Author of

• 30780

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  P2.03 - Biology (ID 162)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30789

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    P2.03-09 - Arf6-Related Invasive Pathway Deteriorated Patients’ Prognosis in Mutant EGFR Lung Adenocarcinoma (ID 2937)

    10:15 - 18:15  |  Author(s): Koji Takahashi
    • Abstract

    Background
    

    Arf6-related pathway has been reported to be activated in the downstream of EGF stimulation and to play pivotal roles in invadopodia formation and integrin recyclying leading to cancer invasion and metastasis. EGFR is well known to be constitutively activated without EGF stimulation in lung cancer harboring the mutations in its kinase domain. Here, we have examined the clinicopathological significance of Arf6-related pathway especially in mutant EGFR (mEGFR) lung adenocarcinomas.

    Method
    

    Clinical samples were obtained from the 239 cases of resected lung adenocarcinoma which were consecutively operated from January 2001 to December 2007 in Kyoto University Hospital. Then, tissue microarrays (TMAs) were made from all the cases. Using DNA samples extracted from fresh frozen tumors, EGFR mutations were detected by SSCP or direct sequencing methods as previouly published.

    Immunohistochemical stainings were performed on TMAs against the molecules of Arf6-related pathway: Grb2, GEP100, Arf6, AMAP1, EPB41L5. The positivity of all molecules was judged according to their H-scores: intensities multiplied by percentages. Clinicopathological data were integrated and reviewed. Statistical analyses for overall (OS) or disease-free survival (DFS) were performed by Kaplan-Meirer methods and log-rank tests. Categorical data were analysed by Pearson’s test. Cox hazard models were applied for multivariate analyses. P-values less than 0.05 were considered significant.

    Result
    

    Among all cases, mEGFR was found in 113 cases, whereas 118 cases had wild type EGFR (wtEGFR) mutations. Common mutations in EGFR were detected in 104 cases (92.0%). Positivity of each molecule in mEGFR cases was the following: Grb2/ GEP100/ Arf6/ AMAP1/ EPB41L5; 11.9/ 27.7/ 48.2/ 52.7/ 56.3%. Positivity in all molecules showed no significant difference between exon 19 and exon21 mutation cases.

    Visceral pleural involvments were significantly increased in AMAP1- or EPB41L5-positive groups and lymph node metastases were significantly increased in Grb2- or EPB41L5-positive groups.

    Univariate analyses showed that 5-year OS rates were significantly low in Grb2 or AMAP1 positive groups specific to mEGFR cases (Grb2-/+: 89.0 vs 69.2%; p=0.0051, AMAP1-/+: 94.1 vs 80.3%; p=0.0057), whereas it was significantly low in EPB41L5 group specific to wtEGFR cases (-/+: 85.1 vs 62.7%; p=0.017).

    For DFS, all molecules were the significant recurrent factors specific to mEGFR cases (Grb2/ GEP100/ Arf6/ AMAP1/ EPB41L5; p=0.0023/ 0.0033/ 0.0411/ 0.0023/ 0.0263), whereas no molecule was significant specifc to wtEGFR cases.

    Multivariate analyses specific to mEGFR cases showed that Grb2 and AMAP1 were the independent prognostic factors for OS and Grb2 was the only independent recurrent factor.

    Conclusion
    

    Arf6-related invasive pathway was significantly associated with poor prognosis specific to mEGFR adenocarcinoma. Grb2 and AMAP1 were the strong worsening effectors on the prognosis. Inhibition of this pathway should be a novel targeted therapy in mEGFR lung adenocarcinoma.