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H.J. Kim



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    MO06 - NSCLC - Chemotherapy I (ID 108)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO06.01 - Clinical features of patients with non small cell lung cancer who harbor EGFR mutation and present with miliary intrapulmonary or disseminated carcinomatosis (ID 1744)

      16:15 - 16:20  |  Author(s): H.J. Kim

      • Abstract
      • Presentation
      • Slides

      Background
      It is reported that epidermal growth factor receptor (EGFR) mutation is frequent in non-small cell lung cancer (NSCLC) patients who are presenting with miliary intrapulmonary carcinomatosis. We often encountered disseminated carcinomatosis as well as intrapulmonary carcinomatosis. This study aims to investigate the clinical characteristics of patients with miliary intrapulmonary or disseminated carcinomatosis.

      Methods
      Patients with advanced NSCLC who harbor EGFR mutation and presented with miliary intrapulmonary or disseminated carcinomatosis were enrolled respectively, from September 2005 to January 2011. EGFR mutations in exons 18-21 were confirmed by pyroseqeuncing method after genomic DNA was extracted from paraffin-embedded tissue specimens. Clinical characteristics, responses to treatment and outcome were collected from medical records.

      Results
      Histology of sixty-four patients with NSCLC who have EGFR mutation revealed adenocarcinoma. The most frequent mutation was in-frame deletions in exon 19 (n=44, 68.7%). An arginine-for-leucine substitution at amino acid 858 (L858R) and point mutation in exon 18 (G719A) were detected in 19 (29.7%) and 1 (1.7%) patient, respectively. Patients with miliary intrapulmonary or disseminated carcinomatosis were more common in female (80.0% vs. 55.1%, p=0.084), non smoker (80.0% vs. 53.1%, p=0.063), and in-frame deletions at exon 19 (86.7% vs. 63.3%, p=0.087), however there were no significant difference statistically. They showed relatively shorter progression free survival (PFS) to EGFR tyrosine kinase inhibitors (median PFS 9.7 vs, 12.8 months, p=0.003) and poorer overall survival (median OS 15.9 vs. 29.0 months, p=0.077) compared to patients without miliary metastasis. In multivariate analysis, higher metabolic tumor volume (MTV) in PET-CT was confirmed to be an independent predictor of shorter overall survival, when considered together with tumor stage, gender and smoking status (hazard ratio for MTV: 1.001; p = 0.027).

      Conclusion
      The data indicate that NSCLC presenting miliary intrapulmonary or disseminated carcinomatosis were more common in female, adenocarcinoma, non smoker and in-frame deletions in exon 19 was comparatively frequently detected in those patients, however there were no statistically significant difference. PFS to EGFR tyrosine kinase inhibitors was less in patients with miliary intrapulmonary or disseminated carcinomatosis and overall survival was poorer compared to patients without miliary metastasis. Poor clinical course of these patients might be associated with high tumor burden represented by metabolic tumor volume or total lesion glycolysis.

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-010 - Tumor-derived microvesicles mediate the transfer of gefitinib resistance in lung cancer cells harboring T790M EGFR mutation (ID 1751)

      09:30 - 09:30  |  Author(s): H.J. Kim

      • Abstract

      Background
      Tumor-derived microvesicles (TMV) contain bioactive molecules including proteins, RNA, microRNA, and DNA, and shed TMV propagate the horizontal transfer of their cargo in tumor microenvironment. TMV play important roles in cancer biology such as tumor progression, angiogenesis, escape from immune surveillance, metastasis and drug resistance. In this study, we investigated whether T790M EGFR mutation-related gefitinib resistance could be transferred via TMV using lung cancer cells harboring exon 19 del mutation (PC-9 cells) ± exon 20 T790M mutation (PC-9/GR cells).

      Methods
      TMV were isolated from the culture medium by serial centrifugations. Isolated TMV were checked by electron microscopy for size and intact structure, and characteristic TMV markers (CD81 and ezrin) were verified by western blot analysis. Cytotoxic assay was done using XTT assay and EGFR mutation testing was done using PNA-clamping method.

      Results
      Incubation of PC-9 cells with TMV (40 μg/ml) derived from PC-9/GR cells confer PC-9 cells gefitinib-resistant. EGFR genotyping of TMV in both cells revealed as the same with cellular DNA and this means that TMV carry cell-specific DNA. Passage study after PC-9/GR cell derived TMV transfer showed, however, regained gefitinib sensitivity suggesting that TMV-mediated gefitinib resistance is phenotypically transient. Genotyping after T790M-containing TMV revealed EGFR WT.

      Conclusion
      T790M-associated gefitinib resistance in lung cancer cells might be horizontally transferred via TMV but this type transfer of gefitinib resistance was phenotypically transient in cell-line system and there was no genotype transfer. Further investigation for TMV-mediated transfer of gefitinib resistance is necessary.