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S. Zhang



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    P2.03b - Poster Session with Presenters Present (ID 465)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P2.03b-015 - Efficacy of the Irreversible ErbB Family Blocker Afatinib in Treatment of an Intracerebral Non-Small Cell Lung Cancer in Mice (ID 4965)

      14:30 - 14:30  |  Author(s): S. Zhang

      • Abstract

      Background:
      The prognosis of brain metastases (BM) from lung cancer is extremely poor. Some studies showed patients with BM responded well to afatinib, while little was known on detail mechanism. This study aimed to evaluate the efficacy of afatinib for BM and address whether it could actively penetrate brain-blood barrier (BBB) and hit its target.

      Methods:
      Tumor burden was evaluated weekly after administration of afatinib and vehicle, and pharmacokinetic and pharmacodynamics characteristics were measured in both normal mice and BM model mice.

      Results:
      Administration of 15mg/kg afatinib inhibited in vivo PC-9 tumor growth in brain with tumor growth inhibitory rate (TGI) of 79.8% and 90.2% on day 7 and 14, respectively. 30mg/kg afatinib exhibited the tumor regression on day 7 and 14 with TGI of 124.7% and 105%. The plasma concentration was 91.4±31.2 nM/L at 0.5h after afatinib administration, reached the peak (417.1±119.9 nM/L) at 1h, and still be detected at 24h. The CSF concentrations followed a similar pattern. A good correlation (R[2]=0.732) between plasma and CSF concentrations was demonstrated. Immunohistochemistry showed the signal of pEGFR was reduce by 90% at 1 hour after administration of 30mg/kg afatinib. A positive correlation between afatinib concentrations in CSF and pEGFR modulation was observed.

      Conclusion:
      Afatinib could penetrate into BBB contributing to brain tumor response. The exposure in CSF correlated with that in plasma, which was correlated with modulations of pEGFR in the tumor tissues. Our findings provide implication of potential application of afatinib in NSCLC patients with brain metastases.

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      P2.03b-059 - Detection of Circulating Tumor Cells Using Multiple mRNA in Situ Hybridization Predicts Metastasis in Non-Small Cell Lung Cancer (ID 6280)

      14:30 - 14:30  |  Author(s): S. Zhang

      • Abstract

      Background:
      Peripheral blood circulating tumor cells (CTCs) are involved in tumor distant metastasis. According to different cell surface markers, CTCs can be divided into epithelial phenotype (EP), hybrid epithelial/mesenchymal phenotype (EMP) and mesenchymal phenotype (MP). An epithelial to mesenchymal transition (EMT) is a process which epithelial cells lose their polarized organization and acquire migratory and invasive capabilities. Emerging evidences have indicated that CTCs with mesenchymal phenotype play important role on cancer metastasis. This study aimed to evaluate the the ability of CTCs to detect distant metastases in non-small cell lung cancer (NSCLC).

      Methods:
      This study was performed between September 2014 and December 2015. Patients were considered eligible and were enrolled in this study if they met the following criteria: 1) histologically confirmed NSCLC; 2) patients who did not undergo any treatment; 3) patients at 18 to 85 years old. Blood samples were collected within 14 days before or after radiographic evaluation. CTCs detection was proceeded by multiple mRNA in situ hybridization. The ability of CTCs in detection of distant metastasis was compared with radiographic results. The counts of different CTCs phenotype were applied by Logistic regression equation, distant metastasis was determined with P≥ 0.5, when 0
      Results:
      In total, fifty-nine patients were enrolled. 15 were females and 44 were males. There are 6, 11, and 22 patients diagnosed as stage I-II, stage III, and stage IV, respectively. Adenocarcinoma accounts for 49.2% (29 cases), 22% (13 cases) for squamous, and 5.1% (3 cases) for adenosquamous. The median of total CTCs detected was 5 counts (0 to 57), 2 counts (0 to 14) for EP, 2 counts (0 to 45) for EMP, and 0 count (0 to 10) for MP. The counts of different CTCs phenotype showed no significant difference in gender, age and pathological type. In patients with stage IV, the detection rate of MP was much higher. Compared with radiographic examination, CTCs detection showed a sensitivity of 75.00%, and the specificity of 71.43%. The overall concordance was 72.41%, indicating well ability of CTCs in detection of tumor distant metastasis.

