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X. Li



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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)

      09:35 - 09:45 AM  |  Author(s): X. Li

      • 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 10 - ALK and EGFR (ID 105)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI10.02 - Intratumoral Heterogeneity of ALK-Rearranged and ALK/EGFR Co-Altered Lung Adenocarcinoma (ID 685)

      04:50 - 04:55 PM  |  Author(s): X. Li

      • Abstract
      • Presentation
      • Slides

      Background:
      Genetic intratumoral heterogeneity has a profound influence on the selection of clinical treatment strategies and addressing resistance to targeted therapy. The purpose of our study is to explore the potential effect of intratumoral heterogeneity on both the genetic and pathologic characteristics of ALK-rearranged lung adenocarcinoma (LADC).

      Methods:
      We tested ALK fusions and EGFR mutations in 629 LADC patients by using laser capture microdissection (LCM) to capture spatially separated tumor cell subpopulations in various adenocarcinoma subtypes and test for ALK fusions and EGFR mutations in ALK-rearranged, EGFR-mutated, and ALK/EGFR co-altered LADCs in order to compare the oncogenic driver status between different tumor cell subpopulations in the same primary tumor.

      Results:
      Among the 629 patients, 30 (4.8%) had ALK fusions, 364 (57.9%) had EGFR mutations, and 2 had ALK fusions coexisting with EGFR mutations. Intratumoral heterogeneity of ALK fusions was identified in 9 patients by RT-PCR. In the 2 ALK/EGFR co-altered patients, intratumoral genetic heterogeneity was observed both between different growth patterns and within the same growth pattern. Genetic intratumoral heterogeneity of EGFR mutations was also identified in EGFR-mutated NSCLC. ALK fusions were positively associated with a micropapillary pattern (P=0.002) and negatively associated with a lepidic pattern (P=0.008) in a statistically-expanded analysis of 900 individual adenocarcinoma components, although they appeared to be more common in acinar-predominant LADCs in the analysis of 629 patients.

      Conclusion:
      Intratumoral genetic heterogeneity was demonstrated to co-exist with histologic heterogeneity in both single-driver and EGFR/ALK co-altered LADCs. As for the latter, one of the dual altered drivers may be the trunk-driver for the tumor.

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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)

      11:50 - 11:55 AM  |  Author(s): X. Li

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

    • Event: WCLC 2015
    • Type: Poster
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 2
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      P3.04-010 - EML4-ALK Fusion Detected by qRT-PCR Confers Similar Response to Crizotinib as Detected by FISH in Patients with Advanced NSCLC (ID 2338)

      09:30 - 09:30 AM  |  Author(s): X. Li

      • Abstract
      • Slides

      Background:
      Quantitative reverse transcriptase polymerase chain reaction assay (qRT-PCR) has been proved to have high sensitivity and specificity to detect anaplastic lymphoma kinase (ALK) rearrangements. The aim of this study was to investigate the response to crizotinib in patients of advanced non-small-cell lung cancer (NSCLC) with ALK rearrangements detected by qRT-PCR.

      Methods:
      Patients with advanced NSCLC who had their ALK rearrangement status detected by qRT-PCR were included in this analysis. The utility of qRT-PCR and fluorescence in situ hybridization assay (FISH) were compared in patients who were treated with crizotinib based on their positive ALK rearrangements.

      Results:
      1010 patients were included in this study. Among them, 104 patients were ALK qRT-PCR positive and 53 of them received crizotinib treatment. Among 255 tumors simultaneously analyzed by FISH and RT-PCR, the latter successfully detected all the 25 tumors with arrangements, including two cases which were missed by FISH. The overall response rate (ORR) and median progression free survival (mPFS) of the 53 patients with ALK rearrangements who received crizotinib treatment were 60.4% (95%CI, 47.2-73.6) and 8.4 months (95% CI 6.75-10.05) respectively, which were similar to the 21 patients detected by FISH with ORR of 57.1% (95% CI 33.3-76.2) (p=0.799) and mPFS of 7.4 months (95% CI 4.43-10.38) (p=0.833) after crizotinib treatment. Interestingly, there were 2 patients responded to crizotinib had their ALK rearrangement detected by qRT-PCR but not FISH.

      Conclusion:
      qRT-PCR should be considered as an alternative assay to detect ALK fusion oncogene in NSCLC patients who might be benefit from crizotinib treatment.

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      P3.04-049 - HER-2 Mutations in Chinese Lung Adenocarcinoma Patients with Negative EGFR Mutations (ID 1345)

      09:30 - 09:30 AM  |  Author(s): X. Li

      • 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.