated for NSCLC.

      Methods:
      As part of Kentucky's LEADS Collaborative, we identified NSCLC patients older than 65 years between 2007 and 2011 on the SEER Kentucky Cancer Registry (KCR). We linked the SEER KCR data with Medicare claims data for therapies provided (surgery, radiation, chemotherapy) for patients who had Medicare PART A and B coverage, had no HMO coverage 12 months prior to their cancer diagnosis, and had the lung cancer as the first primary cancer. Charlson comorbidity index (CCI) was assigned to each patient based on the linked Medicare data. Kaplan-Meier estimates were plotted. Log-Rank test was used to compare survival estimates. Data on age, sex, CCI, stage, and type of therapy received were included in univariate and multivariate Cox proportional hazard analyses.

      Results:
      Between 2007 and 2011, we identified 3905 patients for analysis. The population was Caucasian in 95% and African American in 4.6%. 54.4% were male. There were 2336 patients (59.8%) between ages 66 and 75. 770 patients (19.7%) did not receive any surgery, radiation, chemotherapy or any combination of these modalities. The proportion of untreated patient per stage was 9.45% for Stage I, 4.35% for Stage II, 20.76% for Stage III and 26.7% for Stage IV. The median overall survival was 41 months for stage I, 22 months for stage II, 10.5 months for stage III and 4.1 months for stage IV (Log-rank test, P < 0.001) In the survival analysis, treatment for NSCLC resulted in significantly better survival (LR, P < 0.05), for patients that have no comorbidity burden (CCI score of 0), for those who have a low burden of comorbidities (CCI score of 1-2) as well as for those patients that had a significant comorbidity burden (CCI score of 3 or more). The better survival of patients with high burden of comorbidities who received treatment for their disease was consistently observed on Stage I (HR 0.31, 95% CI 0.20-0.48); Stage III (HR 0.27, 95% CI 0.18-0.40) and Stage IV (HR 0.46, 95% CI 0.34-0.62). The multivariate analysis confirms the established factors that negatively impact survival (older age, being male, higher stage, higher grade, and no treatment).

      Conclusion:
      Undertreatment of lung cancer has many causes, but misconceptions about patients being eligible for treatment play a significant role. The presented SEER-Medicare data demonstrates a significant survival benefit from NSCLC therapy even in those patients with a high burden of comorbidities. The data supports the consideration for therapy even when the comorbidity burden is perceived as high. Further studies are needed to determine the effect of optimal comorbidities management on lung cancer outcomes.

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      ORAL30.03 - Access to Cancer Directed Therapies and Cancer Specialists in Patients with Metastatic Lung Cancer (ID 2899)

      16:45 - 18:15  |  Author(s): A.K. Ganti, F.R. Hirsch, M. Wynes, A. Ravelo, S.S. Ramalingam, R. Ionescu-Ittu, I. Pivneva, P. Lin, H. Borghaei

      • Abstract
      • Presentation
      • Slides

      Background:
      Access to cancer specialists and directed therapies is critical in the management of patients with metastatic lung cancer (mLC). This study aims to assess treatment patterns overall and stratified based on whether patients were seen or not by a cancer specialist in patients with de novo mLC.

      Methods:
      Adult patients diagnosed with de novo mLC between January 1, 2008 and March 31, 2014 were selected from a US commercial health claims database. All patients were followed for a minimum 3 months after the index date, defined as their first biopsy date. Patients who saw an oncologist/hematologist from 6 weeks before index date until the end of follow-up (end of data availability or health plan eligibility) were included in the cohort of patients who saw a cancer specialist. The remaining patients were included in the cohort of patients who did not see a cancer specialist. In both cohorts, the use of systemic antineoplastic therapy (Table 1) and radiation therapy was assessed following the index date.

