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C. Zhou



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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-001 - The prevalence and clinicopathologic feature of ALK, ROS1 and RET fusions in East Asian patients with lung adenocarcinoma (ID 49)

      09:30 - 09:30  |  Author(s): C. Zhou

      • Abstract

      Background
      ALK, ROS1 and RET fusions have been demonstrated as oncogenic drivers in lung cancer. Of these, ALK fusions were shown to occur more frequently in patients with mucinous adenocarcinoma or solid histology with signet-ring cells. The association of ROS1 and RET fusions with the adenocarcinoma component remains unclear. We conducted this study to determine the prevalence and clinicopathologic characteristics of ALK, ROS1 and RET fusions in East Asian patients with lung adenocarcinoma, and investigate the association of the above-mentioned gene fusions with histological subtype of adenocarcinoma according to the IASLC/ATS/ERS Classification.

      Methods
      We screened 620 Chinese patients with histologically confirmed lung adenocarcinoma for ALK, ROS1 and RET fusions using multiplex RT-PCR and validated all fusion-positive patients using direct sequencing. The patterns of gene fusions screened in this study contained EML4-ALK (17 variants), CD74-ROS1, SLC34A2-ROS1, SDC4-ROS1, EZR-ROS1, TPM3-ROS1, LRIG3-ROS1, GOPC-ROS1, KIF5B-RET, CCDC6-RET and NCOA4-RET. The association of ALK, ROS1 and RET fusions with different subtype of adenocarcinoma were analyzed in 331 patients. The data for remaining 289 patients are being analyzed. All patients enrolled in this study were followed up for survival.

      Results
      Of the 620 patients with adenocarcinoma screened, 472 (76.1%) patients were never/light smokers (<10 pack-years), and 148 (23.9%) were smokers (≥10 pack-years), with the median age of 59 (range, 27-82) years; 348 patients were female, accounting for 56.1%. Patients with stage I, II, III, or IV disease accounted for 56.6%, 8.7%, 27.1% and 7.6%, respectively. The prevalence of ALK, ROS1 and RET fusions in this study was 8.1% (50/620), 3.5% (22/620) and 1.9% (12/620), respectively. Among the 331 patients diagnosed by the IASLC/ATS/ERS Classification, 15 patients were identified positive for EML4-ALK fusions (including 8 solid, 2 acinar, 2 colloid, 1 lepidic, 1 papillary and 1 micropapillary predominant), 7 patients were positive for ROS1 fusions (including 2 acinar, 2 papillary, 1 lepidic, 1 solid and 1 mucinous predominant), and 4 patients were positive for RET fusions (including 2 acinar, 1 micropapillary and 1 solid predominant).

      Conclusion
      These fusion-positive patients may have unique pathologic feature compared with fusion-negative patients. EML4-ALK fusions were shown to occur in solid predominant adenocarcinoma with a higher frequency in this study. The association of ALK, ROS1 and RET fusions with the subtype of lung adenocarcinoma and the data of survival are being analyzed in all patients and will be presented at the conference.

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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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      P2.05-008 - Stem Cell transcription factors Oct4 and Nanog involved in chemoresistance and EGFR-TKI resistance of NSCLC (ID 982)

      09:30 - 09:30  |  Author(s): C. Zhou

      • Abstract

      Background
      Despite rapid strategy improvments of advanced lung cancer , traditional chemotherapy or targeted therapies, especially EGFR-TKI (epidermal growth factor receptor) will emerge treatment resistant eventually. The main cause for treatment failure of advanced lung cancer is drug resistance, and it’s molecule mechanism could be key to improve theraputic effect. The transcription factors Oct4 and Nanog were reported to be involved in drug resistance of many malignant tumors, which are closely related with the prognosis of patients. These factors are expected to be potential drug targets. The present study is designed to explore potential mechanisms about stem cell transcription factors’ regulation of epithelial mesenchymal transition (EMT) invlolved in drug resistance of lung cancer.

