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S. Kimura



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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.01-028 - Characteristics of Cell Free DNA in Lung Cancer Patients (ID 8316)

      09:30 - 16:00  |  Author(s): S. Kimura

      • Abstract
      • Slides

      Background:
      A third generation EGFR tyrosine kinase inhibitor, osimertinib, is effective for T790M positive lung cancer patients. Although the tissue re-biopsy of primary or metastatic tumors was required to use osimertinib, cell free DNA (cfDNA) has been recently approved for detection of T790M in Japan. We have reported that cfDNA size distribution was different between lung cancer and healthy individuals using a capillary electrophoresis system, that is one peak around the size of 170 bp in healthy individuals, and two peaks, 170 bp and 5 kb in advanced lung cancer patients. The purpose of this study is to clarify the clinical and biological characteristics of each sized cfDNA.

      Method:
      The plasma collected from 92 lung cancer patients, 18 benign pulmonary disease patients, 20 healthy individuals at Saga University Hospital were analyzed. cfDNA extraction was performed from 1000μl plasma by automated DNA extraction system using cellulose magnetic beads. We first compared the DNA concentrations and cfDNA size among three groups. The DNA concentrations were quantified by Quantus[®], the fluorescent measurement of dsDNA intercalated dye, and cfDNA size was analyzed by the Agilent 2100 Bioanalyzer[®]. We next separately isolated cfDNA 170 bp and 5 kb fragments, and detected the epidermal growth factor receptor (EGFR) L858R point mutation by mutation-biased PCR and quenched probe system (MBP-QP) method.

      Result:
      The DNA concentration was higher in lung cancer patients compared to those in benign pulmonary disease and healthy individuals. Divided by histological types, DNA concentrations were highest in small cell carcinoma, and were increased in patients with advanced stages. Especially, DNA concentrations were higher in presence of metastasis, and 5 kb fragments were significantly increased in these cases. L858R positive patients showed higher DNA concentration with more obvious difference in 5 kb fragments. L858R was detected in both cfDNA fragments, 170 bp and 5 kb, which were separately isolated, suggesting that both sized DNA fragments contain circulating tumor-derived DNA (ctDNA).

      Conclusion:
      cfDNA concentrations were associated with progression of lung cancers, and bimodal characteristic was observed in terms of cfDNA size. Although the 170 bp short fragments of cfDNA are well known as an apoptotic product, the origin of 5 kb long fragments is still unclear. We have continuously examined how ctDNA was released from tumor cell.

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    P2.03 - Chemotherapy/Targeted Therapy (ID 704)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 2
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      P2.03-009 - Clarification of Mechanisms of Acquired Resistance for Afatinib Using Plasma Samples (ID 7570)

      09:30 - 16:00  |  Author(s): S. Kimura

      • Abstract
      • Slides

      Background:
      It is important to clarification of mechanisms of acquired resistance for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to determine the next treatment. EGFR T790M and hepatocyte growth factor (HGF) over expression has been observed in 50 to 60% of lung cancer patients who acquired resistance to the first generation EGFR-TKIs. However mechanisms of acquired resistance for the second generation EGFR-TKI, afatinib have not be clear.

      Method:
      We analyzed plasma T790M and HGF in twenty lung adenocarcimona patients treated with afatinib. Seven patients treated with afatinib as the first EGFR-TKI treatment and thirteen patients treated as EGFR-TKI re-challenge after acquired resistance for first generation EGFR-TKI. EGFR mutations in plasma DNA were detected using the mutation-biased PCR and quenched probe system. HGF level in plasma was measured by enzyme-linked immunosorbent assay.

      Result:
      In patients treated with afatinib as the first line treatment, no patients detected plasma T790M before afatinib treatment, but one of seven patients detected plasma T790M at the time of acquired resistance. Five of seven patients detected elevation of plasma HGF level when they had progressive disease. In patients treated with afatinib as EGFR-TKI re-challenge, ten of thirteen patients detected plasma T790M before afatinib treatment and nine of them had also T790M positive at the time of acquired resistance for afatinib. Two of three patients who had not detected plasma T790M before afatinib treatment become plasma T790M positive at the time of acquired resistance. Six patients who detected T790M treated with osimertiib and five of them demonstrated partial response (PR).

      Conclusion:
      T790M might be also major mechanism of acquired resistance in afatinib. Elevation of plasma HGF level might be detected more high frequency at the time of acquired resistance for afatinib than first generation EGFR-TKIs.

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      P2.03-011 - Correlation and Problems of Re-Biopsy and Liquid Biopsy for Detecting T790M Mutation (ID 8039)

      09:30 - 16:00  |  Author(s): S. Kimura

      • Abstract
      • Slides

      Background:
      T790M mutation test by the approved in vitro diagnostic agent (cobas v2.0) is essential for the use of osimertinib and opportunities for re-biopsy are increasing.

      Method:
      Success rate and T790M mutation detection rate were retrospectively investigated in 22 cases of 18 patients who took resistance to the 1st and 2nd generation EGFR-TKI at the Saga University Medical School Hospital and underwent re-biopsy. T790M with plasma DNA was examined by MBP-QP, a highly sensitive detection system developed in our laboratory, and cobas v2.0.

      Result:
      All patients were adenocarcinoma and the mutation status was 8 patients of del 19 and 10 patients of L858R. Re-biopsy sites were 7 bones, 4 primary sites, 3 cases of liver, pleura, lymph nodes, and 2 other sites, respectively, and surgical excision was 31.8%, median time to biopsy from informed consent was 10.5 days (range:1-39). The success rate was 95.5% and the T790M detection rate by cobas v2.0 was 52.3% for all cases, and there was no significant difference between 55.6% for del 19 and 50.0% for L858R. The plasma T790M detection rate using MBP-QP collected at the same time was 65.0% for all cases and there was no significant difference between 55.6% for del 19 and 72.7% for L858R. We experienced one case of atypical angina as a serious complication. Case presentation: ≪No.1≫ First biopsy as re-biopsy (bone): cobas method was negative and MBP-QP method was positive and could not be administered with osimertinib. Second biopsy as re-biopsy (liver): both cobas method and MBP-QP method were positive and could be administered with osimertinib and had a remarkable response. ≪No.2≫ Axillary lymph node biopsies were performed twice, but cobas method was negative and MBP-QP method was positive, and osimertinib could not be administered. Thereafter, hepatic metastasis was biopsied, but both cobas method and MBP-QP method were negative. When plasma specimens by cobas method were tested after insurance approval, plasma T790M was positive, and osimertinib could be finally administered. Although it was effective for axillary lymph node metastases, it had no effect on liver metastases.

      Conclusion:
      The sensitivity of the test method and the tumor heterogeneity between individuals may influence the detection of T790M mutation. In order to reliably administer osimertinib to patients with indication, it is desirable to establish an appropriate time and site for re-biopsy, and establish examination methods.

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