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C. Lee



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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-002 - Reversal of Resistance to EGFR tyrosine kinase inhibitor by EGFR T790M specific siRNA in Non-Small Cell Lung Cancer (ID 1141)

      09:30 - 09:30  |  Author(s): C. Lee

      • Abstract

      Background
      Analysis for EGFR mutation became new standard in management of lung adenocarcinoma. Mutations in EGFR tyrosine kinase domain such as L858R or small deletions in exon 19 result in sustained phosphorylation of EGFR and become driver oncogenic mutation. EGFR TKI, such as gefitinib, induces dramatic response in lung adenocarcinoma with sensitive mutations. Unfortunately, this dramatic response can not last long and resistance to EGFR TKI emerges and induces treatment failure. More than 50% of resistant mutations are EGFR T790M mutation. In this study, we investigated the role of siRNA specific to EGFR T790M and its clinical significance.

      Methods
      We designed three sequences (siRNA1, 2, 3) specific to EGFR T790M according to siRNA design guideline. Lung cancer cells were used: A549, NCI H460 (EGFR; wild type), NCI H1975 (EGFR L858R + T790M), PC9 (EGFR small deletion in exon 19), PC9-G (EGFR small deletion in exon 19 + T790M). We investigated the effect of three siRNAs on suppression of EGFR T790M and reversal of resistance to gefitinib.

      Results
      Transfection of siRNA 1 and 3 showed marked suppression of EGFR expression in NCI H1975 and PC9-G, however, siRNA 2 failed to suppress. All siRNA don't affect EGFR expression in A549, NCI H460 and PC-9. This finding suggested that suppressions of EGFR by siRNA 1 and 3 were specific to EGFR T790M. EGFR T790M siRNA 1 and 3 not 2, markedly suppressed the growth of NCI H1975 and PC9-G via increased apoptotic cell death and also suppressed in vitro tumorigenicity. No significant effect was found in other cell lines. This finding strongly supports that EGFR T790M is another oncogenic driver mutation. Cotreatment of EGFR siRNA 1 and 3 with gefitinib induced marked increase in sensitivity of NCI H1975 and PC-9 to gefitinib (synergistic interaction), however, no effects were found in A549 and NCI H460.

      Conclusion
      Application of EGFR T790M specific siRNA can reverse the resistance of lung adenocarcinoma and shows its potential to be a breakthrough in EGFR TKI. Further study will focus on preclinical application with efficient delivery system, such as, nanotechnology or viral vectors. (This study was supported by a grant from the National Research Foundation of Korea, 2011-0002169).

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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-032 - The high protein expression of EGFR using a specific internal domain antibody and loss of PTEN can be used as predictive factors for EGFR TKIs in patients with advanced squamous cell lung cancer (ID 2396)

      09:30 - 09:30  |  Author(s): C. Lee

      • Abstract

      Background
      Over the last decade encouraging new targeting agents have afforded benefits to patients with adenocarcinoma (ie. bevacizumab, erlotinib, gefitinib, crizotinib) but, very few advances were made in the treatment of squamous-cell lung cancer (SqCLC). However, many genomic abnormalities (PTEN, PI3KCA and FGFR1 etc.) are present in SqCLC and there is growing evidence of their cell survival, proliferation, and growth. These expressions have also been related to the resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in preclinical models. The objective of this study is to investigate the molecular and clinical factors that predict EGFR-TKI efficacy as a second-line or higher therapy in previously treated patients with SqCLC. We especially focused on the protein expression of EGFR, PTEN and PI3KCA gene amplification.

      Methods
      This retrospective study included 67 SqCLC Korean patients with available tumor tissue and data on EGFR-TKI treatment response and survival. EGFR protein expression in tumor tissue was evaluated by immunohistochemistry (IHC) with a specific antibody that detects the intracellular domain (ID) of EGFR. In addition PTEN expression in tumor tissue was assessed by IHC. PI3KCA gene amplification by quantitative real-time polymerase chain reaction (PCR) and mutational analyses of EGFR exon 19 and 21 by a PCR-based assay were performed.

      Results
      The median age was 70 years. The proportions of males and ever smokers were 85% and 82%. Patients had received a median of 2 prior chemotherapy regimens for advanced disease before treatment with EGFR-TKI. Eighty-four percent (n=56) of the patients received erlotinib treatment and the other (n=11) received gefitinib. Of the 54 patients available for response evaluation at 12 weeks, disease control rate was 35% (2 patients in partial response; 17 patients in stable response). The median progression free survival (PFS) and overall survival (OS) were 1.8 and 4.63 months, respectively. Positive EGFR protein expression in tumor tissue was present in 56 patients (85%), loss of PTEN expression (PTEN-negative) in 26 (39%) and PI3KCA gene amplification in 12 (21%). No cases exhibited EGFR activating mutation. But positive EGFR expression correlated with improved PFS (1.87 vs. 0.9 months, p=0.049). Negative PTEN expression was associated with a significantly higher risk of death (3.7 vs. 5.7 months median OS, p=0.028). Multivariable model confirmed that positive EGFR expression correlated with improved PFS (HR = 0.435, 95% CI = 0.21-0.89, p = 0.024) and positive PTEN expression was associated with an increased OS (HR = 0.437, 95% CI = 1.17-4.45, p = 0.015) after adjusting sex, age, performance status and number of previous chemotherapy regimens. The patients with EFGR-negative / PTEN-negative had poorer clinical outcomes than those with positive EGFR or positive PTEN expression: with shorter median PFS (2.1 vs. 4 months, HR = 1.713, p = 0.036). PI3KCA gene amplification was not related to clinical outcomes.

