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X. Yu



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    P1.03 - Chemotherapy/Targeted Therapy (ID 689)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      P1.03-007 - A Real-World Study of Clinicopathological Characteristics and Survival Outcome in Advanced ALK-Positive Non-Small-Cell Lung Cancer (ID 8775)

      09:30 - 09:30  |  Author(s): X. Yu

      • Abstract

      Background:
      Crizotinib has resulted in substantial benefits for advanced non-small- cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) rearrangement. With limited real-world data available, the present work aimed to explore the clinicopathological characteristics and survival outcome of patients with advanced ALK+ NSCLC in a single center in China.

      Method:
      Data of 83 advanced ALK-rearranged NSCLC patients treated in Zhejiang Cancer Hospital were collected and analyzed retrospectively. Survivals were analyzed using the Kaplan-Meier method and were compared using the log-rank test. Multivariate analysis were performed by the Cox proportional hazard model.

      Result:
      Of the 83 patients enrolled, 33(39.8%) patients received crizotinib, and the other 50(60.2%) patients received chemotherapy as the initial treatment. The first-line use of crizotinib prolonged PFS compared with chemotherapy (median PFS 19.0 m vs. 5.7 m, P < 0.001), but not OS (46.0 m vs. 30.6 m, P=0.797). Till the last follow up, 71(85.5%) patients had received crizotinib, and 12(14.5%) patients were crizotinib-naïve. Patients who had received crizotinib had significantly longer OS than those who did not (48.9 m vs. 19.8 m, P < 0.05). Among the 71 patients who had received crizotinib,33(46.5%) used in first-line therapy, 22(31.0%) used in second-line therapy, and 16(22.5%) used after second-line therapy. There were not significant difference of OS among the three groups (30.6 m vs. 57.7 m vs. 40.8 m, P=0.583). The Cox multivariate analysis identified the following independent negative prognostic factors for OS: smoking (HR=4.725), liver metastasis(HR=4.570), bone metastasis (HR=2.651), and use of crizotinib (HR=0.295).

      Conclusion:
      Our real-world study showed that the use of crizotinib improved long-term survival of patients with advanced ALK-rearrangement NSCLC. There were no difference in survival outcome between patients with initial crizotinib and those with non-initial crizotinib.

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    P3.01 - Advanced NSCLC (ID 621)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.01-027 - TET2 Mutation as a Novel Mechanism of Acquired Resistance to EGFR TKIs Identified by a Mutational Profiling Using NGS (ID 9085)

      09:30 - 09:30  |  Author(s): X. Yu

      • Abstract

      Background:
      Overcoming acquired resistance to EGFR TKIs remains challenging, identification of actionable genetic alterations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. In our previous study, we performed mutational profiling in a cohort of 83 NSCLC patients using targeted next generation sequencing (NGS) and identified TET2 mutations in 12% of patients. This study aims to further explore the role of TET2 mutation in acquired EGFR-TKIs resistance in NSCLC cell lines with mutant EGFR.

      Method:
      CRISPR/Cas9 system was used to knock out TET2 gene in NSCLC cell line PC-9. Quantitative real-time PCR was performed to detect mRNA levels of TET2 gene, and western bot was performed to detect the expression levels of TET2 protein, thus cell line of TET2 silencing can be selected; positive for Annexin V and/or propidium iodide by flow cytometry was used to determine apoptotic rate. Bisulfite sequencing PCR (BSP) and real-time PCR for detection of EGFR promoter methylation status and mRNA expression.

      Result:
      By applying combined analyses of gene expression, apoptotic rate, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of TET2 to segregate EGFR-dependent cells. We show that in EGFR-dependent cells, TET2 loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. Figure 1



      Conclusion:
      Our study is expected to provide new ideas and put forward corresponding relevant tactics for patients with secondary resistance to the first-generation EGFR TKIs.