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J. Hu

Moderator of

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    MO05 - Prognostic and Predictive Biomarkers II (ID 95)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 12
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      MO05.01 - Validation of gene expression biomarker panels in non-small cell lung cancer (ID 2928)

      J. Dong, M. Huebner, I. Azodo, S.C. Tomaszek, Z. Sun, F. Kosari, L. Wang, J. Jen, M.C. Aubry, P. Yang, G. Vasmatzis, D.A. Wigle

      • Abstract
      • Presentation
      • Slides

      Background
      Many studies in the literature have suggested that gene expression biomarkers may guide patient classification and clinical management in NSCLC. Despite minimal external validation and no clinical trial evidence, gene expression biomarker panels have been proposed as tools for making treatment decisions. Recent controversy surrounding the validity of such data and its potential applicability to clinical practice led us to perform an external validation study of published gene expression biomarker panels.

      Methods
      We performed gene expression profiling for a total of 209 patients with both Affymetrix whole transcriptome U133Plus2 arrays in addition to a NSCLC-specific array constructed by our group for assessment of mRNA expression in frozen tumor specimens of NSCLC. Clinical outcome data were collected and analyzed for correlations of gene expression with disease-free and overall survival. Cox proportional hazard models were used to test significance of individual genes and for gene sets defined by each panel. Panels tested included those previously published from Michigan, Mayo Clinic, Taiwan, Toronto, and UCSF.

      Results
      Expression profiling data were generated for a total of 209 patients with NSCLC. This included U133Plus2 arrays of 242 tumor samples and 105 matched surrounding normal lung tissue, as well as 111 tumor profiles using the NSCLC-specific array. There were 98 women and 111 men in the study cohort, with 120 patients having Stage I NSCLC (57.4%), 38 with Stage II (18.2%), 50 with Stage III (23.9%), and one patient with Stage IV disease (0.5%). Mean follow-up time after surgical resection was 62.4 ± 48 months. Seventy-four patients (35.1%) developed post-resection recurrence after a mean of 53.3 ± 49.3 months, of which 62 patients died (83.8%). Known clinical predictors such as TNM stage, histology, and tumor grade were predictive of survival. Although many genes within the published biomarker panels were significantly correlated with disease-free and overall survival, none provided additive prognostic value beyond standard clinical predictors.

      Conclusion
      Although a number of individual gene expression biomarkers have prognostic significance in univariate models, published biomarker panels perform poorly in external validation studies such as this. The additive prognostic value beyond standard, known clinical predictors in the TNM staging system casts doubt as to whether such information will be useful in clinical practice. Despite the success of gene expression biomarkers for molecular subtyping in other cancers, our data suggests that this information has a low likelihood of clinical translation in NSCLC for unselected patients.

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      MO05.02 - Overexpression of FGFR1 mRNA and protein are more frequent than FGFR1 gene amplification in non-small cell lung cancer (NSCLC) patients (ID 2459)

      M.W. Wynes, T. Boyle, S. Wojtylak, A. Sejda, L.E. Heasley, L.A. Henricksen, S. Singh, D.R. Camidge, P.A. Bunn, R. Dziadziuszko, W. Biernat, F. Hirsch

      • Abstract
      • Presentation
      • Slides

      Background
      Somatic mutations and gene fusions have been identified as oncogenic drivers in lung cancer, however, a number of lung cancers have no apparent molecular aberration driving oncogenesis. It appears that gene/protein overexpression may sustain these “pan-negative” cancers. Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate cell proliferation, differentiation, migration and survival and dysregulation of this signaling pathway is observed in a proportion of lung cancers. A number of compounds targeting FGF/FGFR are in clinical development but clinically applicable biomarker assays and companion diagnostics that accurately identify patients with tumors sensitive to these agents are needed. We previously presented cell line data demonstrating that FGFR1 mRNA (ME) or protein expression (PE) better identified FGFR1 inhibitor sensitive tumors compared to gene copy number (GCN). The goal of this study was to examine FGFR1 ME, PE and GCN in a surgically treated NSCLC clinical cohort and explore possible associations with clinical features and prognosis.

