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M. Edelman

Moderator of

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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 12
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      MO12.01 - Novel Mechanisms of Sensitivity and Acquired Resistance to HSP90 inhibition by Ganetespib (ID 2739)

      S. Busacca, H. Pringle, E. Law, L. O’regan, A.M. Fry, K. Matchett, V. Reichert, I. El-Hariry, M. El-Tanani, D.A. Fennell

      • Abstract
      • Presentation
      • Slides

      Background
      HSP90 is a promising anti-cancer target. Inhibition by the Hsp90 inhibitor ganetespib has shown promising activity with improved survival in patients with metastatic lung adenocarcinoma, and it is now being evaluated in malignant pleural mesothelioma. However, the mechanisms underlying resistance are currently unknown. The aims of this study were to establish the role for mitochondrial apoptosis in mediating the anti-cancer activity of ganetespib, and to also identify mechanisms of acquired resistance to support personalised therapy.

      Methods
      We conducted a functional genetic screen to determine the role of the proapoptotic BAX/BAK proteins using double knockout mouse embryonic fibroblasts (MEFs) shRNA and siRNA. Focused RNAi targeting BH3-only proteins, Caspase 8 and MCL1 was conducted in MSTO-211H, H460 and H23 cell lines. Apoptosis was measured by a Caspase3 activity assay and data were validated by western blot and SubG1 population analysis. Prosurvival Bcl2 family regulation was evaluated by western blot, and MCL1 transcriptional suppression monitored by real-time quantitative PCR and luciferase reporter assay. MCL1 amplification was quantified by genomic real-time PCR. Ganetespib resistant cells were generated by increasing drug exposure. Hsp90 ATP-binding site and Caspase8 were sequenced in both parental and resistant cell lines.

      Results
      Ganetespib required a functional mitochondrial pathway for induction of apoptosis. Interrogation of pro-apoptotic BH3-only proteins revealed a co-operation between BID, BIK and PUMA. Caspase8 activates BID and, when silenced, protected cells from ganetespib. MCL1 was transcriptionally suppressed by ganetespib, and when Mcl-1 downregulation was achieved by siRNA, it was sufficient to induce BID/BIK-dependent apoptosis in MCL1-dependent cells. We observed that MCL1 addicted cells were also more sensitive to ganetespib than non-addicted. In addition, amplification of MCL1 was detected only in ganetespib sensitive cell lines. Ectopic MCL1 was not sufficient to rescue from ganetespib-induced apoptosis. To better understand mechanisms of resistance, we established ganetespib-resistant cell lines. Resistant cells did not select for HSP90 mutations, and these cells conserved on-target suppression of PI3K/AKT, MAPK signalling, upregulation of HSP70, and MCL1 downregulation. However addiction to MCL1 was lost as was block of Caspase8 activation with consequent cross-resistance to TRAIL. PCR of Caspase8 cDNA revealed an acquired structural alteration in the 3’-untranslated region.

      Conclusion
      Here we show that HSP90 inhibition requires engagement of the mitochondrial apoptosis pathway, and involves cooperation of multiple BH3-only proteins with parallel suppression of MCL1. Interestingly, ganetespib may exploit tumour dependence on MCL1; this may be clinically relevant given that MCL1 (1q21.2) amplification correlates with dependence and its gene copy number alteration is one of the most frequent across cancers. Acquired resistance involves selection for loss of dependence on MCL1, and a block in Caspase8 signalling which lies upstream of BID. Failure of ectopic MCL1 overexpression to rescue is indicative of redundant death signalling by ganetespib. Clinical significance of core apoptosis gene expression will be explored and presented in a correlative analysis of the 9090-06 ganetespib monotherapy clinical trial in NSCLC.

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      MO12.02 - Association between Gene Expression Profiles and Clinical Outcome of Pemetrexed-Based Treatment in Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer: Exploratory Results from a Phase II Study (ID 185)

      D. Fennell, S. Myrand, T. Nguyen, D. Ferry, K.M. Kerr, P. Maxwell, S. Moore, C. Visseren-Grul, M. Das, M. Nicolson

      • Abstract
      • Presentation
      • Slides

      Background
      We report exploratory gene expression profiling data from a prospective single-arm Phase-II-study in patients with non-squamous non-small cell lung cancer (nsNSCLC) treated with pemetrexed. Main results indicated a significant association of low thymidylate-synthase (TS) expression with longer PFS and OS [1].

      Methods
      Treatment-naive nsNSCLC patients (Stage IIIB/IV) received 4 cycles of first-line pemetrexed/cisplatin; non-progressing patients continued on pemetrexed maintenance [1]. Diagnostic tissue samples were used to assess TS expression (nucleus/cytoplasm) by immunohistochemistry (IHC, H scores), and to extract total mRNA for expression-array profiling (expression of 1,030 genes summarized from 60,000 transcripts). Cox proportional-hazard models were applied to explore the association between each gene and PFS/OS, mRNA gene expression was used both as continuous and binary (cutpoint: median) variable. Unadjusted p-values (significance level =0.01) and false discovery rates (FDR) were calculated. Genes significantly correlated with PFS/OS were further correlated with TS-protein expression (Spearman rank test). Finally, unsupervised clustering was applied to all samples with mRNA expression (n=51) for all 1,030 selected array genes and an overlapping 870-gene subset associated with adenocarcinoma (ADC, n=47) previously described [2].

