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H. Yoon



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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 - 16:30  |  Author(s): H. Yoon

      • 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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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-046 - Heat shock protein 70 as a predictive maker in patients with platinum-based adjuvant chemotherapy in resected non-small cell lung cancer (ID 2735)

      09:30 - 16:30  |  Author(s): H. Yoon

      • Abstract

      Background
      Although adjuvant platinum-based chemotherapy improves survival in completely resected non-small cell lung cancer (NSCLC), its effect is limited. We hypothesized that heat shock protein 70 (Hsp70) would be a biomarker for selecting patients for adjuvant chemotherapy, and evaluated the prognostic or predictive significance of Hsp70 in patients with surgically resected NSCLC.

      Methods
      Patients who underwent curative resection for NSCLC and diagnosed as stage IIA through IIIA between January 1996 and December 2010 were included. We conducted immunohistochemical staining for Hsp70 on surgical specimens and compared survival rates depending on whether of Hsp70 expression and adjuvant platinum-based chemotherapy.

      Results
      Among 327 patients, Hsp70 expression was positive in 220 (67.3%). For the patients without adjuvant chemotherapy, Hsp70 expression did not significantly affect survival. However, for the patients with adjuvant chemotherapy, patients with Hsp70-positive tumors had longer disease-free survival (DFS; 82.4 vs. 29.7 months; P = 0.004) as well as longer overall survival (OS; 101.9 vs. 73.4 months, P = 0.12) than those with Hsp70-negative tumors. Multivariate modeling showed that patients with Hsp70-postitive tumors had a lower risk of recurrence and death than those with Hsp70-negative tumors after adjusting for age, gender, performance status, pathologic stage, and histologic types in adjuvant chemotherapy group (DFS: adjusted hazard ratio [AHR], 0.54; 95% CI, 0.36 to 0.80; P = 0.002; OS: AHR, 0.66; 95% CI, 0.42 to 1.05; P = 0.08). Figure 1

      Conclusion
      Hsp70 is a positive predictive factor in completely resected NSCLC and Hsp70-positive tumors seem to benefit from adjuvant platinum-based chemotherapy.

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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 - 16:30  |  Author(s): H. Yoon

      • 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 - 16:30  |  Author(s): H. Yoon

      • 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.