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T. Takemoto



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    P1.24 - Poster Session 1 - Clinical Care (ID 146)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P1.24-013 - Prophylaxis against pulmonary thromboembolism with unfractionated heparin for the patients undergoing pulmonary resection for lung cancer (ID 1061)

      09:30 - 09:30  |  Author(s): T. Takemoto

      • Abstract

      Background
      Pulmonary thromboembolism (PTE) is a well-recognized potentially fatal complication after lung cancer surgery. In Japan, PTE had been relatively uncommon. However, it has recently been increasing probably due to changes in lifestyle. In our institution, deep vein thrombosis (DVT) is intensively screened by measuring preoperative D-dimer. Unfractionated heparin (UFH) is routinely administered to the patients having lung cancer surgery in addition to mechanical prophylaxis using elastic stockings(ES) or intermittent pneumatic compression devices(IPC). Here, we retrospectively evaluated efficacy and safety of these strategies to prevent PTE.

      Methods
      We retrospectively reviewed charts of 531 patients who underwent lung cancer surgery from January 2009 through April 2013. The patients who were deemed high-risk for DVT (those with past history of thrombosis, or those with elevated preoperative D-dimer (>1.0μg/ml), or those with varicose veins in their lower extremities), in principle, underwent venous ultrasonography of lower extremities. Among high-risk patients, those with or without DVT were classified as a group A and B, respectively. Those who failed to undergo venous ultrasonography were referred to as a group C. Those who did not meet above-mentioned criteria for high-risk group were classified as a group D. As perioperative prophylactic measures against PTE, all the patients in the group A wore ES from two days before surgery to one month after surgery. The patients also received continuous intravenous UFH (6000 units per day) immediately after surgery to postoperative day (POD) 1, and then received subcutaneous UFH (5000 units twice daily) from POD 2 until the patients became ambulatory. The patients in groups B, C and D wore ES during and after surgery. In addition, IPC was applied intraoperatively. The patients also received continuous intravenous UFH (6000 units per day) immediately after surgery to POD 1.

      Results
      Number of patients in each group were 14, 41, 87, and 389 in the group A, B, C, and D, respectively. In the group A, none was diagnosed as having PTE preoperatively. Eleven patients received postoperative UFH. However, two patients with intrathoracic adhesions did not receive UFH to avoid excessive postoperative bleeding. One patient with coronary artery complications underwent perioperative anticoagulation therapy. In this group, one patient without postoperative UFH administration due to adhesion developed symptomatic PTE. One patient was diagnosed asymptomatic exacerbation of DVT by ultrasonography one week after surgery despite UFH administration. In the groups B, C and D, 473 patients received postoperative UFH. Twenty-one patients with intraoperative bleeding or intrathoracic adhesions did not receive UFH. Twenty-three patients with coronary artery complications underwent perioperative anticoagulation therapy. In these groups, none developed symptomatic PTE. In 4 patients of 473 who received UFH, UFH was discontinued before POD 1 due to increase in sanguineous drainage without further complication.

      Conclusion
      Only one patient of 531(0.19%) developed symptomatic PTE after surgery. This patient had had preoperative DVT. Therefore, we regard that our strategies were effective to prevent PTE at least for patients without preoperative DVT. However, it may be necessary to apply even more intensive prophylactic measures for patients with evidence of preoperative DVT or PTE.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-010 - Several receptor tyrosine kinase is activated but orchestrated by EGFR in EGFR-TKI acquired resistant lung adenocarcinoma cells with EGFR mutation (ID 1387)

      09:30 - 09:30  |  Author(s): T. Takemoto

      • Abstract

      Background
      Lung adenocarcinomas with EGFR mutation initially show good responses to EGFR- tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is almost inevitable. To analyze molecular mechanisms underlying acquired resistance, we established a cell line from a patient who acquired resistance to gefitinib/erlotinib.