      Conclusion:
      CTCs detected by multiple mRNA in situ hybridization has well ability in detection of tumor distant metastasis. It might have clinical potential in the future application.

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    P2.05 - Poster Session with Presenters Present (ID 463)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Radiotherapy
    • Presentations: 2
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      P2.05-005 - Mechanism of Radiotherapy in Reduction/Delay of T790M-Mediated EGFR TKI Resistance (ID 6370)

      14:30 - 14:30  |  Author(s): S. Zhang

      • Abstract

      Background:
      EGFR T790M mutation accounts for more than 50% of acquired resistance to TKI. In pre-clinical, EGFR-TKI resistant cells with T790M exhibited enhanced sensitivity to radiation, suggesting the potential of radiotherapy in reduction and delay of T790M-mediated EGFR TKI resistance.

      Methods:
      Under different radiotherapy dose and times, we use droplet digital PCR to observe the emerging time of T790M and its proportion during chronic exposure to gefitinib in TKI-sensitivity cell lines, and to evaluate the anti-tumor effect of early radiation combined with gefitinib in xenograft model with different proportion of T790M. Furthermore, we performed miRNA microarray to screen miRNAs differentially expressed in the paired NSCLC gefitinib-sensitivity cell lines and gefitinib resistant cell lines and find potential molecular markers of T790M mutation.

      Results:
      Our data showed radiation combined with gefitinib delayed the occurrence of EGFR T790M mutation compared to gefitinib alone in T790M wildtype (TKI-sensitive) cell line and it also reduced the T790M mutation abundance in de novo T790M mutation (TKI-resistant) cell line. The phenomena was also confirm in mice xenograft model. In addition, our results showed TKI-resistant (induced T790M mutation) cells had higher radiosensitivity than TKI-sensitive cells. miRNA array showed miR-1275 was the one of the most significantly elevated miRNAs in TKI-resistant cells. Knockdown of miRNA-1275 significantly decreased the radiosensitivity of TKI-resistant cells. Western blot showed knockdown of miR-1275 affected proteins relating to cell proliferation and apoptosis. Bioinformatics showed SPOCK1 might be one of the targets of miRNA-1275.

      Conclusion:
      Our results contribute to understand molecular mechanisms of T790M-mediated EGFR-TKI resistance, but also provide a new therapeutic strategy for patients in advanced NSCLC to aid expansion of the effectiveness of TKI treatment through radiotherapy.

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      P2.05-029 - Microwave Thermal Therapy Enhances Radiosensitivity of Highly Invasive Human Non-Small Cell Lung Cancer H460 Cells via Inhibiting DNA Repair (ID 5129)

      14:30 - 14:30  |  Author(s): S. Zhang

      • Abstract

      Background:
      Hyperthermia has long been recognized as a modality in anticancer therapy. In present study, we provide an update on the recent knowledge about the molecular mechanisms of thermal radiosensitization on highly invasive NSCLC cells.

      Methods:
      In previous study, we isolated invasive subpopulations of cancer cells from established human non-small cell lung cancer (NSCLC) H460 cell lines. The subpopulation of highly invasive NSCLC cells (H460-INV) showed cancer cell stemness, increased DNA damage repair. H460-INV cells were exposed to hyperthermia and irradiation. Cell survival was determined by an in vitro clonogenic assay and growth curve for the cells treated with or without hyperthermia. Immunohistochemical staining assay was performed to detect the expression of Ki67、γH2AX foci. Cell apoptosis was performed by Flow cytometry. Cell-scratches and transwell invasion chamber experiments were performed to detect the ability of cell migration and invasion. Western blot assay was used to detect DNA damage repair related molecular changes.

