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X. Zhang



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    JCES01 - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 413)

    • Event: WCLC 2016
    • Type: Joint Chinese / English Session
    • Track:
    • Presentations: 1
    • Now Available
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      JCES01.13 - Discussant Posters (Now Available) (ID 6821)

      X. Zhang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA08.07 - Prospective Sequential Counts of Total CTC or cKIT+CTC in Advanced NSCLC with 1st Line Chemotherapy (POLICE) (Now Available) (ID 5857)

      X. Zhang

      • Abstract
      • Presentation
      • Slides

      Background:
      Circulating tumor cells (CTCs) have been reported prognostic and predictive in non-small cell lung cancer (NSCLC) and a few of other cancer types. In 1[st] line setting, whether EPCAM[+]CK[+]CD45[-] CTC and/or stem cell-like cKIT[+]EPCAM[+ ]CK[+]CD45[-] CTC enumeration and dynamic changes can be prognostic and/or predictive to standard chemotherapy need further investigation in Chinese patients with NSCLC.

      Methods:
      A prospective study on the CTC enumeration in advanced NSCLC with 1st line chemotherapy (POLICE) was started by China Thoracic Oncology Group (CTONG). Patients with NSCLC naïve for systemic regimens were enrolled since August 2013. CTCs were detected by Cell Search Platform and identified as positive for EPCAM[+]CK[+]CD45[-] phenotype. CD117 (cKIT) marker was added to test the frequency of stem cell-like cKIT[+]EPCAM[+]CK[+]CD45[- ]CTCs. Primary endpoints were CTC counts and its correlation with first line therapy.

      Results:
      Totally 180 patients were enrolled. In 174 case total CTC and cKIT[+]CTC positive (cutoff >=1) rates were 38.5% (67/172) vs 14.3% (24/168), 21.8% (31/142) vs 6.3% (9/142), 13.7% (13/95) vs 6.4% (6/94) and 40.4% (38/94) vs 15.0% (13/93) at time-points of baseline, after first-cycle-chemo, after four-cycles-chemo and disease progression. At time immediately after first-cycle-chemo, patients in CTC=0 group got statistically higher ORR (29.0% VS 7.1%, P=0.017) and DCR (74.2% VS 42.9%, P=0.002) than in CTC>=1 group. At time after four-cycles-chemo, patients in CTC=0 group got statistically higher DCR (88.3% VS 58.3%, P=0.026) than in CTC>=1 group. At time either after first-cycle-chemo or after four-cycles-chemo, patients in CTC>=1 group got worse PFS (5.7m VS 4.0m, P=0.025; 6.3m VS 4.0m, P=0.001 ) than in CTC=0 group. At time after first-cycle-chemo, patients in groups cKIT[+]CTC>=1 and cKIT[-]CTC>=1 got worse PFSs (3.1m vs 4.0m vs 5.7m, P=0.001) and worse DCRs (44.4% vs 42.1% vs 73.9%, P=0.009) than in CTC=0 group. For 142 patients categorized into three groups of dynamic CTC decrease (17), CTC unchanged (82), and CTC increase (43), there were significant differences in terms of DCR (71.8% vs 71.6% vs 33.3%, P=0.018) and PFS (5.2m vs 5.6m vs 3.1m, P=0.037).

      Conclusion:
      In first line setting of advanced NSCLC, at time-points after first-cycle-chemo other than baseline, total CTC or cKIT[+]CTC counts could be predictive for worse DCR or PFS. CTC increase from baseline to after-first-cycle-chemo might be a strong signal for the inefficacy of first line chemotherapy in the NSCLC patients.

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    MA17 - Genetic Drivers (ID 409)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Biology/Pathology
    • Presentations: 1
    • Now Available
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      MA17.05 - Evolutionary Trajectories of Molecular Progression in Different Subtypes of Primary Lung Adenocarcinomas (Now Available) (ID 5712)

      X. Zhang

      • Abstract
      • Presentation
      • Slides

      Background:
      Morphological and genetic heterogeneity predict prognostics, impede continuous responses to systemic regimens and foster inevitable treatment failure. But how morphological and genetic features evolve in tumorigenesis still remains controversial.

      Methods:
      Single(n=1112) and multiple(n=91) primary adenocarcinoma patients receiving surgeries with specific prominent subtypes were screened. Six patients with mixed ground glass opacities and maximum cross-sections of primary tumors were randomly selected. Intra-tumoral regions with different subtypes and imaging densities related to relative distributions, were resected for target region sequencing and further molecular evolutionary analyses.