      Methods
      Immunohistochemistry, brightfield in situ hybridization, and silver in situ hybridization were used to investigate ME, PE and GCN, respectively, in a cohort of 189 NSCLC surgically-treated patients. PE was scored by the H-score method (0-300) and ME on a semiquantative integer scale (0-4+), both evaluating the entire tumor specimen. GCN was scored on continuous scale by counting the individual signals in 50 cells and determining the average GCN per tumor cell.

      Results
      Amplification (GCN >=4) was present in 8% of the entire cohort and in 11% of the squamous cell carcinoma (SCC) or mixed histology subgroup. No amplifications were found in the adenocarcinomas (ADC) or tumors from never smokers. In contrast, 29% of SCC and ADC patients had high ME (= 4+). Elevated PE (>= 100) was observed in 20% of the cohort, with the highest expression observed in SCC/mixed histology, but 6% of ADCs also showed elevated PE. There was no elevated FGFR1 PE in the never smokers. There was significant correlation but incomplete overlap between biomarkers. There were no prognostic associations, either with overall or disease-free survival, for FGFR1 GCN, ME, or PE. There was excellent inter-observer agreement among the readers of all 3 biomarker assays.

      Conclusion
      Overexpression of FGFR1 mRNA and protein are more frequent than FGFR1 gene amplification in NSCLC patients. Although GCN amplification was restricted to SCC, elevated ME and PE were found in both ADC and SCC. There was no prognostic association with FGFR1 GCN, ME, or PE. These data are consistent with our previous cell line data that showed elevated PE and ME in non-amplified cells and suggests that GCN may not identify all the potential patients who could benefit from FGF/FGFR pathway inhibitors.

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      MO05.03 - A gene expression platform to predict benefit from adjuvant external beam radiation in resected non-small cell lung cancer. (ID 268)

      B.C. Creelan, A.A. Chiappori, S.A. Eschrich, W. Fulp, J.F. Torres-Roca

      • Abstract
      • Presentation
      • Slides

      Background
      To date, no personalized decision-making tool exists for adjuvant radiation after resection of non-small cell lung cancer (NSCLC). Our objective was to retrospectively determine if our previously developed 10-gene expression signature, called radiosensitivity index (RSI), would classify patients into radioresistant (RSI-poor) or radiosensitive (RSI-good) using disease-free survival (DFS).

      Methods
      Inclusion criteria: pathologic AJCC v6 stage III NSCLC at time of resection, negative margins, at a single institution between 2000 and 2012. Neo or adjuvant chemotherapy was required. For radiation group (RT), at least 45 Gy of conformal or intensity-modulated radiation was required. An identical stage group (control) did not receive radiation. Gene expression profiling was conducted on primary lung tumor mRNA. DFS was defined as time-to-recurrence or death from any cause. Predefined cut-point was lowest quartile of calculated RSI. Two-sided log-rank and Cox regression were used.

      Results
      Of 144 screened, 95 were eligible (53 RT and 42 control). Demographics: median age 67 yrs, 54% female, 96% white, and 91% current / former smokers. Operations consisted of 56% lobectomy, 26% pneumonectomy, and 18% segmentectomy/wedge. Adjuvant doublet consisted of 48% taxane, 32% gemcitabine, or 20% other. Mean RT dose 54.8 Gy, median follow-up 3.5 yrs. Histology: 64% adenoca, 25% squamous, 10% large-cell. Mean tumor volume 58 cm[3], 77% were pN2, 58% had angiolymphatic invasion and 51% were poorly-differentiated. Mean preoperative PET SUV~max~ was 9.5. No imbalance in clinical factors were observed between RSI-good vs. RSI-poor. On univariate analysis, for RT group, median DFS for RSI-good vs RSI-poor was 5.8 yrs vs. 1.4 yrs, HR 4.2 (95% CI 1.9 – 9.5), p = 0.017. 5-year DFS was 63% vs 22%, p = 0.01. No significant difference was observed for the chemo-only control group, with median DFS for RSI-good vs. RSI-poor: 2.3 vs 2.7 yrs, HR 0.7 (95% CI 0.3 – 1.6), p = 0.98. A test for interaction confirmed that the effect was restricted to the RT group and not the control, with p = 0.04. On multivariate analysis, for the RT group, the RSI was more strongly associated with DFS than any other variable (age, gender, tumor volume, nodal status, baseline SUV~max~, histology, grade, LVI, and operation). After inclusion of covariates, it remained an independent predictive variable with HR 3.8 (95% CI 1.6 – 9.2) p = 0.003. Figure 1