      Results:
      Hyperthermia can significantly enhance irradiation-killing cells. SER was 1.823. Ki67 immunofluorescence results suggested that thermo-radiation can significantly inhibit cell proliferation (p < 0.01). Flow cytometry results showed that the apoptotic cells increased significantly in heat treatment group (p < 0.05). Compared with the control group, H460-INV cell migration and invasion ability significantly reduced. WB results suggested that thermal downregulated the expression of E cadherin, upregulated N-cadherin. Relative persistence of γ-H2A.X nuclear foci in the H460-INV cells after IR treatment was observed, when compared to the no treat H460-INV cells. WB results suggested that thermal combined with radiation inhibited the DNA repair by inhibiting expression of Ku70 and Ku80.

      Conclusion:
      Microwave thermal therapy can increase the sensitivity of highly invasive NSCLC cells to radiation and its mechanism may be related to inhibition of radiation induced DNA damage repair, promoting tumor cell apoptosis, and thermo- radiotherapy can inhibit tumor cell invasion ability. This study suggests a beneficial clinical impact of maicrowave thermal therapy as a radiosensertizer for benefiting highly invasive lung cancer patients.

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    P3.02b - Poster Session with Presenters Present (ID 494)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 3
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      P3.02b-098 - Plasma T790M Mutation Associates with Extensive Progression in Non-small Cell Lung Cancer with Acquired Resistance to EGFR Inhibitors (ID 5598)

      14:30 - 14:30  |  Author(s): S. Zhang

      • Abstract

      Background:
      T790M mutation is a major mechanism for clinical failure in non-small cell lung cancer (NSCLC) patients with EGFR-TKI therapy. Acknowledgement of its frequency/abundance and its correlation with clinical characteristics will be of significant importance for the management of those patients in clinical practice and future trial design. Due to the difficulty of rebiopsy, plasma ctDNA is an ideal biopsy for detection of T790M mutation.

      Methods:
      314 patients with advanced or recurrent NSCLC who had progressed during EGFR-TKIs treatment were enrolled prospectively. T790M mutation was determined in plasma samples by ARMS and ddPCR assay. Disease failure site was defined into three types of chest limited (CP), brain limited (BP) and extensive progression (EP). The T790M mutation status was analyzed for their correlations with failure site and clinical characteristics.

      Results:
      T790M mutations were detected in 30.9% and 46.8% of the patients by ARMS and ddPCR. The concordance rate was 78.3% between two methods. Compared to patients with CP and BP, EP patients showed significant higher rate for T790M[+] determined by both ARMS and ddPCR (73.8% and 54.7%, p<0.001). In T790M positive population, the median T790M abundance was 1.2% (range, 0.04%-70.3%), and the median abundance of CP, BP, and EP was 0.66%, 1.52%, and 2.61%, respectively (p＝0.062). When adjusting for TKI response, worse PFS was found correlated with the plasma T790M mutation by ddPCR.

      Conclusion:
      Plasma T790M status correlates the extensive progression in NSCLC patients with EGFR-TKI therapy, which may provide the important ancillary information for treatment decision-making.

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      P3.02b-100 - Comparison of Three T790M Testing Methods for the Detection of Non-Small Cell Lung Cancer after Tyrosine Kinase Inhibitor Failure (ID 4958)

      14:30 - 14:30  |  Author(s): S. Zhang

      • Abstract

      Background:
      The third generation of TKI showed promising activities in patients with acquired T790M mutation. However, many patients in this setting are unable to undergo rebiopsy due to limited tissue availability and procedural feasibility. Mutation detection in plasma has shown promises to conquer the clinical challenging of re-biopsy, with advantage of non-invasiveness and accessibility. Here, we chose and evaluated the performance of three methods, amplification refractory mutation system (ARMS), modified amplification refractory mutation system (SuperARMS), and droplet digital PCR (ddPCR), to assess their concordance and feasibility for the detection of mutations in plasma samples.