      Results
      51/70 (72.9%) biopsies were evaluable; 9 of 1,030 genes were significantly associated with PFS/OS (unadjusted p<0.01). 8/9 genes were negatively correlated with nuclear TS expression; the test was statistically significant for 5/8 genes (unadjusted p<0.01, Table 1). None of these genes has a known relationship to folate metabolism. Cluster analysis of all 51 samples based on 1,030 genes revealed no clear trend regarding PFS/OS. Cluster-analysis of 47 ADC samples identified 3 groups (n=21, 11 and 15 patients, respectively) with median (95%CI) PFS and OS of 8.1 (6.9, not estimable [NE]) and 20.3 (17.5, N.E) months; 2.4 (1.2, NE) and 4.3 (1.4, NE) months; and 4.4 (1.2, NE) and 8.3 (3.9, NE) months, respectively. Figure 1

      Conclusion
      This exploratory analysis provides insights on key genes potentially linked to low TS expression. Nine genes were significantly associated with PFS/OS; however such association cannot be differentiated as prognostic or predictive since this study is single arm. Further research would be needed to understand the relationship of these markers with clinical outcomes. [1] Nicolson et al, J Thorac Oncol 2013, May 29 [Epub]. [2] Wilkerson et al, PLoS One 2012;7(5):e36530.

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      MO12.03 - Biomarker analysis of a randomized, controlled, multicenter clinical trial comparing pemetrexed/cisplatin and gmcitabine/cisplatin as first-line treatment for advanced nonsquamous non-small cell lung cancer (ID 3483)

      L. Zhang, Y. Huang, Z. Hu, Y. Liu, J. Zhou, N. Xu, B. Li, G. Wu, X. Liu, J. Fang, K. Li, L. Wei, Y. Lu, M. Wang, W. Liu, H. Liang, Y. Zhang, C. Huang, S. Wang, Y. Wang, S. Yu, J. Chang, Z. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      The platinum-based doublet regimen was standard of care in advanced non-small cell lung cancer (NSCLC), but the biomarkers to predict the efficacy of first-line chemotherapy is still controversial.

      Methods
      We collected 239 tumor samples (83.0%) from a a randomized, controlled, multicenter clinical trial, which enrolled 288 treatment naïve nonsquamous NSCLC patients who were randomly assigned (1:1) to experimental group to receive cisplatin plus pemetrexed (PC) or the control group to receive gemcitabine plus cisplatin (GC) every 3 weeks for up to 6 cycles. We evaluated the EGFR mutation by Amplification Refractory Mutation System(ARMS) method and EML4-ALK fusion by real-time PCR. Meanwhile, the mRNA expression of excision repair cross complementation 1 (ERCC-1), thymidylate synthase (TS), ribonucleotide reductase M1(RRM-1), and folatereceptor 1(FR-1) was tested by real-time PCR. All of the EGFR mutation, ALK fusion and mRNA expression were analyzed for the correlation with progression free survival, the primary endpoint in the tiral.

      Results
      The EGFR mutation rate was 46.6%(110/236) in the overall population and the ALK fusion rate was 12.0%(29/233). The median PFS was similar between the EGFR mutated patients and wild-type patients(6.0m vs 5.7m,p=0.85), however, the patients of EGFR wild-type had better PFS in the PC group compared with GC group (5.7m vs 3.5m, p=0.03). There are no significant difference between groups in EGFR mutated patients(5.6m vs 6.1m, p=0.59). The patients with ALK fusion seem to have better PFS compared with fusion negative patients (7.7m vs 5.7m), but the difference is not significant(p=0.48). The mRNA expression level was available in 225 patients(94.1%) and we determined the median expression as the cutoff value. The TS expression is significantly correlated with ERCC-1(r=0.67,p<0.001) and negatively correlated with FR-1 expression(r=-0.21,p=0.002). EGFR mutation correlated with lower TS expression(p=0.034) and ALK fusion correlated with higher FR-1 expression(p=0.017). The differences of PFS between the high and low expression of ERCC-1, TS, RRM-1and FR-1 was not significant, in both PC group and GC group.

      Conclusion
      The expression level of ERCC-1, TS, RRM-1and FR-1 could not effectively predict the progression free survival of NSCLC patients receiving platinum-based doublet regimen. The pemetrexed plus cisplatin regimen should be the priority choice for EGFR wild type patients compared with gemcitabine plus cisplatin regimen.