      Results:
      The study sample consisted of 25,191 mLC patients, followed for a median of 9 months. Median age was 63 years (interquartile range: 57-73). 28.4% of the patients did not see a cancer specialist. Overall, 89.9% of the mLC patients received a cancer directed therapy during the follow-up (Table 1). The proportion of patients who received a cancer directed therapy during the follow-up was larger among patients seen by a cancer specialist (91.2% vs. 86.7%, p < .0001) (Table 1). Among patients who did not see a cancer specialist, 86.7% received antineoplastic therapy and/or radiotherapy during the follow-up, 2.6% were untreated and admitted to hospice, and 10.6% were untreated and were not admitted to hospice. The majority of patients who were not seen by a cancer specialist and received treatment were seen prior to the initiation of therapy by pulmonologists, internists, family physicians, and/or radiologists. Figure 1



      Conclusion:
      Approximately one in ten patients with de novo mLC did not receive any cancer directed therapy and a little more than one in four patients were not seen directly by a cancer specialist. Among patients not seen by a cancer specialist many received some form of cancer directed therapy. However, the access to cancer directed therapy of these patients remained significantly lower than that of mLC patients seen by a cancer specialist. Further research should be directed towards understanding and addressing disparities in access to appropriate cancer care.

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      ORAL30.04 - Discussant for ORAL30.01, ORAL30.02, ORAL30.03 (ID 3365)

      16:45 - 18:15  |  Author(s): S. Swisher

      • Abstract
      • Presentation

      Abstract not provided

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      ORAL30.05 - Clinical Implementation of the NextDaySeq Lung Panel for Identification of Clinically Actionable Variants in Non-Small Cell Lung Cancer (ID 3099)

      16:45 - 18:15  |  Author(s): J. Gao, H. Wu, X. Shi, Z. Huo, J. Zhang, Z. Liang

      • Abstract
      • Presentation
      • Slides

      Background:
      Molecular testing-directed targeted therapies are transforming treatment paradigms for non-small cell lung cancer (NSCLC). The clinical application of next-generation sequencing (NGS) technologies has offered a more comprehensive understanding of the mutational landscape. Efforts have been made in the past three years in the Department of pathology at the Peking Union Medical College Hospital, to adopt NGS in the clinical setting allowing rapid and reliable detection of actionable mutations that facilitate therapeutic decision making and disease prediction for at-risk patients

      Methods:
      The NextDaySeq Lung panel on Ion Torrent[TM] System and DanPA bioinformatics pipeline have been implemented in our clinical laboratory. The workflow employs novel chemistry in library preparation and innovation in informatics, which allows a 48-hour turnaround from FFPE samples to identification of variants with demonstrated clinical importance. The test sequences 16 exons in EGFR, KRAS, BRAF, PIK3CA, ALK, DDR2 and PDGFRA, covering 82 well recognized hotspots. The end-to-end test performance has been established with analytical sensitivity and specificity as well as the assay’s repeatability and reproducibility. Up to date, more than 200 samples have been examined including both lung adenocarcinoma and lung squamous carcinoma. To characterize the analytical performance, the NGS results have been compared with Sanger sequencing that covers the same exons, as well as QPCR assays (CFDA approved IVD kits) that cover a majority of hotspots within these exons.

      Results:
      Analysis of 200 cases indicated 100% concordance for reportable variants mutually covered in both NGS and QPCR assays. Eight cases reported at least one additional potentially clinically relevant variant, for example, in EGFR and PIK3CA, that would not have been identified in previously implemented QPCR assays. The mutation rates reported in 200 cases ranged from 2.4% to 84.3% according to DanPA analysis, while Sanger sequencing failed to detect variants in 32 cases with mutation rates lower than 20%. The Indel analysis had been a challenge for previous NGS tests in the lab, and the current test resolved the issue with the DanPA pipeline, demonstrating 100% PPV and NPV values compared with QPCR, and Sanger when mutation rates higher than 20%. Additionally, we documented multiple cases that carry double and triple mutations, which were rare in lung cancer, and also identified several novel mutations.

      Conclusion:
      Therefore, we reported the validation of NextDaySeq Lung panel for high throughput detection of mutations in NSCLC, and the development of a wet-bench and informatics workflow enabling timely and informative molecular diagnosis. The implementation of the test offers significantly improved information benefit over previous tests, and holds the promise to impact patient management.

