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X. Han



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    MO12 - Prognostic and Predictive Biomarkers III (ID 96)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO12.05 - A new biomarker Heat shock protein 90 alpha as therapeutic monitor and predictor for lung cancer patients (ID 2628)

      10:30 - 12:00  |  Author(s): X. Han

      • Abstract
      • Presentation
      • Slides

      Background
      Heat shock proteins are a group of proteins termed stress proteins. The family of Hsp90 includes Hsp90α and Hsp90β, but only Hsp90α has been described to be extracellular, and the presence of Hsp90α on cell surface has been shown to correlate with malignancy in cancer patients, especially with the tumor metastasis. However, to the best of our knowledge, no large clinical samples have been reported to verify above standpoint. The aim of the present multicenter clinical study was to evaluate the expression level of Hsp90α in lung cancer patients and whether Hsp90α was monitor and predictor for response to therapy in lung cancer.

      Methods
      A total of 2284 lung cancer patients were enrolled in this study which was randomly assigned into two groups as static and dynamic groups. The static group (2036 samples) consisted of healthy subjects (592 samples), lung cancer (1046 samples), non-cancerous lesions of the lung patients(361 samples ) and other cancer patients(37 samples). Samples of peripheral blood from all subjects were collected in sterile EDTA-K2-coated vials. Whereas the dynamic group included lung cancer patients who received surgical treatment and underwent chemotherapy, with number of above mentioned parts 79 and 169, respectively. For surgical patients, plasma samples were collected at following time points: 3 days before surgery, 3-7 days after surgery and 3 days after clinical efficacy evaluation. Similarly, plasma samples of chemotherapy patients were also collected before treatment, after each chemotherapy cycle until the forth cycle. The concentrations of Hsp90α in plasma were measured by enzyme-linked immunosorbent assay.

      Results
      The concentration of Hsp90α in lung cancer patients was significantly higher than in other control groups (P <0.05). The cut-off value was 56.33 ng/mL for diagnosis, with high sensitivity and specificity (72.18% and 78.70%, respectively). Advanced lung cancer (stage III-Ⅳ) patients were with higher Hsp90α levels than the early patients(stage I-II) (251.38 ng/ml vs 111.50ng/ml, P<0.001), no significant relationship was found between non-small cell lung cancer（NSCLC,910 samples）patients and small cell lung cancer （SLCL, 136 samples）patients, and patients with adenocarcinoma(537 samples) and squamouscarcinoma (218 samples). Furthermore, a statistically significant association was observed between pre-operative and post-operative patients in surgical patients group (P<0.01). In chemotherapy patients group, Hsp90α level was correlated significantly with the effect of treatment [concentration of Hsp90α was higher in progressive disease(PD)group than in partial response(PR)/stable disease(SD) group].

      Conclusion
      This study firstly developed large clinical samples and elucidated the role of Hsp90α in the lung cancer patients. The cut-off value of 56.33 ng/mL was recommended to assess the expression level of Hsp90α in lung cancer patients. Hsp90α may be a potential biomarker for therapeutic monitor and prediction for lung cancer.

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    P1.22 - Poster Session 1 - Epidemiology, Etiology (ID 166)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.22-005 - A Prospective, Molecular Epidemiological Study of EGFR Mutations in Asian Patients with Advanced Non-Small-Cell Lung Cancer with Adenocarcinoma Histology (PIONEER study) - China Subset Analysis (ID 2241)

      09:30 - 16:30  |  Author(s): X. Han

      • Abstract

      Background
      PIONEER (A molecular ePIdemiOlogy study in Asian patients with advanced NSCLC of adEno histology to assess EGFR mutation status; NCT01185314) was a multinational prospective epidemiological study planned to investigate EGFR mutation frequency in patients from Asia with newly diagnosed advanced lung adenocarcinoma (ADC) and the influence of demographic and clinical factors on EGFR mutation frequency. Here we report analysis results for the subset of patients from China.