      Methods
      MTT，immunohistochemistry, immunofluorescence, Western blot, RT-PCR experiments in vitro and in vivo were employed. Clinical samples (104 postoperation and 94 advance stage samples) were collected to assess the clinical prognostic value of stem transcription factors( Oct4 and Nanog), （CD133 and ABCG2）and epithelial mesenchymal transition (EMT) markers（E-Cadherin and N-Cadherin）with clinical features. Down-regulation of Nanog by RNA interference were used to find the change of chemosensitivity and EGFR-TKI sensitivity. Combined with the specific mechanisms in vitro and clinical samples to interpret the regulation of EMT involved in drug resistance.

      Results
      The immunocytochemistry experiments showed that expression pattern of A549 cell line are CD133 (+), ABCG2 (+ +), Oct4 (-) and Nanog (-); A549/DDP cell line are CD133 (+ + +), ABCG2 (+ +), Oct4 (+ +) and Nanog (+ + +). There are significant differences in expression of CD133, Oct4 and Nanog between the two cell lines. Cell immunofluorescence experiments showed that stem cell transcription factors expressed in cell nucleus of A549 cell line, and stem cell surface marker CD133 located on the cell membrane. RT-PCR and Western blot were used to the examination of A549 and A549/DDP cell lines for CD133, ABCG2 and Oct4, Nanog’ expression. The results showed that the expression of these markers in cisplatin resistance cell line. Examination by RT-PCR of the samples from 40 paired cases of lung cancer and adjacent tissue, showed that Oct4 and Nanog in lung cancer group was higher than those in paracancerous tissues, suggesting that Oct4 and Nanog might play an important role in lung cancer initiation and malignant growth process. The expression of these transcription factors in 104 samples from lung cancer patients, analysed by immunohistochemical method, showed the expression level of these factors were significantly higher in stage III and IV patients than in stage I and II patients. It also showed that the higher the Oct4 and Nanog expressed, the poorer prognosis were (54.3 vs 68.5 months, P=0.053) and (52.7vs.72.1months, P= 0.022). The patient with negative expression of CD133 or ABCG2 survived longer than those with positive expression (72.8 vs. 50.2 month, P = 0.021) and (76.5 vs.47.7 months, P=0.000). Patients with positive expression of E-Cadherin survived longer than those with negative markers (67.6 vs 54.1 months, P=0.035), While N-Cadherin+ patients survived shorter than N-Cadherin- patients (55.1 vs. 77.1 months, P=0.025). In overall survival between patients with and those without chemotherapy, there is no significant difference (63.8 vs. 60.6 months, P=0.851). But subgroup analysis revealed patients undergoing chemotherapy with positive expression of CD133 enjoyed significantly longer survival (53.8 vs. 32.3 months). A subgroup analysis also showed that patients with negative expression of Nanog with chemotherapy survived longer than those without chemotherapy (69.3 vs. 76.4 months), while patients with positive Nanog treated with chemotherapy could survive longer than those without chemotherapy (57.0 vs. 38.7 months). In the 74 patients received chemotherapy after progression, we found that many patients with PR are Nanog- (82.1% vs. 17.9%), while patients with Nanog+ tend to have progression diease (61.4% vs. 38.6%). K-M survival analysis indicated that patients with Nanog (-) N-Cadherin (-) CD133 (-) survived longer than those with Nanog (+) N-Cadherin (+) CD133 (+), Nanog (+) N-Cadherin (-) CD133 (-), Nanog (+) N-Cadherin (-) CD133 (+) and Nanog (-) N-Cadherin (-) CD1 33 (-) patients (101.9 vs. 60.0, 101.9 vs. 54.6, 101.9 vs. 38.2 months). Multivariate regression analysis showed that stage of lung cancer, CD133, N-Cadherin and Nanog were independent prognostic factors. Downregulation of Nanog could partially restore the cell sensitivity to cisplatin in cisplatin-resistant cell line under RNA interference. In the EGFR primary drug resistance experiment, we found that CD133 and ABCG2 were higherly expressed in H23 (EGFR primary resistance cell line) than PC-9 (EGFR sensitive cell line). Detection of CD133, ABCG2 and Oct4, Nanog expression by RT-PCR and western blot in PC-9 and H23 cell lines showed that these markers expressed significantly higher in H23; Using immunohistochemical method, we analysed EGFR, C-met and CD133, ABCG2 and Oct4，Nanog in 104 cases of postoperative samples and analysed the relationship between their expression and prognosis. The results showed that C-met expressed in patients in advanced stage (P=0.0860), adenocarcinoma(P=0.0355) and non-smoking patients. K-M analysis showed that C-met expressed in patients with wild type EGFR(P= 0.0436). We further tested stem cell factors in 94 cases of advanced stage who received ERFG-TKI and analysed relationship between drug efficacy and prognosis. The results suggest that Nanog tend to express in smokers (39.4%vs.14.8%, P=0.0071), and Oct4 in adenocarcinoma (38% vs.8.3%, p=0.0170). Patients with negative Oct4 expression have longer PFS (time to progression of disease) (11 vs.7.0 m, P=0.041), patients with negative expression of Nanog have significantly longer PFS than patients with higher expression (13.5 vs.3.8m, P=0.000). Patients with high E-cadherin expression have longer PFS than patients with lower expression (13.5m vs 6.8., P=0.015), Patients with lower N-cadherin expression have longer PFS than patients with high expression (12.3 vs.7.4m, P=0.020). Multiple regression analysis suggested that Nanog, ECOG score and RR are independent prognostic factor. RNA interference results showed that down-regulation of Nanog expression can increase sensitivity to EGFR-TKI in H23.

