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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
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): Likun Chen
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.
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).
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.
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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P1.07 - Immunology and Immunotherapy (ID 693)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
P1.07-026 - Predicting Tumor Mutational Burden (TMB) and Tumor Neoantigen Burden (TNB) of East Asian ANSCLC Patients by a Targeted Genomic Profiling (ID 9724)
09:30 - 16:00 | Presenting Author(s): Likun Chen
High tumor mutational burden (TMB) and High tumor neoantigen burden（TNB）is an emerging biomarker of sensitivity to immune checkpoint inhibitors. However, analysis of TMB and TNB by Whole Exome Sequencing (WES) is complicated and highly cost. Recent studies have also shown that TMB can be accurately measured in smaller gene assays. We aim to find and validate such a panel of genes to predict both TMB and TNB, as well as benefit to anti-PD-(L)1 blockade in East Asian aNSCLC patients.
We compare TMB and TNB measured by a Targeted Genomic Profiling (TGP, targeting 811 genes) assay and by WES using the data from previously publication including efficacy data of patients treated with Pembrolizumab. Then, we validated this 811 gene panel in Chinese aNSCLC patients(n=27), and analysis the correlation between TMB and TNB. Comparisons of TMB were also made to a cohort of eight aNSCLC patients obtained from tumor tissue and ctDNA.
We first sought to determine whether TMB, as measured by a TGP assay targeting 811 genes could provide an accurate assessment of whole exome. We performed targeted TGP and WES on the same biopsy specimen for a cohort of 27 NSCLC patients. In this cohort, median TMB was 5.3/Mb and median TNB was 2.7/Mb. We found that the tumor mutation burden calculated by these two methods was highly correlated(R2=0.71, p<0.05). We use the cutoff point of 11/Mb of TMB and 3/Mb of TNB respectively, 5/27(18.5%) and 8/27(29.6%) patients were identified with high TMB and high TNB, respectively. MMR genes were mutated only in high TMB patients(one in MSH2 and another in PMS2). Then, using the efficacy data from previous publication, including aNSCLC patients(n=34) treated with pembrolizumab, the AUC estimate for response was 0·80 of TGP and 0.84 of WES, respectively. For eight patients with paired tumor tissue and ctDNA, the TMB calculated from tumor tissue and ctDNA was also highly correlated(R2=0.80, p<0.05). Further analyses of ctDNA analyses in context of patient and trial outcomes are in progress.
These results show that TGP（targeting 811 genes）can accurately assess TMB compared with sequencing the whole exome and this finding will be clinically actionable. Using this targeted NGS panel, we find TMB is highly correlation with TNB, which also imply the accuracy of this panel. Finally, We may also use ctDNA to evaluate TMB by a non-invasive method.