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Li Liu



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    MA 07 - ALK, ROS and HER2 (ID 673)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA 07.13 - NGS Sequencing Based Liquid / Tissue Biopsy Identified Coexistence of HER2 Amplification and Mutation in Advanced NSCLC Patients (ID 9737)

      15:45 - 17:30  |  Author(s): Li Liu

      • Abstract
      • Presentation
      • Slides

      Background:
      Human epidermal growth factor 2 (HER2, ERBB2) mutations / amplifications have been identified as oncogenic drivers in 2-5% of lung cancers. It has been reported that hybridization capture-based next-generation sequencing (NGS) could reliably detect HER2 amplification in qualified breast and gastroesophageal tumor tissue samples. However, there is little data in lung cancer, especially for advance NSCLC with only ctDNA samples available.

      Method:
      We reviewed 2000 consecutive samples from advanced NSCLC patients sequenced in our institute between 2015 and 2016. Tumor biopsy and/or ctDNA samples were analyzed using hybridization capture-based NGS ER-Seq method, which enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and somatic copy-number alterations at least 59 genes (range 59 – 1021 genes).

      Result:
      We identified 54 samples from 48 patients with HER2-mutation or amplification in the cohort (54/2000=2.7%). The 54 samples included 14 tissue biopsy samples, 37 ctDNA samples, and 3 pleural effusion samples. Thirty-six samples carried HER2 mutations, and 23 samples carried HER2 amplification with 5 samples have concurrent HER2 mutation and amplification. A 9-base pair (bp) in-frame insertion in exon 20 (Y772_A775dup) was detected in 18 samples (18/36=50%). In addition, there were 5 other insertions in exon 20; eight single bp substitutions (S310F) in exon 8; three exon 17 V659E mutations (from the sample patient with 3 ctDNA samples submitted at different time); one exon 19 D769H mutation; and one exon 21 V842I mutation. Amplification were identified in 23 samples, with copy number range from 3.8 to 19.6 in tissue samples (n=7, medium 11.6); from 4.3 to 51.8 in ctDNA samples (n=16, medium 7.3); 3.2 and 6 in the 2 pleural effusion samples. Interestingly, the allele frequency (AF) of HER2 mutation was the maximal in 4 of the 5 patients with concurrent HER2 mutation and amplification. Two patients were EGFR-TKI resistant with EGFR L858R mutation remaining and HER2 mutation and amplification might be the major reason for the resistance.

      Conclusion:
      HER2 mutations might coexist with HER2 amplification in advanced NSCLC patients, and it could be detected simultaneously with hybridization capture-based NGS sequencing both in tissue and liquid biopsy samples. Further quantative analysis of HER2 amplification / mutation and anti-HER2 therapeutic effects are underway.

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    P1.01 - Advanced NSCLC (ID 757)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 1
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      P1.01-037 - Circulating Tumor DNA Clearance During Treatment Associates with Improved Progression-Free Survival (ID 9653)

      09:30 - 16:00  |  Author(s): Li Liu

      • Abstract

      Background:
      Therapeutic selection has been shown to lead to marked clonal evolution, thus revealing limitations in imaging scan as a monitoring method, which does not reflect biological processes at a molecular level. However, currently, response assessment of patients with non-small cell lung cancer (NSCLC) primarily relies on imaging scans, necessitating the development of methodologies for dynamic monitoring of treatment response. We evaluated ctDNA as a tumor clonal response biomarker.

      Method:
      We screened 831 advanced NSCLC patients with a mixture of prior treatment exposure by performing capture-based ultra-deep targeted sequencing on plasma samples using a panel consisting of 168 NSCLC-related genes. Eighty-six patients with driver mutations and a minimum of 2 evaluation points in addition to baseline were included for further analysis.

      Result:
      At baseline, 79.9% patients harbored at least one mutation from this panel; the remaining 20.1% had no mutation detected. Sixty-nine percent of patients (570/831) harbored driver mutation. Patients harboring 2 mutations or fewer at baseline had a median progression-free survival (PFS) of 7.4 months; in contrast, patients harboring more than 2 mutations had a median PFS of 3.8 months (P=6.6x10[-5 ]HR=0.34), suggesting a significant inverse correlation between number of mutations at baseline and PFS. Next, we evaluated the ability of ctDNA as a tumor clonal response biomarker in 86 patients with a minimum of 2 follow-ups. After a median follow-up of 314 days, 64 patients (74.4%) reached disease progression. During treatment, 46 patients, treated with either matched targeted therapy (MTT) or chemotherapy, had a minimum of one time of ctDNA clearance, occurring from 1.6 months to 7.5 months after the commencement of treatment, with a median PFS of 8.07 months, an overall response rate (ORR) of 41% and a disease control rate (DCR) of 93%. Median overall survival (OS) for this group has not reached. In contrast, 40 patients who had consistent detectable ctDNA throughout the course of treatment had a median PFS of 3.47months, a median OS of 425 days, an ORR of 20% and a DCR of 53%. Our data revealed that patients with a minimum of one time ctDNA clearance are associated with a better ORR (p=0.05), DCR (p=5.9x10[-5]), a longer PFS (p=5.4x10[-10 ]HR=0.21) and OS (p=2.3x10[-5 ]HR=0.21), regardless the type of treatment commenced and the time of evaluation.

      Conclusion:
      This real world study comprising a heterogeneous population reveals the predictive and prognostic value of ctDNA and warrants further investigations to explore its clearance as a surrogate endpoint of efficacy.