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C. Chen



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    ORAL 35 - Surgical Approaches in Localized Lung Cancer (ID 155)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      ORAL35.01 - Surgical Approach and Disease Recurrence in NSCLC Patients in the MAGRIT Study (ID 318)

      16:45 - 18:15  |  Author(s): C. Chen

      • Abstract
      • Presentation
      • Slides

      Background:
      Surgical resection is the standard treatment for early stage Non-Small Cell Lung Cancer (NSCLC). Anatomical resection with lymphadenectomy is recommended in surgically treated patients with Stage I-IIIA NSCLC. Whether mediastinal lymph node dissection (MLND) or mediastinal lymph node sampling (MLNS) should be performed remains controversial, and there is currently no consensus within the literature. We describe surgical approaches and patterns of disease recurrence in patients enrolled in MAGRIT: a large global randomized study of the MAGE-A3 Cancer Immunotherapeutic versus placebo after complete tumor resection (Phase III trial, MAGRIT, NCT00480025).

      Methods:
      Study participants were aged ≥18 years, with histologically-proven, MAGE-A3-positive Stage IB, II or IIIA NSCLC (AJCC 6.0) who had undergone R0 anatomic resection of their tumor (lobectomy or pneumonectomy) with mediastinal lymphadenectomy. Patients were randomized to MAGE-A3 or placebo in a 2:1 ratio. A total of 2,272 patients were treated at 556 centers in 34 countries. Because MAGRIT did not demonstrate efficacy overall, and because the number of recurrences in the placebo arm was small (n=271), recurrence patterns by surgical technique are presented in the overall population. An analysis of the placebo population was also conducted as the overall population results are subject to potential bias (a limited treatment effect in small sub-groups cannot be excluded). Cox regression models were used to explore whether lymphadenectomy procedure could be prognostic for disease-free survival (DFS) or overall survival (OS).

      Results:
      In the total treated population, 76% were men, 52% had squamous cell carcinoma, and 52% received adjuvant chemotherapy. More than half (57%) of patients were enrolled in Europe, with 23% in East Asia, 16% in North America and 4% in other countries. 47% of patients had Stage IB, 6.5% IIA, 30% IIB, and 17% IIIA disease. Lobectomy (including bi- and sleeve-lobectomy) was performed in 85% of patients, and 14% required pneumonectomy. MLNS was performed in 53% and MLND in 47% of patients. MLNS and MLND patients had a similar disease stage distribution. By region, the percentage of patients who underwent MLNS was: 36% in Europe, 65% in East Asia, 94% in North America and 59% in other countries. Among patients who had undergone MLNS or MLND, 37% (n=447/1202) and 36% (379/1067) developed recurrent disease, respectively. Loco-regional recurrence was observed in 40% (177/447) of patients after MLNS and 31% (118/379) after MLND, with distant recurrence observed in 55% (244/447) and 64% (244/379), respectively. There was no difference in the pattern of distant metastases between patients who had MLNS or MLND. Cox modeling showed no impact of the extent of lymphadenectomy on either DFS or OS. A separate analysis of patients in the placebo arm demonstrated similar trends to those of the total study population.

      Conclusion:
      Lobectomy (including bi- and sleeve-lobectomy) was the most frequently used treatment for patients who participated in the MAGRIT study. Important regional differences in lymphadenectomy were observed. Although the patterns of recurrence varied to some extent with the type of lymphadenectomy, our study did not demonstrate any prognostic impact related to the type of lymphadenectomy performed.

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    P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P3.01-004 - Paxillin Confers Resistance to TKI via Modulating BIM and Mcl-1 Protein Stability (ID 152)

      09:30 - 17:00  |  Author(s): C. Chen

      • Abstract
      • Slides

      Background:
      Tyrosine kinase inhibitors (TKIs) have been documented to have substantial clinical benefits to non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation. TKI resistance occurs in nearly all patients who receive TKI targeting therapy, resulting in a modest overall survival benefit. Therefore, establishing a biomarker for early prediction and exploring the mechanism of primary TKI resistance is essential for improving the therapeutic efficacy in NSCLC patients.

      Methods:
      In this study, we provide evidence indicating that paxillin (PXN) overexpression may confer gefitinib resistance in EGFR-mutant lung cancer cells.

      Results:
      Mechanistically, PXN-mediated ERK activation is responsible for gefitinib resistance via decreased BIM and increased Mcl-1 expression due to modulating their protein stabilities by phosphorylation of BIM at Serine 69 and Mcl-1 at Threonine 163. The mechanistic action in the cell model was further confirmed by the observation of xenograft tumors in nude mice, revealing that the PXN-mediated gefitinib resistance was conquered by ERK inhibitor (AZD6244) and Bcl-2 family inhibitor (obatoclax), but the gefitinib resistance overcome by AZD6244 is more effective than that of obatoclax.

      Conclusion:
      Therefore, we suggest that PXN expression may be useful in predicting primary TKI resistance, and combining TKI with ERK inhibitors may clinically benefit EGFR-mutant NSCLC patients whose tumors exhibit high PXN expression.

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