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Z. Wang



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    MO16 - Prognostic and Predictive Biomarkers IV (ID 97)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO16.03 - Cytoplasmic ERβexpression predicts poorly efficacy and survival of EGFR-TKI in EGFR mutant NSCLC (ID 2563)

      16:25 - 16:30  |  Author(s): Z. Wang

      • Abstract
      • Presentation
      • Slides

      Background
      Estrogen receptor pathway has been reported to be interacted with epidermal growth factor receptor (EGFR) signal pathway. This study focused on the impact of intracellular ERβ localization (cytoplasmic or nuclear) on the efficacy of EGFR-TKI.

      Methods
      Tumor tissue specimens from 149 stage IV NSCLC patients treated with EGFR-TKI were analyzed using immunohistochemistry (IHC) for ER expression (ERαorβ) and their associations with clinicopathological variables and clinical outcomes. Significance of cyto-ERβ expression was further examined in NSCLC cell lines.

      Results
      The expression of ERα and ERβ was detected in 15% and 28.9% of the patients, respectively. Cyto-ERβ positive cases showed shortened progression free survival (PFS) compared with cyto- ERβ negative ones (3.1 months vs. 7.3 months, p=0.061). In the subgroup with concurrent EGFR mutation, the differences of PFS were enlarged with significant statistics (4.7 months vs. 10.9 months, p=0.042). COX’s proportional hazard model showed that female, EGFR mutation and c- ERβ negative expression were independent predictive factors for PFS. PC-9 cells present ERβ in cytoplasma as well as nucleus. Estrodial (E2) induced PC-9 cells moderately resistant to erlotinib with a 3-fold increase of IC50, and the resistance can be reversed by ER blocker (fulvestrant) or siRNA directed to ESR2. The function of E2 was accomplished by nongenomic activation (MAPK phosphorylation) caused by E2 via cyto- ERβ. Combination therapy with erlotinib and fulvestrant turned out to be far more effective than either treatment alone in PC-9 cells. Furthermore, 2 patients harboring both EGFR mutation and cyto-ERβ expression underwent PD of EGFR-TKIs, and re-obtained disease control after receiving combined EGFR-TKIs with fulvestrant.

      Conclusion
      Cyto-ERβ expression may predict relatively poor efficacy to EGFR-TKI compared with non- cyto-ERβ expression in NSCLC patients harboring EGFR mutation.

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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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      P1.06-038 - Single Cell Genomic Analyses of Circulating Tumor Cells from Lung Cancer Patients (ID 2509)

      09:30 - 09:30  |  Author(s): Z. Wang

      • Abstract

      Background
      Circulating tumor cells (CTCs),which can be detected from peripheral blood, offer the potential for the assessment of clinical outcome. Whole genome sequencing of CTCs may provide comprehensive information related to tumor invasion and metastases, but has been hampered by their low abundance

      Methods
      From 7.5 ml peripheral blood, we captured with the CellSearch platform a small numberof CTCs, which, after further isolation with 95% specificity, were subject to whole genome amplification with Multiple Annealing and Looping-Based Amplification Cycles (MALBAC). The individual CTCs’ copy number variations (CNVs) were determined by whole-genome sequencing, and their single nucleotide variations (SNVs) and insertions/deletions (INDELs) were detected by exome sequencing.

      Results
      We sequenced 24 CTCs from four patients with advanced lung adenocarcinoma and compared them with the matched primary/metastatic tumors. Patient 1 with EGFR mutation experienced a phenotypic transition from lung adenocarcinoma to small cell lung cancer in liver, and resistance to EGFR-TKIs. Individual CTCs from each patient exhibited reproducible copy number variation (CNV) patterns, which resembled those of the metastatic tumors. CTCs from different patients showed similar CNV patterns on certain chromosomes. Some rare single nucleotide variations (SNVs) and insertions/deletions (INDELs) in primary tumor, including those that may relate to drug resistance and phenotypic transition, were enriched in CTCs.

      Conclusion
      CTCs exhibit highly reproducible CNV patternswhich offer a potential biomarker for cancer diagnosis and classification. The SNVs/INDELS in individual CTCs can be detected and provide molecular targets for personalized treatment.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-034 - Analysis of Sensitivity of Lung Squamous Carcinoma with EGFR Mutation to EGFR-TKIs and Resistant Mechanism (ID 2537)

      09:30 - 09:30  |  Author(s): Z. Wang

      • Abstract

      Background
      Epidermal growth factor receptor (EGFR) gene variation is one common driver mutation in lung cancer. In lung adenocarcinoma, EGFR mutations are the powerful predictors to the efficacy of EGFR-TKIs. However, the phenomenon seemed to be inconsistent in lung squamous carcinoma. The present study aims to investigate the sensitivity of lung squamous cell carcinoma (SCC) harboring EGFR mutation to EGFR-TKIs, and explore the likely molecular mechanisms through constructing EGFR mutant lung SCC cell lines and analyzing the results transcriptomics.

      Methods
      This study retrospectively enrolled 91 patients with advanced lung SCC who received EGFR-TKIs in Beijing University Cancer Hospital. Denaturing high-performance liquid chromatography (DHPLC) and immunohistochemistry (IHC) were used for the detection of EGFR mutations and protein expressions of P63 and TTF-1, respectively. Stable cell lines were constructed through lipofectamine and confirmed by western-blot, soft agar cloning formation and tumoregeneity in nude mice. Cell titer Glo was used for cell number counting. RNASeq was used for the analysis of transcriptomics and related signaling pathways were screened in KEGG website. SPSS (17.0 version) was used for statistics.

      Results
      The frequency of EGFR mutation was 16.2% (64/396) in lung SCC. In lung cancer patients with EGFR mutation, lung SCC patients accounted for 7% (64/863), commonly in male (71.9%), smoker (59.4%) and EGFR exon 19DEL (64.1%). In total 91 patients who received EGFR-TKIs, the objective response rate (ORR) and the disease control rate (DCR) were 11.0% (10/91) and 56.0% (51/91) respectively and the progression-free survival (PFS) and the overall survival (OS) were 2.9 months and 16.3 months. In terms of 60 patients who provided EGFR mutated status, 29 patients harbored EGFR mutation and the other 31 without EGFR mutation. The PFS of the subgroup with EGFR mutation after EGFR-TKIs showed prolonged trend compared with that of the subgroup without EGFR mutation, however, the statistics failed to amount to significant difference (2.4 months vs. 1.8 months, p=0.071). No statistical differences were observed in PFS ORR, DCR and OS between the two subgroups. IHC results demonstrated that most of lung SCC patients harboring EGFR mutation showed P63 positive and TTF-1 negative (15/18). We then constructed lung SCC cell lines with EGFR mutation (Beas-2B/EGFR 19DEL cell line and Beas-2B/EGFR 21L858 cell line), which showed resistant to erlotinib with the IC50 of 3.43±0.56μM和11.9±1.18μM. After the treatment of erlotinib, the mainly up-regulated signaling pathways included TGFβ pathway and hedgehog pathway, and RNA levels of some mesenchymal genes were also up-regulated.

      Conclusion
      Lung SCCs with EGFR mutation were not uncommon, who showed insensitivity and even resistance to EGFR-TKIs. The likely molecular mechanisms included TGFβ related epithelial-mesenchymal transition (EMT) and tumor stem cell like differentiation, and the upregulation of bone morphogenetic protein 4 (BMP4).