Author of

• 25921

  +

  P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 26333

    +

    P1.01-103 - Leukocyte Telomere Length as a Novel Biomarker in Advanced Lung Adenocarcinoma Patients Treated with Gefitinib (ID 11748)

    16:45 - 18:00  |  Author(s): Huaixin Xing
    • Abstract

    Background
    

    Gefitinib is currently one of the mostly used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for treating non-small cell lung cancer. However, drug resistance was observed among the majority of patients after initial treatment. The factors that predict treatment prognosis and drug resistance to EGFR-TKIs remain elusive. Leukocyte telomere length has been previously proved to be associated with lung cancer risk. However, it is still unclear whether telomere length can be used as biomarker of EGFR-TKIs therapy. The objective of this study is to exam the association between leukocyte relative telomere length (RTL) and prognosis or drug resistance of advanced lung adenocarcinoma to gefitinib treatment.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    In this study, three hundred and sixty-nine patients with stage IIIB or IV lung adenocarcinoma were recruited between January 2009 and June 2013. All patients were treated with gefitinib orally at a daily dose of 250 mg as first-line monotherapy. Leukocyte RTL of each patient was measured using quantitative polymerase chain reaction (qPCR) protocol on an ABI PRISM 7900HT Sequence Detection System (Applied Biosystems) and calculated according to Cawthon’s formula. Differences in patients’ characteristics were calculated by Pearson’s χ² tests or Student’s t test. Cox proportional hazard regression analyses were used to calculate univariate and multivariate hazard ratios (HRs) and their 95% confidence interval (95% CIs). Multivariate analyses were adjusted for sex, age, smoking status and EGFR mutation status, as appropriate. Survival differences were examined using the log-rank test. A P value of less than 0.05 was used as the criterion of statistical significance, and all statistical tests were two-sided.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Among 369 patients, EGFR mutations were positive in 181 patients (49.1%). Compared to long RTL, short leukocyte RTL was significantly associated with poor prognosis in all patients after gefitinib treatment (overall survival: 12.9 months vs. 17.8 months, P=1.2×10^-4; progression free survival: 7.8 months vs. 13.0 months, P=0.043 for log-rank test). Additionally, statistically significant association between short leukocyte RTL and shorten OS still existed among the EGFR mutant patients with gefitinib treatment (HR = 1.65, 95% CI=1.28-2.12; P = 0.006). Besides EGFR mutation status, short RTL also contributed to significantly elevated risk of gefitinib primary resistance (HR = 1.50, 95% CI = 1.05-2.15, P = 0.027).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    Our results highlight the potential of leukocyte RTL as a novel biomarker in advanced lung adenocarcinoma patients treated with EGFR-TKIs and the possibility of patient-tailored decisions based on leukocyte RTL.

    6f8b794f3246b0c1e1780bb4d4d5dc53

• 25933

  +

  P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

  • Event: WCLC 2018
  • Type: Poster Viewing in the Exhibit Hall
  • Track:
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall

  • 26618

    +

    P1.13-28 - The Functional MDM4 Genetic Polymorphsim as Prognostic Biomarker for Advanced Lung Adenocarcinoma Patients' Survival to EGFR-TKIs Therapy (ID 11773)

    16:45 - 18:00  |  Author(s): Huaixin Xing
    • Abstract

    Background
    

    As a mostly used epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), gefitinib significantly prolongs survival of lung adenocarcinoma patients with sensitizing EGFR mutations. However, more than 10% of EGFR mutation-positive patients do not respond and a substantial fraction of responded patients progress after 8-12 months’ treatment. Identification of new biomarkers associated with EGFR-TKIs prognosis would have great clinical potential for individualized treatments. The objective of this study is to investigate associations between the functional MDM4 genetic variant and survival of lung adenocarcinoma patients treated with gefitinib, especially in the patients with active EGFR mutations.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    In this study, a total of 384 patients with stage IIIB or IV lung adenocarcinoma were recruited between January 2009 and June 2013. All patients were treated with gefitinib orally at a daily dose of 250 mg as 1st-line monotherapy. MDM4 rs4245739 A>C genotypes were determined using the MassArray system (Sequenom Inc., San Diego, USA). Dual luciferase reporter gene assays were used to evaluate the function of MDM4 rs4245739 genetic variant in lung adenocarcinoma cell lines A549 and H1299. The differences of patient clinical characteristics and different reporter gene assays were calculated using student's t test or χ² test. The genotype effects on PFS or OS was estimated using the Kaplan-Meier method and a comparison between survival curves was done with log-rank test. Multivariate Cox regression analysis assessed prognostic factors for PFS or OS. A P value of less than 0.05 was used as the criterion of statistical significance, and all statistical tests were two-sided.

    4c3880bb027f159e801041b1021e88e8 Result
    

    Among 384 patients, EGFR mutations were positive in 181 patients (47.1%). Median progression-free survival (PFS) and overall survival (OS) for all patients with the rs4245739AC genotype were significantly longer than that of the AA carriers (PFS: 22.9 vs. 10.9 months, P < 0.001; OS: 27.3 vs. 16.5 months, P = 0.003). Notably, in the EGFR mutation-positive subgroup, individuals with MDM4 rs4245739AC genotype showed 14.1 months prolonged PFS (28.8 months vs. 14.7 months; P = 0.022) and 12.2 months prolonged OS (31.4 months vs. 19.2 months; P = 0.047）compared to the AA group. In support of this, reporter gene assays showed that the rs4245739A allele leads to significantly increased MDM4 expression in lung adenocarcinoma cells compared to the C allele (P < 0.05).

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    MDM4 rs4245739 genotypes may act as prognostic biomarker for patients’ survival to gefitinib therapy and offer help to patient-tailored treatment strategy in lung adenocarcinoma patients with EGFR mutations.

    6f8b794f3246b0c1e1780bb4d4d5dc53