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Y. Xu



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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 - 16:10  |  Author(s): Y. Xu

      • 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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    P3.01 - Poster Session with Presenters Present (ID 469)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P3.01-039 - JAK2 Participates in Lung Cancer Cells Proliferation, Migration and Invasion (ID 4247)

      14:30 - 14:30  |  Author(s): Y. Xu

      • Abstract

      Background:
      Lung cancer ranks as the first most common cancer and the first leading cause of cancer-related death in China and worldwide. Due to the difficulty in early diagnosis and the onset of cancer metastasis, the 5-year survival rate of lung cancer remains extremely low. JAK2 has emerged as pivotal participant in biological processes, often dysregulated in a range of cancers, including lung cancer. Recently we found that JAK2 might play an important role in lung cancer pathogenesis as an oncogene. While our understanding of JAK2 in the onset and progression of lung cancer is still in its infancy, there is no doubt that understanding the activities of JAK2 will certainly secure strong biomarkers and improve treatment options for lung cancer patients.

      Methods:
      The expression levels of JAK2 mRNA and protein were assayed using the RT-PCR and Western Blot assay respectively. MTT assay, Scratch-wound healing assay, Transwell migration and invasion assay were conducted to study the proliferation, migration and invasion abilities of lung cancer cells independently. The shRNA and overexpression plasmids of JAK2 were conducted.

      Results:
      JAK2 is up-regulated in lung cancer tissues when compared with their adjacent non-tumor tissues, and was associated with lymph node metastasis. Downregulation of JAK2 inhibits the proliferation, migration and invasion abilities of lung cancer cells. Moreover, overexpression of JAK2 induced the proliferation, migration and invasion abilities of lung cancer cells.

      Conclusion:
      These findings demonstrate that JAK2, whose expression is up-regulated in lung cancer, may participate in lung cancer progression by regulating cancer cells proliferation, migration and invasion.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P3.02b-079 - Effects of Icotinib with and without Radiation Therapy on Patients with EGFR Mutant Non-Small Cell Lung Cancer and Brain Metastases (ID 4475)

      14:30 - 14:30  |  Author(s): Y. Xu

      • Abstract

      Background:
      EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined.

      Methods:
      A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone.

      Results:
      The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9-30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P=0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P=0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P=0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P=0.043).The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9-30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P=0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P=0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P=0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P=0.043).

      Conclusion:
      Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT.