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EMBO Mol Med. 2018 Jun;10(6). pii: e7945. doi: 10.15252/emmm.201707945.

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

Tsui DWY1,2, Murtaza M1,2,3, Wong ASC4, Rueda OM1,2, Smith CG1,2, Chandrananda D1,2, Soo RA4,5, Lim HL6, Goh BC4,5, Caldas C1,2,3,7, Forshew T1,2, Gale D1,2, Liu W1,2, Morris J1,2, Marass F1,2, Eisen T3,7,8, Chin TM9,5,10, Rosenfeld N11,2.

Author information

1
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
2
Cancer Research UK Major Center - Cambridge, Cambridge, UK.
3
Department of Oncology, University of Cambridge, Cambridge, UK.
4
Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.
5
Cancer Science Institute, Centre for Translational Medicine, National University of Singapore, Singapore, Singapore.
6
Parkway Cancer Center, Singapore, Singapore.
7
Department of Oncology, Addenbrooke's Hospital, Cambridge University Health Partners, Cambridge, UK.
8
Oncology Early Clinical Development, AstraZeneca, Cambridge, UK.
9
Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore csictm@nus.edu.sg nitzan.rosenfeld@cruk.cam.ac.uk.
10
Raffles Cancer Centre, Raffles Hospital, Singapore, Singapore.
11
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK csictm@nus.edu.sg nitzan.rosenfeld@cruk.cam.ac.uk.

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.

KEYWORDS:

circulating tumour DNA; liquid biopsy; lung cancer; resistance mechanisms; targeted therapy

PMID:
29848757
PMCID:
PMC5991591
DOI:
10.15252/emmm.201707945
[Indexed for MEDLINE]
Free PMC Article

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