Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer.
Identifieur interne : 000C38 ( Main/Exploration ); précédent : 000C37; suivant : 000C39Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer.
Auteurs : Dana Wai Yi Tsui [Royaume-Uni] ; Muhammed Murtaza [Royaume-Uni] ; Alvin Seng Cheong Wong [Singapour] ; Oscar M. Rueda [Royaume-Uni] ; Christopher G. Smith [Royaume-Uni] ; Dineika Chandrananda [Royaume-Uni] ; Ross A. Soo [Singapour] ; Hong Liang Lim [Singapour] ; Boon Cher Goh [Singapour] ; Carlos Caldas [Royaume-Uni] ; Tim Forshew [Royaume-Uni] ; Davina Gale [Royaume-Uni] ; Wei Liu [Royaume-Uni] ; James Morris [Royaume-Uni] ; Francesco Marass [Royaume-Uni] ; Tim Eisen [Royaume-Uni] ; Tan Min Chin [Singapour] ; Nitzan Rosenfeld [Singapour]Source :
- EMBO molecular medicine [ 1757-4684 ] ; 2018.
Descripteurs français
- KwdFr :
- ADN tumoral (sang), Analyse de mutations d'ADN, Analyse de survie, Antinéoplasiques (usage thérapeutique), Carcinome pulmonaire non à petites cellules (anatomopathologie), Carcinome pulmonaire non à petites cellules (génétique), Carcinome pulmonaire non à petites cellules (traitement médicamenteux), Humains, Hydroxychloroquine (usage thérapeutique), Mutation, Pronostic, Protéine p53 suppresseur de tumeur (), Protéine p53 suppresseur de tumeur (génétique), Récepteurs ErbB (génétique), Résistance aux médicaments antinéoplasiques (génétique), Résultat thérapeutique, Tumeurs du poumon (anatomopathologie), Tumeurs du poumon (génétique), Tumeurs du poumon (traitement médicamenteux), Variations de nombre de copies de segment d'ADN, Études longitudinales.
- MESH :
- anatomopathologie : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- génétique : Carcinome pulmonaire non à petites cellules, Protéine p53 suppresseur de tumeur, Récepteurs ErbB, Résistance aux médicaments antinéoplasiques, Tumeurs du poumon.
- sang : ADN tumoral.
- traitement médicamenteux : Carcinome pulmonaire non à petites cellules, Tumeurs du poumon.
- usage thérapeutique : Antinéoplasiques, Hydroxychloroquine.
- Analyse de mutations d'ADN, Analyse de survie, Humains, Mutation, Pronostic, Protéine p53 suppresseur de tumeur, Résultat thérapeutique, Variations de nombre de copies de segment d'ADN, Études longitudinales.
English descriptors
- KwdEn :
- Antineoplastic Agents (therapeutic use), Carcinoma, Non-Small-Cell Lung (drug therapy), Carcinoma, Non-Small-Cell Lung (genetics), Carcinoma, Non-Small-Cell Lung (pathology), DNA Copy Number Variations, DNA Mutational Analysis, DNA, Neoplasm (blood), Drug Resistance, Neoplasm (genetics), ErbB Receptors (genetics), Gefitinib (therapeutic use), Humans, Hydroxychloroquine (therapeutic use), Longitudinal Studies, Lung Neoplasms (drug therapy), Lung Neoplasms (genetics), Lung Neoplasms (pathology), Mutation, Prognosis, Survival Analysis, Treatment Outcome, Tumor Suppressor Protein p53 (chemistry), Tumor Suppressor Protein p53 (genetics).
- MESH :
- chemical , blood : DNA, Neoplasm.
- chemical , chemistry : Tumor Suppressor Protein p53.
- chemical , genetics : ErbB Receptors, Tumor Suppressor Protein p53.
- chemical , therapeutic use : Antineoplastic Agents, Gefitinib, Hydroxychloroquine.
- drug therapy : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- genetics : Carcinoma, Non-Small-Cell Lung, Drug Resistance, Neoplasm, Lung Neoplasms.