      Methods
      Patients were aged ≥20 years, with treatment naïve stage IIIB/IV lung ADC. The primary objective was assessment of overall EGFR mutation frequency. The secondary endpoints included investigation of the correlation between EGFR mutation status and demographic and clinical factors and attrition rates of EGFR mutation testing. The acquisition, preparation, and processing of tumor material was performed in line with the routine clinical practice of the participating hospital laboratories. Tumor EGFR mutation status was determined in central labs using amplification refractory mutation system (ARMS)-based EGFR mutation detection kit (Scorpion ARMS IVD2, Qiagen, Crawley, UK). 29 mutations were detectable by this method across Exons 18, 19, 20, and 21.

      Results
      747 patients were registered in 17 investigational sites in China (50.4% of the overall study population). 46.9% of the patients were female, mean age was 58 years (range 17-83), and 56.4% were never-smokers. 72.4% (541/747) of the samples used for mutation testing were primary tumor. Sample locations include lung (73.5%), local lymph nodes (10.3%), distant lymph nodes (6.3%), pleural effusion (2.5%), pleura (2.0%), and others. sample types include image-guided core biopsy (29.7%), bronchoscopic biopsy (24.1%), incisional biopsy(12.7%), cytology and others. The median time interval taken from order to report of mutation test was 16 days with a range from 3 days to 62 days. EGFR mutation status was successfully evaluated in 741 patients: 372 (50.2%) were mutation positive, 369 (49.8%) were mutation negative. Smoking status and pack years had a statistically significant association with presence of EGFR mutation, but even in regular smokers, the mutation frequency was 35.3%. 12 patients provided both histology and cytology samples. Among these 11 had concordant EGFR mutations status and 1 had mutation results that did not match.

      Conclusion
      Locations and types of the samples used for EGFR mutation testing were various in clinical practice. The overall EGFR mutation frequency in clinically unselected Chinese ADC was 50.2%. Smoking status and pack years had a statistically significant association with presence of EGFR mutation.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-027 - Generation and Biological Character Analysis of EGFR-TKI Resistant Cell Line (ID 2030)

      09:30 - 16:30  |  Author(s): X. Han

      • Abstract

      Background
      Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive remarkable benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs). But drug-resistant problem appears sequentially and novel therapeutic strategies should be explored to overcome EGFR-TKI resistance. As the first EGFR-TKI in China and the third in world, icotinib shows good efficacy and tolerability in patients with advanced NSCLC. This study aims to establish icotinib resistant cell line-HCC827/IR and analyze it’s biological character for further study of EGFR-TKIs resistance.

      Methods
      HCC827 is a cell line with a deletion in the exon 19 of EGFR gene. HCC827 cells were exposed to increasing concentrations of icotinib (10nM to 20uM). Cells with the ability to grow in 20uM of icotinib were obtained 8 months after the initial drug exposure. The cell proliferation, viability, distribution of cell cycle, EGFR gene sequence (exon 18, 19, 20 and 21), EGFR-TKIs cross-resistance and the response to a histone deacetylases inhibitor (Chidamide, CS055) were evaluated after allowing the cells to grow in drug-free conditions for 2 months.

      Results
      Population doubling time (PDT) of HCC827/IR was not different from HCC827 (32.3±6.0h vs. 36.3±2.4h, P=0.198). In the cell cycle distributions of HCC827/IR, the cell number in G0/G1 phase were decreased (P=0.035), but the cell number in S and G2/M phase had no significant change compared with parent cells (P=0.388 and P=0.205, respectively). The resistance index (RI=HCC827IR~IC50~/ HCC827~IC50~) of HCC827/IR to icotinib was (1.98±0.15)×10[3]. And HCC827/IR cells also showed high resistance to the other two EGFR-TKIs (gefitinib and erlotinib), the RI of gefitinib and erlotinib was (2.36±0.082)×10[3 ]and (1.069±0.004)×10[3], respectively. But, the sequence of EGFR gene did not changed before and after resistance to EGFR-TKIs. In addition, HCC827/IR was sensitive to CS055 (IC~50~=254±32nM).

      Conclusion
      This study successfully established icotinib resistant NSCLC cell line-HCC827/IR. HCC827/IR cells had some different biological characters compared with parent cells and showed high cross-resistance to other EGFR-TKIs, but it was sensitive to CS055. The results could provide experimental reference for clinical application of TKIs and provide cell line model for further study of TKI-resistance.