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      ORAL30.06 - Genomic Analysis of Lung Cancer Tumors from Hispanic Patients Living in the US (ID 420)

      16:45 - 18:15  |  Author(s): L.E. Raez, J. Mourafetis, A. Kim, B. Hunis, C. Sareli, E. Velis, N. Abrahams, M. Block, F. Tarrazzi, D. Dumercy

      • Abstract
      • Presentation
      • Slides

      Background:
      The frequency of epidermal growth factor receptor mutations (EGFR-mut) in tumors from Hispanic (HIS) patients (pts) in Latin-America (LA) might be higher than the rate registered in the world literature from data coming mainly from Non-Hispanic White (NHW) pts with NSCLC (CLICaP: J Clin Oncol. 2012;30:(suppl; abstr e18114)). We wanted to verify this and investigate the gene expression profile (GEP) in tumors from HIS pts with NSCLC living in the US.

      Methods:
      To identify EGFR-mut and other molecular markers (MM) (ALK and ROS-1 translocations (trans), KRAS, c-Met and BRAF) genomic analysis by next generation sequencing (NGS) and FISH was done in tumors of pts with NSCLC at Memorial Cancer Institute in Florida. All MM were not available for all pts. Pts were divided into groups based on ethnic background. Chi-square and Fisher’s Exact tests were used to assess associations between genetic profile and ethnicity. All summary statistics on time-to-event variables were calculated according to the Kaplan-Meier method and were compared by means of the log-rank test. Adjusted hazard ratios (AHR) and 95% confidence intervals (95% CI) were reported based on the results of a multivariate Cox regression model for overall survival (OS) with adjustment for gender, age, and race. A p value 0.05 was significant. SPSS® software 21 was used for analyses.

      Results:
      MM were ordered in 282 pts and tumor samples were sufficient in 254 (90%). Of these pts: 35% were HIS, 59% were women, 92% had adenocarcinoma and 38% were non-smokers. EGFR-mut were seen in 21% of the tumors [93 % in exons 19 and 21]. EGFR resistant mutations [exon 20] in 1%. ALK and ROS-1 trans were 3% and 10%. c-MET in 25%, KRAS 24%, and BRAF 4%.

      MM % in HIS % in NHW # samples
      EGFR mut 23% 20% 231
      ALK trans 4% 3% 209
      ROS-1 trans 8% 11% 63
      KRAS mut 26% 22% 149
      c-MET mut 25% 25% 51
      BRAF mut 10% 0% 49
      There was no significant association between HIS vs. NHW with any MM: EGFR-mut [χ[2 ]=0.22, p=0.64] or ALK and ROS-1 trans [Fisher’s Exact Tests, p=0.49 and 0.55] or other MM: KRAS, χ[2 ]=0.25, p=0.62, c-MET, χ[2 ]=0.00, p=1.00, or BRAF, Fisher’s Exact Tests, p=0.17. No differences in survival between HIS and NHW regardless of MM. Log Rank (Mantel-Cox) 0.73, p=0.39.

      Conclusion:
      GEP of NSCLC tumors in HIS pts in the US are similar to NHW contrary to what is found in LA. There might be selection bias in the data from LA due to the fact that very few of the eligible pts in LA are being tested yet, all of our NSCLC pts get GEP in our practice.

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      ORAL30.07 - Different Mutation Profiles and Clinical Characteristics Among Hispanic Patients with NSCLC Could Explain The 'Hispanic Paradox' (ID 748)

      16:45 - 18:15  |  Author(s): M.A. Castillo, L. Ramírez-Tirado, R. Báez-Saldaña, O. Peña-Curiel, E.O. Macedo, G. Saco-Chafre, O. Arrieta Rodriguez

      • Abstract
      • Presentation
      • Slides

      Background:
      Sixteen percent of the U.S. population is Hispanic, predominantly of Mexican ancestry. Recently, two independent American reports demonstrated a higher overall survival (OS) in Hispanic populations compared with non-Hispanic-white populations (NHW) in patients with non-small-cell lung cancer (NSCLC) diagnosis. The latter even when most of the Hispanics are diagnosed at advanced stages of disease and are low-income patients. The aim of our study was to analyze the clinical, pathological, and molecular characteristics as well as the outcomes in a cohort of NSCLC Hispanic patients from the National Cancer Institute of Mexico that could explain this "Hispanic Paradox".

