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C.M. Choi



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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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      P1.05-008 - The HSP 90 inhibitors suppress cell growth by suppression of ALK and TGF-beta1 signaling in crizotinib-resitant H2228 cells by Epithelial to mesenchymal transition (ID 2544)

      09:30 - 16:30  |  Author(s): C.M. Choi

      • Abstract

      Background
      Epithelial to mesenchymal transition (EMT) is related with reduced sensitivity to many chemotherapeutic drugs including EGFR tyrosine kinase inhibitors. We investigated whether EMT also could contribute to the resistance to crizotinib and there are other therapeutic options overcoming EMT-mediated resistance.

      Methods
      We established a crizotinib-resistant subline (H2228/CR), which was derived from the parental H2228 cell line by long-term exposure to increasing concentration of crizotinib. Characteristics related with EMT including morphology, EMT marker proteins and cellular mobility were analyzed. We examined whether the induction of EMT affect sensitivity to Hsp90 inhibitors.

      Results
      Compared with the H2228 cell, the growth of H2228/CR cells was independent on EML4-ALK, and they showed cross-resistance to TAE-684 (a 2[nd]-generation ALK inhibitor). Phenotypic change of a spindle-cell shape was found in H2228/CR, which was accompanied by a decrease of E-cadherin and an increase of vimentin and AXL. In addition, they showed the increased secretion and expression of TGF-β1. The capability of invasion and migration was dramatically increased in H2228/CR cells. TGF-b1 treatment for 72 h in parental H2228 cells induced reversible EMT leading to crizotinib-resistance while this was reversed through the removal of TGF-β1. Suppression of vimentin by siRNA treatment in H2228/CR cells restored the sensitivity to crizotinib. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitors similar to parental cells, H2228. HSP90 inhibition resulted in downregulation of TGF-β receptor II in addition to ALK.

      Conclusion
      EMT should be considered as one of possible acquired resistant mechanisms to crizotinib and HSP90 inhibitors can be a promising therapeutic option for EMT-mediated resistance.

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    P1.09 - Poster Session 1 - Combined Modality (ID 212)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P1.09-005 - The optimal timing of SRS add to EGFR-TKI treatment for brain metastasis from activating EGFR mutant NSCLC (ID 692)

      09:30 - 16:30  |  Author(s): C.M. Choi

      • Abstract

      Background
      Lung cancer is the most frequent cause of cancer-related death worldwide. Brain metastasis is an important issue because its incidence of 20-40% in non small cell lung cancer (NSCLC) patients and association of significant mortality and morbidity. There are several therapeutic modalities for CNS lesions such as whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) and metastasectomy. It is well known that conventional chemotherapy is not effective for brain metastasis because of blood brain barrier (BBB). On the other hand, tyrosine kinase inhibitors (TKI) have showed efficacy in patients with brain metastasis from activating epithelial growth factor receptor (EGFR) mutant NSCLC. We assumed that SRS for brain metastasis could be delayed for the patients with activating EGFR mutation on taking gefitinib or erlotinib.

      Methods
      We retrospectively identified patients with brain metastasis from NSCLC harboring a sensitizing mutation of EGFR who were treated with SRS for the brain metastasis combined with TKI. EGFR mutations in exons 18, 19, 20 and 21 were analyzed by direct sequencing. SRS treatment was indicated for brain metastasis less than 6 lesions and not exceeding 4cm each of them. The patients in SRS first group were treated by SRS for brain metastasis, and then TKI was administrated. The other patients were treated with TKI before SRS and they were assigned to TKI first group. Progression free survival time was compared with each group.

      Results
      Forty-three patients were eligible (SRS first: 29, TKI first 14). Twenty-nine patients of them (67.4%) were women, median age was 56 (range 36-78). Most of them were adenocarinoma, except 1 squamous cell carcinoma and 1 NSCLC NOS. All patients have activating EGFR mutations, 2 patients had also T790M mutation known as TKI resistant mutation. TKI was used as 2[nd] line treatment for twenty five patients (58.1%). WBRT and brain metastasectomy were additionally employed for 9 and 6 patients. Although eight patients complained headache after SRS, it was self-limited. The median duration of TKI treatment were not different from each group (13.4 months in SRS first group, 14.7 months in TKI first group, p=0.986) As a result, the median progression free survival time was prolonged in SRS first group than in the TKI first group (12.6 months versus 2.3 months, p<0.001). And there was no significant adverse effect related with SRS in both groups.

      Conclusion
      It is better to consider SRS for brain metastasis as soon as possible, even if TKI is effective for patients with brain metastasis from activating EGFR mutant NSCLC. Also, the combined treatment of TKI with SRS was well tolerated by all patients in this study.

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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): C.M. Choi

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P1.24-024 - Acute Exacerbation of Idiopathic Interstitial Pneumonia After Resection of Lung Cancer: Investigation of Pre Operative CT predictor (ID 1819)

      09:30 - 16:30  |  Author(s): C.M. Choi

      • Abstract

      Background
      To investigate the ‘preoperative CT predictor’ of postoperative acute exacerbation (AE) of lung cancer with underlying idiopathic interstitial pneumonia (IIP) compared to those without AE as control.

      Methods
      The 78 pulmonary resections for lung cancer with underlying IIP in a single tertiary center, 72 males (92.3%) and 6 females (7.7%), aged from 47 to 80 years old, with a median age of 66 years were retrospectively included. This study was approved by the Institutional Review Board and informed consent was waived. Underlying IIP was retrospectively assessed histological (n=46, 59.0%) and clinico-radiological (n=32, 41.0%) according to ATS/ ERS guidelines. We divided them in two groups, one acute exacerbation (AE group) and the other without acute exacerbation (non AE group) after operation of lung cancer. Records of patients who experienced postoperative acute exacerbation were extracted from the clinical data-base. Two independent expert chest radiologists analyzed CT findings in two times (four data sets) for one month interval. We analyzed age, gender, smoking history and pulmonary function test (PFT) differences between two groups. We analyzed HRCT findings as follows; extent of reticulation, honeycombing, ground-glass opacity, and emphysema in overall extent with area percentage. Fibrotic score (sum of reticulation and honeycombing) was also assessed. We performed the correlation between HRCT findings and presence of acute exacerbation. We used binary logistic regression analysis and student t-test with SPSS 21.0 version as statistics.

      Results
      Of the 78 lung cancer patients, six patients experienced postoperative acute exacerbation (7.7%). Smoking history and PFT between two groups were not significantly different except age and gender. Inter- and intra-reader correlation coefficient were 0.496~0.928 and 0.667~0.936/0.657~0.949, respectively, good to fair. Honeycombing (p=0.001; OR, 1.243; CI, 1.087~1.422) and fibrotic score (p=0.007; OR, 1.188; CI, 1.047~1.347) and abnormal area (p=0.042; OR, 1.059; CI, 1.002~1.119) were significantly high in AE group.

      Conclusion
      Physicians should consider the high extent of honeycombing, as well as high fibrotic score in CT, a potential risk factor for acute exacerbation after pulmonary resection for lung cancer.