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W. Mao



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    OA08 - Targeted Therapies in Brain Metastases (ID 381)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA08.01 - Exploration of the Underlying Mechanisms of Leptomeningeal Metastasis in NSCLC Patients through NGS of Cerebrospinal Fluid (ID 5058)

      16:00 - 17:30  |  Author(s): W. Mao

      • Abstract
      • Presentation
      • Slides

      Background:
      About 10% of non-small cell lung cancer (NSCLC) patients with EGFR mutations will develop leptomeningeal metastasis (LM) either at initial diagnosis or during treatment. LM is a devastating complication of NSCLC associated with poor prognosis. The median overall survival is 4.5-11 months, with ~60% death due to LM or LM together with systemic lesions. However, the underlying mechanisms of the metastasis process are still poorly understood.

      Methods:
      we performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF) and matched normal controls from 11 EGFRm+ NSCLC patients with LM. Among them, 2 patients had LM at initial diagnosis, and 8 patients developed LM during 1[st] generation EGFR-TKI treatment, while such clinical information was missing for 1 patient.

      Results:
      The status of EGFR active mutations was the same in the primary tumor and CSF of all the patients, except one whose EGFR mutation was undetectable in the primary site probably due to low sequence coverage. In total, there were 8 patients with EGFR L858R, 1 with 19Del, and 2 with L858R & 19Del dual mutation. One patient also had de novo EGFR T790M in the primary site. None of the CSF samples showed EGFR T790M mutation, suggesting that it was not the resistance mechanism for the 8 patients who developed LM during TKI treatment. PIK3CA E545K and H1047L, and PTEN R130Q were identified in primary site and/or CSF of 6 patients. Although with small sample size, this ratio is much higher than what was reported in general EGFR L858R or 19Del positive lung adenocarcinoma patient population (~2% from 4 datasets), implicating that alternations in PI3K pathway may associate with LM risk. Interestingly, in 9 of the 11 patients, only 0.9%-7.8% of variants in CSF samples overlapped with those in primary site, suggesting tumor heterogeneity, divergence and clonal evolution during LM development. Moreover, when we cataloged the recurrent CSF-unique somatic genomic alterations existing in >5 patients, we identified genes involved in DNA repair pathway, cell cycle regulation and epigenetic reprogramming (NPM1, RAD50, MRE11A, POLE, CHEK1, XPC, KMT2B, KMT2C, KMT2D, and ATRX).

      Conclusion:
      In summary, our study has shed light on the genomic variations of LM and paved the way for potential therapeutic approaches to this unmet medical need.

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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P2.03b-020 - EGFR Exon 19 Deletion Mutation Patients Obtain Optimal Survival in Icotinib Treated Non–Small-Cell Lung Cancer Patient with Brain Metastases (ID 6365)

      14:30 - 15:45  |  Author(s): W. Mao

      • Abstract

      Background:
      Lung cancer is characterized by the highest incidence of solid tumor-related brain metastases. This is also one of the reasons why it can cause significant mortality. Molecular targeted therapy plays a major role in the management of brain metastases in lung cancer, which has become the novel methods for treatment of lung cancer with brain matastases. Our study aims to explore the efficacy of the EGFR targeted treatments in NSCLC brain metastases, specially according to EGFR mutation sub-types.

      Methods:
      We collected 116 patients with NSCLC brain metastases who underwent EGFR-TKIs therapy from 2011-2015 of Zhejiang cancer hospital. The data were analysed to get progression-free survival for intracranial disease(MPFSI)、median progression-free survival for extracranial disease(MPFSE)、median overall median progression-free survival(MPFS)、median overall survival (MOS), which were evaluated by Kaplan-Meier and multivariate analysis were performed by Cox model.

      Results:
      The overall response rate for 116 patients with Icotinib treatment was 61%. No increase in neurotoxicity was detected. The overall response rate was significant higher with EGFR exon 19 deletion mutation than with EGFR exon 21 mutation, other type EGFR mutations or EGFR-wildtype (68% VS 42%). MPFSI, MPFSE and MOS was also significantly longer with EGFR exon 19 deletion mutation than with EGFR exon 21 mutation, other type EGFR mutations or EGFR-wildtype (P<0.05).

      Conclusion:
      Icotinib was well tolerated with a favorable objective response. In sub-group analysis, the NSCLC with brain metastases patients with EGFR exon 19 deletion mutation obtain better survival than those patients with EGFR exon 21 mutation, other type EGFR mutations or EGFR-wildtype.