      Methods:
      A cohort of 1260 consecutive NSCLC patients treated at the National Cancer Institute of Mexico from 2007-2014 was analyzed. Their clinical- pathological characteristics, the mutation-status of EGFR and KRAS and the prognosis were evaluated.

      Results:
      Patients presented with stages of disease: II (0.6%), IIIa (4.8%), IIIb (18.4%) and IV (76.3%). NSCLC was associated with smoking in 56.5% of the patients (76.7% of male vs. 33.0% of female patients). Wood smoke exposure (WSE) was associated with 37.2% of the cases (27.3% in men vs. 48.8% in women). The frequency of EGFR mutations was 28.1% (18.5% in males vs. 36.9% in females, p<0.001) and the frequency for KRAS mutations was 10.2% (10.3% men vs. 10.1% in women p= 0.939). The median OS for all patients was 23.0 months [CI95% 19.4-26.2], whereas for patients at stage IV, it was 20.1 months [CI 95% 16.5-23.7]. The independent factors associated with the OS were as follows, the ECOG Performance Status, stage of disease, EGFR and KRAS mutation status.

      Conclusion:
      The high frequency of EGFR mutations and low frequency of KRAS mutations in Hispanic populations and different prevalence in lung cancer-related-developing risk factors compared with Caucasian populations, such as the lower frequency of smoking exposure and higher WSE, particularly in women, might explain the prognosis differences between foreign-born-Hispanics, US-born-Hispanics and NHWs.

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      ORAL30.08 - Discussant for ORAL30.05, ORAL30.06, ORAL30.07 (ID 3366)

      16:45 - 18:15  |  Author(s): E.S. Kim

      • Abstract
      • Presentation

      Abstract not provided

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    ORAL 36 - Translational Science/Radiation (ID 151)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 8
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      ORAL36.01 - Prognostic Value of Tumor-Infiltrating Lymphocytes for Patients with Completely Resected Stage IIIA(N2) Non-Small Cell Lung Cancer (ID 1061)

      16:45 - 18:15  |  Author(s): W. Feng, Y. Li, X. Fu, L. Shen, X. Cai, Z. Zhu, J. Chang, J. Xiang, Y. Zhang, H. Chen

      • Abstract
      • Slides

      Background:
      Patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. Accumulating evidence suggests that the host immune response might determine tumor behavior and influence the survival prognosis; however, the clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC.

      Methods:
      From January 2005 to June 2012, all consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection in our hospital were retrospectively reviewed. Inclusion criteria for this study were as follows: complete resection through a surgical procedure of either lobectomy or pneumonectomy with microscopically tumor-free resection margins; systematic nodal dissection with a minimum of three N2 stations dissected; and histologically proven NSCLC of stage pT1-3N2M0 (according to the 7th UICC TNM classification). Patients who received neoadjuvant chemotherapy and/or radiotherapy were excluded. Full-face hematoxylin- and eosin-stained sections from surgical specimens from each case were evaluated for the density of TILs by two qualified specialized pathologists. A published recommended TILs scoring scale was followed. The degree of lymphocyte infiltration into the tumor was scored as none (score 0), low (score 1), moderate (score 2), or high (score 3). Patients were stratified into TIL-negative (none to low infiltration) or TIL-positive (moderate to high infiltration) group based on pathologic evaluation.

