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G.K. Lee



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.11 - The predictive role of common BIM deletion polymorphism and BIM expression on the EGFR-TKI therapy in never-smoking lung adenocarcinoma (ID 2161)

      10:30 - 12:00  |  Author(s): G.K. Lee

      • Abstract
      • Presentation
      • Slides

      Background
      The BCL-2 homology domain 3 (BH3)-only protein, B-cell lymphoma 2 interacting mediator of cell death (BIM) is a potent pro-apoptotic protein. Recent data suggest that pretreatment BIM level may predict responsiveness to EGFR-TKI in EGFR-mutant non-small cell lung cancer (NSCLC). In addition, a common BIM deletion polymorphism contributes to the heterogeneity of response to EGFR-TKI in EGFR-mutant NSCLC. We investigated whether BIM expression and BIM deletion polymorphism (BIM-DEL) are predictive for response rate (RR) and progression-free survival (PFS) to EGFR-TKI therapy in never-smoking lung adenocarcinoma (NSLA).

      Methods
      We analyzed EGFR mutation status by Sanger sequencing, BIM-DEL genotyping by polymerase-chain reaction and BIM expression by immunohistochemistry using archival tissues or blood from 203 patients who participated in the FIRST-SIGNAL trial (1[st] line gefitinib vs. Gemcitabine/cisplatin in advanced NSLA).

      Results
      EGFR mutation test, BIM-DEL genotyping and BIM-IHC analysis were available in 82, 126 and 60 patients, respectively. Forty-five (55%) patients had EGFR mutations, 22 (18%) showed BIM-DEL and 22 (37%) showed negative BIM expression. BIM expression was significantly associated with EGFR mutation status; more patients with EGFR-mutant NSCLC showed negative BIM expression (48% vs. 21%, P=0.030). BIM-DEL was not associated with EGFR mutation status or BIM expression. Among 181 patients who received EGFR-TKI as 1[st] or 2[nd]-line therapy, EGFR mutation, BIM-DEL and BIM expression data were available in 74, 11, 56 patients, respectively. EGFR mutation was predictive for higher RR (66% vs. 15%, P<.001) and longer PFS (4.5 vs. 1.9 months, P=.061) to EGFR-TKI therapy. Negative BIM expression also showed a trend toward higher RR (68% vs. 42%, P=.061) and longer PFS (6.9 vs. 2.3 months, P=.233) with EGFR-TKI. However, BIM-DEL was not predictive for RR (41% vs. 47%, P=.645) or PFS (3.5 vs. 3.7 months, P=.892) to EGFR-TKI.

      Conclusion
      Both BIM-DEL and BIM expression were not predictive for responsiveness to EGFR-TKI in NSLA. The trend between negative BIM expression and favorable response to EGFR-TKI may be resulted from higher frequency of EGFR mutation in these patients.

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    O28 - Endoscopy (ID 124)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      O28.01 - EBUS-centered vs. EUS-Centered Mediastinal Staging in Lung Cancer:<br /> a randomized controlled trial. (ID 1037)

      10:30 - 12:00  |  Author(s): G.K. Lee

      • Abstract
      • Presentation
      • Slides

      Background
      The impact of primary procedure and procedure sequence has not been studied in combined application of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in lung cancer staging.

      Methods
      In a randomized controlled trial, 160 patients with histologically confirmed or strongly suspected potentially operable non-small cell lung cancer were enrolled (Group A, n=80, EBUS-centered; Group B, n=80, EUS-centered). In Groups A and B, EBUS-TBNA and EUS-FNA with ultrasound bronchoscope were used as the first procedure, respectively, and secondary procedures were added.

      Results
      Diagnostic values were evaluated in 148 patients (74 in each group). In Groups A and B, the diagnostic accuracy (93.2% vs. 97.3%, respectively, p=0.2454) and sensitivity (85.3% vs.92.0%, respectively, p=0.4312) in detecting mediastinal metastasis were not statistically different. In Group A, adding EUS-FNA to EBUS-TBNA did not significantly increase the accuracy (91.9% to 93.2%; p=0.7540) and sensitivity (82.4% to 85.3%; p=0.7419). In group B, adding EBUS-TBNA to EUS-FNA increased the accuracy (86.5% to 97.3%; p=0.0160) and sensitivity (60.0% to 92.0%; p=0.0081). There were no inter-group differences in procedure time, cardio-respiratory parameters during procedures, complications, or patient satisfaction.

      Conclusion
      In combination of EBUS-TBNA and EUS-FNA in mediastinal staging, diagnostic values and patient satisfaction were not different between EBUS-centered and EUS-centered group. However, the necessity of EBUS-TBNA following EUS suggests EBUS-TBNA is a better primary procedure in endoscopic mediastinal staging.

