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Toshiki Takemoto



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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
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      MA09.10 - Comprehensive Analysis of Secondary Mutation as Resistance Mechanism to Seven MET-TKIs for MET Exon 14 Skipping in Vitro (Now Available) (ID 117)

      15:15 - 16:45  |  Author(s): Toshiki Takemoto

      • Abstract
      • Presentation
      • Slides

      Background

      MET exon 14 skipping mutation have been attracting attentions of thoracic oncologists as a new target of therapy for lung cancer. The efficacy of MET-TKI has been reported, while these tumors, almost always acquire resistance, as in the case of other oncogene-addicted lung cancers. However, its resistance mechanisms are not fully understood.

      Method

      MET exon14 skipping mutation was introduced to Ba/F3 cell retrovirally. Using N-ethyl-N-nitrosourea mutagenesis, we derived resistant clones to seven MET-TKIs and searched for secondary MET mutations. We evaluated their sensitivities to following different TKIs. Type Ia, crizotinib; Type Ib, capmatinib, tepotinib and savolitinib; Type II, cabozantinib, merestinib and glesatinib.

      Result

      We sequenced 201 resistant clones and could obtain 80 clones which had secondary mutations in the MET tyrosine kinase domain. A total of 26 different missense mutations occurring at 12 codons were identified. Of them, D1228 and Y1230 in the activation loop were common sites for type I TKIs that bind to active kinase form (DFG-in), while L1195 and F1200 were those for type II TKIs that bind to inactive form (DFG-out). In general, resistant mutations against type I were sensitive to type II, and vice versa.

      figure.png

      Conclusion

      We identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 skipping.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-55 - Comparison of PD-L1 Expression Status Between Pure-Solid Versus Part-Solid Tumors in Lung Adenocarcinomas (ID 169)

      09:45 - 18:00  |  Author(s): Toshiki Takemoto

      • Abstract

      Background

      Recent studies have reported clinicopathological and prognostic differences between lung adenocarcinomas with ground-glass opacity (GGO) versus those without GGO (pure-solid tumors). However, it is unknow if the expression status of PD-L1 protein differs between these two groups.

      Method

      One-hundred twenty-four stage IA – IB lung adenocarcinoma patients who received pulmonary resection between 2007 – 2009 were included in this study. PD-L1 staining was performed in our previous study using E1L3N antibody. PD-L1 status was classified as positive if 1% or more tumor cells showed membrane staining; and was classified as strong positive if 50% or more tumor cells did so.

      Result

      Among 124 lung adenocarcinoma patients, 45 had lung adenocarcinomas with GGO and 79 had pure-solid lung adenocarcinomas. We observed no significant differences between these two groups in terms of clinical factors (gender, age, and smoking status). However, the rates of PD-L1 positive tumors (4% vs 25%, p < 0.01) and PD-L1 strong positive tumors (2% vs 16%, p = 0.02) were significantly lower in lung adenocarcinomas with GGO. In multivariate analyses, these correlations between the presence / absence of GGO and PD-L1 expression status were still evident as shown in Table 1.table 1..png

      Conclusion

      Lung adenocarcinomas with GGO were less frequent to express PD-L1 compared to pure-solid lung adenocarcinomas.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-37 - Lower Risk of Hypercoagulability in Non-Small Cell Lung Cancer Patients with EGFR Mutations (ID 1602)

      10:15 - 18:15  |  Author(s): Toshiki Takemoto

      • Abstract

      Background

      Hypercoagulability is sometimes observed in cancer patients, including non-small cell lung cancer (NSCLC) patients. Plasma levels of fibrinogen or D-dimer are used as markers for hypercoagulability, and several previous studies have reported that upregulation of these markers are poor prognostic factors in NSCLCs. On the other hand, recent studies have highlighted clinical differences between NSCLCs with EGFR mutation and those without. However, there is no data about the difference in hypercoagulability between NSCLCs with EGFR mutation and those without.

      Method

      Between January 2007 to December 2016, 270 surgically resected NSCLC patients received EGFR mutation testing and were included in this study. Plasma fibrinogen and D-dimer levels were examined as one of pre-surgical examinations in all patients. We analyzed the correlation between plasma fibrinogen / D-dimer levels and EGFR mutation status.

      Result

      Among 270 patients in our cohort, 123 patients had EGFR mutation and 147 patients were wild type (WT) for the EGFR. In our cohort, plasma fibrinogen level was upregulated in 39 patients, while plasma D-dimer level was upregulated in 75 patients. Plasma fibrinogen was upregulated in 9 patients (7%) and in 30 patients (20%) in EGFR mutation group and in WT EGFR group, respectively (p = 0.0017). Plasma D-dimer was upregulated in 27 patients (22%) and in 48 patients (33%) in EGFR mutation group and in WT EGFR group, respectively (p = 0.049). These correlations were still significant after the adjustment with clinical factors including smoking status, age, and histology. In multivariate analysis, odds ratio and 95% CI in EGFR mutation group for upregulated plasma fibrinogen were 0.40 and 0.17 – 0.94, respectively (p = 0.037). On the other hand, odds ratio and 95% CI in EGFR mutation group for upregulated plasma D-dimer were 0.48 and 0.26 – 0.90, respectively (p = 0.022).

      Conclusion

      Plasma levels of fibrinogen and D-dimer were significantly lower in NSCLCs with EGFR mutation.

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    P2.17 - Treatment of Early Stage/Localized Disease (ID 189)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.17-41 - Treatment Outcomes of Pulmonary Resection in NSCLC Patients with Autoimmune Diseases (ID 3102)

      10:15 - 18:15  |  Author(s): Toshiki Takemoto

      • Abstract

      Background

      Surgical resection for early stage non-small cell lung cancer (NSCLC) patient with autoimmune disease(s) is a relatively rare occasion. Most of such patients have received steroid therapy with/without immunosuppressant agent for a long period before the surgery. However, short-term or long-term treatment outcomes of NSCLC patients with autoimmune disease are unclear.

      Method

      Between January 2007 to December 2018, thirty-nine NSCLC patients with autoimmune disease(s) received pulmonary resection with curative intent in our department. Patients with interstitial lung disease were excluded from this study. Patient clinical and pathological characteristics and treatment outcomes were evaluated.

      Result

      There were 17 males and 22 females in out cohort. The median age was 68 years old (39 – 84), and thirty patients were smokers. Twenty-three patients had rheumatoid arthritis, and among them, three patients had additional autoimmune disease (autoimmune hepatitis, Sjogren syndrome, or polyneuropathy). Other autoimmune diseases included Hashimoto disease (n = 4), systemic lupus erythematosus (n = 3), Behcet’s disease (n = 2), primary biliary cirrhosis (n = 2), and others. Only three patients received limited resections (2 partial resections and one segmentectomy), and 36 patients received lobectomy or bi-lobectomy. At the post-operative pathological diagnosis, there were 13 patients with squamous cell carcinomas, 21 patients with adenocarcinomas, four patients with pleomorphic carcinomas, and one patient with adenosquamous cell carcinoma. Post-surgical complications included pneumonia (n = 1, 3%), prolonged air leakage (n = 1, 3%), and no patient experienced bronchopleural fistula or empyema. The median post-surgical hospital stay was eight days ( 4 – 28 days).

      Conclusion

      Pulmonary resection for NSCLC patients with autoimmune disease(s) were safely performed. We will also report the long-term outcome for this cohort at the conference.