      Results:
      Of the eligible 320 patients included in the analysis, 135 (42%) patients were categorized as TIL-positive; and the 185 (58%) patients were defined as TIL-negative. The median follow-up duration was 30.8 months (range, 12-101.4 months) for the living patients. In the entire cohort, the median survival time (MST) was 42.5 months, and the 1-, 3-, and 5-year overall survival (OS) rates were 90.9%, 54.3%, and 35%, respectively. For the patients in the TIL-negative and TIL-positive groups, the MST was 35.7 and 45.5 months, respectively. The 1-, 3-, and 5-year OS rates were 88.6%, 49.5%, and 34%, respectively, in the TIL-negative group and 94.1%, 61.2%, and 35.6%, respectively, in the TIL-positive group. A higher density of TILs (TIL-positive) was associated with improved OS and the differences trended toward significance (P=0.06). Multivariate analyses confirmed that TIL-positive was an independent prognostic factor for improved OS (HR=0.70, 95%CI 0.50-0.99, P=0.05). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; HR=0.44, 95%CI 0.21-0.94, P=0.03). Of the 93 patients with SCC, TIL-positive was significantly associated with improved distant metastasis-free survival (DMFS; P=0.02) and OS (P=0.03). The TIL-positive was a strong prognostic factor in the multivariate model, both for prolonged DMFS (HR=0.39, 95%CI 0.17-0.87, P=0.02) and OS (HR=0.47, 95%CI 0.22-1.00, P=0.05).

      Conclusion:
      Our data suggested a potential role of TILs in predicting the survival prognosis of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced for the prediction of DMFS and OS in patients with SCC. Studies assessing outcomes and therapeutic efficacies in prospective clinical trials should consider stratification for this immunological parameter.

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      ORAL36.02 - Efficacy of Chemo-Radiotherapy (CRT) in Stage III Non-Small Cell Lung Cancer (NSCLC) and PD-L1 Expression (ID 2432)

      16:45 - 18:15  |  Author(s): J. Adam, A. Boros, B. Lacas, L. Lacroix, J. Pignon, C. Caramella, D. Planchard, A. Levy, B. Besse, C. Le Pechoux

      • Abstract
      • Presentation
      • Slides

      Background:
      Inhibition of the PD1/PD-L1 axis has been successfully developed in advanced NSCLC, and its role in locally advanced NSCLC is under investigation. The prognostic and predictive values of PD-L1 expression is still debated in advanced NSCLC and unknown in stage III NSCLC patients definitely treated by CRT

      Methods:
      We reviewed all consecutive patients that received CRT or RT with a curative intentfor stage III NSCLC in a single institution. Paraffin embedded tissue block were collected, immunohistochemistry was performed on a Ventana Benchmarck Ultra platform using the E1L3N clone (Cell Signaling Technologies). All tumors were centrally reviewed and tumor cells were scored accordingly (Herbst et al., Nature 2014).Kaplan-Meier methods, log-rank test, and Cox proportional hazards models were used for survival analysis, adjusting for performance status (0, ≥1), stage (IIIA, IIIB) and thoracic surgery (yes, no). Median follow-up was estimated by the Schemper method

      Results:
      Between January 2002 and June 2013, clinical data from 190 patients were collected. Median dose of RT was 66 Gy (46-70). Chemotherapy, mostly based on doublets with platin salt was administrated concomitantly in 108 patients, as induction/consolidation treatment in 170 patients, and 15 patients did not receive any chemotherapy. Fifty NSCLC were evaluable for PD-L1 expression, 22 (44%) being positive. Fourteen (28%) were female, 24 (48%) were current-smoker, 17 (34%) had adenocarcinoma and there were 23/27 stage IIIA/IIIB. Evaluable and unevaluable populations for PD-L1 were not different. There were no clinical or pathological factors related to PD-L1 positivity. Median follow-up was 7.6 years (minimum: 0.7 year). Median OS was 1.1year(95% confidence interval (CI) 0.6-1.5) in PD-L1 positive (pos) and 2.0 years (95% CI 1.5-3.8) in PD-L1 negative (neg) (p=0.01), HR=2.3 (95% CI 1.2-4.5, p=0.01). Median PFS was 0.7 year (95% CI 0.6-0.8) in PD-L1pos and 1.0 year (95% CI 0.8-1.5) in PD-L1neg (p=0.04), HR=2.1 (95% CI1.1-4.0, p=0.03). There was no difference in terms of acute toxicity according to PD-L1 status (positive or negative):25 had oesophagitis (grade≥2) and 16 had pneumonitis (p=0.57 and p=0.23 respectively).