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    P1.21 - Poster Session 1 - Diagnosis and Staging (ID 169)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.21-002 - A survey of EGFR mutation frequency and testing practices in Asia Pacific (ID 1213)

      09:30 - 16:30  |  Author(s): G.K. Lee

      • Abstract

      Background
      The efficacy of EGFR TKIs in EGFR mutation-positive NSCLC patients has led to a need for accurate, timely EGFR mutation testing worldwide. Although EGFR mutation testing has been adopted by many laboratories in Asia, accurate data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods. The objectives are to investigate the practice of EGFR mutation analysis in Asian Pacific countries and document the prevalence of routine testing in this population.

      Methods
      This is a retrospective database survey of records from NSCLC patients tested for EGFR mutations from 1 January 2011 to 1 January 2012 at participating sites across the Asia Pacific region. The majority of eligible hospitals/laboratories that participated had performed ≥ 100 EGFR mutation tests during that period. Accessible patient records were used to complete an online questionnaire, with data being stored in a central database. Primary objectives were to determine the number of NSCLC patients tested for EGFR mutations and the rate of EGFR mutation positivity: overall, by histological subtype, and by demography. Other variables included the number of NSCLC cases diagnosed, EGFR mutation testing methods used, and tumour sample characteristics and processing. The proportion of EGFR mutation-positive patients and 95% CI were calculated; other variables will be summarized descriptively. An interim analysis has been conducted using data collected from more than 18,000 newly diagnosed NSCLC patients at 29 sites.

      Results
      The data from surveyed sites indicates that the overall proportion of NSCLC patients tested for EGFR mutations was 31.9% (95% CI 31.2-32.6%), with an EGFR mutation positivity rate of 40.2% (95% CI 39.1-41.4%) overall, ranging from 28.7% to 53.4% (Table). Additional data on demographic and histological subgroups and current testing practices (methods, sample types, sample preparation) will be presented. [*: Wilson score confidence interval. **: Note that the sites from Vietnam (one site) and Philippines (one site) did not test ≥ 100 patients. N.D.: No data.]

      Table: Proportion of Patients Tested and EGFR Mutation Rates at Participating Sites
      Country Total number of newly diagnosed NSCLC patients Proportion of patients tested, % (95% CI*) EGFR mutation positivity, % (95% CI*)
      Total 18,050 31.9 (31.2-32.6) 40.2 (39.1-41.4)
      Japan 2,379 64.8 (62.9-66.7) 30.2 (28.0-32.6)
      China 12,086 18.3 (17.6-19.0) 38.1 (36.3-39.9)
      Taiwan 2,530 52.9 (50.9-54.8) 53.4 (50.7-56.0)
      Hong Kong 399 31.1 (26.7-35.8) 49.2 (40.6-57.9)
      Malaysia 357 98.6 (96.8-99.4) 45.7 (40.6-51.0)
      Thailand 249 57.8 (51.6-63.8) 45.1 (40.6-49.8)
      Vietnam** 50 100.0 (92.9-100.0) 36.0 (24.1-49.9)
      Philippines** N.D. Not Known 38.9 (29.5-49.2)
      Indonesia N.D. Not Known 28.7 (20.8-38.2)

      Conclusion
      The data collected in this survey indicate that, in 2011, testing practices varied widely across the region, despite the well-known high incidence of the mutation. The data provide an insight into these practices and provide a reference platform on which to compare and build on for the future of EGFR mutation testing and molecular diagnosis of NSCLC in Asia Pacific.

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    P2.03 - Poster Session 2 - Technology and Novel Development (ID 151)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.03-004 - Clinical application of targeted deep sequencing as a molecular screening for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in never-smoking lung adenocarcinoma (ID 2170)

      09:30 - 16:30  |  Author(s): G.K. Lee

      • Abstract

      Background
      The molecular screening is a key step to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. We investigated the clinical relevance of targeted next generation sequencing (NGS) as a molecular screening for EGFR-TKI therapy in never-smoking lung adenocarcinoma (NSLA).

      Methods
      We obtained DNA from 48 NSLA received gefitinib or erlotinib for their recurrent disease after surgery. The Sanger sequencing and peptide nucleic acid clamp polymerase chain reaction (PCR) were used to analyze EGFR, KRAS, BRAF and PIK3CA mutations. We analyzed ALK, RET and ROS1 rearrangements by fluorescent in situ hybridization or reverse transcriptase-PCR and quantitative real-time PCR. Finally, Ion Torrent NGS was performed in 31 cases harboring only EGFR exon 19 deletions (19DEL) or L858R mutation or none of above mutations.

