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K. Sato



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    ORAL 42 - Drug Resistance (ID 160)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      ORAL42.02 - Qualitative and Quantitative Heterogeniety in Acquiring Resistance to EGFR Kinase Inhibitors in Lung Cancer (ID 572)

      18:30 - 20:00  |  Author(s): K. Sato

      • Abstract
      • Presentation
      • Slides

      Background:
      Acquisition of resistance to EGFR- tyrosine kinase inhibitors (TKIs) is one of important issues in lung cancer researches. Several resistance mechanisms have been identified. However, inter-tumor heterogeneity in acquisition of resistance to EGFR-TKIs is currently unclear.

      Methods:
      Eleven autopsied patients who developed acquired resistance to EGFR-TKI monotherapy were included in this study. All patients harbored activating EGFR mutations (exon 19 deletion or L858R mutation), and developed acquired resistance to EGFR-TKI after initial response to the drug. Details of patient characteristics are summarized in Table 1. The resistance mechanisms of seven patients have been reported in our previous analyses (Suda K, et al. Clin Cancer Res 2010, and Suda K, et al. APLCC 2014). In this study, we analyzed acquired resistance mechanisms in twenty-eight tumor samples obtained from the four additional patients using target sequencing technique by next-generation sequencer.

      Results:
      Among eleven patients, four developed T790M EGFR secondary mutation in all TKI-refractory lesions. One patient developed MET amplification in all TKI-refractory lesions. Three patients harbored both TKI-refractory lesions with T790M mutation and those with MET amplification. The other three patients showed respective resistance mechanisms (Table 1).

      Table 1. Summary of resistant mechanisms in eleven patients.
      Pt. ID Age/Sex Pack-Year Resistant Mechanisms TTF (m)
      C1 57/F 0 T790M or MET 13.8
      C2 48/F 0 T790M or MET 11.0
      C3 58/M 34 MET 14.5
      C4 75/M 0 T790M 43.9
      C5 93/F 0 T790M 14.8
      C6 62/M 26 T790M 9.1
      P1 86/F 0 T790M 10.8
      P2 72/M 27 T790M or MET 3.8
      P3 89/F 0 EGFR loss with MET or Unknown 9.0
      P4 84/F 0 Unknown 22.6
      A1 76/F 0 SCLC transformation or T790M 5.0
      In the target sequence analysis, allele count data were further analyzed in tumor samples with T790M mutation, and we observed diverse T790M/activating EGFR mutation allele ratio ranging from 2 – 51%. In the analysis for time to treatment failure (TTF), we observed longer TTF in patients who developed single resistance mechanism compared with those who developed multiple resistance mechanisms (Fig. 1; p = 0.055). Figure 1



      Conclusion:
      In this study, we observed qualitative heterogeneity and quantitative heterogeneity of T790M allele ratio in acquisition of resistance to EGFR-TKIs in lung cancers. Qualitative heterogeneity in resistance mechanisms would have a correlation with TTF of EGFR-TKIs.

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    P1.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 209)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      P1.02-016 - Prevalence of Preoperative DVT in Japanese Patients Who Underwent Thoracic Surgery by Intensive Screeng (ID 3038)

      09:30 - 17:00  |  Author(s): K. Sato

      • Abstract
      • Slides

      Background:
      Pulmonary thromboembolism (PTE) is a well-recognized potentially fatal complication after thoracic surgery. In Japan, PTE had been relatively uncommon. However, it has recently been increasing probably due to changes in lifestyle. Therefore the first guideline for the prevention of venous thromboembolism (VTE) were published in February 2004 in Japan. In this guideline, the patients with history of VTE are classified as highest risk group for PTE. Recently, it has been reported that the presence of normal D-dimer levels can exclude acute-phase deep vein thrombosis (DVT). Therefore, in our institution, DVT had been intensively screened by measuring preoperative D-dimer. The objective of this study was to investigate prevalence of preoperative DVT in Japanese patients scheduled for thoracic surgery.

      Methods:
      A total of 276 patients who underwent thoracic surgery from June 2013 through July 2014 in our institution were reviewed. The patients who were deemed high-risk for DVT (those with elevated preoperative D-dimer (≧1.0μg/ml), with past history of thrombosis, or with varicose veins in their lower extremities) were defined as preoperative screening positive. They were examined with venous ultrasonography of lower extremities. Those with DVT underwent contrast-enhanced computed tomographic scan (CT) for PTE.

      Results:
      Of all patients, only 1 failed to undergo preoperative measurement of D-dimer because of emergency surgery. Among the remaining 275 patients, a total of 113 patients ( 95 with elevated D-dimer, 15 with varicose veins in their lower extremities, one with swelling in his extremities, one with paralyzed inferior limbs, and one with previously diagnosed PTE ) were examined with venous ultrasonography of lower extremities. Of them, 34 patients (12.6%) were diagnosed DVT (Figure 1) Proximal and distal DVT were diagnosed in ten patients ( three with isolated DVT, three with multiple DVT, and four with a wide range of huge clots ) and 24 patients ( 15 with isolated DVT and nine with multiple DVT ) , respectively. Of them, none was diagnosed preoperative PTE. For a peri-operative management, all the patients received unfractionated heparin. In addition, of four patients with a wide range of huge clots, three had prophylactic inferior vena cava filter placed. Of 34 patients, one was diagnosed asymptomatic exacerbation of DVT by ultrasonography one week after surgery, but none developed symptomatic PTE. Figure 1



      Conclusion:
      This study showed an DVT prevalence of 12.6% in patients undergoing thoracic surgery in Japan. However, none developed symptomatic PTE in the peri-operative period.

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