      Conclusion
      RSI appears to be predictive for benefit from adjuvant radiation. Additional independent prospective validation is required.

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      MO05.04 - A prospective study of innovative non-invasive tools to assess the response to anti-angiogenic therapies in non small cell lung cancer patients (ID 2676)

      F. Wallyn, A. Claret, N. Tacelli, E. Wasielewski, J. Lafitte, J. Remy, H. Porte, J. Salleron, M. Willemin, A. Cortot, G. Marchandise, M. Remy-Jardin, P. Lassalle, A. Scherpereel

      • Abstract
      • Presentation
      • Slides

      Background
      Therapies targeting tumor angiogenesis, such as anti-VEGF antibodies (bevacizumab), are a major step in the treatment of non small cell lung cancer (NSCLC) but are costly drugs and may be responsible for significant toxicities. The goal of our study was to assess the value of non-invasive tools evaluating early the response to bevacizumab in NSCLC.

      Methods
      56 consecutive patients with stage IIIB-IV non-squamous NSCLC were prospectively recruited. According to multidisciplinary committee advice, one group of patients (bevacizumab group, n =24) had a chemotherapy combined with bevacizumab, the second one (control group, n = 32) had a similar chemotherapy but without bevacizumab. Quantitative tumor perfusion was sequentially evaluated with CT-scan before (T0) and after 1 cycle (T1) and 3 cycles (T2) of chemotherapy. CT-scan parameters included: (a) tumor height and diameter; (b) tumoral blood volume (BV) and capillary permeability (CP). Blood biomarkers (Endocan, VEGF, Angiopoïetin-2, VEGFR-2, VE-cadherin) were measured at the same time points.

      Results
      We observed an early and quite specific decrease of BV, CP and blood levels of VEGF, Angiopoïetin-2 and VE-cadherin in the bevacizumab group compared to control group. In the bevacizumab group, the decrease of BV between T0 and T1 was more important in patients responding to treatment than in subjects with progression on clinical (ΔBVT0-1 =-2.72ml vs 0.32ml, p=0.004) or RECIST criteria (ΔBVT0-1 =-3.35ml vs 0.04ml, p=0.011). An initial high Endocan level appeared as a marker of bad prognosis (overall survival) (HR=1.469 [1.120-1.925]; p=0.005) using a cut-off value of 0.72ng/ml (HR=2.276 [1.074-4.82]; p=0.032). Moreover, in the bevacizumab group, a significant decrease of Endocan level between T0 and T1 was a marker of good prognosis (HR=0.141 [0.022-0.889]; p=0.037).

      Conclusion
      Whole tumor perfusion analysis by CT-scan exhibited a promising predictive value for patients treated by chemotherapy combined with anti-angiogenic drug, whereas blood Endocan appeared as the most interesting blood marker, having a significant prognostic value in the same patients. These two exciting non-invasive tools deserve further and larger studies to confirm their value in monitoring NSCLC patients with therapies targeting tumor angiogenesis.

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      MO05.05 - Lung Cancer Explorer (LCE): an open web portal to explore gene expression and clinical associations in lung cancer (ID 2512)

      J.D. Allen, G. Xiao, H. Tang, J. Yang, B. Chen, J. Yoder, J.D. Minna, Y. Xie

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer is the leading cause of death from cancer for both men and women in the United States with a 5-year survival rate of approximately 15%. Many gene expression microarray datasets have been collected through different studies, while a single genomics study usually contains no more than 500 microarrays due to the high cost. We collected and manually curated mRNA expression microarrays together with clinical information for 5,218 lung cancer patients from 40 studies. The wealth of these large-scale datasets provides us great opportunities to generate significant scientific findings, while also posing great challenges for data integration.