      Conclusion
      This study will reveal the mechanisms of drug resistance in lung cancer from a new point of view. To provide the evidence of stem cell factor and EMT related pathway as a new target for reverse the drug resistance in the future.

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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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      P2.06-014 - Quantitative test of mutant EGFR and its effect on efficacy of EGFR TKI in advanced NSCLC (ID 1327)

      09:30 - 09:30  |  Author(s): C. Zhou

      • Abstract

      Background
      It is reported that abundance of EGFR mutations is related with efficacy of EGFR TKI in advanced NSCLC patients with mutant EGFR. This study was designed to investigate influence of EGFR mutations and their abundance on efficacy of EGFR TKI by a quantitative method.

      Methods
      190 NSCLC treated with EGFR TKI and available tissue for EGFR mutations were enrolled into the study; 113 were FFPE specimen, and 62 were fresh tissue. EGFR mutation was detected with the kit of AmoyDx ARMS and percentage of mutant EGFR was tested with the method of an Allele Specific PCR with Competitive Blocker (ASB-PCR). In this assay, copies of EGFR mutants were calibrated by standard curve, and the mutation rates were estimated through normalizing by copies of a conserved sequence in EGFR exon2. The relationship between abundance of EGFR mutations and efficacy of EGFR TKI was analyzed.

      Results
      Of 190 samples, 15 were censored due to EGFR exon2 copies less than 100; finally, 175 enrolled into data analysis. Mutant percentage less than 0.1% was defined as wild-type, 0.1%~2% as low abundance, 2%~20% as moderate abundance, and more than 20% as high abundance. The mutant rate was 56.6% and 62.3% by using AmoyDx ARMS and ASB-PCR methods, respectively. The accordance rate of EGFR mutations was 89.7% by two methods. Of 175 samples, 20, 27 and 62 harbored low, moderate and high abundances of mutant EGFR, respectively; 66 were wild-type EGFR. Median progress free survival (mPFS) was 4.9 (95% CI, 3.4 to 6.4), 8.3 (95% CI, 3.3 to 13.3) and 16.0 months (95% CI, 10.4 to 21.7) in patients with low, moderate and high abundances of mutant EGFR (p =0.012). The mPFS of low abundance was not longer than that of those patients with wild-type EGFR (2.0 months, 95% CI, 0.2 to 4.1; p=0.261). Objective response rate (ORR) was 67.7%, 44.4%, 25.0% and 19.7%, and disease control rate (DCR) was 90.3%, 81.5%, 55.0% and 45.5% in patients with high, moderate, low abundance and wild-type EGFR, respectively (p<0.001). But ORR and DCR were no difference between low abundance and WT groups (p=0.754; p=0.610, respectively).

