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https://doi.org/10.15252/emmm.201707945
Title: | Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer | Authors: | Tsui, D.W.Y Murtaza, M Wong, A.S.C Rueda, O.M Smith, C.G Chandrananda, D Soo, R.A Lim, H.L Goh, B.C Caldas, C Forshew, T Gale, D Liu, W Morris, J Marass, F Eisen, T Chin, T.M Rosenfeld, N |
Keywords: | circulating tumor DNA epidermal growth factor receptor gefitinib hydroxychloroquine phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase antineoplastic agent DNA EGFR protein, human epidermal growth factor receptor gefitinib hydroxychloroquine protein p53 TP53 protein, human Article cancer patient clinical article controlled study drug response EGFR gene gene gene dosage gene mutation human longitudinal study molecularly targeted therapy non small cell lung cancer overall survival PIK3CA gene priority journal progression free survival PTEN gene tumor suppressor gene whole genome sequencing blood chemistry copy number variation dna mutational analysis drug resistance genetics lung tumor mutation non small cell lung cancer pathology prognosis survival analysis treatment outcome Antineoplastic Agents Carcinoma, Non-Small-Cell Lung DNA Copy Number Variations DNA Mutational Analysis DNA, Neoplasm Drug Resistance, Neoplasm ErbB Receptors Gefitinib Humans Hydroxychloroquine Longitudinal Studies Lung Neoplasms Mutation Prognosis Survival Analysis Treatment Outcome Tumor Suppressor Protein p53 |
Issue Date: | 2018 | Citation: | Tsui, D.W.Y, Murtaza, M, Wong, A.S.C, Rueda, O.M, Smith, C.G, Chandrananda, D, Soo, R.A, Lim, H.L, Goh, B.C, Caldas, C, Forshew, T, Gale, D, Liu, W, Morris, J, Marass, F, Eisen, T, Chin, T.M, Rosenfeld, N (2018). Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer. EMBO Molecular Medicine 10 (6) : e7945. ScholarBank@NUS Repository. https://doi.org/10.15252/emmm.201707945 | Rights: | Attribution 4.0 International | 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. © 2018 The Authors. Published under the terms of the CC BY 4.0 license | Source Title: | EMBO Molecular Medicine | URI: | https://scholarbank.nus.edu.sg/handle/10635/178087 | ISSN: | 17574676 | DOI: | 10.15252/emmm.201707945 | Rights: | Attribution 4.0 International |
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