      Methods
      To facilitate clinicians and researchers to access and use the resource, we developed an open web portal, The Lung Cancer Explorer, to explore gene expression and clinical associations in lung cancer. This database aggregates over 40 public clinically-annotated lung cancer gene expression studies, along with some private data from the University of Texas Southwestern Medical Center, and presents a user-friendly, web-based interface to explore and analyze this data. The database stores various information about patients including demographics, histology, stage classifications, clinical outcomes, and also stores the probe-level genome-wide mRNA expression information, allowing users to perform very rich analysis on the data.

      Results
      From the user’s perspective, usage is as easy as logging in and clicking a button to perform any of our current analysis functions: · Survival Analysis: Test the association between the gene expression level and patients’ overall survival time in one study. · Meta-Survival Analysis: Summarize the association between the gene expression level and patients’ overall survival time across multiple studies. · Comparative Analysis: Test the association between the gene expression level and patients’ characteristics, such as gender, age, histology types, disease stages, etc. · Tumor vs. Normal: Test whether the gene expression levels different significantly between tumor samples and normal samples. · Co-expression analysis: Calculate the correlations among a list of user-specified genes based on the gene expression levels. The web application is now online and available for usage: http://qbrc.swmed.edu/lce/ . I will talk about the data curation, quality control, database development and the usage of this resource.

      Conclusion
      The Lung Cancer Explorer is a highly interactive open resource for lung cancer research and it can greatly facilitate the translational lung cancer research.

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      MO05.06 - DISCUSSANT (ID 3911)

      E. Kim

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO05.07 - Nomogram combining clinicopathologic factors and molecular markers for predicting survival in patients with resected non-small cell lung cancer (ID 3317)

      W. Liang, J. He, D. Wang, Q. Deng, H. Pan, X. Shi, C. Zhong, L. Mo, J. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      Nomogram is a recognized method for individually predicting prognosis of cancer patients through combining various significant prognostic factors. Although the prognostic value of molecular biomarkers has been well studied, previous published nomograms are basically built based on only clinical factors. We sought to combine the clinicopathologic variables with the molecular markers to develop a more precise nomogram for predicting survival for early stage NSCLC patient who underwent surgery.

      Methods
      Based on data from the China Clinical Trials Consortium (CCTC) that included 1038 patients with resected NSCLC for whom the 14-gene molecular assay (BAG1, BRCA1, CDC6, CDK2AP1, ERBB3, FUT3, iL11, LCK, RND3, SH3BGR, WNT3A with ESD, TBP and YAP as internal reference) was tested, we conducted multivariate stepwise Cox regression analyses to identify significant factors which were then integrated to establish the nomogram. Nomogram based on clinicopathologic variables only (c-nomogram) or both clinical and molecular factors (cm-nomogram) were established respectively. Eighty percents of randomly sampled data were used to build the nomogram while the remaining data were used to validate it. The predictive accuracy and discriminative ability of the nomogram was determined by concordance index (C-index). Risk group stratification within a certain stage was proposed for the nomograms.

      Results
      We identified 15 independent prognostic factors, including 7 clinicopathologic variables (age, sex, histology, differentiation, tumor location, T and N stage) and 8 genes (with only CDK2AP1, FUT3, iL11, BAG1, CDC6, and RND3 were selected), then incorporated them to build the nomogram (Figure 1). The calibration curves for probability of 1, 3, 5-year overall survival (OS) showed good concordance between prediction by nomograms and actual observation in the validation set. The C-index of the cm-nomogram was statistically higher than that of the 7[th] edition TNM stage for predicting survival (0.72 vs 0.66, P=0.02) whereas the c-nomgram did not show superior performance than TNM stage system (0.69 vs 0.66, P=0.463). The stratification into three risk groups according to cm-nomogram allows significant distinction between Kaplan-Meier curves in each TNM stage respectively (P<0.01 for all stages, Figure 2).Figure 1

      Conclusion
      We developed a novel and validated nomogram that combines clinicopathologic factors and molecular markers, which provided more accurate predictions for OS of resected NSCLC patients compared with the TNM staging system and nomogram considering only clinical variables. This prognostic model lent support to clinicians and patients in decision making. In addition, it indicated that it is feasible and essential to incorporate molecular markers when building a nomogram to obtain more accurate prediction.