      Methods
      A 64-year-old woman underwent a pulmonary resection for lung adenocarcinoma in February 2009 (pT2aN0M0, EGFR L858R mutation). In April 2010, pulmonary metastases, mediastinal lymph node metastases, and right pleural effusion were identified. Gefitinib was started and this led to a complete response. However, despite continuous treatment with gefitinib, pleural effusion and serum carcinoembryonic antigen (CEA) levels gradually increased. In December 2010, gefitinib was switched to erlotinib but the serum CEA level continued to increase, and erlotinib was stopped on March, 2011. Even though she received no treatment after erlotinib withdrawal, interestingly, the serum CEA level was decreased significantly (from 89.5ng/ml on March 2011 to 19.2ng/ml on April 2011), and erlotinib was re-started on April 2011. The serum CEA level increased after re-administration of erlotinib (55.7ng/ml on May 2011). Therefore the regimen was switched to cisplatin/pemetrexed and she responded to this combination chemotherapy (CEA 9.1ng/ml on July 2011). This clinical experience may be an actual case of “drug addiction phenomenon” that we and others have observed in preclinical acquired resistance models (Suda K, et al. Lung Cancer 2012; Das Thakur M, et al. Nature 2013). We established a cell line from her pleural effusion obtained on March 2011 in drug-free condition (designated as ACC-GR1 cells). We analyzed this cell line to evaluate the efficacy of erlotinib and dacomitinib, an irreversible EGFR-TKI. In addition, we examined phosphorylation status of 42 receptor tyrosine kinase (RTK) of ACC-GR1 cells using Human Phospho-RTK Array Kit (R&D Systems) with/without erlotinib or dacomitinib. We also examined PC9 lung adenocarcinoma cell line for phosphorylation status of RTKs with/without erlotinib.

      Results
      ACC-GR1 cells harbored the T790M mutation, in addition to the original L858R mutation in the EGFR gene. ACC-GR1 cells do not have amplification of MET proto-oncogene. IC~50~ values for erlotinib and dacomitinib were 2.9 uM and 0.05 uM, respectively. Phospho-RTK array analysis revealed marked activation of EGFR and MET, in addition, activation of ERBB2, ERBB3, RET, and AXL in a culture condition without EGFR-TKI. Treatment with 1 uM of erlotinib led to mild inhibition of EGFR and MET phosphorylation (71% and 58%, respectively, compared with control), and phosphorylation of other RTKs fell below detectable limits. Treatment with 1 uM of dacomitinib led to further inhibition of EGFR phosphorylation (35% compared with control). In PC9 cells, phosphorylation of EGFR and MET were also observed in drug-free condition, and remarkably inhibited by 1 uM erlotinib treatment (10% and 64%, respectively, compared with control).

      Conclusion
      A cell line model established from pleural effusion of a patient who acquired resistance to gefitinib/erlotinib harbored T790M mutation and responded to dacomitinib in vitro. The acquired resistant cells showed activation of several RTKs in drug free condition, and these are remarkably inhibited by EGFR-TKI treatment.

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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
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      P2.06-033 - Identification f IGF-1R activation as a candidate molecular target in KRAS-mutated lung cancer (ID 2519)

      09:30 - 09:30  |  Author(s): T. Takemoto

      • Abstract

      Background
      KRAS mutations are common driver mutations in 30% of non-small cell lung cancer. However, treatment for lung cancer patients with KRAS mutations remains unestablished. Therefore, to screen other targetable receptor tyrosine kinases (RTKs) in lung cancers with KRAS mutations, we performed phospho-RTK array analyses using 6 KRAS mutated lung cancer cell lines.

      Methods
      Sixteen NSCLC cell lines were analyzed using Human-Phospho-RTK Array Kit (R&D Systems, MN) and relative phosphorylation levels of 42 RTKs were examined. Phosphorylation levels of RTKs were quantified relative to the average of positive controls using image analysis software JustTLC (Sweday, Lund, Sweden). We also examined growth inhibitory effect of small interfering RNA (siRNA) and erlotinib in KRAS mutant lung cancer cell lines. In addition, we developed erlotinib-resistant cell lines from erlotinib-sensitive H358 cells by chronic drug exposure for 3 months.

      Results
      In the phospho-RTK array analysis, phosphorylation levels of EGFR were lowest in the cell lines with KRAS mutation (Table1). Three of six cell lines with KRAS mutation showed IGF-1R phosphorylation and the difference was statistically significant compared with 0 of ten cell lines without KRAS mutation (P=0.03, Fisher's Exact test). KRAS siRNA did not induce apoptosis in 5 cell lines with KRAS mutation but mild apoptosis in H358 cells. Moreover, only H358 showed mild sensitivity to erlotinib (IC~50~ 120nmol/L). Analysis for erlotinib-resistant H358 cells identified increased phosphorylation of IGF-1R compared with H358 parent cells (18.0 times).Figure 1

      Conclusion
      These results suggest IGF-1R may be a candidate molecular target in lung cancers with KRAS mutation.