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S. Ren



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    JCHS - Joint IASLC - Chinese Society for Clinical Oncology - Chinese Alliance Against Lung Cancer Session (ID 239)

    • Event: WCLC 2015
    • Type: Joint Chinese/ English Session
    • Track: Other
    • Presentations: 1
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      JCHS.09 - Circulating Tumor Cells and Evaluation of Targeted Therapy Effect in EGFR Mutation/ALK Translocation Metastatic Non-Small Cell Lung Cancer (ID 3526)

      S. Ren

      • Abstract
      • Presentation
      • Slides

      Background:
      Targeted therapies have considerably improved the prognosis of patients with non-small cell lung cancer (NSCLC).Although not precision enough, RESIST criteria was still the most often used response assessment method to reflecting the clinical benefits. We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values in EGFR mutation/ALK translocation advanced NSCLC.

      Methods:
      One hundred and thirty eight patients were enrolled in our study. Peripheral blood was analyzed for CTCs enumeration on negative enrichment by immunomagnetic beads. Changes of CTCs levels were correlated with radiological response. Sequential analyses were conducted to monitor CTC signals during therapy and correlate radiological effects with treatment outcome.

      Results:
      CTCs were detected (≥8.7CTC) in 84.8% of patients. Pretreatment and pro-treatment blood samples from all 118 EGFR-mutant (19deltion:56, L858R:57, G719x:3, L861Q:1, 19 deletion + L858R:1), 14 ALK translocation lung cancer patients and 6 EGFR wild type patients were collected. Of 89 eligible and evaluable patients, baseline CTC counts were not associated with response to treatment by RECIST (P=0.353). There is no difference between exon 19 deletion and L858R of baseline CTC values. (19deletion:19.4 CTCs, L858R:20.9 CTCs,P=0.222) The change of CTCs values increased correlation with radiological response (P=0.042) after treatment of targeted therapy. There is no significant difference between exon 19 deletion and L858R of CTCs values pre and pro EGFR-TKI treatment.(3.32 vs.12.1, P=0.783)

      Conclusion:
      This study confirms the predictive significance of CTCs in patients with EGFR mutation/ALK translocation NSCLC receiving targeted therapy. The change of CTCs value correlated significantly with radiological response. This strategy may enable non-invasive, specific biomarker assessment method for using CTC decreases as an early indication of response to targeted therapy and monitoring in patients undergoing targeted cancer therapies.

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    MINI 12 - Biomarkers and Lung Nodule Management (ID 109)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Screening and Early Detection
    • Presentations: 1
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      MINI12.03 - Comprehensive Analysis of MicroRNA Expression Patterns in Lung Adenocacinoma Presenting with GGNs and Non-Tumorous Tissues (ID 701)

      S. Ren

      • Abstract
      • Presentation
      • Slides

      Background:
      Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) accounts for about 80% of primary lung cancer cases and approximately two thirds of them are diagnosed at an advanced stage . The poor prognosis of this disease is partially due to the lack of an effective means of early diagnosis. Discovery of an effective and reliable tool for early diagnosis of lung cancer would play a pivotal role in improving the prognosis of patients with lung cancer. Pulmonary ground-glass nodules (GGNs) are increasingly detected in clinical practice. GGNs are related to lung cancer, especially lung adnocacinoma . The subject of how to manage the pulmonary GGNs remains controversial. It is necessary to identify biological markers that can be used to screen high-risk patients in order to allow better lung adenocacinoma presenting with GGNs detection, earlier intervention and increase the likelihood of successful treatment. MicroRNAs are small non-coding RNAs of 18–24 nucleotides, typically excised from 60–110 nucleotide foldback RNA precursor structures . MicroRNAs have drawn significant attention in cancer research after it was linked to oncogenesis and tumor metastasis. Abnormal expression of microRNAs has been found in both haematopoietic and solid tumours by various genome-wide techniques. There is no report about the relationship between microRNA and pulmonary GGNs. It is necessary to identify biological markers that can be used to screen high-risk patients presenting GGNs in order to allow early lung adenocacinoma detection. Our study investigated microRNA expression with the intention to identify a panel of microRNAs for the diagnosis of lung adenocarcinoma presenting with GGNs.