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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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      P2.06-051 - Clinical significance of pretreatment plasma biomarkers in advanced non-small cell lung cancer patients (ID 1160)

      09:30 - 16:30  |  Author(s): X. Han

      • Abstract

      Background
      The use of biomarkers for selecting patients with non-small cell lung cancer (NSCLC) for treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is essential for achieving a satisfactory therapeutic outcome. EGFR mutations have been found to be predictive of response to EGFR-TKIs. The aim of this study was to explore whether biomarkers which can be identified in plasma, such as EGFR mutations, circulating free DNA, and levels of expressed cytokines are predictive for response to EGFR-TKIs and patient survival time.

      Methods
      Formalin-fixed and paraffin-embedded biopsies from tumor tissues and paired plasma samples were collected from 134 patients with advanced NSCLC, EGFR mutations in both types of specimens were assessed by an ARMS/Scorpion assay using real-time PCR. Expression levels of transforming growth factor-alpha and beta one (TGF-α and TGF-β1) were assessed using an enzyme-linked immunosorbent assay (ELISA). Concentrations of circulating free DNA were detected in both NSCLC patients and healthy subjects by a colorimetric assay using ultraviolet spectrometry. The clinical significance of EGFR mutations, levels of cytokines, and circulating free DNA was assessed in advanced NSCLC patients treated with EGFR-TKIs.

      Results
      EGFR somatic mutations were detected in the tumors from 68 of 134 (50.7%) advanced NSCLC patients, and EGFR mutations were detected in the plasma samples from 17 (12.7%) NSCLC patients. Also, the concentrations of circulating free DNA were higher in NSCLC patients than in healthy subjects (P<0.01). EGFR-TKI treatment produced significant effects on progression-free survival (PFS) and overall survival (OS) that were related to the presence of EGFR mutations detected in the tumor tissues (P<0.01).Patients with high levels of TGF-β1 showed shorter OS and worse response to EGFR-TKI treatment than patients with low TGF-β1 levels (P<0.01); however, patients with different expression levels of TGF-α showed no difference in either PFS or OS (P>0.05). Multivariate analysis showed that younger age, adenocarcinoma, never smoking and EGFR somatic mutation were associated with a longer PFS time, and adenocarcinoma, never smoking, low performance status (PS) score, EGFR somatic mutation and low levels of TGF-β1 were associated with greater OS (P<0.05).

      Conclusion
      Plasma levels of TGF-β1 may be a marker for predicting response to EGFR-TKIs and survival time in NSCLC patients, and levels of circulating free DNA could be a biomarker for differentiating between NSCLC patients and healthy individuals.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-043 - Analysis of clinicopathological features for Chinese patients with advanced non-small cell lung cancer harboring EML4-ALK fusion genes (ID 2968)

      09:30 - 16:30  |  Author(s): X. Han

      • Abstract

      Background
      The echinoderm microtubule-associated protein like-4—anaplastic lymphoma kinase (EML4--ALK) fusion oncogene defines a novel molecular subset of non-small cell lung cancer (NSCLC). Crizotinib (Xalkori) has been approved for patients with locally advanced or metastatic NSCLC that is ALK positive. However, the clinicopathological characteristics of patients with the EML4-ALK gene have not been identified completely.

      Methods
      The clinicopathological characteristics of 200 Chinese patients with advanced NSCLC were analyzed retrospectively．Clinical factors including age, sex, smoking history, pathological type, biopsy method, site of biopsy and interval between biopsy and the identification of EML4-ALK fusions and the status of epidermal growth factor receptor (EGFR) mutation were analyzed to investigate possible correlations with EML4-ALK fusions.