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      MO12.04 - Biomarker Analysis of NCIC Clinical Trials Group IND.196, a Phase I study of erlotinib plus foretinib in advanced pretreated non-small cell lung cancer patients (ID 3148)

      N. Leighl, M.S. Tsao, S. Sakashita, D. Tu, C. Ho, N. Murray, F.A. Shepherd, G. Nicholas, J.R. Goffin, L. Kim, S. Kamel-Reid, J. Ho, T. Zhang, M. Sukhai, L. Seymour, G. Goss, P. Bradbury

      • Abstract
      • Presentation
      • Slides

      Background
      Upregulation of MET and more recently AXL have been described as potential mechanisms of resistance to EGFR tyrosine kinase inhibitors in NSCLC. We explored the impact of baseline MET and AXL tumour expression and circulating hepatocyte growth factor levels, (HGF), in advanced NSCLC patients receiving erlotinib plus foretinib, an oral multi-targeted kinase inhibitor of MET, RON, AXL, TIE-2 and VEGFR.

      Methods
      Advanced NSCLC patients that previously received one or two lines of chemotherapy were treated in IND.196, a phase I dose-finding trial with an initial two-week run-in of single agent erlotinib (100-150 mg daily). If erlotinib was well tolerated, foretinib was then added (30-45 mg daily). Submission of tumour samples (archival or fresh) was mandatory, and circulating HGF levels were determined at baseline and on treatment. Tumour samples were genotyped using Sequenom MassARRAY analysis. MET and AXL expression were determined by immunohistochemistry. For AXL, the human Axl affinity purified polyclonal goat IgG antibody (R&D systems, AF154, Minneapolis MN) was scored manually. For MET, the anti-total MET (SP-44) rabbit monoclonal antibody (Ventana Medical Systems, Tucson AZ) was scored using the Benchmark XT autostainer. Staining intensity (0-3+) and percent cells stained were used to calculate the H-score; H-scores >100 were deemed positive for AXL, and >200 positive for MET.

      Results
      Of 31 patients enrolled, 28 were evaluable for response to combination therapy, with a recommended phase II dose of erlotinib 150 mg daily for a 2-week run-in and then foretinib 30 mg daily added. The overall response rate in the intent to treat population (RECIST 1.1) was 16.1% (95% CI 5.5-33.7%), with partial responses (PR) seen in 5/31 patients and a median response duration of 17.9 months (range 3.6-17.9). Stable disease was seen in 42% (13/31), with a median duration of 4.8 months (95% CI 2.4-15.4). Tumour samples were submitted for 25 patients; 15 had sufficient tissue for genotyping, 17 for assessment of MET, and 16 for AXL expression. 2/5 responding patients had confirmed EGFR mutations, (1 wildtype, 2 unknown). Another 5 had KRAS mutations, one with >20% reduction in tumour size but SD by RECIST. Of 17 patients with MET IHC results, 71% (12/17) were positive. PR was seen in 3/12 patients with MET-positive tumours, (2 with EGFR mutations, 1 wildtype). No response was seen in those with MET-negative tumours. Of 16 samples with AXL IHC results, 9 were positive (56%). PR was seen in 2/9 with AXL-positive tumours and 2/6 with AXL-negative tumours. AXL expression was not seen in samples with EGFR mutations, but 3/5 KRAS mutant samples were AXL positive. Assessment of circulating HGF levels will be presented at the 2013 WCLC meeting.

      Conclusion
      Baseline MET expression, uncontrolled for EGFR status, may be associated with response to combination erlotinib/foretinib. No correlation between baseline AXL expression and response was seen although the sample size is small. Further study is needed to control for the impact of EGFR mutation status on response, and to assess whether combination erlotinib/foretinib can overcome resistance to EGFR TKI therapy mediated by MET and AXL.

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      MO12.05 - A new biomarker Heat shock protein 90 alpha as therapeutic monitor and predictor for lung cancer patients (ID 2628)

      Y. Shi, X. Liu, J. Lou, X. Han, L. Zhang, Q. Wang, B. Li, M. Dong, Y. Zhang

      • Abstract
      • Presentation
      • Slides

      Background
      Heat shock proteins are a group of proteins termed stress proteins. The family of Hsp90 includes Hsp90α and Hsp90β, but only Hsp90α has been described to be extracellular, and the presence of Hsp90α on cell surface has been shown to correlate with malignancy in cancer patients, especially with the tumor metastasis. However, to the best of our knowledge, no large clinical samples have been reported to verify above standpoint. The aim of the present multicenter clinical study was to evaluate the expression level of Hsp90α in lung cancer patients and whether Hsp90α was monitor and predictor for response to therapy in lung cancer.

      Methods
      A total of 2284 lung cancer patients were enrolled in this study which was randomly assigned into two groups as static and dynamic groups. The static group (2036 samples) consisted of healthy subjects (592 samples), lung cancer (1046 samples), non-cancerous lesions of the lung patients(361 samples ) and other cancer patients(37 samples). Samples of peripheral blood from all subjects were collected in sterile EDTA-K2-coated vials. Whereas the dynamic group included lung cancer patients who received surgical treatment and underwent chemotherapy, with number of above mentioned parts 79 and 169, respectively. For surgical patients, plasma samples were collected at following time points: 3 days before surgery, 3-7 days after surgery and 3 days after clinical efficacy evaluation. Similarly, plasma samples of chemotherapy patients were also collected before treatment, after each chemotherapy cycle until the forth cycle. The concentrations of Hsp90α in plasma were measured by enzyme-linked immunosorbent assay.