      Methods:
      73 pairs of samples (tumorous and non-tumorous) were surgically resected from lung adnocacinoma patients presenting with GGNs from Shanghai Pulmonary Hospital between May 2012 and June 2014. After obtaining the approval of the patient consent, fresh tissues samples were taken during surgical resection, snap-frozen on dry ice and stored at−80◦C. MicroRNA expression of tumor and non-tumorous tissues was investigated in 3 participants by the next generation sequencing. Then, we analyzed the difference expression microRNA profiles which were identified by second generation sequencing in 73 pairs of lung adenocacinoma presenting with GGNs and adjacent non-tumorous tissues using a quantitative reverse-transcriptase polymerase chain reaction assay (qRT-PCR).

      Results:
      When we compared microRNA expression among lung cancer tissues versus corresponding noncancerous lung tissues via next-generation sequencing, 23 microRNAs had statistical differences in expression between groups. Five microRNAs (hsa−miR−548ar−5p, chr10_7330_star, chr17_10932_star, hsa−miR−148a−3p, hsa−miR−210−3p) exhibited higher expression in the adnocacinoma samples than that in the non-tumorous samples, eighteen microRNAs (hsa−miR−548x−5p, hsa−miR−144−3p, hsa-miR-106a-5p, hsa−miR−548ay−5p, hsa−miR−199a−3p, hsa−miR−378d, hsa−miR−4732−3p, hsa−miR−486−3p, chr7_5517, hsa−miR−1307−5p, chr17_10880, hsa−miR−127−3p, hsa−miR−411−5p, chr1_1402, chr16_10269, hsa−miR−138−5p, hsa−miR−212−3p, hsa−miR−33b−5p) demonstrated lower expression in adnocacinoma samples than that in the non-tumorous samples (P<0.05). Further validated by qRT-PCR, six microRNAs (chr17_10932_star, hsa−miR−148a−3p, hsa−miR−210−3p, chr1_1402, hsa−miR−378d, hsa−miR−138−5p) were statistically differentially expressed in tumorous compared with non-tumorous tissues.

      Conclusion:
      We found a microRNA panel that has considerable clinical value in diagnosing lung adenocacinoma presenting with GGNs. Thus, patients who would have otherwise missed the curative treatment window can benefit from optimal therapy.

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    MINI 13 - Genetic Alterations and Testing (ID 120)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI13.12 - The Abundance of EGFR Mutations Could Be More Better Predictor for EGFR-TKI Therapy in Advanced Non-Small Cell Lung Cancer (ID 1481)

      S. Ren

      • Abstract
      • Presentation
      • Slides

      Background:
      Incresing data show advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutant have discrepant response to EGFR-TKI. The abundance of EGFR mutations may be a powerful explanation for the uneven clinical benefit. This study was designed to investigate the influence of EGFR mutant abundance on efficacy of EGFR-TKI by a quantitative method.

      Methods:
      201 NSCLC patients treated with EGFR-TKI with available tissue samples for EGFR mutation test were enrolled into the study. EGFR common mutations were detected by amplification refractory mutation system (ARMS) and percentage of mutant EGFR was tested with the method of an Allele Specific Quantitative PCR with Competitive Blocker (ASB-qPCR). In this assay, the copies of all mutations and EGFR locus were calculated by standard curve respectively. The cutoff values were obtained by the receiver operating characteristics (ROC) curve in training set. Further, the cutoff values were confirmed in validation set and the whole population. The relationship between the abundance of EGFR mutations and efficacy of EGFR-TKI was statistically analyzed.

      Results:
      Of the 201 samples, 72 harbored 19DEL mutation, 63 carried L858R mutant, and 66 with wild-type. The cohort was randomly divided into training and validation sets. The cutoff values of 19DEL and L858R mutation abundance were 4.84% and 9.47% determined by ROC curve in training set. 9.7% of patients with 19DEL positive were low abundance (<4.84%, LA group), while 33.3% of L858R-positive patients were LA (<9.47%).High abundance (HA) group, regardless of 19DEL or L858R positive had more longer median progression free survival (PFS) compared with LA and wild-type groups in either validation set or the whole population (15.0 vs 2.0 vs 1.9, 8.0 vs 1.9 vs 1.9; 15.0 vs 4.0 vs 2.0, 12.0 vs 2.0 vs 2.0; p<0.001). COX regression analysis showed that EGFR mutation abundance, together with smoking status, were independent factors of response to EGFR-TKI.

