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C. Lee
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-024 - NGS reveals potential druggable targets and molecular heterogeneity in EGFR mutant NSCLC with acquired resistance to EGFR TKIs (ID 2884)
09:30 - 09:30 | Author(s): C. Lee
- Abstract
Background:
Although patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), acquired resistance to these agents eventually occurs. To date, there has been no study on the comprehensive genome-wide alterations using next-generation sequencing (NGS).
Methods:
At pre-EGFR-TKI and post-progression, we collected formalin-fixed paraffin-embedded tumor/normal pairs form 19 NSCLC patients. Ion AmpliSeq[TM] Comprehensive Cancer Panel was used to identify alterations across all exons of 409 target genes. The predicted mutated gene associated with resistance to EGFR-TKIs was subjected to in vitro functional assay.
Results:
All patients satisfied the clinical definition of acquired resistance to the EGFR-TKIs. The patients characteristics were as follows; median age of 58 years, male/female (n=7/12), pretreatment with erlotinib/gefitinib (n=2/17), and exon 19 deletion/L858R/others (n=14/3/2). Median progression-free survival (mPFS) of all patients on EGFR-TKIs was 6.7 months (2.4 to 27.8) and best overall response was partial responses in 10 patients and stable diseases in 8 patients. Tumors were sequenced to a median coverage of 607x. Cancer genomes are characterized by 1,398 somatic single-nucleotide variants (788 missense, 74 nonsense, and 20 splice-site) and 1,774 frameshift and in frame insertions/deletions, with a median of 93.42 mutations per Mb (18.03 to 692.03 mutations per Mb). Overall, there was no significant difference in number and type of somatic mutation between pre-EGFR-TKI and post-progression tumors. In post-progression samples, patients with T790M mutation (n=12, 63.2%) had significant better mPFS and median overall survival (mOS) compared to patients who maintained EGFR activating mutation without evidence of acquired T790M (n=5) or without T790M nor EGFR activating mutation (n=2) (12.4 vs. 3.9 months for mPFS, P=<0.0001; 28.9 vs. 11.7 months for mOS, P=0.0306). No pre-EGFR-TKI tumor had a preexisting T790M mutation, suggesting that tumors acquired T790M mutations during progression or after the acquisition of resistance to EGFR-TKI. Statistical analysis confirmed that T790M (-) patients group had significant enrichment of mutated genes belonging to the angiogenesis (P=0.003394) and extracellular matrix (P=0.00905) pathways before treatment of EGFR-TKI compared to T790M (+) patients. One patient with poor response (PFS = 3.6 months) lost EGFR activating mutation (allele frequencies from 20.8% to 0%) without detectable T790M mutation after EGFR-TKI treatment. We identified a novel missense mutation (T263P) of the extracellular domain (subdomain II) of EGFR, concurrently with an activating EGFR G719A mutation in pre- and post-EGFR-TKI samples of a lung adenocarcinoma showing poor response to erlotinib. Transfection of T263P vectors conferred resistance to erlotinib in PC-9 cells.
Conclusion:
NGS of pre-EGFR-TKI and post-progression tumor samples provides insight into the complex molecular mechanisms of acquired resistance to EGFR-TKIs in EGFR-mutant NSCLC.