      Results
      Among the 200 patients with NSCLC enrolled, 56 (28.0%) harbored the EML4-ALK gene in this retrospective study. EML4-ALK fusions could not be detected in 22 of 200 patients (11.0%) because of insufficient tissue. The median age was 53 as a whole. The median ages of ALK positive and negative groups were 48 and 55 years, respectively. Patients with the EML4-ALK gene were significantly younger than patients without EML4-ALK (p＜0.001). The detection rate of EML4-ALK rearrangement in patients with tumor or metastatic lymph nodes resection was significantly higher than patients with needle biopsy(p=0.003). If the interval between biopsy and the identification of EML4-ALK fusions was less than 48 months, the detection rate of EML4-ALK rearrangement was significantly higher compared with the interval more than 48months(p=0.020). Among the 200 patients, 103(51.5%) patients had received EGFR mutation detection. Only 1 case harbored both EML4-ALK rearrangement and EGFR mutations. The incidence of EML4-ALK rearrangement in patients with EGFR wide type（42.5%,37/87）was significantly higher than EGFR mutant type（6.3%,1/16）. No significant difference in the distribution of sex, smoking history, pathological type, and site of biopsy(lung tumor compared with metastatic lymph nodes) was observed between ALK positive and negative groups (p = 0.140, 0.103, 0.438 and 0.217, respectively).

      Comparisons of patient characteristics according to genotype
      EML4-ALK gene
      Characteristics Total,n Positive,n Negative,n P value
      56 122
      Age(years)
      Median 53 48 55 ＜0.001
      Range 25-76 25-74 27-76
      Sex
      Male 78 20 58 0.140
      Female 100 36 64
      Smoking history
      Never/light smokers 143 49 94 0.103
      Smokers 35 7 28
      Pathological type
      Adenocarcinoma 161 52 109 0.438
      Non- adenocarcinoma 17 4 13
      Biopsy method
      Tumor and metastatic lymph nodes resection 158 49 109 0.003
      Needle biopsy 20 7 13
      Site of biopsy
      Lung tumor 99 27 72 0.217[$]
      Metastatic lymph nodes 72 26 46
      Pleura 2 1 1
      Others 5 2 3
      Interval between biopsy and the identification of EML4-ALK fusions (months)
      ≤48 167 55 112 0.020
      ＞48 11 1 10
      EGFR mutation(n=103)
      Mutant type 16 1 15 0.005
      Wide type 87 37 50
      $:lung tumor compared with lymph nodes

      Conclusion
      We identified younger age and EGFR wide type as clinicopathological features of patients with advanced NSCLC harboring EML4-ALK fusion genes. The detection rate of EML4-ALK rearrangement was significantly higher in patients with tumor or metastatic lymph nodes resection and the interval less than 48 months between biopsy and the identification of EML4-ALK fusions.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-043 - Survival of patients with advanced lung adenocarcinoma before and after approved use of Gefitinib in China: a comparative clinical study in a single center (ID 2973)

      09:30 - 16:30  |  Author(s): X. Han

      • Abstract

      Background
      Since approved use of Gefitinib in March 2005 in China, more patients with lung cancer, especially those with lung adenocarcinoma, have chosen it for treatment. It is of clinical significance to compare survival of lung adenocarcinoma patients who received Gefitinib treatment after March 2005 and that of those who did not receive it so as to provide clinical clues for selection of Gefitinib in Chinese lung adenocarcinoma patients.

      Methods
      Clinical data of 558 patients with advanced lung adenocarcinoma who received palliative chemotherapy from January 2002 throughout December 2010 were reviewed retrospectively. According to the matched-pair case-control study design, 255 patients who only received palliative chemotherapyand 255 patients who received Gefitinib treatment after approved use of Gefitinib were stringently matched by age, sex and smoking history and finally enrolled in this study. Clinical factors including age, sex, smoking history, Eastern Cooperative Oncology Group performance status (ECOG PS), tumor stage, organ metastasis and the number of prior cytotoxic chemotherapies were analyzed to determine their correlations with OS.

      Results
      The median survival time (MST) of the 510 enrolled patients with advanced lung adenocarcinoma was 22.8 months. MST of the patients who received Gefitinib treatment was significantly longer than that of the patients without (33.5 months vs. 14.1 months, p<0.001). OS in patients who received Gefitinib treatment was significantly longer than that in patients without receiving Gefitinib treatment in almost all clinical factor-based subgroups, including age, sex ,smoking history, ECOG PS 0-1, tumor stage, the presence or absence of lung, pleural, bone, brain, adrenal gland and liver metastasis, and the number of prior cytotoxic chemotherapies (all p<0.001), except in ECOG PS ≥2 subgroup.

      Conclusion
      Gefitinib treatment significantly improved the survival of patients with advanced lung adenocarcinoma in China.