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

Open access
Date
2018-06-01Type
- Journal Article
Citations
Cited 45 times in
Web of Science
Cited 51 times in
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ETH Bibliography
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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 resistance mechanisms, including non‐druggable genetic information that may guide clinical management. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000271162Publication status
publishedExternal links
Journal / series
EMBO Molecular MedicineVolume
Pages / Article No.
Publisher
WileySubject
circulating tumour DNA; liquid biopsy; lung cancer; resistance mechanisms; targeted therapyMore
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Citations
Cited 45 times in
Web of Science
Cited 51 times in
Scopus
ETH Bibliography
yes
Altmetrics