      Results:
      Clinical data revealed certain preferences of driver gene mutations and discrepant survival benefits. Driver gene heterogeneity was higher in multiple primary lung cancers(51.7%, 15/29) than single ones(1.4%, 1/70). Copy number alterations implied more consistence within the same subtype and tended to be higher in lepidic subtype. Somatic nucleotide variants revealed highest homogeneity between different regions within the same tumor lesion. Sequencing data indicated larger fractions of geographically ubiquitous mutations than pathologically ones, and higher mutation frequencies of shared mutations in the lepidic than acinar subtype. Phylogenetic trees exhibited higher geographically private mutation burdens of lepidic than acinar region in lesions with mixed subtypes; while in lesions with the same subtype, the central region bore higher mutation burdens than in the periphery, implying a linear accumulation of genetic mutations. Functional analyses of private mutations verified that lepidic subtypes promoted intracellular organism and structure development, promoting growth and proliferation. Acinar subtypes lead to metabolic and signaling transduction pathway. Preferences of divergent pathway alterations delineated branched evolutions from low to higher grade subtypes. Figure 1



      Conclusion:
      We propose a model that the same morphological subtype evolves with a linear accumulation and mixed subtypes in branched evolutionary trajectories with preferences to pathway alterations. Couple with relatively geological distributions of different subtypes, tumor microenvironment might contribute more to genetic instability and thus tumor evolutions.

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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
    • Now Available
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      P2.03b-041 - Cerebrospinal Fluid Tumor Cells for Diagnosis of Leptomeningeal Metastases in Non-Small Cell Lung Cancer (Now Available) (ID 4479)

      X. Zhang

      • Abstract
      • Slides

      Background:
      The diagnosis of leptomeningeal metastases (LM) relied on tumor cells found in cerebrospinal fluid (CSF) and/or typical magnetic resonance imaging (MRI) findings, but both lack sensitivity. The CellSearch Assay™ had been validated to detect CTCs for follow-ups of cancer patients, and we adapted it to identify CSF tumor cells (CSFTCs) in non-small cell lung cancer (NSCLC) with suspected LM, and moreover detected their gene statuses of epidermal growth factor receptor (EGFR).

      Methods:
      Twenty-one NSCLC patients with suspicious LM had CSF analyzed through both traditional Thinprep cytologic test (TCT) and CellSearch, and peripheral blood were detected for circulating tumor cells (CTCs) in fourteen patients. The statuses of EGFR were tested in primary tissues of all twenty-one patients and in CSFTCs of eight patients.

      Results:
      All twenty-one patients were identified as LM, CSFTCs were captured by CellSearch in twenty patients (median 969 CSFTCs/ 7.5 mL, range: 27-14888), while CTCs were captured in only five patients (median 2 CTCs/7.5 mL, range: 2-4), which were much lower than CSFTCs. The sensitivity of CellSearch was 95.2%, while that of TCT from the same CSF puncture was 57.1%, and that of MRI was 52.4%, and that of combined MRI and TCT was 90.5%. Moreover, the specificity of CSFTCs was 100%. Among eight patients with EGFR tested in CSFTCs, six patients matched with primary tissues and resistant gene T790M was identified in two cases.Figure 1



      Conclusion:
      Cerebrospinal fluid tumor cells could be more sensitive and effective to diagnose LM, and may serve as the potential way of liquid biopsy for EGFR mutation in NSCLC with LM.

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      P2.03b-043 - Peripheral Blood CD45RA+ CCR7+ Naive T Cells Were Correlated with Prognosis in Non-Small Cell Lung Cancer Patients (Now Available) (ID 5999)

      X. Zhang

      • Abstract
      • Slides

      Background:
      CD45RA+ CCR7+ naive T cells were reported to generate effectors possessed the high potent cytotoxic activity and low level of "exhaustion" T cells in vitro. However the relationship between frequency of naïve T cells in peripheral blood and prognosis in non-small cell lung cancer (NSCLC) is not clear. In order to elucidate this relationship, we first analyzed the frequency of CD45RA+ CCR7+ naïve T cell in peripheral blood of healthy population and patients with NSCLC.

      Methods:
      The frequency of CD45RA+ CCR7+ naïve T cells was calculated by flow cytometry from healthy volunteers and NSCLC patients. The correlation of naive T cell frequency and overall survival (OS) of NSCLC patients who were treated with tyrosine kinase inhibitors (TKIs) or chemotherapy was statistically analyzed.

      Results:
      105 healthy volunteers (age rank 23-85year-old) and 137 NSCLC patients (age rank 33-86year-old) were enrolled in our study from 2013 October 1st to 2015 December 1st. Our results showed that the frequency of peripheral blood naïve T cells in NSCLC patients’ (Mean=17.8±5.7%) was significantly lower than that in healthy subjects’ (Mean=31.2±5.2%) (p<0.05). The frequency of naïve T cell was negatively correlated with the frequency of PD-1+CD8+ T cells (R[2]=0.1111, p<0.001) in peripheral blood of NSCLC patients, whereas, which was positively associated with the immune activity of CD8+ T cells and with the frequency of lymphoid stem cells or lymphoid progenitor cells in peripheral bloods (R[2]=0.1521, p<0.001). In the patients who were treated with TKIs,mOS in the group of high frequency of naïve T cells (>17.8%) was not reached, while that of group with low frequency (17.8%) was 19.0m (HR=0.3057, 95% CI 0.1127- 0.8291, p=0.0199). In patients who were administered chemotherapy, the mOS in the naïve T cells low frequency group was 12.0m, but in the high frequency group the median OS was undefined (HR=0.3286, 95% CI 0.1100 0.9817, p=0.0463).