      Methods:
      This study was performed between March 2015 and March 2016. Patients were considered eligible and were enrolled in this study if they met the following criteria: 1) histologically confirmed stage IIIB/IV NSCLC; 2) clinically resistant to first-generation EGFR-TKIs according to Jackman’s criteria. Blood samples were collected within 14 days after TKI resistance. Each sample was simultaneously detected by three methods.

      Results:
      In total, 169 patients were enrolled. 54.4% were female and 72.2% were diagnosed as stage IV; 97.6% were adenocarcinoma. The rates of patients in response to EGFR-TKI treatment were 35.5% for stable disease, 52.1% for partial response and 12.4% for complete response, respectively. T790M mutations were detected in 54 of 169 (32.0%) samples by ARMS, 33 of which simultaneously carried exon19 deletions and 21 of which carried L858R. For SuperARMS assay, 59 (34.9%) samples were detected T790M mutation and 110 (65.1%) were not detected. ddPCR results showed that 61 (36.1%) samples were with detectable T790M mutation and 108 (63.9%) samples were detected with wildtype T790M. T790M abundance ranged from 0.04% to 38.2%. The median T790M abundance was 0.15% for total samples and 2.98% for T790M mutation samples. The overall concordance was 81.1% (137/169) among ARMS, SuperARMS, and ddPCR. The crude and adjust agreement between ARMS and SuperARMS was 87.6% and 86.1%, 88.8% and 87.7% between ARMS and ddPCR, 85.8% and 84.5% between SuperARMS and ddPCR, respectively. We also found that detection of T790M with ddPCR showed a sensitivity of 94.6% (95%CI: 90%-97.5%) and a specificity of 59.9% (95%CI: 51.2%-67.9%) when took ARMS as reference.

      Conclusion:
      Liquid biopsy showed promises with advantage of non-invasiveness and accessibility. T790M detection based on plasma circulation tumor DNA showed high concordance. Compared with non-digital platforms, ddPCR showed higher sensitivity and provided both frequency and abundance information, which might be important for treatment decision-making.

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      P3.02b-123 - Lysimachia Capillipes Capilliposide Inhibits AKT Activation and Restores Sensitivity to Gefitinib in NSCLC with Acquired Gefitinib Resistance (ID 4970)

      14:30 - 14:30  |  Author(s): S. Zhang

      • Abstract

      Background:
      Most non-small cell lung cancer (NSCLC) patients responding to gefitinib will eventually develop the resistance. Lysimachia capillipes (LC) capilliposide extracts from LC hemsl shows both in vitro and in vivo anti-cancer effects. We investigated whether LC capilliposide combined with gefitinib could overcome the resistance of NSCLC cells to gefitinib, and to identify the involved molecular signaling.

      Methods:
      NSCLC cell lines with different sensitivities to gefitinib were studied. Cell proliferation was assessed with MTT assay. Cell apoptosis and cell cycle distribution were measured using cytometry. EGFR-related signaling proteins and Human Phospho-Kinase were analyzed using Western blotting and protein array, respectively. Tumor growth inhibition were evaluated in PC-9-GR xenograft. CC3, Ki67 and pEGFR were assessed by IHC on tumor tissues.

      Results:
      LC capilliposide inhibited cell growth in gefitinib-sensitive and -resistant cells. In gefitinib resistant cell PC-9-GR with T790M mutation, the LC capilliposide combined with gefitinib was potent in cell growth inhibition and apoptosis induction, but no obvious effect on gefitinib-induced G0/G1 arrest. LC capilliposide remarkable blocks the phosphorylation of EGFR downstream signaling molecule AKT, on which LC capilliposide and gefitinib alone had no obvious effect. The Human Phospho-Kinase array further confirmed the enhanced inhibitory effect on the AKT signaling. LC capilliposide treatment also enhanced tumor growth inhibition when combined with gefitinib in PC-9-GR xenografts.

      Conclusion:
      LC capilliposide restored the sensitivity to gefitinib in NSCLC cells with acquired gefitinib resistance, suggesting that combination of LC and gefitinib may be a promising therapeutic strategy to overcome gefitinib resistance in NSCLCs with T790M mutation.