      Conclusion:
      PD-L1 positivity was associated to a poorer survival in stage III NSCLC patients treated by definitive chemo-radiotherapy. Its prognostic and/or predictive value should be further evaluated in this population.

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      ORAL36.03 - Discussant for ORAL36.01, ORAL36.02 (ID 3566)

      16:45 - 18:15  |  Author(s): E.E. Vokes

      • Abstract
      • Presentation

      Abstract not provided

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      ORAL36.04 - Nintedanib Safely Reduces Late Radiation-Induced Lung Damage: A Preclinical Study with a High Precision Image-Guided Small Animal Irradiator (ID 1456)

      16:45 - 18:15  |  Author(s): D. De Ruysscher, P.V. Granton, N.G. Lieuwes, S. Van Hoof, L. Wollin, F. Verhaegen, L. Dubois

      • Abstract
      • Presentation
      • Slides

      Background:
      The indolinone small-molecule derivative nintedanib has been originally designed as an anti-angiogenic drug targeting the receptor tyrosine kinases VEGFR, FGFR and PDGFR for the treatment of cancer. Additionally, preclinically nintedanib has demonstrated potent anti-fibrotic and anti-inflammatory activity. Nintedanib was recently approved in the US and EU for the treatment of idiopathic pulmonary fibrosis (IPF). The aim of this study was to assess the efficacy and safety of nintedanib in a mouse model of partial lung irradiation.

      Methods:
      266 C57BL/6 adult male mice were irradiated with a single fraction radiation dose of 0, 4, 8, 12, 16 or 20 Gy using 5-mm circular parallel-opposed fields targeting the upper right lung with a precision image-guided small animal irradiator (PXRAD225Cx, PXI Inc, USA) sparing heart and spine based on micro-CT images acquired at 200 µm resolution. One week post irradiation, mice were randomized across nintedanib daily oral gavage treatment with 0, 30 or 60 mg/kg respectively for a total of 39 weeks. Micro-CT imaging was repeated on a monthly basis. At the end of the experiment, lungs were removed and processed for H&E, Van Gieson’s and Masson’s trichrome staining to evaluate the fibrotic phenotype.

      Results:
      Increased lung density could be visually observed by CT in the late stage imaging time points of irradiated mice after 20 Gy and was spatially limited to the irradiated portion of the lung. This increased density was consistent with the development of fibrosis, confirmed by an increased fibrotic phenotype scored by an increase in alveolar wall thickness, interstitial edema, interstitial and perivascular fibrosis and inflammation, interstitial and alveolar macrophages, atelectasis and vasculitis. Although no macroscopic decrease in CT density could be observed, nintedanib was able to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation and vasculitis, without adverse effects.

      Conclusion:
      Nintedanib efficiently and safely reduces radiation-induced lung fibrosis after partial lung irradiation. Since, as expected, nintedanib did not affect alveolar wall thickness and macrophage involvement, no significant changes in lung density could be observed by CT imaging. Based on its protective effect, nintedanib might be safely introduced in clinical trials for patients treated with irradiation to the lungs.

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      ORAL36.05 - Results of a National Database Review of Video-Assisted Thoracoscopic versus Open Lobectomy after Induction Therapy (ID 1533)

      16:45 - 18:15  |  Author(s): J.L. Wilson, T. Curran, S.P. Gangadharan, R.I. Whyte, M.S. Kent

      • Abstract
      • Presentation
      • Slides

      Background:
      Minimally invasive lobectomy has become the standard of care approach for early stage non-small cell lung cancer (NSCLC); however video assisted thoracoscopic (VATS) lobectomy after induction therapy remains controversial. We sought to evaluate perioperative outcomes of VATS and open lobectomy after induction therapy using a national database.

