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Xue Wu



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    JCSE01 - Perspectives for Lung Cancer Early Detection (ID 779)

    • Event: WCLC 2018
    • Type: Joint IASLC/CSCO/CAALC Session
    • Track: Screening and Early Detection
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/23/2018, 07:30 - 11:15, Room 202 BD
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      JCSE01.22 - Differential Molecular Mechanisms Associated with Dramatic and Gradual Progression in NSCLC Patients with Intrathoracic Dissemination (ID 14713)

      11:15 - 11:15  |  Author(s): Xue Wu

      • Abstract
      • Slides

      Background
      Lung cancer is a highly heterogeneous disease with diverse clinical outcomes. The pleural cavity is a frequent metastasis site of proximal lung cancer. Better understanding of its underlining molecular mechanisms associated with dramatic and gradual progression of pleural metastasis in patients with non-small cell lung cancer (NSCLC) is essential for prognosis, intervention and new therapy development.We performed whole-exome sequencing (WES) of matched primary lung adenocarcinoma and pleural metastatic tumors from 26 lung cancer patients with dramatic progression (DP, n=13) or gradual progression (GP, n=13). Somatic alterations at both genome-wide level and gene level were detected. Kaplan-Meier survival analysis and multivariate Cox regression models were applied to analyze the association between different somatic alterations and clinical parameters.We first analyzed the differences in somatic alterations between AP and RP group in the primary tumors, and identified higher somatic copy number alteration (SCNA) level in DP group compared to GP group, which is significantly (p=0.016) associated with poorer progression-free survival (PFS). More specifically, patients with chromosome 18q loss in the primary tumor showed a trend (p=0.107) towards poorer PFS. PTEN (p=0.002) and GNAS (p=0.002) mutations are enriched in the primary tumors of DP group, and are associated with poorer PFS. Furthermore, pleural metastatic tumors harbor a relatively higher level of mutation burden (p=0.105) and significantly increased SCNA (p=0.035) compared to the primary tumors.NSCLC patients in the attenuated progression group have more stable genomes. High level of genomic instability, GNAS and PTENmutations, as well as chromosome 18q loss are associated with rapid progression.

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    MA26 - New Therapies and Emerging Data in ALK, EGFR and ROS1 (ID 930)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/26/2018, 13:30 - 15:00, Room 201 BD
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      MA26.01 - Accumulation of Concomitant Mutations Involved in Drug Resistance in the Sequential ALK TKI Treatments of ALK-Positive NSCLC (Now Available) (ID 12550)

      13:30 - 13:35  |  Author(s): Xue Wu

      • Abstract
      • Presentation
      • Slides

      Background

      ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next-generation TKIs, have shown promising clinical outcomes for ALK-positive lung cancer patients. However, distinct resistant-mechanisms have been suggested for different ALK fusion variants in response to various TKIs. The genomic alterations associated with these heterogeneous resistant-mechanisms have not been adequately investigated, especially for patients received sequential ALK TKI treatments.

      Method

      The distribution of ALK fusion variants in 475 ALK-positive lung cancer patients (cohort I) out of 11842 lung cancer patients (4%) tested by next-generation sequencing were analyzed. In addition, mutation profiles of 416 cancer-relevant genes in the post-ALK TKI treatment tumor samples from 52 non-small cell lung cancer (NSCLC) patients (cohort II) who represent the similar distribution of ALK fusion variants as in cohort I were analyzed. Thirty-five patients received crizotinib treatment only (crizotinib group), whereas the other 17 patients were treated with multiple lines of ALK TKIs (multi-TKI group), including lorlatinib, alectinib, ceritinib and brigatinib.

      Result

      EML4-ALK v3 and v1 are the two most common ALK fusion variants in both cohorts. In cohort II, 18 different ALK activating mutations were found in 17 patients (49%) of the crizotinib group and 10 patients (59%) of the multi-TKI group, although with different mutation patterns. In the multi-TKI group, G1202R was the most frequent ALK activating mutation found in 35% of the patients, while L1196M (14%) and G1269A (11%) were more common in the crizotinib cohort. Of note, there was a significant enrichment of concomitant ALK activating mutations in the multi-TKI group (p=0.031), as well as a trend of increased number of patients carrying activation of ALK by-pass/downstream pathways (p=0.056) in this group compared with the crizotinib group, resulting in a significantly higher recurrence of dual activation of ALK and ALK by-pass/downstream pathways in the multi-TKI group (29%) than that in the crizotinib group (6%) (p=0.031). Patients with concomitant TP53 mutation had significantly shorter progression free survival (PFS) compared with TP53 wildtype patients upon crizotinib treatment (median PFS: 8 vs 13 months, HR 1.494, p=0.019) regardless of fusion variant types.