      Conclusion
      The abundance of EGFR mutations could affect the efficacy of EGFR-TKI, and quantitation of mutant EGFR could better predict for efficacy of EGFR TKI in advanced NSCLC.

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    P2.21 - Poster Session 2 - Diagnosis and Staging (ID 170)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P2.21-011 - Persistent Ground-Glass Opacity Lung Nodules < 20 mm in Diameter at CT: Histopathologic Comparisons with imaging features (ID 2357)

      09:30 - 09:30  |  Author(s): C. Zhou

      • Abstract

      Background
      Differentiation of atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma(IA) on computed tomography (CT) is useful for determining ‘‘follow-up or resection’’ strategies for lesions displaying ground-glass opacity nodules(GGN). The purpose of this study is to compare the morphologic features of persistent GGNs of <20 mm in diameter at thin-section CT (TSCT) with histopathology.

      Methods
      Jan 2010 and Dec 2012, a total of 200 nodules in 191 resected GGNs that were evaluated with TSCT were included in this study. Correlations between histopathology and CT characteristics were examined.

      Results
      The nodules included 45 AAH (22.5%), 99AISs (49.5%), 11 MIAs (5.5%), and 45 invasive adenocarcinomas (22.5%). The mean CT value (P < .0001), size of nodule (P < .0001) were significant factors that differentiated AAH lesions from invasive adenocarcinoma or AIS or MIA. While the size of nodule (P < .0001) and mass of nodule (P < .0.001) were significant factors that differentiated invasive adenocarcinoma from AIS or MIA.

      Conclusion
      Size of nodule less than 10 mm and mean CT value less than -510Hu are determinants of AAH, while size and mass of the nodule are determinants of invasive adenocarcinoma in Chinese population.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-025 - T790M mutation associated with better efficacy of continuous EGFR-TKI treatment in advanced NSCLC patients with acquired resistance to EGFR-TKI (ID 2280)

      09:30 - 09:30  |  Author(s): C. Zhou

      • Abstract

      Background
      The strategy for EGFR-TKI acquired resistance including continuous EGFR-TKI with chemotherapy or local therapy or chemotherapy alone. The aim of this study was to investigate the association of T790M mutation status with the efficacy of different modalities after acquired resistance to EGFR-TKI.

      Methods
      From Mar 2011 to Mar 2013, the advanced NSCLC patients who performed a rebiopsy after acquired resistance to EGFR-TKI in Shanghai Pulmonary Hospital were included into this study, Scorpion ARMS was used to detected the EGFR mutation status. SPSS 13.O was used to perform the statistical analysis.

      Results
      53 patients were enrolled in the study with a median age of 51.2 years old. 45.3% (25/53) were females and 54.7% (29/53) of patients had T790M mutation. Among them, 16 people with local disease progression received local therapy combined with TKI therapy, while 21 with a slow progress received chemotherapy plus TKI therapy. The median progression-free survival time (PFS1) of all patients according to RECIST criteria was 11.8 months. The median progression-free survival time (PFS2) of patients who received continuous EGFR-TKI treatment was 3.5 months (95% CI 2.689-4.311). Patients with T790M mutation had significantly longer PFS2 than those without T790M mutation (6.3 vs 3.0 months, p = 0.001), while there were no significant differences found in PFS1 between the two groups (13.0 vs 8.5 months, p = 0.999).

      Conclusion
      NSCLC patients who had T790M mutation after acquired resistance to EGFR-TKI benefited more from the continuous EGFR-TKI treatment and should be recommend to adopt this modality.