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      MO05.08 - Individualized Surgical Treatment for Locally Advanced Non-small Cell Lung Cancer Based on Molecular Biomarkers. (ID 2314)

      Q. Zhou

      • Abstract
      • Presentation
      • Slides

      Background
      Approximately 35%-40% of NSCLC have locally advanced disease. The average survival time of these patients only have 6-8 months with chemotherapy and radiotherapy. The aim of this study is to explore and summarize the probability of molecular biomarker detection in cancer tissues, mediastinal lymph nodes and peripheral blood for molecular stages and types of lung cancer, and for individual surgical treatment and postoperative adjuvant therapy and for prediction of postoperative recurrence of lung cancer in stage III disease; to summarize the long-time survival result of personalized surgical treatment of 1036 patients with LANSCLC based on molecular biomarker detection.

      Methods
      CK19 and Muc-1 mRNA expression of peripheral blood was detected in 1036 patients by RT-PCR before and after operation for individual molecular staging and personalized surgical treatment and postoperative adjuvant therapy. micro-RNA and gene chips were used to detect the differential micro-RNAs and gene profiles between the primary cancer tissues and metastatic mediastianl lymph nodes for individual postoperative adjuvant therapy and prediction of prognosis of the patients with LANSCLC. The long-term survival of personalized surgical treatment was retrospectively analyzed in the 1036 patients based on molecular staging and typing.

      Results
      There were 678 squamous cell carcinoma and 358 adenocarcinoma. 212 patients had IIIA disease and 824 had IIIB disease according to P-TNM staging. 126 patients had M-IIIA disease, 603 had M-IIIB disease and 307 had M-IV disease according to molecular staging. Of the 1036 patients, bronchoplastic procedures and pulmonary artery reconstruction was carried out in 356 cases; double sleeve lobectomy combined with resection and reconstruction of partial left atrium, superior vena cava, carina, aorta and postcava was performed in 680 cases in this series. Thirteen patients died of operative complications and the operative mortality was 1.16%. CK19 and Muc-1 mRNA positive expression in peripheral blood was found in 265(25.6%) patients. The differential micro-RNAs and gene profiles between the primary cancer and metastatic mediastinal lymph nodes divide the 1036 patients into high and low recurrence risk groups. The median survival time was 51.74 months. The 1, 3, 5 and 10 year survival rates of the 1036 cases was 81.1%, 49.3%, 30.8% and 21.4%, respectively.The postoperative survival rate was remarkably correlated with individual molecular staging and typing, micrometastasis, histological classification and size of primary cancer and LN metastasis (P<0.05). Multivariable Cox model analysis showed that “personalized molecular staging”, micrometastasis, the differential micro-RNAs and gene profiles and mediastinal lymph node metastasis were the most significant factors for predicting prognosis in the patients with LANSCLC.

      Conclusion
      Detection of micrometastasis in peripheral blood will be helpful for individual surgical treatment and postoperative adjuvant therapy in LANSCLC patients. The differential micro-RNAs and gene profiles can predict the recurrence and prognosis of the cancer. Individualized surgical treatment can significantly improve prognosis and increase curative rate and long-term survival rate of LANSCLC based on personalized molecular staging and typing.

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      MO05.09 - Activation of the classical complement pathway: a novel biomarker for the early diagnosis and prognosis of lung cancer (ID 964)

      D. Ajona, M.J. Pajares, L. Corrales, J.L. Perez-Gracia, J. Agorreta, M.D. Lozano, W. Torre, P.P. Massion, J.P. De-Torres, E. Jantus-Lewintre, C. Camps, J. Zulueta, L. Montuenga, R. Pio

      • Abstract
      • Presentation
      • Slides

      Background
      Numerous diagnostic and prognostic molecular markers have been proposed for lung cancer. However, genetic heterogeneity has limited the success of these initiatives. This limitation may be overcome by the use of biomarkers related to the host response to cancer. In this study we tested the capacity of lung cancer cells to activate the complement system and evaluated the diagnostic performance of complement-activation fragments. We demonstrate for the first time that lung cancer cells efficiently activate the classical complement pathway and that fragments of complement activation are of value for detection and prognosis of lung cancer at a very early stage.