      Conclusion

      Significantly higher frequency of concomitant mutations, including concomitant ALK activating mutations, and dual activation of ALK and ALK by-pass/downstream pathways, was observed after multiple lines of ALK TKI treatments, indicating the diversity and complexity of resistance-mechanisms in response to next-generation ALK TKIs. Concomitant TP53 mutation might serve as a prognosis biomarker for worse clinical outcomes treated with crizotinib.

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    P1.01 - Advanced NSCLC (Not CME Accredited Session) (ID 933)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.01-85 - The Prevalence of Different EGFR exon20 Mutations in 12,833 Chinese Lung Cancer Patients (Now Available) (ID 14141)

      16:45 - 18:00  |  Author(s): Xue Wu

      • Abstract
      • Slides

      Background

      Mutations in EGFR exon20 are relatively rare in lung cancers compared to L858R/exon19 mutations, some of which have shown sensitivity to EGFR tyrosine kinase inhibitors (TKIs), and have been actively tested in clinical trials. However, due to the high-variety of EGFR exon20 alterations, it becomes increasingly difficult for their functional studies in related to clinical practice.

      Method

      We retrospectively screened 12,833 Chinese lung cancer patients that have underwent genotyping on their tumor and/or liquid biopsy samples using targeted next-generation sequencing between 2014 and 2017 for EGFR exon20 mutations as well as other concurrent EGFR mutations in the same patient.

      Result

      A total of 442 patients (3.4%) were found harboring 493 different EGFR exon20 variations, among which 49 patients (11%) carried more than one exon20 mutations. The frequencies of the most prevalent alterations were summarized in Table 1. 18% of these mutations have concurrent TKI-sensitive mutations L858R or exon19 deletion. In-frame deletion/insertions (delins or ins) and missense mutations were identified at a frequency of 53% and 47%, respectively. The short delins/ins occurred between 763~773 residues, while missense mutations dwelled at 768~820 residues, suggesting that these two types of alterations have their own manners for regulating EGFR kinase domain function. The most prevalent insertion is p.M766delinsMASV, occurred in 15.2% of all patients. Meanwhile, the diversity of inserted peptides at p.D770 and p.D771 positions is much higher than other positions with a total of 17 and 19 different insertion peptides composed of 1-5 amino acids, respectively. Missense mutations at S768 were detected in 20.4% of patients, but 60% of them were accompanied by mutations at G719. table 1.jpg

      Conclusion

      This is the largest cohort of Chinese lung cancers for studying EGFR exon 20 mutations, which should be informative for functional studies, the design of targeted drugs, and the testing for existing therapies.

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    P1.13 - Targeted Therapy (Not CME Accredited Session) (ID 945)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.13-24 - EGFR-KDD is Rare and Demonstrates Variable Anti-Tumor Response to Tyrosine Kinase Inhibitors in East Asian NSCLC Population (Now Available) (ID 13253)

      16:45 - 18:00  |  Author(s): Xue Wu

      • Abstract
      • Slides

      Background

      The kinase domain duplication of epidermal growth factor receptor (EGFR-KDD) has been identified and implicated to be oncogenic in non-small cell lung cancer (NSCLC). However, its frequency and clinical outcomes in lung cancer patients are largely uncertain.

      Method

      We conducted a multi-center record review of 8064 East Asian NSCLC patients who underwent genetic testing using next-generation sequencing (NGS) targeting the whole exons of EGFR gene as well as introns involved in EGFR-KDD and gene rearrangements. Patients’ demographic and clinical data, including age, gender, histology type, pathological stage, and their responses to tyrosine kinase inhibitor (TKI) treatments were analyzed.

      Result

      EGFR-KDD was identified in 11 patients, which is approximately 0.012% of the total NSCLC population reviewed (N=8064), and also consists of 0.05% of all patients with EGFR aberrations (N=2289). Nine patients were identified with the canonical EGFR-KDD form involving the duplication of exon 18 throughout exon 25, while the remaining two cases harbor EGFR exon 14-26 and exon 17-25 duplication, respectively, which have not been previously described. Importantly, all these patients were not identified with any other co-existing known driver mutations, highlighting the potential oncogenic role of this alteration. Three out of five patients with exon 18-25 KDD who received TKI treatments showed partial anti-tumor responses to the therapy, while the other two patients progressed shortly. Our data further indicated that EGFR T790M mutation and EGFR amplification may represent the major resistance mechanisms against targeted therapy in tumors bearing EGFR-KDD.

