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J. Chung



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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.10-003 - Alteration of the E-cadherin/β-catenin complex predicts poor response to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment (ID 161)

      09:30 - 16:30  |  Author(s): J. Chung

      • Abstract

      Background
      Epidermal growth factor receptor (EGFR) mutation alone may be insufficient to predict clinical outcomes in the response to EGFR-tyrosine kinase inhibitor (TKI) therapy. The secondary mutation T790M and MET amplification are mechanisms of acquired resistance to EGFR-TKI in approximately 50% of patients, but the remaining mechanisms are unknown.

      Methods
      Eight metastatic lesions and specimens from 41 non-small cell lung carcinoma (NSCLC) patients harbouring activating EGFR mutations who underwent surgical resection and EGFR-TKI therapy were available. Immunohistochemistry was used to evaluate E-cadherin, β-catenin, and PTEN. Chromogenic in situ hybridisation and silver-enhanced in situ hybridisation were used to evaluate EGFR and MET amplification.

      Results
      Patients with E-cadherin/β-catenin alteration showed a poor objective response rate (ORR) (p=0.005) and shorter overall survival (p=0.059). Additionally, β-catenin alteration was associated with a poor ORR (p=0.012). In the metastatic tumours, 3 cases (37.5%) showed the acquisition of altered E-cadherin/β-catenin and PTEN loss, and 2 cases (25.0%) demonstrated MET/EGFR amplification.

      Conclusion
      Altered E-cadherin/β-catenin expression in NSCLC harbouring EGFR mutations was associated with a poor response to EGFR-TKI. During metastatic progression, changes in E-cadherin/β-catenin were found. These results may suggest that E-cadherin/β-catenin alteration is related to poor TKI response and resistance.

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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): J. Chung

      • 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): J. Chung

      • 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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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-002 - A comprehensive comparative analysis of the histomorphological features of ALK-rearranged lung adenocarcinoma based on driver oncogene mutations : frequent expression of epithelial-mesenchymal transition markers than other genotype (ID 221)

      09:30 - 16:30  |  Author(s): J. Chung

      • Abstract

      Background
      Molecular classification of lung cancer correlates well with histomorphologic features. However, detailed histomorphologic features which differentiate ALK rearranged tumors from ALK wild type has not been fully evaluated. To investigate histomorphologic features of tumors harboring ALK rearrangement to evaluate the predictive significance of morphologic characterization, we compared the histomorphological analysis between ALK-rearranged and ALK negative lung adenocarcinomas based on driver oncogene mutations.

      Methods
      Eighty resected ALK rearranged lung adenocarcinomas and two hundred thirteen resected ALK negative adenocarcinomas (91 EGFR mutated, 29 K-ras mutated and 93 triple-negative) were analyzed for several histomorphological parameters and histologic subtype based on newly proposed IASLC/ATS/ERS classification.

      Results
      ALK rearranged tumors were associated with a younger age at presentation, frequent nodal metastasis and higher stage at diagnosis, compared with patients with other genotypes. ALK rearranged tumors were more likely to show solid predominant pattern (43.8%, 35/80) than other genotypes (p<0.001) and a lepidic predominant histology was not observed in ALK rearranged tumors (p<0.001). In ALK rearranged tumors, considerable number of the tumors (67.5% , 54/80) contained at least 5% solid pattern but only small number of the tumors (12.5%, 12/80) contained at least 5% lepidic pattern, compared with other genotypes (p<0.001). The most significant morphological features distinguishing ALK rearranged tumors from ALK negative tumors were cribriform formation (OR: 3.253, p=0.028), presence of mucin-containing cells (OR: 4.899, p=0.008), close relation to adjacent bronchioles (OR: 5.361, p=0.001), presence of psammoma body (OR: 4.026, p=0.002) and solid predominant histological subtype (OR: 13.685, p=0.023). ALK-rearranged tumors exhibited invasive histomorphological features, aggressive behavior and frequent expression of epithelial-mesenchymal transition markers (loss of E-cadherin and expression of vimentin) compared with other genotype (p =0.015). Spatial proximity between bronchus and ALK-rearranged tumors and frequent solid histologic subtype with p63 expression may cause diagnostic difficulties to differentiate squamous cell carcinoma in the small biopsy, whereas p40 was rarely expressed in ALK-rearranged adenocarcinoma.

      Conclusion
      Knowledge of these features may improve the diagnostic accuracy and lead to a better understanding of the characteristic behavior of ALK-rearranged tumors.