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M. Shimoji
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ORAL 03 - New Kinase Targets (ID 89)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:F. Blackhall, R. Juergens
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 4a-4f
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ORAL03.03 - EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Sensitivity to Afatinib or Neratinib but Not to Other EGFR-TKIs (ID 1748)
11:07 - 11:18 | Author(s): M. Shimoji
- Abstract
- Presentation
Background:
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKIs),whereas exon 20 insertions (Ins20) are known to be resistant to these drugs. However, little is known about the role of mutations in exon 18. Inspired by clinical observation that a patient with adenocarcinoma harboring exon 18 deletion (Del18: delE709_T710insD) responded to afatinib, this study aimed to establish a rational therapeutic strategy for lung cancers harboring exon 18 mutations.
Methods:
The mutational status of lung cancers registered in Aichi Cancer Center (ACC) database between 2001 and 2015 was reviewed. Three representative mutations in exon 18, Del18, E709K, and G719A, were introduced into Ba/F3, NIH3T3, and HEK293 cells using retroviral vector. The 90% inhibitory concentrations (IC90s) of first generation (1G) (gefitinib and erlotinib), second generation (2G) (afatinib, dacomitinib, and neratinib), and third generation (3G) TKIs (AZD9291 and CO1686) in these cells were determined and compared with the corresponding IC90s in cells expressing exon 19 deletion (Del 19) and with the trough concentration (C~trough~) at the recommended doses for each drug. Clinical data on the treatment response of tumors harboring exon 18 mutations were collected from the ACC and Catalogue of Somatic Mutations in Cancer (COSMIC) databases.
Results:
Among the 1355 EGFR mutations registered in the ACC database, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Of note, exon 18 mutations including G719X, E709X, and Del18 were present in 3.2% (n=43), accounting for 38% of the remaining. According to the COSMIC database, exon 18 mutations accounted for 4.1% (654/16,138) of all EGFR mutations present from exons 18-21. Mutations at codons 709 and 719 accounted for 84% of all exon 18 mutations. Ba/F3 cells expressing Del18, E709K, or G719A grew in the absence of interleukin 3, and NIH3T3 cells transfected with these mutations formed foci with marked pile-up, indicating that these mutations act as oncogenic drivers. IC90s of 1G and 3G TKIs in cells transfected with Del18, E709K and G719A were much higher than those in cells transfected with Del19 (by >50-, >25-, and >11-fold, respectively). In contrast, IC90 of afatinib in these three mutations ranged from only 2- to 6-fold greater than that in Del19 and was <1/40 of its C~trough~. Notably, cells transfected with exon 18 mutations exhibited higher sensitivity to neratinib (by 25-fold for E709K, by 5-fold for G719A, and by a comparable extent for Del 18) than those expressing Del19. Western blot analyses showed that these differential sensitivities corresponded to different degrees of suppression of EGFR phosphorylation in HEK293 cells. Furthermore, analyses of the ACC and COSMIC databases clearly indicated that patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (~80%) than to 1G TKIs (35-56%).
Conclusion:
Our data indicated that lung cancers harboring exon 18 mutations, although rare, should not be overlooked in clinical practice and that these cases are best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits do not detect all exon 18 mutations.
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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
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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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 - 09:30 | Author(s): M. Shimoji
- Abstract
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.