      Conclusion

      EGFR-KDD is rare in East Asian NSCLC population with different duplication variants. Tyrosine kinase inhibitors demonstrated variable anti-tumor efficacy in patients harboring EGFR-KDD alteration.

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    P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.01-108 - Temporal Heterogeneity of Resistant Mutations in Sequential ALK TKI Treated Lung Cancer Revealed by NGS-Based Liquid Biopsy (Now Available) (ID 13488)

      16:45 - 18:00  |  Author(s): Xue Wu

      • Abstract
      • Slides

      Background

      Crizotinib and several next-generation ALK TKIs have been widely applied in the treatment of ALK-positive lung cancer patients. However, drug resistance is eventually developed to these ALK TKIs via heterogeneous resistance mechanisms, which is needed to be further explored. Due to the invasiveness and feasibility of repetitive tissue biopsies, liquid biopsy has become a promising alternative for dynamically monitoring tumor genomic evolution and guides decision-making for treatment adjustment.

      Method

      Primary tumor sample of a 71-year-old male patient diagnosed with stage IV lung adenocarcinoma was subjected for targeted next-generation sequencing (NGS) for identification of driver mutations. Mutation profiles of circulating tumor DNA (ctDNA) from seven sequential plasma samples during the treatment course of crizotinib, brigatinib, and lorlatinib were closely monitored.

      Result

      The dynamic mutation profiles during the disease course were represented in the Figure. As EML4-ALK v1 fusion was detected in the primary tumor, the patient was administrated with crizotinib and reached a progression-free survival (PFS) of 11 months when ALK G1269A was identified upon progression. As a result, brigatinib, a second generation ALK TKI overcoming G1269A-driven resistance, was applied. Dynamic monitoring of patient’s ctDNA during brigatinib treatment showed a dramatic drop of G1269A mutant allele frequency (MAF) to undetectable level, whereas a novel F1174L became the dominant clone. The disease progressed after 9-month of brigatinib treatment, and the patient was switched to lorlatinib. A third mutation E1210K quickly overtook F1174L as the dominant clone with the accumulation of more concomitant mutations towards the end of the treatment (8 different mutations) with a PFS of 9 months. Interestingly, brigatinib-sensitive G1269A came back after 6-month of lorlatinib treatment.

      fish plot.tif

      Conclusion

      Temporal heterogeneity of ALK activating mutations was observed along the treatment course of different TIKs via NGS-based liquid biopsy, which could provide guidance for stepwise treatment strategy for better patient care.

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    P2.03 - Biology (Not CME Accredited Session) (ID 952)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.03-12 - EGFR and ERBB2 Germline Mutations in Chinese Lung Cancer Patients and Their Roles in Genetic Susceptibility to Cancer (Now Available) (ID 12560)

      16:45 - 18:00  |  Author(s): Xue Wu

      • Abstract
      • Slides

      Background

      Inherited genetic determinants of lung cancer risk remains relatively elusive. Rare germline mutations in EGFR and ERBB2 have previously been reported in lung cancer patients, which may be associated with the genetic susceptibility to lung cancer.

      Method

      We retrospectively analyzed the next-generation sequencing (NGS) results targeting 416 cancer-relevant genes, including the whole exons of EGFR and ERBB2, in a cohort of 9091 Chinese lung cancer patients.

      Result

      Of the 9091 Chinese lung cancer patients, nine germline mutations from 12 patients were identified within or adjacent to the kinase domain of EGFR: K757R (two patients), D1014N (two patients), I646S, G724S, V786M, T790M, L792F, R831H, and L844V, and one germline mutation was identified adjacent to the kinase domain of ERBB2: V1128I. The incidence of EGFR T790M germline mutation is much lower compared with the reported frequency in the Caucasian patients. Somatic mutations detected in the 12 patients carrying rare EGFR/ERBB2 germline mutations were most commonly EGFR exon19 deletion, L858R, and G719S mutations, and rare EGFR: S768I mutation and a novel D770delinsDNPH indel mutation. The superior response to afatinib of the patient carrying only EGFR L844V germline mutation suggests that this germline mutation might be sensitive to TKI treatment.

      Conclusion

      Here we indentified eight novel EGFR germline mutations and the ERBB2: V1128I germline mutation were linked to the genetic susceptibility of lung cancer in Chinese population.