      Conclusion
      EGFR and PTEN protein expression could be used to identify which patients with SqCLC are likely to gain a benefit from EGFR-TKIs. The potential clinical application of specific EGFR-ID antibody for prediction of clinical outcomes in SqCLC needs validations.

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-009 - Clinicopathologic and Radiologic Characteristics of Lung Cancer Patients with Epidermal Growth Factor Receptor (EGFR), K-ras Mutation and Anaplastic Lymphoma Kinase (ALK) Rearrangement Presented as Nodular Ground-glass Opacity (ID 1388)

      09:30 - 09:30  |  Author(s): C. Lee

      • Abstract

      Background
      Nodular ground-glass opacity (nGGO) lesion at computed tomography (CT) is a pattern of lung cancer at early stage, and a few studies revealed the characteristics of lung cancer presented as nGGO. Recently, several driver mutations of lung adenocarcinoma such as epidermal growth factor receptor (EGFR), K-ras mutation and anaplastic lymphoma kinase (ALK) rearrangement were found, and EGFR mutation is considered to play a role in early tumorigenesis of nGGO lesion, but the role of ALK rearrangement and K-ras mutation in nGGO lesion is still unknown.

      Methods
      We studied 217 nGGO lesions of 215 patients with lung cancer presented as nGGO, who had undergone surgical resection, retrospectively. We measured sizes of nGGO lesions at chest CT and calculated tumor disappearance rate (TDR). Pathologic analysis and molecular biomarker examination of surgical specimens were performed. Correlation between clinicopathologic and radiologic characteristics and molecular biomarker status was investigated.

      Results
      EGFR mutations were found in 119 among 217 cases (54.8%), positive ALK FISH in 6 among 217 cases (2.8%), and K-ras mutations in 7 among 154 cases (4.5%). Progressed disease stage (p=0.018), larger tumor size (p=0.035-0.037) were observed in ALK-positive group. Lower TDR, i.e. more solid portion in nGGO were observed in ALK-positive group, but it was not statistically significant (TDR 0.533 vs. 0.700, p=0.209). Female (p=0.004) and non-smoker or less smoker (p<0.001) were characteristics of EGFR-positive group, but tumor size and TDR revealed no significant difference. K-ras-positive group revealed no meaningful clinicopathologic and radiologic difference compared to K-ras-negative group. Histologic invasiveness was associated with advanced disease stage (p<0.001), lower TDR (p<0.001), and tumor size (p<0.001), but could not predict molecular biomarkers status. Low TDR was associated with nodal involvement (p<0.001), advanced disease stage (p<0.001), but not with molecular biomarkers status.

      Conclusion
      ALK rearrangement is not common in lung cancer presented as nGGO lesion, and associated with progressive stage and larger tumor size, suggestive of aggressive feature in the progression of lung adenocarcinoma. Role of K-ras mutation in nGGO lesion is indefinite. The status of three molecular biomarkers was not associated with histologic invasiveness or proportion of GGO portion itself.

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    P2.17 - Poster Session 2 - Bronchoscopy, Endoscopy (ID 183)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      P2.17-007 - Misclassification of mediastinal lymph nodes by endobronchial ultrasound (EBUS) (ID 2478)

      09:30 - 09:30  |  Author(s): C. Lee

      • Abstract

      Background
      Endobronchial ultrasound-guided transbronchial aspiration(EBUS-TBNA) is reported to show relatively high sensitivity and specificity in mediastinal node staging of non-small cell lung cancer (NSCLC). But discrepancies exist between bronchoscopic, radiologic, and surgical classification of mediastinal lymph nodes and thus can lead to misclassification. However, the impact of the misclassification on diagnostic performance of EBUS-TBNA has never been evaluated.

      Methods
      Medical records of NSCLC patients who underwent surgery after EBUS-TBNA for mediastinal staging from November 2010 until March 2013 in a tertiary hospital were reviewed. Of those, only lymph nodes which have been aspirated by EBUS-TBNA and removed by surgery were analyzed. Patients who received neoadjuvant chemotherapy between EBUS-TBNA and surgery were excluded. Detailed review of medical records and radiological imaging was done to infer the causes for false negative or positive results.

      Results
      A total of 105 lymph nodes from 96 patients were included in our analysis. Median interval between EUB-TBNA and surgery was 11 days. A total of 8 lymph nodes(7.6%) showed false negative results and only one lymph node (0.9%) showed false positive result. Sensitivity, specificity, accuracy, positive and negative predictive value (PPV and NPV) of EBUS-TBNA for malignancy were 65.2%, 97.5%, 88.5%, 88.5%, 90.6%, respectively. After detailed review of cases who had false positive or negative results, 3 false negative lymph nodes and 1 false positive lymph node (44%) were recognized to be due to misclassification. Other false negative cases were due to sampling errors.

      Conclusion
      Misclassification of lymph nodes can cause false positive or false negative results of EBUS-TBNA.