      Methods:
      A cohort study of patients that underwent VATS and open lobectomy after induction chemotherapy and/or radiotherapy was conducted using the National Surgical Quality Improvement Program (NSQIP) database from 2005 through 2012. Perioperative complications and mortality were compared between groups. Comparisons were made using two-sided student’s t-test or chi square test as appropriate.

      Results:
      A total of 6730 patients underwent lobectomy during the study period and 166 patients had prior induction therapy (open = 132, VATS = 34). There were no statistically significant differences in age, comorbidities or ASA class between groups. There were no significant differences in the surgeon specialty between groups (cardiac, thoracic, general, and vascular). Operative time was similar (VATS: 228 minutes, Open: 190 minutes; p = 0.07). Perioperative complications, return to OR, respiratory complication, mortality, and hospital length of stay were similar between groups. Table 1. Patient Demographics

      N (%) All (N = 166) Open (N = 132) VATS (N = 34) P-value
      Age, yrs; Mean (SD) 62.9 (10.2) 62.4 (10.7) 65.2 (7.6) 0.077
      Female 88 (53) 72 (55) 16 (49) 0.563
      Diabetes 16 (10) 11 (8) 5 (15) 0.325
      COPD 35 (21) 26 (20) 9 (27) 0.479
      Creatinine > 1.2 17 (10) 13 (10) 4 (12) 0.757
      ASA Class ≥4 18 (11) 14 (11) 4 (12)
      VATS = video assisted thoracoscopic, COPD = chronic obstructive pulmonary disease, ASA= American Society of Anesthesia class Table 2. Post-Operative Outcomes
      N (%) All (N = 166) Open (N = 132) VATS (N = 34) P-value
      LOS, days; mean (SD) 7.3 (6.1) 7.4 (6.1) 6.6 (6.3) 0.471
      Wound complication 5 (3) 5 (4) 0 0.584
      Pneumonia 16 (10) 15 (11) 1 (3) 0.197
      Reintubation 18 (11) 15 (11) 3 (9) 1.000
      Respiratory complication 25 (15) 22 (17) 3 (9) 0.419
      Return to OR 15 (9) 14 (11) 1 (3) 0.311
      In hospital mortality 9 (5) 8 (6) 1 (3) 0.687
      30 day mortality 13 (8) 12 (9) 1 (3) 0.471
      VATS= video assisted thoracoscopic, LOS = length of stay, OR= operating room

      Conclusion:
      This is the first review of a prospective national database comparing outcomes for VATS and open lobectomy after induction therapy for NSCLC. VATS lobectomy appears to be safe with no increased morbidity or mortality compared to open in patients that had prior induction therapy. A larger series of matched VATS and open approaches after induction therapy is needed.

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      ORAL36.06 - 4D-VQ-PET/CT Imaging Allows Strong Correlation Between Radiotherapy Dose and Change in Lung Ventilation, Perfusion and Density (ID 211)

      16:45 - 18:15  |  Author(s): S. Siva, N. Hardcastle, T. Kron, M. Bressel, J. Callahan, M. Macmanus, M. Shaw, N. Plumridge, R. Hicks, D.P. Steinfort, M. Hofman, D. Ball

      • Abstract
      • Presentation
      • Slides

      Background:
      [68]Ga-V/Q PET/CT is a novel imaging modality for assessment of perfusion(Q), ventilation(V) and lung density changes in the context of radiotherapy (RT) for non-small cell lung cancer.

      Methods:
      In a prospective clinical trial, 20 patients underwent 4D-V/Q PET/CT before treatment, 4 weeks into treatment and 3 months after definitive lung RT. Eligible patients were prescribed 60 Gy in 30 fractions with or without concurrent chemotherapy. Functional images were registered to the RT planning 4D-CT and isodose volumes averaged into 10 Gy bins. Within each dose bin, relative loss in SUV was recorded for ventilation and perfusion, and loss in air-filled fraction was recorded to assess RT-induced lung fibrosis. A dose-effect relationship was described using both linear and 2-parameter logistic fit models and goodness of fit assessed using Akaike Information Criterion (AIC).

