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Y. Shi



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    O01 - Prognostic and Predictive Biomarkers I (ID 94)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O01.02 - MicroRNA Signature Predicts Survival in Resectable Small-Cell Lung Cancer (ID 1641)

      10:40 - 10:50  |  Author(s): Y. Shi

      • Abstract
      • Slides

      Background
      Small-cell lung cancer (SCLC) is one of the most aggressive types of cancer, yet the molecular mechanisms underlying its devastating clinic outcome remain elusive. In this study, we investigated whether microRNA (miRNA) expression profiles can predict clinical outcomes of SCLC patients.

      Methods
      A total of 82 patients with very limited SCLC, who received surgical resection followed by adjuvant chemotherapy according to the standard of care, were enrolled in this study. All the tumor samples used for miRNA profiling were required to contain at least 60% tumor cells and RNA was isolated from formalin-fixed paraffin-embedded specimens. First, we surveyed 924 miRNAs for their expressions from 42 SCLC patients to discover survival relevant miRNAs and develop prognostic models, which were then validated in an independent cohort of 40 cases. A risk score of miRNA signature for survival prediction was calculated according to a combination of expression level of the miRNA weighted by the regression coefficient derived by univariate Cox regression analysis. Kaplan-Meier overall survival curves were compared using the log-rank test and multivariate Cox regression model was used to test if the miRNA signature was an independent prognostic factor.

      Results
      For all the patients, the median follow up time was 57.2 months. Forty-four patients (53.7%) are still alive. Forty-two patients (51.2%) had recurrent disease and the median time to diagnosis of relapse was 12.3 months. In the training set, we identified that two miRNAs, miR-150 and miR-886-3p, were significantly associated with poor OS. The results compared between NL and SCLC tissues also verified that the miR-150 and miR-886-3p expression levels in SCLC were much lower than in normal lung samples (884±126 vs 2954±1652 for miR-150 and 1873±256 vs 3154±448 for miR-150 ). We then derived a miRNA signature 0.545×miR-150 + 0.617 ×miR-886-3p. Compared with patients with low-risk miRNA signature, patients with high-risk signature had significantly shorter median OS (12.6 months versus not reached, P=0.02). This signature was also demonstrated to be a significant predictor of survival in the validation set. Patients with high risk miRNA signatures had poor overall survival (P=0.005) and progression-free survival (P=0.017) compared to those with low-risk scores. It retained statistical significance in a model adjusting for age, gender and smoking status (HR 0.27, 95% CI 0.10-0.72, P=0.008), which suggesting that the miRNA signature may be an independent predictor of survival.

      Conclusion
      In this study, we developed a prognostic miR-150/miR-886-3p signature and validated in an independent dataset for resectable SCLC. Our results indicated that microRNAs may serve as promising molecular prognostic markers as well as new therapeutic targets for SCLC. Larger sample size studies are needed to further validate our findings.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-038 - The significance of ALK rearrangement in selected advanced non-small cell lung cancer: ALK expression provides insights into ALK target therapy (ID 2757)

      09:30 - 09:30  |  Author(s): Y. Shi

      • Abstract

      Background
      ALK rearrangements are detected in 3%~7% in unselected non-small cell lung cancer (NSCLC) and accurate determination of ALK rearrangements are the key importance to screen appropriate candidates for ALK inhibitor therapy. Previous studies showed that IHC could be a promising prescreening method. However, the correlation between IHC results and clinical outcomes had not been confirmed. This study aimed to elucidate clinical significance of ALK rearrangement in selected advanced NSCLC patients and evaluate a possible association between ALK expression and clinical outcomes in ALK positive crizotinib-treated patients.

      Methods
      ALK status was assessed by FISH, immunohistochemistry (IHC) and quantitative RT-PCR(qRT-PCR) in 173 selected advanced NSCLC patients who were aiming at undergoing ALK screening for crizotinib therapy. Clinicopathologic data, genotype status and survival outcomes were analyzed. In addtion, we correlated ALK expression with clinical outcomes in crizotinb treated patients including two patients with concurrent ALK rearrangement and EGFR mutation.