      Methods
      We first assessed complement activation in bronchial epithelial and lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; in bronchoalveolar lavage supernatants from 50 patients with lung cancer and 22 non-malignant respiratory diseases; and in plasma samples from different cohorts, including: advanced (n=133) and early (n=84) non-small cell lung cancer patients, subjects with inflammatory lung diseases (n=133) and asymptomatic individuals enrolled in a lung cancer CT-screening program (n=190; 32 of them with lung cancer).

      Results
      Lung cancer cells treated with normal human serum activated complement and deposited C3 more efficiently than non-malignant bronchial epithelial cells. Incubation of cells with different buffer conditions, complement depleted sera and complement inhibitors showed that lung cancer cells bind C1q and activate complement through the classical complement pathway. In a set of lung cancer cell lines, a significant correlation was found between C1q binding and C4 or C3 deposition. The presence of phosphatidylserine inhibited C1q binding and diminished complement activation. Based on these results, C4d, a classical pathway-derived split product, was evaluated as a possible diagnostic or prognostic biomarker in lung cancer. Many lung primary tumors (adenocarcinomas and squamous cell carcinomas) deposited C4d. More importantly, survival was decreased in patients with high C4d deposition in their tumors (HR=3.06; 95% CI=1.18-7.91). Moreover, C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients as compared to patients with non-malignant respiratory diseases (0.61 ± 0.87 vs. 0.16 ± 0.11 µg/ml, respectively; P<0.001). C4d levels in plasma samples from lung cancer patients at both advanced (III and IV) and early (I and II) stages were also increased compared with control subjects (4.13 ± 2.02 vs. 1.86 ± 0.95 µg/ml, P<0.001; and 3.18 ± 3.20 vs. 1.13 ± 0.69 µg/ml, P<0.001, respectively). In addition, C4d plasma levels were associated with shorter survival in patients at advanced (HR=1.59; 95% CI=0.97-2.60) and early stages (HR=5.57; 95% CI=1.60-19.39). Plasma C4d levels were dramatically reduced after surgical removal of lung tumors. Finally, plasma C4d levels were associated with increased lung cancer risk in asymptomatic individuals: OR=4.38; 95% CI=1.61-11.93.

      Conclusion
      Lung tumors activate the classical complement pathway and generate C4d, a stable complement split product. Moreover, C4d is increased in biological samples from lung cancer patients, is associated with poor prognosis, and may be of clinical value for the early detection of lung cancer.

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      MO05.10 - Metformin as a Radiosensitizer for Lung Cancer (ID 3306)

      I. Csiki, C.B. Simone, M. Heskel, P. Gabriel, H. Kim, M.N. Corradetti, S. Dey, C. Koumenis

      • Abstract
      • Presentation
      • Slides

      Background
      In vitro data and early clinical results suggest that metformin, an agent commonly used in diabetes therapy, has direct cancer growth inhibition potential via mammalian target of rapamycin (mTOR) pathway suppression. Furthermore, a number of observational studies have associated lower cancer incidence and a lower risk of nonspecific cancer-related mortality with metformin use. Our first objective is to determine whether the use of metformin is associated with improved local recurrence (LRR) and overall survival (OS) rates in diabetic patients with non-small cell lung cancer (NSCLC) treated with definitive chemoradiation. Based on encouraging retrospective clinical results, we moved on to establish an in-vivo murine model of lung cancer and to evaluate the tumor growth delay from using metformin as a radiosensitizing agent.

