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L. Ma



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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-038 - The significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK target therapy (ID 2757)

      09:30 - 09:30  |  Author(s): L. Ma

      • Abstract

      Background
      ALK rearrangements are detected in 3%~7% in unselected non-small cell lung cancer (NSCLC) and accurate determination of ALK rearrangements are the key importance to screen appropriate candidates for ALK inhibitor therapy. Previous studies showed that IHC could be a promising prescreening method. However, the correlation between IHC results and clinical outcomes had not been confirmed. This study aimed to elucidate clinical significance of ALK rearrangement in selected advanced NSCLC patients and evaluate a possible association between ALK expression and clinical outcomes in ALK positive crizotinib-treated patients.

      Methods
      ALK status was assessed by FISH, immunohistochemistry (IHC) and quantitative RT-PCR(qRT-PCR) in 173 selected advanced NSCLC patients who were aiming at undergoing ALK screening for crizotinib therapy. Clinicopathologic data, genotype status and survival outcomes were analyzed. In addtion, we correlated ALK expression with clinical outcomes in crizotinb treated patients including two patients with concurrent ALK rearrangement and EGFR mutation.

      Results
      ALK positive detection rate was 35.5% (59/166), 36.3% (61/168), 27.9% (34/122) by FISH, IHC and qRT-PCR, respectively. Among the 166 advanced NSCLC patients who were successfully underwent ALK screening by FISH, 20 patients with EGFR mutation, 87 patients with wild type status and 2 (3.4%, 2/59) patients with concurrent ALK rearrangement and EGFR mutation. Of the 59 patients with FISH-positive ALK rearrangement, 45 received crizotinib in the phase II clinical trial (PROFILE 1005), 8 were enrolled in the phase III clinical trial (PROFILE 1014) and 6 did not participate in any clinical trial. ALK-positive patients have distinct clinicopathological features. ALK FISH-positive and crizotinib-treated patients (PROFILE 1005) had a median progression-free survival (PFS) of 7.6 months and longer overall survival (OS) compared with crizotinib-naïve (P<0.0001) or wild type cohorts (P=0.0138), but there was no significant difference in OS compared with EGFR mutation patients(P=0.8959). ALK positive and negative patients divided by qRT-PCR in the ALK FISH crizotinib-treated patients had no different in clinical outcomes. ALK expression was not associated with PFS (P=0.792) and OS (P=0.325). However, when used IHC expression as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P=0.026). The two patients with concurrent EGFR mutation and ALK rearrangement had difference in ALK expression, response to TKIs and crizotinib, and overall survival.

      Conclusion
      In the era of ALK-targeted inhibitors, enriching NSCLC patients according to clinicopathologic characteristics could highly improve ALK detection rate for molecular target therapy. IHC could be a supplementary method to provide more clues for clinical trial design and therapeutic strategies for NSCLC patients who harbor ALK rearrangement including patients with double genetic aberration of ALK and EGFR.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-027 - Generation and Biological Character Analysis of EGFR-TKI Resistant Cell Line (ID 2030)

      09:30 - 09:30  |  Author(s): L. Ma

      • Abstract

      Background
      Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive remarkable benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). But drug-resistant problem appears sequentially and novel therapeutic strategies should be explored to overcome EGFR-TKI resistance. As the first EGFR-TKI in China and the third in world, icotinib shows good efficacy and tolerability in patients with advanced NSCLC. This study aims to establish icotinib resistant cell line-HCC827/IR and analyze it’s biological character for further study of EGFR-TKIs resistance.

      Methods
      HCC827 is a cell line with a deletion in the exon 19 of EGFR gene. HCC827 cells were exposed to increasing concentrations of icotinib (10nM to 20uM). Cells with the ability to grow in 20uM of icotinib were obtained 8 months after the initial drug exposure. The cell proliferation, viability, distribution of cell cycle, EGFR gene sequence (exon 18, 19, 20 and 21), EGFR-TKIs cross-resistance and the response to a histone deacetylases inhibitor (Chidamide, CS055) were evaluated after allowing the cells to grow in drug-free conditions for 2 months.

      Results
      Population doubling time (PDT) of HCC827/IR was not different from HCC827 (32.3±6.0h vs. 36.3±2.4h, P=0.198). In the cell cycle distributions of HCC827/IR, the cell number in G0/G1 phase were decreased (P=0.035), but the cell number in S and G2/M phase had no significant change compared with parent cells (P=0.388 and P=0.205, respectively). The resistance index (RI=HCC827IR~IC50~/ HCC827~IC50~) of HCC827/IR to icotinib was (1.98±0.15)×10[3]. And HCC827/IR cells also showed high resistance to the other two EGFR-TKIs (gefitinib and erlotinib), the RI of gefitinib and erlotinib was (2.36±0.082)×10[3 ]and (1.069±0.004)×10[3], respectively. But, the sequence of EGFR gene did not changed before and after resistance to EGFR-TKIs. In addition, HCC827/IR was sensitive to CS055 (IC~50~=254±32nM).

      Conclusion
      This study successfully established icotinib resistant NSCLC cell line-HCC827/IR. HCC827/IR cells had some different biological characters compared with parent cells and showed high cross-resistance to other EGFR-TKIs, but it was sensitive to CS055. The results could provide experimental reference for clinical application of TKIs and provide cell line model for further study of TKI-resistance.