      Results
      The concentration of Hsp90α in lung cancer patients was significantly higher than in other control groups (P <0.05). The cut-off value was 56.33 ng/mL for diagnosis, with high sensitivity and specificity (72.18% and 78.70%, respectively). Advanced lung cancer (stage III-Ⅳ) patients were with higher Hsp90α levels than the early patients(stage I-II) (251.38 ng/ml vs 111.50ng/ml, P<0.001), no significant relationship was found between non-small cell lung cancer(NSCLC,910 samples)patients and small cell lung cancer (SLCL, 136 samples)patients, and patients with adenocarcinoma(537 samples) and squamouscarcinoma (218 samples). Furthermore, a statistically significant association was observed between pre-operative and post-operative patients in surgical patients group (P<0.01). In chemotherapy patients group, Hsp90α level was correlated significantly with the effect of treatment [concentration of Hsp90α was higher in progressive disease(PD)group than in partial response(PR)/stable disease(SD) group].

      Conclusion
      This study firstly developed large clinical samples and elucidated the role of Hsp90α in the lung cancer patients. The cut-off value of 56.33 ng/mL was recommended to assess the expression level of Hsp90α in lung cancer patients. Hsp90α may be a potential biomarker for therapeutic monitor and prediction for lung cancer.

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      MO12.06 - DISCUSSANT (ID 3913)

      V. Papadimitrakopoulou

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MO12.07 - The prevalence of MET expression by immunohistochemistry (IHC) in the MetLung (OAM4971g) trial: a randomized, placebo-controlled, phase III study with erlotinib + onartuzumab (MetMAb) vs erlotinib + placebo in patients with previously treated non-small cell lung cancer (NSCLC) (ID 2709)

      M.J. Edelman, D. Spigel, K. O'Byrne, T. Mok, S. Mocci, W. Yu, V. Paton, L. Paz-Ares Rodriguez

      • Abstract
      • Presentation
      • Slides

      Background
      MET signaling is correlated with a poor prognosis in multiple tumor types, including NSCLC. A randomized, controlled, phase II clinical trial demonstrated a PFS and OS benefit of inhibiting MET signaling with erlotinib + onartuzumab, a humanized monovalent antibody to the MET receptor, in patients whose NSCLC over-expressed MET by IHC (in press). A phase III trial (OAM4971g) is ongoing to confirm the benefit of onartuzumab when combined with erlotinib in patients with previously treated NSCLC whose tumors over-express MET by IHC (2+/3+ only). Here, we present the prevalence rates of MET expression and EGFR mutation status for patients whose tumor tissues were screened and for those enrolled in the phase III study.

      Methods
      Archival or fresh biopsy tumor specimens were submitted to a central laboratory for both MET IHC and EGFR mutation assessment. MET IHC status was determined using the CONFIRM SP44 anti-MET monoclonal antibody (Ventana Medical Systems, Inc., Tucson, AZ). Patients were selected based on expression of MET by IHC, as defined by moderate or strong staining in at least 50% of tumor cells (clinical score 2+/3+). The cobas[®]EGFR mutation test was used to stratify enrollment.

      Results
      Between November 2011 and June 2013, 1605 tumor tissue samples were submitted for MET IHC and EGFR activating mutation analysis, from 188 clinical study centers. The majority of screened and enrolled patients were over 60 years of age, Caucasian, male, and had non-squamous NSCLC histology (see table). MET IHC results are available for 1474 (92%) of all submitted samples: IHC 0 (n=118, 8%), IHC 1+ (n=619, 42%), IHC 2+ (n=575, 39%), IHC 3+ (n=162, 11%). The incidence of MET IHC 2+/3+ in screened patient subgroups is as follows: non-squamous 52.5%; squamous 29.2%; non-Asian 45.9%; Asian 48%; EGFR wild type 50.3%; EGFR mutant 57.5%. Table: Patient characteristics for screened and enrolled patients in the OAM4971g study

      Screened (n=1605) Enrolled (n=443)
      Age (years)
      n 1482 442
      Median 63.0 62.5
      Range 24–89 24–84
      Race
      n 1482 443
      White 1187 (80.1%) 316 (71.3%)
      Asian 185 (12.5%) 72 (16.3%)
      Black or African American 44 (3.0%) 11 (2.5%)
      Sex
      n 1483 443
      Male 937 (63.2%) 244 (55.1%)
      Histology
      n 1451 440
      Non-squamous 1096 (75.5%) 374 (85.0%)
      MET IHC score
      n 1474 443
      3+ 162 (11.0%) 97 (21.9%)
      2+ 575 (39.0%) 346 (78.1%)
      1+ 619 (42.0%) 0 (0.0%)
      0 118 (8.0%) 0 (0.0%)
      EGFR activating mutation
      n 1422 443
      Yes 114 (8.0%) 46 (10.4%)
      No 1308 (92.0%) 397 (89.6%)

