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  P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11580

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    P2.06-037 - Transforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrheaTransforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrheaTransforming growth factor-β1 genetic polymorphisms relate to erlotinib induced diarrhea (ID 2681)

    09:30 - 09:30  |  Author(s): T. Suzumura
    • Abstract

    Background
    Rash, liver dysfunction, diarrhea and pneumonitis are known as adverse events of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Transforming growth factor-β1 (TGF-β1) is a cytokine and acts as an anti-proliferative factor in normal epithelial cells and epithelial-mesenchymal transition (EMT) with invasion and metastasis in cancer cells. TGF-β1 mediated Smad activation caused EMT, and activation of the EGFR. TGF-β1-mediated EGFR activation was abolished by EGFR suppression or extracellular EGF depletion pathway. TGF-β1 genotypes are associated with serum level of TGF-β1. It has been hypothesized that TGF-β1 genotypes may be implicated in clinical outcomes of EGFR-TKIs.

    Methods
    Patients were identified through a query of patient information for subjects enrolled in the Medical Information System in Osaka City University Hospital between January 1999 and February 2012. The associations between three genetic polymorphisms of TGF-β1 (C-509T, T869C, and G915C) and adverse events of erlotinib and gefitinib have been studied. Genomic DNA was extracted from peripheral blood or formalin-fixed and paraffin-embedded tissues. TGF-β1 genotypes were determined using RT-PCR method. The primers were designed to amplify the target fragments of TGF-β1 rs1800469, rs1800471, and rs1982073, respectively. In order to identify the risk factors for the adverse events, gender, age, stage and three genetic polymorphisms of TGF-β1 were selected and estimated for their potential confounding effects on rash, diarrhea, and liver dysfunction by multivariate analysis. Unconditional logistic regressions were used to compute the odds ratios (ORs) and their 95% confidence intervals (CIs). All analyses were two-sided, and p values of less than 0.05 were considered statistically significant. This study was approved by the ethics committee of Osaka City University (approval number, 1700).

    Results
    A total of 255 patients received gefitinib, and 75 patients received erlotinib. In the gefitinib group, the rates of rash, diarrhea, and liver dysfunction of grade 1 or more were 66.7%, 26.0% and 48.5%, respectively. In the erlotinib treatment group, the rates of rash diarrhea, and liver dysfunction of grade 1 or more were 84.1%, 43.5% and 33.3%, respectively. The C-509T consisted of TT in 26.6%, CT or CC in 73.3% of patients (n=289), respectively. The T869C consisted of CC in 26.1%, TC or TT in 73.9% of patients (n=272), respectively. The G915C consisted of GG in 100% of (n=313) patients. TT of the C-509T and CC of the T869C were significantly associated diarrhea of grade 1 or more in erlotinib group (OR 0.21, 95% confidence interval [CI] 0.054-0.72, p < 0.001, and OR 0.21, 95% CI 0.05-0.73, p = 0.014, respectively). No associations were observed between TGF-β1 genotypes and any adverse events in gefitinib group.

    Conclusion
    Minor alleles of TT of the C-509T and CC of the T869C were associated with erlotinib induced diarrhea. These alleles are generally associated with high level of TGF-β1 in serum. The increase level of TGF-β1 may be a risk factor for mucosal damage of the gastrointestinal tract in patients treated with erlotinib.