      Results
      After excluding mutations other than EGFR 19DEL or L858R, samples were divided into 4 groups; 1) responders to EGFR-TKIs with only 19DEL or L858R (n=15); 2) primary resistance to EGFR-TKI with only 19DEL or L858R (n=4); 3) primary resistance to EGFR-TKI without any mutations (n=8); 4) responders to EGFR-TKI without any mutations (n=4). All conventionally detected mutations were confirmed with NGS. Additionally uncovered predictive mutations include; one PIK3CA E542K and one BRAF in group 2; two KRAS (G12V and G12D), one PIK3CA E542K and one concomitant PIK3CA and EGFR L858R in group 3; one EGFR 19DEL in group 4. Newly detected mutations were validated by Sanger sequencing.

      Conclusion
      Targeted NGS provided more accurate and clinically useful molecular classification of NSLA. It may improve personalized therapy for individual patients.

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    P2.09 - Poster Session 2 - Combined Modality (ID 213)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P2.09-018 - Incorporating erlotinib into induction chemotherapy followed by concurrent chemoradiation of unresectable stage III non-small cell lung cancer according to EGFR mutation status: preliminary result of a randomized phase II study (ID 3178)

      09:30 - 16:30  |  Author(s): G.K. Lee

      • Abstract

      Background
      EGFR tyrosine kinase inhibitors (TKIs) showed great survival benefit in the selected patients with stage IV non-small cell lung cancer (NSCLC) harboring TKI-sensitive EGFR mutations. Assuming that if the cases were properly selected, EGFR-TKIs would be integrated into treatment paradigms of stage III NSCLC as more effective systemic therapy, we designed this study to evaluate the efficacy and toxicity of erlotinib and chemotherapy in the combined-modality treatment of unresectable stage III NSCLC patients according to EGFR mutation status.

      Methods
      Patients over 18 years with unresectable stage IIIA (N2) or stage IIIB NSCLC, ECOG performance status 0–1, and adequate organ function are eligible. The mutational analysis of EGFR (exon 18–21) is performed using direct sequencing in tissue sample. EGFR mutation-positive patients initially receive 3 cycles of erlotinib and then are treated by concurrent chemoradiotherapy (CRT) with either erlotinib (Arm A) or irinotecan-cisplatin (IP) (Arm B). After CRT, patients in Arm A receive consolidation therapy with 6 cycles of erlotinib while those in Arm B are observed until progression. EGFR mutation-negative or unknown patients are treated either with 3 cycles of IP followed by CRT with IP (Arm C) or vice versa (Arm D). Erlotinib is given at 150mg daily with 3-week cycle. IP is given with cisplatin 30mg/m[2] (day 1 and 8) and irinotecan 60mg/m[2] (day 1 and 8) during radiotherapy (total 60 Gy/ 2.4 Gy/fr) or with cisplatin 30mg/m[2] (day 1 and 8) and irinotecan 65mg/m[2] (day 1 and 8) during induction or consolidation therapy with 3-week cycle. The primary endpoint is response rate (RR), toxicity, and survival estimation. Erlotinib and irinotecan were provided by Roche Korea and Pfizer, Inc., respectively

      Results
      From February 2008 to February 2013, 62 patients were screened and 50 patients were randomized into Arm A (n= 6), Arm B (n= 4), Arm C (n= 19), and Arm D (n= 21). The EGFR mutation status was positive in 10 (20.0%) patients, negative in 23 (46.0%), and unknown in 17 (34%). The median age was 65 years. The proportion of never smoker and adenocarcinoma histology was 80% (event/ total No. = 8/10) and 90% (9/10) in the EGFR mutation-positive group, 13% (3/23) and 48% (11/23) in the EGFR mutation-negative group, and 6% (1/17) and 18% (3/17) in the EGFR mutation-unknown group. The median follow-up time was 34.7 months (range, 3.8−53.8 months). The completion rate of planned treatment was 66.7% (4/6), 100% (4/4), 78.9% (15/19), and 76.2% (16/21) from Arm A to Arm D. For induction therapy, the RR to elrotinib of the EGFR mutation-positive group was 70.0% (7/10). Moreover, the subgroup harboring TKI-sensitive EGFR mutations (exon 19 deletion and exon 21 L858R mutations) showed the RR to erlotinib of 87.5% (7/8). The RR to IP induction therapy was 41.7% (5/12) in the EGFR mutation-negative group, 0% (0/4) in the EGFR mutation-unknown group, and thus 31.1% (5/16) in the EGFR mutation-negative or unknown patients.

      Conclusion
      The combined-modality treatment by molecular diagnostics was feasible in stage III NSCLC and accrual is ongoing.