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Poster display session

5024 - EGFR copy number aberrations detected in cfDNA from advanced NSCLC patients.

Date

11 Sep 2017

Session

Poster display session

Topics

Cancers in Adolescents and Young Adults (AYA);  Translational Research;  Non-Small Cell Lung Cancer

Presenters

Grainne O'Kane

Citation

Annals of Oncology (2017) 28 (suppl_5): v22-v42. 10.1093/annonc/mdx363

Authors

G.M. O'Kane1, T. Li2, M. Tsao3, G. Liu1, T.J. Pugh2, N.B. Leighl1

Author affiliations

  • 1 Dmoh, Princess Margaret Cancer Centre, M5G 2M9 - Toronto/CA
  • 2 Toronto Medical Discovery Tower, Princess Margaret Cancer Centre, M5G 1LZ - Toronto/CA
  • 3 Pathology, Princess Margaret Hospital, M5G 2M9 - Toronto/CA
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Resources

Abstract 5024

Background

Copy number aberrations (CNA) in the epidermal growth factor receptor (EGFR) represent a mechanism of tyrosine kinase activation and oncogenic signaling in advanced non-small cell lung cancers (NSCLC). High copy number gains (CNG) may predict TKI sensitivity but when acquired are postulated to reflect resistance. Treatment with monoclonal antibodies may have a role and therefore CNA integration in molecular diagnostics is potentially important.

Methods

Cell free (cf) DNA was from extracted from NSCLC patients undergoing treatment with EFGR-TKIs. A validated Liquid Biopsy Sequencing (LB-Seq) method for hybrid capture followed by ultra deep sequencing (> 20,000X) evaluated coding exons of KRAS, NRAS, BRAF, PIK3CA, and EGFR (18 kb). Subsequent filtering of mutation calls using a novel algorithm enabled detection of tumor-derived fragments at concentrations down to 0.2%. EGFR CNAs were assessed using a modified version of the VisCap algorithm. Mutation calls were compared to tissue biospy results for EGFR mutations.

Results

Targeted sequencing has been performed on 12 samples to date: 10 patients with classical EGFR mutations in L858R and del19, 1 with an exon 20 insertion and 1 with an exon 18 G718X mutation. All patients had progressed on at least one EGFR-TKI. % mutant reads ranged from 0.25% to 33%. EGFR CNGs were detected in 3 patients: 1 patient with T790M+ve disease confirmed in both tissue and cfDNA was found to have a co-occurring BRAF mutation (p.33_34insGA). The remaining 2 patients’ tissue samples tested negative for T790M; T790M was detected in cfDNA in 1 patient, who is currently receiving osimertinib, and in the other patient rapid progression on gefitinib occurred with an EGFR-G719X mutation. Copy number losses were detected in 2 patients. 2 of 6 patients with EGFR-T790M positive tissue were confirmed in cfDNA, the remaining 4 negative results were verified by ddPCR. An intronic variant of unknown significance (c.747 + 9C>T), not covered in tissue testing, was also captured in cfDNA.

Conclusions

Copy number aberrations in EGFR can be detected from targeted sequencing of cfDNA in patients with EGFR mutated NSCLC. Longitudinal evaluation in patients receiving EGFR-TKIs may provide insights into mechanisms of resistance.

Clinical trial identification

Legal entity responsible for the study

Natasha Leighl

Funding

None

Disclosure

N.B. Leighl: Research funding (institution): Novartis. Travel/honoraria: AstraZeneca, Merck Sharp Dohme, Pfizer, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

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