      Conclusion:
      Our study shows that the CD45RA+ CCR7+ naïve T cells in peripheral blood closely related with immune response, and the frequency of naïve T cells in peripheral blood is positively associated with prognosis of NSCLC, which can be worked as a valuable prognostic factor for NSCLC 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: 2
    • Now Available
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      P3.02b-016 - An Exploration Study of Mechanisms Underlying Primary Resistance to EGFR-TKIs in Patients Harboring TKI-Sensitive EGFR Mutations (Now Available) (ID 4280)

      X. Zhang

      • Abstract
      • Slides

      Background:
      Primary resistance to EGFR-TKIs was generally defined as disease progression in less than 3 months without any evidence of objective response. Although possible mechanisms have been investigated in several preclinical and retrospective studies, little is known about the molecular backgrounds of primary resistance.

      Methods:
      Random Sample of Cases was used to screen TKI-sensitive patients to match with the primary resistant patients on the basis of clinical characteristics (smoking history, EGFR mutations etc.). DNA was extracted from the tumor and their matched normal material. The paired-end whole exome sequencing (WES) of DNA was performed on the Illumina HiSeq 2500 sequencing platform.

      Results:
      Totally, five patients exhibiting primary resistance to EGFR-TKIs were enrolled and each was randomly matched with one patient possessing TKI sensitivity (Table1). The mean depth of the WES was 100x. The mean number of nonsynonymous SNV per sample was 195 (range 97 to 348) in TKI-resistant group versus 84 (range 60 to 101) in TKI-sensitive group (P=0.059). Consistent with the initial result of Sanger sequencing, all 10 patients were found with EGFR sensitizing mutations (exon 19 deletions or L858R point mutation in exon 21), but no T790M mutation; the resistance group present with a lower EGFR mutant allele frequency than the sensitive group. Next generation sequencing of TKI-resistant specimens detected KRAS amplification (CN~tumor ~/ CN~normal ~= 2.6) in one of five patients, and MET amplification (CN~tumor ~/ CN~normal ~= 2.3) in another one. The recurrent mutation genes included FAT4, RBM10, TANC2, ACAN, PPFIA2, UBR4, XIRP2 and PRAMEF1. Figure 1



      Conclusion:
      Next-generation sequencing offers more complete genomic analysis to understand the mechanism of differential responses to EGFR-TKIs, which can lead to more precision therapy. KRAS amplification appears to be a newly mechanism underlying primary resistance to EGFR-TKIs in patients harboring TKI-sensitive EGFR mutations. However, it needs to be validated in a larger cohort.

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      P3.02b-095 - Tracing Spatiotemporal T790M Heterogeneity in Patients with EGFR-Mutant Advanced NSCLC after Acquired Resistance to EGFR TKIs (Now Available) (ID 6057)

      X. Zhang

      • Abstract
      • Slides

      Background:
      With the marketing of osimertinib, epidermal growth factor receptor (EGFR) T790M mutation has become a clinically significant biomarker for advanced EGFR-mutant non-small-cell lung cancer (NSCLC) after acquired resistance to previous EGFR TKIs. However, T790M status might vary spatiotemporally and consequently hinder the initiation and clinical efficacy of third generation EGFR TKIs. Till now, the spatiotemporal traces of T790M under treatment pressure have not been fully elucidated.

      Methods:
      We retrospectively reviewed T790M status and clinical courses of 93 patients who underwent multiple (≥2) rebiopsies after acquired resistance to first or second generation EGFR TKIs from 2010 to 2015 in Guangdong General Hospital. Patients underwent synchronous rebiopsies at the same lesion or paired tissue and plasma rebiopsies were enrolled to evaluate the spatial T790M heterogeneity. Patients received heterochronous rebiopsies at the same lesion or different lesions were enrolled to evaluate the temporal and spatiotemporal T790M heterogeneity respectively.Tissue EGFR detection was performed by SNAPSHOT or Amplification Refractory Mutation System (ARMS). Plasma EGFR was detected by ARMS.

      Results:
      A total of 99 evaluations were performed with 6 of 93 enrolled patients underwent both synchronous and heterochronous rebiopsies. Among 20 patients who underwent synchronous rebiopsies at the same lesion, 13 revealed T790M heterogeneity. Among 17 patients who had paired tissue and plasma rebiopsies, 8 showed T790M heterogeneity. Spatial T790M heterogeneity ratio was 57% (21/37) in general. 33% (10/30) patients who received heterochronous rebiopsies at the same lesion revealed temporal T790M heterogeneity. Spatiotemporal T790M heterogeneity was observed in 53% (17/32) of patients who received heterochronous multiple sites rebiopsies. Of abovementioned patients with heterochronous T790M heterogeneity, T790M status in 67% (18/27) switched from negative to positive after chemotherapy or continuation of EGFR TKIs and in 33% (9/27) switched from positive to negative after chemotherapy or combined regimens of chemotherapy and EGFR TKIs.

      Conclusion:
      T790M status could vary spatiotemporally at a ratio of 33-57% in patients with acquired resistance to previous EGFR TKIs. Repeated rebiopsies both at the same lesion and various lesions might be valued particularly in T790M-negative cases in this subset of patients.

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