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T. Hase



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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.02-010 - Evaluation of the oncogenic ability of EML4-ALK to transform human bronchial epithelial cells (HBECs) (ID 1503)

      09:30 - 09:30  |  Author(s): T. Hase

      • Abstract

      Background
      Lung cancer is a highly lethal disease, and is believed to develop through a multistep carcinogenic process, which involves numerous genetic and epigenetic alterations. Among these alterations, mutations in “driver genes” such as KRAS and EGFR are found in non-small cell lung cancer (NSCLC) and they are demonstrated to contribute to a phenomenon, oncogene addiction. Recently, the EML4-ALK (echinoderm microtubule-associated protein–like 4 anaplastic lymphoma kinase) fusion gene has been discovered as a novel driver gene in a subset of NSCLC. We evaluated the oncogenic transformation ability of EML4-ALK by using an hTERT/CDK4-immortalized normal human bronchial epithelial cell (HBEC) model.

      Methods
      We used two HBEC lines, HBEC3 and HBEC4. Mutant KRAS[V12]-expressing HBEC was used as a positive control for oncogenic transformation. A lentiviral vector system was used to generate HBECs stably expressing EML4-ALK. EML4-ALK protein expression was confirmed by westernblotting, and downstream pathways were analyzed by westernblotting with phospho-specific antibodies. Malignant phenotypes of EML4-ALK-expressing HBECs were examined by WST-1 proliferation assay and liquid and soft agar colony formation assays.

      Results
      Westernblotting analysis showed that EML4-ALK was expressed in HBECs. Analysis of downstream pathways did not show significant differences between EML4-ALK-expressing and control HBECs. Introduction of EML4-ALK in HBECs increased the number of soft agar colonies but its effect was not as strong as KRAS[V12].Figure 1 A. Soft agar colony formation assay showing that EML4-ALK increased the number of colonies compared to control cells to a lesser extent than did KRAS[V12]. B. Cell proliferation assay (MTS-1) showing no significant difference between EML4-ALK-expressing and control HBECs.

      Conclusion
      EML4-ALK alone did not induce dramatic oncogenic changes in HBECs. To acquire more malignant phenotype, additional genomic alterations may be required and this is now under investigation.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-041 - A phase II trial of erlotinib for previously treated Japanese patients with advanced non-small cell lung cancer harboring EGFR mutations: results of the Central Japan Lung Study Group trial (CJLSG0904). (ID 2283)

      09:30 - 09:30  |  Author(s): T. Hase

      • Abstract

      Background
      Several prospective studies have demonstrated activating mutations in the epidermal growth factor receptor (EGFR) gene are a predictor of response to EGFR tyrosine kinase inhibitor (TKI). Erlotinib is one of EGFR-TKIs available in Japan. However, there are a few prospective reports on the efficacy and safety of erlotinib therapy in Japanese patients with previously treated advanced EGFR mutation-positive non-small cell lung cancer (NSCLC).

      Methods
      We undertook a multicenter, open-label, single-arm, phase II study. Patients with performance statuses of 0 to 2 and stage IIIB/IV NSCLC with EGFR-sensitive mutations (exon19 and 21) were eligible if they were treated with one or two prior chemotherapy regimens containing at least one platinum-based doublet. They received oral erlotinib at a dose of 150mg daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), while secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) as well as toxicity. This study is registered with UMIN (University Hospital Medical Information Network in Japan), number 000002716.

      Results
      Between November 2009 to July 2012, 29 patients (median age, 68 years; range, 40-77 years) were enrolled. No complete response and 17 partial responses were observed, giving the ORR was 58.6% (95% confidence interval (CI): 38.9-76.5%). Ten patients had stable disease and 2 patients had progressive disease. Thus, the DCR was 93.1% (95% CI: 77.2-99.2%). After a median follow-up of 14.7 months (range, 5.3-37.0 months), the median PFS was 9.5 months (95% CI, 5.9-13.2 months). The median OS has not yet been reached. The most common adverse events were skin rash (96.6%; 13.8% grade ≥ 3), and hepatic function disorder including increased ALT (65.5%) and increased AST (48.3%). No interstitial lung disease events or cases of toxic death were reported.

      Conclusion
      These results indicate that erlotinib monotherapy could be a potential treatment option with favorable clinical outcomes for Japanese patients with previously treated advanced NSCLC with EGFR mutations.