      Conclusion
      In this large population, the prevalence of MET IHC 2+/3+ was 50% in screened samples, consistent with prior IHC results for MET prevalence. The prevalence of MET IHC 2+/3+ was higher in non-squamous vs squamous tissue samples, but equally distributed across ethnicity and EGFR mutation status. The ongoing OAM4971g study will prospectively confirm whether blocking MET signaling in patients with MET IHC 2+/3+ over-expressing NSCLC provides clinically meaningful benefit in all enrolled patients and in important clinical subpopulations.

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      MO12.08 - Hepatocyte growth factor (HGF) serum levels predict for outcome in patients with Small Cell Lung Carcinoma (SCLC) (ID 2720)

      I. González, I. Cañadas, A. Taus, D. Casadevall, A.I. Luque, X. Villanueva, A. Rovira, J. Albanell, E. Arriola

      • Abstract
      • Presentation
      • Slides

      Background
      Small cell lung cancer (SCLC) accounts for approximately 15% of lung cancers. Treatment for SCLC has not changed in recent years and no targeted therapy has shown an increase in survival. We have previouly shown that Met phosphorylation is an adverse prognostic factor in this disease, suggesting a potential interest of Met targeted therapies in the treatment of SCLC patients. The aims of our study were to evaluate serum levels of the Met ligand, the hepatocyte growth factor (HGF) in patients with SCLC and to assess the correlations with other clinical variables and survival.

      Methods
      This is a prospective study conducted between 2009 and 2012. Serum samples were obtained from patients with SCLC at diagnosis, at first evaluation of response to standard chemotherapy by computerized tomography (CT) and at progression/relapse (first event). HGF levels were assessed by ELISA using the Quantikine commercial kit (R&D Systems, Minneapolis, MN). We evaluated the association between HGF levels and clinical-pathological variables by the Mann-Whitney tests and with survival in univariate (log-rank test) and multivariate analysis (Cox regression), assuming a statistical significance of p <0.05.

      Results
      Fifty-nine patients were included in this study. Median follow-up was 11 months. Patients’ characteristics are summarized in Table 1. The median serum HGF (range) at diagnosis, response and progression were 1750 pg/ml (651-9853), 1573 pg/ml (593-8518) and 1461 pg/ml (553-12956), respectively. In 72.5% of cases HGF levels decreased after 3 cycles of chemotherapy (platinum+etoposide). From the response time point to progression, 50% patients showed an increase in the HGF levels. The median overall survival (OS) for the entire population was 11,8 months(95% CI 6.4-14.8). The median OS for patients with high basal HGF (above 1750pg/ml) was 7,9 months vs 16,7 months for patients with basal HGF below the median. Patients whose HGF levels increased at progression presented a decreased survival (9,23 months) vs. those with a decrease (15,11 months) (p=0.032). In the multivariate analysis, PS> 1 (HR: 5.57, 95% CI 2.63-11.77 p < 0.001), stage IV (HR: 4.28, 95% CI 1.76-10.44 p = 0.001) and elevated HGF basal levels were independently associated with worse OS (HR: 3.32, 95% CI 1.57-7.03, p =0.002).

      Patients' characteristics
      N (%)
      Median age 65.6 (46-86)
      Gender Male 48 (81.4)
      Female 11 (18.6)
      Smoking status Current 40 (67.8)
      Former 18 (30.5)
      Never 1 (1.7)
      Performance status 0-1 44 (74.6)
      2-3 15 (25.4)
      Stage I-III 16 (27.1)
      IV 43 (72.9)

      Conclusion
      HGF serum levels at diagnosis and changes during treatment are predictors of survival in patients with SCLC treated with standard first-line chemotherapy.

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      MO12.09 - BIM deletion polymorphism in Asian and treatment outcome to chemotherapy in advanced non-small cell lung cancer (ID 2530)

      J. Lee, Y. Lin, W. Hsu, H. Chen, Y. Chang, C. Yu, J. Shih, P. Yang, K. Chen, J.C. Yang

      • Abstract
      • Presentation
      • Slides

      Background
      BIM deletion polymorphism was reported to be associated with poor outcome to epidermal growth factor receptor (EGFR) inhibitor in advanced non-small cell lung cancer (NSCLC) harboring mutant EGFR gene. Little is known whether BIM deletion polymorphism influences treatment outcome to chemotherapy in NSCLC.

      Methods
      We prospectively collect blood samples and clinical data from two independent cohorts of advanced NSCLC patients. The first cohort is composed of 52 patients who received first-line chemotherapies, and the second cohort is composed of 69 patients who received chemotherapy after front-line gefitinib. BIM deletion polymorphism was determined from blood using polymerase chain reaction. EGFR gene was studied in 94 tumors and were classified as wild type, common EGFR mutation (deletion 19 or L858R), or other mutations.