      Conclusion:
      The abundance of EGFR mutation could more precisely predict EGFR-TKI efficacy. NSCLC patients with LA mutation had inferior clinical benefit with EGFR-TKI. The heterogeneity in EGFR mutant abundance partly explain the efficacy discrepancy in patients with 19DEL or L858R positive.

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    P2.06 - Poster Session/ Screening and Early Detection (ID 219)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Screening and Early Detection
    • Presentations: 1
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      P2.06-008 - Diagnostic Yield of Autoantibody Panel for Patients with Ground-Glass Nodules (GGNs) or Solid Nodules in Chinese Population (ID 3069)

      S. Ren

      • Abstract

      Background:
      Autoantibodies is an attractive diagnostic approach for early detection of malignant tumors. Our previous studies found a panel of 7 TAAs(p53,PGP9.5,SOX2,GAGE7,GBU4-5,MAGE A1,CAGE) was associated with lung cancer. We performed this large-scale clinical trial to validate their ability to aid early diagnosis of lung adenocarcinoma presenting with GGNs or solid nodules in Chinese population.

      Methods:
      The 7 TAAs were selected from 43 candidate TAAs from our previous studies. These samples including lung adenocarcinoma presenting with GGNs (n = 170) or solid nodules (n = 100) and healthy volunteers (n = 200). The sensitivity and specificity from 7 TAAs and the traditional cancer biomarkers CEA, NSE, and CYFRA21-1 were compared.

      Results:
      The sensitivity and specificity of autoantibody assay were 53% and 91% respectively, which were similar in different subgroups such as age, gender, smoker status and histological type. The sensitivity of autoantibody assay was 50% in lung adenocarcinoma presenting with GGNs. The sensitivity of autoantibody assay was 58% in lung adenocarcinoma presenting with nodules. The results were significantly higher than 27% when using the combination of CEA, NSE, and CYFRA21-1 to detect patients with lung cancer.

      Conclusion:
      Our study suggested that the 7 TAAs autoantibody panel might be helpful to aid diagnosis of lung cancer with GGNs or solid nodule. Large scale trial to validate our finding of patients with GGNs is ongoing in our institute.

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    P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      P3.04-049 - HER-2 Mutations in Chinese Lung Adenocarcinoma Patients with Negative EGFR Mutations (ID 1345)

      S. Ren

      • Abstract

      Background:
      To determine the prevalence and clinicopathological features of epidermal growth factor receptor 2 (HER-2) mutations in Chinese lung adenocarcinoma patients with negative EGFR mutations.

      Methods:
      Formalin-fixed and paraffin-embedded (FFPE) tissue sections from 398 lung adenocarcinoma patients with wild-type EGFR were screened for HER-2 mutations by amplification refractory mutation system (ARMS) assay and all HER-2 mutations were validated by direct sequencing. The protein expression of HER-2 was evaluated by immunohistochemistry (IHC). Of the 398 samples, 331 were also detected ALK and ROS1 fusions by multiplex RT-PCR, and all fusions positive were verified by direct sequencing. The relationship between HER-2 mutations and clincopathological features and the prognostic effect of its status on disease free survival (DFS) were analyzed.

      Results:
      21 of 398 (5.3%) harbored HER-2 mutations; 7.6% of 278 samples with triple-negative lung adenocarcinoma ( EGFR-, ALK-, ROS1-) were found to have HER-2 mutations. 17 samples (81.0%) were A775_G776insYVMA, two with G776>VC, one with V777_G778insGSP and the last one with 2340_2341ins12 in-frame insertions of exon 20. 59 of 398 (14.8%) were positive of HER-2 expression. No association was found between HER-2 mutations and expression, only two patients coexisted the positive in mutation and expression. There was no statistically significant difference in age, sex, smoking history, and pathological stage between patients with HER-2 mutations and those with negative patients. The DFS of patients with HER-2 mutations have no significant difference compared with those patients with negative mutations.

      Conclusion:
      5.3% of Chinese lung adenocarcinoma with wild-type EGFR harbored HER-2 mutations. The HER-2 mutations had no association with HER-2 expression.