      Results:
      A total of 179 imaging datasets were available for analysis (1 scan unrecoverable). An almost perfectly linear dose-response relationship was observed for perfusion and air-filled fraction (r[2] = 0.99, p < 0.01), with ventilation also strongly linear (r[2] = 0.95, p < 0.01) [Figure]. Logistic models did not provide a better fit as evaluated by AIC [Table]. Perfusion, ventilation and the air-filled fraction changed by -7.5% ± 0.3%, -7.1% ± 0.6% and 4.9% ± 0.02% per 10 Gy, respectively. Within high-dose regions, higher baseline SUV was associated with greater rate of loss. At 50Gy and 60Gy the rate of loss was 1.35% (p = 0.07) and 1.73% (p = 0.05) per SUV, respectively. Of 8/20 patients with peri-tumoral reperfusion / re-ventilation during treatment, 7/8 did not sustain this effect post-treatment. Figure 1 Figure 2





      Conclusion:
      RT induced regional lung functional deficits occur in a dose dependent manner and can be estimated using simple linear models with 4D-V/Q PET/CT imaging. These findings may inform functional lung sparing by planning RT using this novel imaging technology.

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      ORAL36.07 - Results of a National Test Run of Treatment Plans for the Standard Arm of a Dose Escalation Trial for Locally Advanced NSCLC (ID 1766)

      16:45 - 18:15  |  Author(s): T.B. Nielsen, C. Brink, D.S. Møller, L. Hoffmann, C.M. Lutz, A.L. Appelt, M.D. Lund, M.S. Nielsen, P. Sibolt, C. Larsen, W. Ottoson, T. Schytte

      • Abstract
      • Presentation
      • Slides

      Background:
      A national quality assurance program was conducted in order to compare standard radiation treatment plans for locally advanced non-small cell lung cancer (NSCLC) patients in Denmark.

      Methods:
      The five participating centres represented 71% of all radiotherapy centres in Denmark. They were provided with the CT images and delineations of GTV, CTV, PTV and organs at risks for five different NSCLC patients. Each centre created treatment plans based on the following optimization objectives: required dose distribution for target coverage 95%-107% of the prescribed dose of 66Gy/33fr to at least 95% of the PTV volume (90% for volume located in lung tissue); constraints for organs at risks D(max) < 50Gy to the spinal cord, D(max) < 70Gy to the oesophagus, V50 < 20% to the heart, V20 < 35% and D(mean) < 20Gy for the total lung volume (excluding the GTV). The treatment planning was done in accordance with the local centre practice; i.e. choice of IMRT versus VMAT, coplanar vs. non-coplanar technique, feasible functionalities for treatment planning optimisation (mean value versus different points at the DVH curve), and any additional local dose constraints (e.g. D(max) < 45Gy to spinal cord and/or V5 < 60% to the total lung volume). Finally, all treatment plans were collected and analysed cooperatively.

      Results:
      All objectives for target coverage and organs at risk were met. There was a wide variability in the dose volume histograms (DVHs) for some of the organs at risk, especially the lungs. This is illustrated in the figure, where the lung DVH from seven different treatment plans, created for the same patient by the five participating centres, is shown. The lung DVHs are overlapping around 20Gy, as all centres had a dose constraint on V20. Some centres had an additional local dose constraint on V5, which resulted in decreased doses to the lungs and increased doses to the mediastinal structures compared with centres that had no dose constraints on V5 for the lungs. Figure 1



      Conclusion:
      Differences in the dose distribution to the organs at risk can have an impact on treatment morbidity (e.g. pneumonitis, oesophagitis). These differences were seen for standard treatment plans, which are often used in multicentre clinical trials as the baseline compared to an experimental arm, where such differences can be even more pronounced. It is highly recommended to perform test runs across centres prior to entering clinical trials in order to uncover differences as the ones presented.

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      ORAL36.08 - Discussant for ORAL36.04, ORAL36.05, ORAL36.06, ORAL36.07 (ID 3567)

      16:45 - 18:15  |  Author(s): P. Van Houtte

      • Abstract
      • Presentation

      Abstract not provided

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