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X. Xia



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    MA 01 - SCLC: Research Perspectives (ID 650)

    • Event: WCLC 2017
    • Type: Mini Oral
    • Track: SCLC/Neuroendocrine Tumors
    • Presentations: 1
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      MA 01.03 - The Potential of ctDNA Sequencing in Disease Monitoring and Depicting Genomic Evolution of Small-Cell Lung Cancer Under Therapy (ID 9682)

      11:00 - 12:30  |  Author(s): X. Xia

      • Abstract
      • Presentation
      • Slides

      Background:
      Although small cell lung cancer (SCLC) is sensitive to initial therapy, almost all patients relapse and survival remains poor. Outgrowth of treatment-resistant subclones could be responsible for recurrence. However, genomic evolution of SCLC after treatment hasn’t been well investigated, partially due to the challenge of obtaining longitudinal samples. CT is the standard modality for response assessment and disease monitoring. But it doesn’t always accurately assess the disease status. SCLC is characterized by early hemagenous spread, which makes circulating tumor DNA (ctDNA) analysis a promising modality for genomic profiling and disease monitoring of SCLC.

      Method:
      Targeted-capture deep sequencing (mean target coverage 538x-1866x) of 545 cancer genes was performed to 44 ctDNA samples collected before therapy as baseline and at different timepoints during treatment from 23 SCLC patients. Pretreatment tumor biopsies from 8 patients were also sequenced (mean target coverage 348x-1281x) of the same gene panel. DNA from peripheral blood mononuclear cells was served as the germline control.

      Result:
      Mutations were identified in all 44 ctDNA samples with a median of 16 mutations per sample (average mutation burden of 6.6/Mb). TP53 and RB1 were the most frequently mutated genes, detected in 91% (21/23) and 65% (15/23) patients, respectively. 74 mutations were identified from the 8 tumor biopsies, among which, 69 (93.2%) were detected in matched ctDNA. We inferred subclonal architecture of each ctDNA sample based on cancer cell fraction derived using PyClone. A median of 10 (ranging 2-26) subclones was inferred from each ctDNA sample and only 17% (2% to 60.%) of mutations were clonal mutations suggesting substantial genomic heterogeneity. Single gene mutations were not associated with survival. However, mean variant allele frequency of clonal mutations (clonal-VAF) at baseline was associated with progression-free survival (PFS) and overall survival (OS) independent of stage, age, or platinum sensitivity. The median PFS of patients with higher versus lower than median clonal-VAF was 5.2 months (95% CI, 4.6 to 5.8 months) versus 10.0 months (95% CI, 9.3 to 10.7 months), p=0.002. The median OS was 8.1 months (95% CI, 5.5 to 10.7 months) versus 24.9 months (95% CI, 0.0 to 51.2 months) in patients with higher versus lower than median clonal-VAF, respectively, p=0.004. Analysis of serial ctDNA before and during treatment showed that clonal-VAF closely tracked closely with treatment responses.

      Conclusion:
      ctDNA sequencing is a promising modality for genomic profiling and disease monitoring for SCLC patients. Clonal VAF may be a better ctDNA metric than single gene mutations.

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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): X. Xia

      • 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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    OA 18 - Lung Cancer Pathology and Genetics (ID 687)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 18.01 - Paired Tumor-Normal Next-Generation Sequencing (NGS) to Identify Pathogenic / Likely Pathogenic Germline Mutations in Lung Cancer Patients (ID 10326)

      14:30 - 16:15  |  Author(s): X. Xia

      • Abstract
      • Presentation
      • Slides

      Background:
      Comprehensive NGS panel based genetic testing is becoming more common to help clinicians select appropriate therapies. It has been recommended that matched tumor-normal sequencing analyses are essential for precise identification and interpretation of genetic somatic mutations. Though it has been reported germline EGFR T790M mutations result in a unique hereditary lung cancer syndrome, little is known about germline mutation of other common hereditary cancer syndrome genes in lung cancer patients.

      Method:
      We reviewed the germline variants of 1000 consecutive lung cancer patients who had paired tumor-normal NGS panel sequencing in our institute between 2016 and 2017. Hybridization capture-based NGS panel sequencing enables simultaneously assess single-nucleotide variants, insertions/deletions, rearrangements, and copy-number alterations at least 59 genes (range 59 – 1021 genes). Germline variants were interpreted following ACMG guidelines, and the variants were classified into pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign 5 classes.

      Result:
      Twenty-seven cases were identified to carry germline pathogenic or likely pathogenic mutations in 12 gene (2.7%): 5 with ATM ; 4 with BRCA1, BRCA2 or MSH2 respectively; 2 with CHEK2 or PMS2 respectively; 1 in ATR, CDKN2A, FANCC, MSH3, PTCH2 or RET respectively (details in table). Mean age at diagnosis was 58 (30 – 84 years) for the patients with germline mutations and 61 (29-93 years) for those without. Interestingly, none of the patients had been diagnosed with other tumors. The incidence of actionable somatic mutations of the 27 patients was similar to others: 10 patients with EGFR mutation, 3 patients with KRAS mutation, 1 patient with KIF5B-RET fusion, MET copy number gain or BRCA1 mutation respectively.

      No. Gene cHGVS pHGVS Mutation type
      1 ATM c.1402_1403delAA p.K468Efs*18 frameshift
      2 ATM c.1898+1G>C . splice
      3 ATM c.2143_2144delCT p.L715Cfs*22 frameshift
      4 ATM c.6019dupG p.E2007Gfs*11 frameshift
      5 ATM c.903dupT p.A302Cfs*3 frameshift
      6 ATR c.80_81insA p.N27Kfs*16 frameshift
      7 BRCA1 c.4185+1G>A . splice
      8 BRCA1 c.962G>A p.W321* nonsense
      9 BRCA1 c.3340delG p.E1114Kfs*3 frameshift
      10 BRCA1 c.81-2A>G . splice
      11 BRCA2 c.3968_3971delAATA p.K1323Ifs*11 frameshift
      12 BRCA2 c.5054C>G p.S1685* nonsense
      13 BRCA2 c.6132_6135delCTTT p.F2045Hfs*5 frameshift
      14 BRCA2 c.6485_6486delAA p.K2162Tfs*13 frameshift
      15 CDKN2A c.73delG p.V25* frameshift
      16 CHEK2 c.1010delC p.A337Efs*10 frameshift
      17 CHEK2 c.1684C>T p.R562* nonsense
      18 FANCC c.1257_1258insC p.T420Hfs*15 frameshift
      19 MSH2 c.1165C>T p.R389* nonsense
      20 MSH2 c.1A>T p.0? init-loss
      21 MSH2 c.2785C>T p.R929* nonsense
      22 MSH2 c.340delG p.E114Rfs*60 frameshift
      23 MSH3 c.802C>T p.R268* nonsense
      24 PMS2 c.1053delG p.L351Ffs*5 frameshift
      25 PMS2 c.943C>T p.R315* nonsense
      26 PTCH2 c.2441_2442delCT p.S814* frameshift
      27 RET c.2410G>A p.V804M missense


      Conclusion:
      Germline mutations in common hereditary cancer syndrome genes is not rare in lung cancer patients, and it can be identified on routine matched tumor-normal NGS sequencing. Retrospective family history analysis and genetic counseling for those patients are underway.

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