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I. Lopez



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    MINI 35 - Biology (ID 161)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI35.02 - Inhibitor of Differentiation 1 (Id-1) Gene Silencing Reduces Liver Metastases Formation in a NSCLC Animal Model (ID 2995)

      18:30 - 20:00  |  Author(s): I. Lopez

      • Abstract
      • Presentation
      • Slides

      Background:
      Around 30% of non-small cell lung cancer (NSCLC) patients present LM during the disease course causing a negative clinical impact on survival and quality of life. The expression of certain genes in cancer cells might be crucial for allowing tumor cells to spread to the liver. According to this hypothesis Id1 and Id3 genes, part of the signature that facilitates breast cancer cells to disseminate to the lungs, might be determinant for NSCLC LM development.

      Methods:
      Three cohorts including totally 80 mice were compared; Id1 wild-type C57BL/6 (WT) female mice (n = 40) vs. Id1 knock out (IDKO) female animals (n = 28) vs Id1/Id3 knock out mice (Id1Id3KO) (n = 12). In both groups of mice 500,000 Lewis Lung Carcinoma cells (LLC) Id1 WT (Id1+/+) Id3 WT (Id3+/+), or Id1 homozygously deficient (Id1-/-) and Id3 WT (Id3+/+) or Id1-/- and Id3 heterozygously deficient (Id3+/-) were generated through gene silencing, and intrasplenically injected. Thereafter, both groups of mice were weekly monitored with FDG-micro-positron emission tomography (mPET) scans for LM formation. Animals were sacrificed (and tissues microscopically analyzed) by the time LM were developed and clinical deterioration was evident.

      Results:
      Expression of Id1 in both the host and the tumor cell line injected were independent predictive factors for the presence of LM. In fact, silencing Id1 expression in tumor cells (OR = 0.04; CI 95% 0.2 (0.04-0.9) or knocking down Id1 in the host tissues (OR: 0.2; CI 95% 0.06-0.7), impaired LM presentation. Silencing Id3 seemed not to diminish the risk of LM presentation.

      Conclusion:
      Absence of Id1 expression in the host partially impairs LM presentation. Silencing Id1 in tumor cells diminish the odds of presenting LM. Knocking down Id1 in the host or targeting Id1 in the tumor cell may represent a new approach to prevent LM presentation, and thus, improving the outcome in NSCLC patients.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-013 - EGFR Mutations and Targeted Treatment Reverse the Bad Prognosis of Stage IV NSCLC Associated to Liver Metastasis (ID 2961)

      09:30 - 17:00  |  Author(s): I. Lopez

      • Abstract
      • Slides

      Background:
      Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between molecular profile, liver infiltration and response to treatment. response to Liver metastases appear in 20-30% of patients diagnosed with non-small cell lung cancer (NSCLC) and represent a poor prognosis feature of NSCLC and a possibly more treatment-resistant condition. Potential clinical outcome differences in NSCLC patients with liver metastases harboring molecular alterations in EGFR, KRAS and EML4-ALK genes are still to be determined. This study aims to evaluate the incidence of liver metastasis in a single population and look for potential correlations between molecular profile, liver infiltration and response to treatment.

      Methods:
      A total of 236 consecutive stage IV NSCLC patients treated at the Clínica Universidad de Navarra were analyzed.

      Results:
      At onset, liver metastases were present in 16.9% of patients conferring them a shorter overall survival (OS) compared to those with different metastatic locations excluding liver infiltration (10 mo. vs. 21 mo.; p =0.001). Patients with EGFR wild-type tumors receiving standard chemotherapy and showing no liver involvement presented a superior median OS compared to those with liver metastases (23 mo. vs 13 mo.; p=0.001). Conversely, patients with EGFR-mutated tumors treated with EGFR tirosin-kinase inhibitors (TKI’s) presented no significant differences in OS regardless of liver involvement (median OS not reached vs. 25 mo; p=0.81).

      Conclusion:
      Overall, liver metastases at onset negatively impact OS of NSCLC patients. EGFR TKIs however, may reverse the effects of an initial negative prognosis in first-line treatment of EGFR mutated tumors and, more interestingly, in patients with EGFR wild-type NCSLC receiving EGFR TKIs after progression to chemotherapy. Table 1. Multivariate regression model.

      Variable HR p
      Sex 1.28 0.32
      Age 1 0.9
      N 1.28 0.06
      EGFR 0.24 0.001
      TKIs (after progression) 0.44 0.03
      Liver metastases at onset 1.5 0.28
      Liver metastases during disease 1.28 0.43
      Bone metastases at onset 1.6 0.22
      Bone metastases during disease 1.19 0.64
      Skin metastases at onset 2.2 0.31
      Adrenal metastases at onset 1.37 0.29


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