      Methods
      Data from 760 consecutive patient treatment courses from our institution for patients with NSCLC and small cell lung cancer treated with radiation therapy between 6/2008 and 6/2013 were analyzed. All patients with diabetes and stage IIIA and IIIB NSCLC who received metformin during definitive radiotherapy were analyzed to determine clinical outcomes. For the in-vivo murine study, H1299 adenocarcinoma cells were injected in the flanks of nude mice for the subcutaneous tumor model. On day 2, mice began receiving daily intraperitoneal injection of metformin or vehicle for 5 days, after which they underwent irradiation to the flanks of 3Gy X 3 fractions. Tumor measurements were taken every other day and tumor growth delay was plotted. In order to assess the effect of metformin in the lungs as well as in-situ tumor effects, an orthotopic mouse model using bioluminiscence imaging (BLI) will be developed to allow serial lung tumor measurements as well as assessment of metformin effects on the normal lung when combined with irradiation.

      Results
      Of 760 patient treatment courses analyzed, 16 distinct patients with stage III NSCLC were identified that received metformin for diabetes while undergoing definitive chemoradiation. Patients were predominantly female (63%) and had stage IIIA disease (69%). They were treated to a median of 66.6/1.8 Gy with concurrent (81%) or sequential (19%) chemotherapy.A dramatic improvement in LLR in patients receiving metformin was seen compared to historical controls. With a median follow-up time of 10.4 months, only 2 local recurrences (9.6 and 14.9 months post-radiotherapy) have occurred. The median disease-free survival and OS have not been reached. From our in vivo murine data, early data supports the use of metformin as a radiosensitizing agent in the treatment of locally advanced NSCLC.

      Conclusion
      Our clinical experience demonstrates patients receiving definitive chemoradiation for stage III NSCLC who took metformin for diabetes had improved local control and OS compared with our patients not taking metformin and compared with historical controls. Additional evidence is needed to supporting radiation potentiation effects of metformin in the setting of definitive chemoradiation for locally advanced NSCLC patients. Such findings, along with our clinical retrospective data, will lead to institutional prospective clinical trials, for the first-time, using metformin as a radiosensitizing agent in combination with radiation therapy and chemotherapy in the treatment of lung and potentially other cancers.

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      MO05.11 - The Effect of Two BRM Promoter Polymorphisms on the Risk of Advanced Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) in Smokers (ID 1987)

      S. Cuffe, X. Qiu, D. Patel, A.K. Azad, Z. Chen, D. Cheng, K. Boyd, N. Leighl, W. Xu, F.A. Shepherd, M.S. Tsao, D.N. Reisman, G. Liu

      • Abstract
      • Presentation
      • Slides

      Background
      BRM, an ATPase subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in lung cancer. Loss of BRM expression occurs in 15% of lung cancers. Two BRM promoter insertion polymorphisms (BRM-741 and BRM-1321) lead to epigenetic silencing of BRM and highly correlate with loss of BRM expression and function in lung tumors. Pharmacologic reversal of the epigenetic changes of BRM is feasible. We previously demonstrated a strong risk association between these two polymorphisms and susceptibility to early stage NSCLC. Here, we evaluate the association between the two BRM polymorphisms and risk of developing: 1) advanced NSCLC, and 2) SCLC among smokers.

      Methods
      Genotyping for BRM promoter polymorphisms was performed using TaqMan. The cohorts analyzed were: 1) 417 stage III-IV NSCLC cases and 2) 111 SCLC cases treated at the Princess Margaret Cancer Centre (PMCC), Toronto; and 3) 43 SCLC cases from the University of Florida (U of F), all with a smoking history of ≥1 pack-year. Cases were matched to healthy controls by frequency distribution (1:2 for PMCC cases; 1:1 for U of F cases) based on age, gender, pack-year smoking history, and either current smoking status (PMCC) or ethnicity (U of F). Adjusted odds ratios (aORs) with their 95% confidence intervals (CI) of the association between polymorphisms and lung cancer risk were estimated by multiple logistic regression models.