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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-07 - CUX1-ALK: A Novel ALK Rearrangement That Responds to Crizotinib in Non-Small-Cell Lung Cancer (ID 12736)

      16:45 - 18:00  |  Author(s): Xue Wu

      • Abstract
      • Slides

      Background

      Lung cancer is the leading cause of cancer-related deaths worldwide. ALK rearrangement has been identified in 3% to 5% non-small-cell lung cancer (NSCLC) patients. The most common ALK rearrangement is EML4-ALK. Other rare ALK arrangements, such as KIF5IB-ALK and KLC-ALK, have also been identified that might be potential therapeutic targets, although the efficacy of ALK inhibitors on the majority of these rare ALK rearrangements has not been assessed in clinic.

      Method

      In this study, using comprehensive next-generation sequencing targeting 416 pan-cancer genes and introns of 16 genes frequently rearranged in cancer, we identified a novel CUX1-ALK fusion gene in a lung adenocarcinoma patient. The exact CUX1-ALK fusion transcript was determined via RNA-seq, and confirmed by RT-PCR. The oncogenic ability of CUX1-ALK fusion gene was further validated in 293T cells for the activation of ALK self-phosphorylation and downstream signaling pathways.

      Result

      After the detection of CUX1-ALK fusion gene, RNA-seq analysis of FFPE sections from the primary tumor specimen was applied to reveal a 97 nt fragment from CUX1 intron 8 inserted before the 53 nt position in ALK exon 20. Expression of the CUX1-ALK fusion protein in 293T cells confirmed the self-phosphorylation of the fusion protein and the activation of ALK downstream signaling pathways, including MAPK, JAK-STAT, and PI3K/AKT signaling pathways, which all could be inhibited by the addition of crizotinib. Furthermore, the patient showed a superior response to crizotinib with a progression-free survival of 20 months.

      Conclusion

      This study provides the novel finding of CUX1-ALK fusion gene from NSCLC patient which could provide personalized treatment solutions for the maximum benefit to NSCLC patients.

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      P2.13-46 - Comprehensive Investigation of ERBB2 Transmembrane Domain Mutations (V659/G660) in 12,833 Chinese Lung Cancer Patients (Now Available) (ID 13466)

      16:45 - 18:00  |  Author(s): Xue Wu

      • Abstract
      • Slides

      Background

      The ERBB2/HER2 receptor tyrosine kinase belongs to the human EGFR family and is a known oncogenic driver in many cancers including lung cancer. Majority of ERBB2 mutations are within its kinase domain in non-small cell lung cancer (NSCLC). Rare transmembrane domain (TMD) mutations of ERBB2 have also been identified at V659/G660 residues, which potentially stabilize ERBB2 heterodimerization with EGFR, favour a kinase activating conformation, and have shown to respond to afatinib (Ou et al, JTO 2017).

      Method

      We interrogated next-generation sequencing data from 19,800 Chinese cancer patients, including 12,833 lung cancers between 2014 and 2017. Sample types include formalin-fixed paraffin-embedded (FFPE) or fresh tumor samples, and/or circulating tumor DNA (ctDNA) from pleural effusion or plasma. Patients’ demographic and clinical data were further analyzed.

      Result

      ERBB2 TMD mutations at V659 were identified in twelve adenocarcinomas patients (five with V659D and seven with V659E), accounting for 0.14% of lung adenocarcinomas and 0.09% of all lung cancers. However, no G660 mutations were observed in this patient cohort. There is no gender preference for patients carrying such mutations (50%:50%). The median age of these patients is 56 with a trend to be younger in female patients. Two cases also carry other known driver alterations, EGFR L858R mutation and PIK3CA amplification, respectively. One case has two tumor tissue samples from the right upper and lower lobe of the lung, respectively. One lobe harbors EGFR exon19del mutation and EGFR amplification, whereas the other lobe carries ERBB2 V596D and EGFR G719A mutation. No other driver mutations were identified in the remaining cases. Interestingly, a novel TMD mutation I649R on ERBB3 was found in two patients together with ERBB2 V659D mutation, which might involve in the regulation of heterodimerization between ERBB2 and ERBB3. All these ERBB2 TMD mutations present at a relatively high mutant allele frequency (MAF) in tumor tissues, ranging from 15% to 71%, as well as liquid biopsy samples up to 47.5% of MAF, indicating a high tumor burden in these patients and potential ERBB2 amplification. Three patients received afatinib treatment though with progressive disease for various potential reasons, and the details of their treatment course will be presented.

      Conclusion

      Among Chinese patients, ERBB2 TMD mutation V659D/E is rare and unique to lung adenocarcinomas (0.14%). The efficacy of ERBB2-specific targeted therapy on these patients especially ERBB2 antibody and/or TKI need to be further investigated.

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