      Results
      The median progression-free survival (PFS) to the first cohort and second cohort were 4.6 and 5.7 months, respectively (p=0.94). The PFS for tumors carrying wild-type, common mutant, and other mutant EGFR genes were 5.8, 4.4, and 7.2 months, respectively (p=0.31). The BIM deletion polymorphism was detected in 19 samples (15.7%). The PFS of patients with normal BIM (solid line of the figure) and BIM deletion polymorphism (dashed line of the figure) were 5.6 and 3.5 months (p=0.03). BIM deletion was related to shorter PFS in tumors carrying mutant EGFR gene (p=0.006) but not those carrying wild-type or other mutant EGFR genes. A multivariate analysis suggested BIM deletion was an independent predictor for shorter PFS to chemotherapy (harzard ratio=2.71, p=0.003).

      variate hazard ratio p-value
      BIM deletion 2.71 0.003
      Male gender 1.57 0.04
      stage IV disease 1.93 0.18
      EGFR mutation 1.0 0.96
      Old age 1.01 0.21
      Figure 1

      Conclusion
      BIM deletion polymorphism is associated with shorter PFS to chemotherapy in advanced NSCLC.

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      MO12.10 - Analysis of BIM Deletion polymorphism in Chinese Patients with NSCLC (ID 1083)

      J. Zhong, J. Wang, Z. Li, X. Yang, H. Bai, J. Duan

      • Abstract
      • Presentation
      • Slides

      Background
      Drug resistance significantly weakens the effect of treatment. BIM deletion polymorphism has emerged as a potential drug resistant biomarker. This study aimed at assessing the correlation of BIM deletion with the outcome of Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs ) and chemotherapy in Chinese NSCLC patients

      Methods
      290 patients with advanced NSCLC who received EGFR-TKIs and chemotherapy were included in this retrospective study. BIM deletion polymorphism and EGFR mutations were detected by Polymerase Chain Reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC) respectively.

      Results
      BIM deletion polymorphism occurs commonly in Chinese NSCLC patients (15.5%, 45/290). No associations were observed between BIM deletion polymorphism with clinicopathology characteristics including sex, smoking and EGFR mutation status. BIM deletion polymorphism predicts shorter PFS in Chinese patients with EGFR-mutant NSCLC received EGFR-TKIs (6.69 vs 8.47months, P=0.023). Meanwhile, we found that BIM deletion polymorphism is an effective predictor of short PFS in individuals with EGFR-mutant NSCLC treated with pemetrexed contained chemotherapy (3.32vs5.30, P=0.012) or with second-/beyond-line Taxanes contained chemotherapy (1.53 vs 2.61months, P=0.025) However, In the EGFR-wild type group, the difference is not significant for the former two groups. patients with this deletion are prone to suffering serious adverse event (SAE) (4.5% vs. 15.6%, P=0.018). BIM deletion lacks for correlation with OS. (21.87vs21.90months, P=0.627), even in the EGFR-mutant group.

      Conclusion
      BIM deletion polymorphism occurs in 15.5% Chinese NSCLC patients. BIM deletion polymorphism is a drug resistance biomarker for TKIs and chemotherapy in NSCLC. BIM deletion possibly affects OS, but not a decisive factor.

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      MO12.11 - The predictive role of common BIM deletion polymorphism and BIM expression on the EGFR-TKI therapy in never-smoking lung adenocarcinoma (ID 2161)

      J. Han, G.K. Lee, S.J. Yoon, S.R. Goo, J.S. Lee

      • Abstract
      • Presentation
      • Slides

      Background
      The BCL-2 homology domain 3 (BH3)-only protein, B-cell lymphoma 2 interacting mediator of cell death (BIM) is a potent pro-apoptotic protein. Recent data suggest that pretreatment BIM level may predict responsiveness to EGFR-TKI in EGFR-mutant non-small cell lung cancer (NSCLC). In addition, a common BIM deletion polymorphism contributes to the heterogeneity of response to EGFR-TKI in EGFR-mutant NSCLC. We investigated whether BIM expression and BIM deletion polymorphism (BIM-DEL) are predictive for response rate (RR) and progression-free survival (PFS) to EGFR-TKI therapy in never-smoking lung adenocarcinoma (NSLA).

      Methods
      We analyzed EGFR mutation status by Sanger sequencing, BIM-DEL genotyping by polymerase-chain reaction and BIM expression by immunohistochemistry using archival tissues or blood from 203 patients who participated in the FIRST-SIGNAL trial (1[st] line gefitinib vs. Gemcitabine/cisplatin in advanced NSLA).

