Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer.

EMBO Molecular Medicine
Dana Wai Yi TsuiNitzan Rosenfeld

Abstract

Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR-mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small-cell lung cancer-associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resis...Continue Reading

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Citations

Aug 17, 2019·International Journal of Molecular Sciences·Marzia Del ReRomano Danesi
Mar 21, 2019·Frontiers in Oncology·Jatta SaarenheimoAntti Jekunen
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Sep 12, 2020·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Jianchun DuanJie Wang

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Methods Mentioned

BETA
PCR
biopsy

Clinical Trials Mentioned

NCT00809237
NCT02108964

Software Mentioned

Picard
R
BWA
R package survival
CollectInsertSizeMetrics
QDNAseq
‐ Tools
SAMtools
CGHcall
OncoKB

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