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J. Duan



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    ORAL 25 - Biology and Other Issues in SCLC (ID 125)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Small Cell Lung Cancer
    • Presentations: 1
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      ORAL25.03 - Establishment of Lung Cancer Xenograft Models Derived from Bronchoscopy Biopsy and Investigating Mechanism of Refractory Small Cell Lung Cancer (ID 3097)

      11:07 - 11:18  |  Author(s): J. Duan

      • Abstract
      • Presentation

      Background:
      There were mainly two kinds of lung cancer xenograft models, xenograft models derived from stable cell lines and patient derived xenograft (PDX) models which adopted tissues resected by surgeries. However, these animal models may not reflect biological and genetic characteristics of advanced lung cancer, especially small cell lung cancer (SCLC). We utilized bronchoscopy-guided biopsy tumor tissues of advanced lung cancer to establish xenograft models and analyzed fidelity of histopathology, genetic profile and chemotherapeutic efficacy with their parental tumors. At last the molecular mechanism of drug resistance in refractory SCLC was studied.

      Methods:
      Primary pulmonary tumor tissues taken from bronchoscopy were implanted to NOD-SCID (nonobese diabetic-severe combined immunodeficiency disease) mice subcutaneously for model establishment and consecutive passage. The histopathology and genetic profile in samples of bronchoscopy-guided biopsy tumor tissues-derived xenograft (BDX) models and their parental tumors were detected. Parental fidelity of BDXs’ chemotherapeutic response was detected by chemosensitivity in vivo. Next generation sequencing (NGS) of target gene was taken in SCLC BDXs to analyze high-fidelity with their parental samples. Based on bioinformatic analysis, molecular mechanism of sensitive and refractory SCLC was discussed.

      Results:
      66 BDXs from 188 patients (35%) were successfully established. Successful rate of BDXs in SCLC was significantly higher than that in squamous cell cancer (SCC) (50.72% vs. 32.00%, p=0.005) and in adenocarcinoma (ADC) (50.72% vs. 16.22%, p=0.025). The growth rate of passage 1 BDXs in SCLC was slower than it in SCC or ADC (P<0.0001). Almost all BDXs kept similar histology, pathological marker and driver-gene mutations with their corresponding patients’ tissues. The gene mutations of which frequency was more than 10% in patient’s SCLC were kept consistent in BDXs with same genotype and frequency. Gene mutations which regulated mitogen activated protein kinase (MAPK) pathway as KRAS, KIT, MET were only detected in refractory SCLC and corresponding BDXs rather than sensitive disease. In further functional verification, the percentage of positive pERK was 100% (5/5) in refractory BDXs, but 20% (1/5) in sensitive BDXs (p=0.0476).

      Conclusion:
      BDXs which were successfully established with high-fidelity of histopathology, genetic profile and chemotherapeutic response could be utilized as animal models in research of unresectable lung cancer. MAPK pathway related gene mutations found in both BDXs and primary tumor tissues may be associated with resistance in refractory SCLC. PERK was promising to be used as molecular markers in genotype and prediction of chemotherapy-resistance for SCLC.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-062 - Efficacy and Safety of Weekly Albumin-Bound Paclitaxel for Non-Small-Cell Lung Cancer Patients Who Have Failed ≥ 2 Prior Systemic Regimens (ID 2375)

      09:30 - 09:30  |  Author(s): J. Duan

      • Abstract
      • Slides

      Background:
      To evaluate the efficacy and safety of weekly intravenous Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) for the patients with advanced non-small-cell lung cancer (NSCLC) who have failed prior multilines treatments, and to investigate the association of status of secreted protein, acidic and rich in cysteine (SPARC) expression and clinipathological factors with clinical outcome.

      Methods:
      We retrospectively analyzed the efficacy and toxicities of NAB-paclitaxel monotherapy in treating 84 patients who had progression disease after at least two lines standard chemotherapy from May 1, 2011 to June 31, 2014. All patients were treated with NAB-paclitaxel 130mg/m2 on days 1 and 8 of a 21-day cycle. Radiologic tumor assessment was performed every 6 weeks or when the patient’s symptoms deteriorated obviously. We also detected the SPARC status expression (by immunohistochemistry) in 35 patients who had tumor tissue available. 76 of 84 patients had EGFR mutation status. The date of last follow-up was March 31, 2015.

      Results:
      Of these 84 patients, 76 patients had complete follow-up data, 5 patients lost of follow-up for overall survival, and 3 patients couldn’t tolerate the continuous NAB-paclitaxel therapy due to serious adverse events and had only the evaluation of safety data.. EGFR mutation were found in 22 of 76 patients and their median PFS and OS were 4.4 months and 11.5months. The median treatment line of weekly NAB-paclitaxel therapy was 4 line (range: 2~7 line). The median follow-up interval time was 11.2 months. The objective response rate (ORR) and disease control rate (DCR) (N=81) were 14.8% (12/81) and 67.9% (55/81), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95% CI: 2.8~5.0 months) and 11.0 months (95%CI: 7.6~14.4 months), respectively. Pearson’s correlation analysis showed that previous treatment with Solvent-based Paclitaxel or Docetaxel didn’t affect the response to NAB-paclitaxel. However, the patients who reached disease control after previous Solvent-based Paclitaxel or Docetaxel presented better DCR than the patients who failed to previous Solvent-based Paclitaxel or Docetaxel (DCR: 77.1% vs 47.6%, p=0.040) (by Fisher’s Exact Test). Cox regression analysis showed that ORR was related with both PFS and OS. The common adverse events (N=84) included leukopenia (36.1%), neutropenia (29.2%), peripheral neurotoxicity (23.6%), et al. The main grade 3/4 toxicities included neutropenia (9.7%) and leukopenia (6.9%). 3 patients had discontinued chemotherapy due to drug induced lung injury, serious fatigue and serious anorexia, separately. In this study, no association between SPARC expression and efficacy was observed.

      Conclusion:
      Advanced NSCLC patients who have experienced multiline chemotherapy with disease progression could benefit from weekly NAB-paclitaxel therapy with good safety and clinical outcome. It seemed that SPARC expression could not predict efficacy to NAB-paclitaxel.

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