      Results
      Of the 417 NSCLC cases, 59% were male; 41%, current smokers; 63%, adenocarcinoma; 51%, stage IV; median age, 63 years. The frequency of homozygosity was BRM-741, 21%; BRM-1321, 20%; both, 11%. The homozygous variants of BRM-741 and BRM-1321 were associated with an increased risk of advanced NSCLC compared to the wild types, with aOR’s of 1.6 (95% CI: 1.1-2.2; p=0.008) and 1.4 (95% CI: 1.0-2.0; p=0.04), respectively. Being homozygous for both BRM promoter variants carried an even greater risk (aOR 2.4 [95% CI: 1.4-4.0; p=0.0009]), with the strongest effect observed among current smokers (aOR 3.4; p=0.0005), and those with a histological diagnosis other than adenocarcinoma (aOR 3.2; p=0.0005). Among the 111 PMCC SCLC cases, 62% were male; 56%, current smokers; median age 65 years; of the 43 U of F SCLC cases, 35% were male; median age, 63 years. The presence of double homozygous variants of BRM-741 and BRM-1321 had no effect on the risk of developing SCLC in either of the two cohorts analyzed, with aOR’s of 1.1 (95% CI: 0.3-3.5; p=0.94) and 0.3 [95% CI: 0.04-2.41; p=0.27), respectively.

      Conclusion
      The presence of double homozygous variants of the BRM promoter polymorphisms, BRM-741 and BRM-1321, significantly increases the risk of advanced NSCLC among individuals with a smoking history greater than one year, with the strongest effect observed among current smokers. In contrast, the same two polymorphisms had no effect on the risk of developing SCLC in either of the two cohorts analyzed. Thus, this study offers further insight into potential mechanisms underlying the genetic susceptibility to developing advanced NSCLC among smokers. Validation in larger populations is warranted.

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      MO05.12 - DISCUSSANT (ID 3912)

      T. Lynch

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    CALC - Chinese Alliance Against Lung Cancer Session (ID 79)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 2
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      CALC.11 - MicroRNA Biomarkers in Lung Cancer (ID 3878)

      J. Hu

      • Abstract
      • Slides

      Abstract
      ABSTRACT Rationale: Effective treatment for lung cancer requires accuracy in sub-classification of carcinoma subtypes. Objectives: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC). Methods: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung tissues. Quantitative reverse-transcriptase PCR was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung tissues to evaluate 7 microRNA candidates discovered from microarrays. Two microRNA panels were constructed based on a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and SQ from AC in 207 bronchial brushing specimens. Measurements and Main Results: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375, AUC 0.991 and 0.982 for training and validation dataset, respectively) and in differentiating SQ from AC (miR-205 and miR-34a, AUC 0.977 and 0.982 for training and validation dataset, respectively) in FFPE surgical lung tissues. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC 0.947) and SQ from AC (AUC 0.962) in bronchial brushing specimens. Conclusion: We found 2 microRNA panels that accurately discriminated between the 3 subtypes of lung carcinoma in bronchial brushing specimens. The microRNA panels could have considerable clinical value in differential diagnosis and play an important role in determining optimal treatment strategies based on the lung carcinoma subtype.

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      CALC.13 - Novel Lung Cancer Plasma Immunoinflammatory Complexes (ID 3880)

      J. Hu

      • Abstract
      • Slides

      Abstract
      The plasma protein complexes level was measured by electrophoresis analyses in 31 patients with advanced NSCLC treated with 125 or 150 mg/day icotinib hydrochloride until disease progression or unacceptable toxic effects or the patient refused further treatment. Eligibility criteria include performance status≤2, age≥18 years, and stage ⅢB-Ⅳ disease. Herein we found more than 87 % of the change in plasma IIRPCs appears at earlier time than histopathology occurs during the treatment with icotinib hydrochloride: (1) having a crest; (2) having a trough. The increasing or discreasing point always appears at earlier time in the treatment before histopathology occurs. There are no significant differences of the median PFS among the other clinical information groups, including: ages, gender, smoking history and EGFR mutation. Therefore, we showed that measurement of plasma protein complexes level during the treatment in patients with NSCLC may be a new surrogate marker for monitoring the therapeutic efficacy of icotinib and predicting the progression of the disease.

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