      Results
      EGFR mutation test, BIM-DEL genotyping and BIM-IHC analysis were available in 82, 126 and 60 patients, respectively. Forty-five (55%) patients had EGFR mutations, 22 (18%) showed BIM-DEL and 22 (37%) showed negative BIM expression. BIM expression was significantly associated with EGFR mutation status; more patients with EGFR-mutant NSCLC showed negative BIM expression (48% vs. 21%, P=0.030). BIM-DEL was not associated with EGFR mutation status or BIM expression. Among 181 patients who received EGFR-TKI as 1[st] or 2[nd]-line therapy, EGFR mutation, BIM-DEL and BIM expression data were available in 74, 11, 56 patients, respectively. EGFR mutation was predictive for higher RR (66% vs. 15%, P<.001) and longer PFS (4.5 vs. 1.9 months, P=.061) to EGFR-TKI therapy. Negative BIM expression also showed a trend toward higher RR (68% vs. 42%, P=.061) and longer PFS (6.9 vs. 2.3 months, P=.233) with EGFR-TKI. However, BIM-DEL was not predictive for RR (41% vs. 47%, P=.645) or PFS (3.5 vs. 3.7 months, P=.892) to EGFR-TKI.

      Conclusion
      Both BIM-DEL and BIM expression were not predictive for responsiveness to EGFR-TKI in NSLA. The trend between negative BIM expression and favorable response to EGFR-TKI may be resulted from higher frequency of EGFR mutation in these patients.

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      MO12.12 - DISCUSSANT (ID 3914)

      A. Adjei

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    Y - Young Investigator & First Time Attendee Session (ID 77)

    • Event: WCLC 2013
    • Type: Other Sessions
    • Track: Other Topics
    • Presentations: 8
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      Refreshment Break (ID 647)

      N. n/a

      • Abstract

      Abstract not provided

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      Y.1 - Planning an Academic Career in Lung Cancer (ID 642)

      N. Leighl

      • Abstract
      • Presentation
      • Slides

      Abstract
      There are many academic career opportunities for the young oncologist. Examples of career tracks include basic, translational and clinical research, education and administration. Finding a niche, or an unique area of contribution, is essential. Key elements for success include: 1. Finding a mentor - you can have more than one, and s/he doesn't need to be at your institution; 2. Spending time in academic training, such as pursuing formal research methodology training, administration or education training (e.g. Masters of Public Health, Business Administration or Education, and higher); 3. Developing a team to support you - include clinical support, research support or the personnel you need to achieve your career goals; 4. Build strategic partnerships and build a collaborative network - for example if you're not a scientist and wish to do translational research, partner with scientists. Engage statisticians, methods experts, and remember that collaboration is a two-way street; 5. Challenge yourself to ask important questions in your area of study, and focus on key issues - aim high and trust yourself; 6. Be a mentor to junior trainees - this is your best investment; 7. Publish your work; 8. Apply for grants (and don't give up - you will get some!); 9. Focus on your areas of interest - your areas of priority may not be where you spend most of your time, but they should be; 10. Keep your passion for your career alive - have a life outside academic oncology, enjoy your work and keep it fun. 11. Take advantage of opportunities for development - presentation skills, teaching skills, grant writing, paper writing, research methods - essential for a successful career, and not taught in medical school. 12. If you pursue a career in clinical research, join a cooperative group. Accrual is one way that young investigators can get themselves noticed, in addition to new ideas.

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      Y.2 - How to Present Data at a Conference (ID 643)

      M. Boyer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      Y.3 - How to Write a Grant Application for the IASLC (ID 644)

      K. Kelly

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      Y.4 - How to Get your Papers Published (ID 645)