      Results
      ALK positive detection rate was 35.5% (59/166), 36.3% (61/168), 27.9% (34/122) by FISH, IHC and qRT-PCR, respectively. Among the 166 advanced NSCLC patients who were successfully underwent ALK screening by FISH, 20 patients with EGFR mutation, 87 patients with wild type status and 2 (3.4%, 2/59) patients with concurrent ALK rearrangement and EGFR mutation. Of the 59 patients with FISH-positive ALK rearrangement, 45 received crizotinib in the phase II clinical trial (PROFILE 1005), 8 were enrolled in the phase III clinical trial (PROFILE 1014) and 6 did not participate in any clinical trial. ALK-positive patients have distinct clinicopathological features. ALK FISH-positive and crizotinib-treated patients (PROFILE 1005) had a median progression-free survival (PFS) of 7.6 months and longer overall survival (OS) compared with crizotinib-naïve (P<0.0001) or wild type cohorts (P=0.0138), but there was no significant difference in OS compared with EGFR mutation patients(P=0.8959). ALK positive and negative patients divided by qRT-PCR in the ALK FISH crizotinib-treated patients had no different in clinical outcomes. ALK expression was not associated with PFS (P=0.792) and OS (P=0.325). However, when used IHC expression as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P=0.026). The two patients with concurrent EGFR mutation and ALK rearrangement had difference in ALK expression, response to TKIs and crizotinib, and overall survival.

      Conclusion
      In the era of ALK-targeted inhibitors, enriching NSCLC patients according to clinicopathologic characteristics could highly improve ALK detection rate for molecular target therapy. IHC could be a supplementary method to provide more clues for clinical trial design and therapeutic strategies for NSCLC patients who harbor ALK rearrangement including patients with double genetic aberration of ALK and EGFR.

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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 - 09:30  |  Author(s): Y. Shi

      • 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 - 09:30  |  Author(s): Y. Shi

      • 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 - 09:30  |  Author(s): Y. Shi

      • 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 - 09:30  |  Author(s): Y. Shi

      • 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 - 09:30  |  Author(s): Y. Shi

      • 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.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-035 - Evaluating health related quality of life and symptoms by using the electronic (ePRO) version of the LCSS (eLCSS-QL) in a 622 patient prospective multinational NSCLC trial (AP-QL Trial) with good cross-cultural reliability. (ID 2397)

      09:30 - 09:30  |  Author(s): Y. Shi

      • Abstract

      Background
      Major goals in advanced NSCLC include accurate evaluation of survival and quality of life. Few trials evaluate both of these major endpoints well. In many studies, only a minority of patients have quality of life and other patient reported outcomes (PROs) such as symptoms systematically followed over time, which decreases the value of the assessment of the treatment. Prior studies have identified barriers to measuring quality of life in clinical trials and in practice. To overcome these barriers, we used a computer-assisted version of the validated LCSS measure and tested this prospectively in a large study in patients with Stage IV and IIIB NSCLC. The eLCSS-QL requires only two minutes for completion of the patient version and proved to be highly acceptable in earlier studies (Hollen, Supp Care Cancer 2012).

      Methods
      This trial was conducted at 65 sites in 9 Asian countries. 622 patients received first-line treatment with docetaxel -based chemotherapy. Patient demographics included: 70% male; 65% adenocarcinoma; median: KPS = 90; ECOG = 1 (27% ECOG 0). Stages: IV (72%), IIIB (28%). 84% had two or more major symptoms. 80% received combination chemotherapy with cisplatin (52%) or carboplatin (28%). The eLCSS-QL was completed every 3 weeks at the clinic. We also surveyed 98 physicians and nurses treating these patients regarding their experiences concerning communication, usefulness and acceptability of the eLCSS-QL.

      Results
      Ninety-seven percent of patients completed the eLCSS-QL at baseline; 90% completed follow-up evaluations. Over 90% found the eLCSS-QL easy to use and acceptable to complete at each visit. More than 80% of patients reported increased awareness of symptoms and that the quality of life evaluation made it easier to speak with doctors and nurses. 1% refused eLCSS-QL completion. Of physicians and nurses, more than 90% found the eLCSS-QL easy to use and increased symptom awareness; 80% reported improved communication, enhanced satisfaction with the patient visit, and would recommend its use to others. Nearly 90% of physicians reported they could identify benefit from chemotherapy earlier; 76% would order fewer imaging tests and 80% said the eLCSS-QL could save time. Cross-cultural testing was performed in this 9 nation trial. Cronbach’s alpha scores were high for each country, and exceeded 0.85 overall, demonstrating good cross-cultural reliability. Treatment outcomes: major response rate 37%; median survivals: 13.9 months (docetaxel + cisplatin), 12.7 months (docetaxel + carboplatin).

      Conclusion
      Placing the well validated LCSS onto an electronic platform (eLCSS-QL) helped overcome barriers to evaluating QL in this large clinical trial, with 90% of patients completing baseline and repeated QL measures. Patients, physicians, and nurses all found the eLCSS-QL to be highly acceptable and easy to use. The good cross-cultural aspects of the eLCSS-QL indicate that the electronic platform is particularly suitable for multinational trials. This large prospective trial demonstrates that improved compliance with quality of life and PRO evaluation is feasible and can easily be accomplished in large clinical trials. Additionally, the electronic format enhances the potential for the use of PROs in decision making in clinical practice.