      J.R. Jett

      • Abstract
      • Presentation
      • Slides

      Abstract
      HOW TO GET YOUR PAPERS PUBLISHED? James R. Jett, M.D. Professor of Medicine National Jewish Health Denver, Colorado, USA 80206 Scientific writing is not something that comes easily to most of us. I personally struggled with my own publications for the first five years of my academic career. However, I advise young colleagues that they should aim for three to five publications per year. If this is accomplished, then at the end of ten years, you would have 30-50 publications on your curriculum vitae. This would be enough to result in promotion from Assistant Professor to Associate Professor in most institutions. How does one get started with publishing articles? Before starting, I would suggest that you read about publishing scientific articles. An excellent book that covers all aspects of scientific writing is “How to Write and Publish a Scientific Paper” by Robert Day and Barbara Gastel. This book has individual chapters on preparing Abstract, Introduction, Methods, Results, Discussion, and References. This text is an excellent source on “how to do it”. There are also chapters on writing review papers, editorials, book chapters, and writing for the public. Additional chapters address ethics in publication, use and misuse of English, use of abbreviations. Especially useful to authors whose first language is not English is the chapter, “How to Write Science in English as a Foreign Language”. Another good source, available on the internet, is the International Committee of Medical Journal Editors (ICMJE) web site. Just type those initials into your web browser and review the “Uniform Requirements for Manuscript Submitted to Biomedical Journals: Preparing a Manuscript for Submission to a Biomedical Journal.” Major ethical issues include simultaneous submission to two journals, duplicate publication of the same data, plagiarism, and ghost writing. Violation of any of these issues will likely result in significant damage to your reputation and potential punishment by your institution. Violations often result in authors being banned from publishing in journals for several years. It can destroy your academic career. Needless to say, it will make your boss very unhappy! Before you submit a manuscript to any journal, it is mandatory that you review the “Instructions to Authors” for the specific journal. When I was Editor of Journal of Thoracic Oncology, one of the most common reasons for rejection was that authors did not follow the instructions. It is also advisable that you should read several articles, in the journal where you wish to publish, to be sure that you follow a similar style to articles that the journal has published. I also recommend searching for articles on the same topic in the journal for which you are planning the submission. If they have published several articles in the past year or two on this same topic, then you may want to consider a different journal, unless your article contains new and original information. The following are some of the most common reasons for articles to be rejected: Failure to read and follow instructions to authors Poor quality of English Non-structured Abstract Lack of novelty (me too articles) Dataset too small; flawed statistics The title and the abstract are extremely important. Often they are the only part of the article that is read. Readers decide, after reviewing these, if they wish to read the entire article. The words in the title should be carefully chosen. Pay careful attention to syntax. Avoid the temptation to be “too clever” in the title. Titles are used by indexing and abstracting services and help readers find your article in the morass of the medical literature. Write the abstract last. It should be a condensed version of the manuscript. Readers look at the abstract to see if they wish to read more. Sometimes an editor will read only the abstract and make a decision on rejection. I have done this many times. A poor abstract frequently means a poor manuscript. Most journals have a word limit for the abstract, frequently 250 words or fewer, and require a four-part structured abstract. Make sure that all of the numbers in the abstract match the numbers in the results section. This is a common error and reflects poorly on the author. Be concise! Remember that the abstract is your chance to get the attention of the reader (reviewer). Lastly, do not let a rejection discourage you. Pay careful attention to the critique that you have received and consider revising your article accordingly. Remember that the “peer review” process is not perfect. Reviewers can make mistakes and not recognize the merits of your manuscript. Revise your manuscript and send it to another journal. The majority of my own peer-reviewed publications were not accepted in the first journal where they were submitted. I have personally been rejected by many of the best medical journals. Do not take rejection personally. Try, try again!!!

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      Y.5 - Using the Published Literature Effectively (ID 646)

      M. Stockler

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      Y.6 - Making the Most of the WCLC: A Guide for First Time Attendees (ID 648)

      P. Lara

      • Abstract
      • Presentation
      • Slides

      Abstract
      The 15[th] World Conference on Lung Cancer (WCLC) is a highly interactive, collaborative, and intellectually enriching forum that focuses on the biology, diagnosis, and management of thoracic malignancies. For first-time attendees, the sheer scope and depth of the WCLC can be quite daunting. This educational session is designed for the young investigator or first time attendee. It aims to provide practical tools that will help the attendee navigate the 15[th] WCLC. This year, the Core Program Committee has organized a scientific program that includes more than 250 internationally renowned speakers and chairs participating in more than 100 sessions. The program can essentially be categorized as a component of either the Education Program or Scientific Program. The Education Program includes Invited Sessions wherein key faculty present state-of-the-art talks on relevant topics, as well as “Meet The Expert Sessions” that provide opportunities for attendees to directly interact with faculty . The Scientific Program includes cutting-edge and late-breaking research presented in oral, mini-oral, and poster formats. The Scientific Program also includes the Plenary Sessions, the Presidential Symposium (where the top rated abstracts are presented), and Highlights of the Day (where expert faculty summarize the past day’s most outstanding presentations), among others. There are also additional educational sessions such as Industry-Sponsored Symposia, a Patient Advocacy session, a Cochrane Workshop, and new to the 2013 meeting, a Chinese Alliance Against Lung Cancer session. First timers must carefully note that WCLC sessions can either be stand-alone (i.e, with no competing sessions such as the Plenary Sessions) or concurrent (e.g., oral and mini-abstract sessions). The organizers have developed a color-coded “session at a glance” diagram that clearly denotes each session’s schedule relative to others. (An online “virtual WCLC” will soon be developed to provide attendees access to concurrent sessions that they may miss because of a competing session.) There are also social events such as the Welcome Reception and the Gala Dinner that provide additional opportunities for first time attendees to interact with colleagues and faculty. It is thus anticipated that the 15[th] WCLC will provide young investigators and first time attendees a unique framework on which to build new collaborations that will ultimately have an impact on the future care of the patient with thoracic cancer.

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      Y.7 - Q&A and Networking Opportunity with Longstanding IASLC Members (ID 649)

      N. n/a

      • Abstract

      Abstract not provided



Author of

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    HOD2 - Mondays Highlights of the Day - Medical Oncology, Biology and Pathology (ID 225)

    • Event: WCLC 2013
    • Type: Highlight of the Day Session
    • Track: Medical Oncology
    • Presentations: 1
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      HOD2.1 - Medical Oncology (ID 4039)

      M. Edelman

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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