- pathology : Carcinoma, Non-Small-Cell Lung, Lung Neoplasms.
- DNA Copy Number Variations, DNA Mutational Analysis, Humans, Longitudinal Studies, Mutation, Prognosis, Survival Analysis, Treatment Outcome.
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.
DOI: 10.15252/emmm.201707945
PubMed: 29848757
Affiliations:
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Le document en format XML
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Soo</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Lim, Hong Liang" sort="Lim, Hong Liang" uniqKey="Lim H" first="Hong Liang" last="Lim">Hong Liang Lim</name><affiliation wicri:level="1"><nlm:affiliation>Parkway Cancer Center, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Parkway Cancer Center, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Goh, Boon Cher" sort="Goh, Boon Cher" uniqKey="Goh B" first="Boon Cher" last="Goh">Boon Cher Goh</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Caldas, Carlos" sort="Caldas, Carlos" uniqKey="Caldas C" first="Carlos" last="Caldas">Carlos Caldas</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Forshew, Tim" sort="Forshew, Tim" uniqKey="Forshew T" first="Tim" last="Forshew">Tim Forshew</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Gale, Davina" sort="Gale, Davina" uniqKey="Gale D" first="Davina" last="Gale">Davina Gale</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Liu, Wei" sort="Liu, Wei" uniqKey="Liu W" first="Wei" last="Liu">Wei Liu</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Morris, James" sort="Morris, James" uniqKey="Morris J" first="James" last="Morris">James Morris</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Marass, Francesco" sort="Marass, Francesco" uniqKey="Marass F" first="Francesco" last="Marass">Francesco Marass</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Eisen, Tim" sort="Eisen, Tim" uniqKey="Eisen T" first="Tim" last="Eisen">Tim Eisen</name><affiliation wicri:level="4"><nlm:affiliation>Department of Oncology, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Oncology, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Chin, Tan Min" sort="Chin, Tan Min" uniqKey="Chin T" first="Tan Min" last="Chin">Tan Min Chin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore csictm@nus.edu.sg nitzan.rosenfeld@cruk.cam.ac.uk.</nlm:affiliation><country wicri:rule="url">Singapour</country><wicri:regionArea>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Rosenfeld, Nitzan" sort="Rosenfeld, Nitzan" uniqKey="Rosenfeld N" first="Nitzan" last="Rosenfeld">Nitzan Rosenfeld</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK csictm@nus.edu.sg nitzan.rosenfeld@cruk.cam.ac.uk.</nlm:affiliation><country wicri:rule="url">Singapour</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:29848757</idno><idno type="pmid">29848757</idno><idno type="doi">10.15252/emmm.201707945</idno><idno type="wicri:Area/PubMed/Corpus">000106</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000106</idno><idno type="wicri:Area/PubMed/Curation">000106</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000106</idno><idno type="wicri:Area/PubMed/Checkpoint">000111</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000111</idno><idno type="wicri:Area/Ncbi/Merge">000447</idno><idno type="wicri:Area/Ncbi/Curation">000447</idno><idno type="wicri:Area/Ncbi/Checkpoint">000447</idno><idno type="wicri:Area/Main/Merge">000C38</idno><idno type="wicri:Area/Main/Curation">000C38</idno><idno type="wicri:Area/Main/Exploration">000C38</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer.</title><author><name sortKey="Tsui, Dana Wai Yi" sort="Tsui, Dana Wai Yi" uniqKey="Tsui D" first="Dana Wai Yi" last="Tsui">Dana Wai Yi Tsui</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Murtaza, Muhammed" sort="Murtaza, Muhammed" uniqKey="Murtaza M" first="Muhammed" last="Murtaza">Muhammed Murtaza</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Wong, Alvin Seng Cheong" sort="Wong, Alvin Seng Cheong" uniqKey="Wong A" first="Alvin Seng Cheong" last="Wong">Alvin Seng Cheong Wong</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Rueda, Oscar M" sort="Rueda, Oscar M" uniqKey="Rueda O" first="Oscar M" last="Rueda">Oscar M. Rueda</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Smith, Christopher G" sort="Smith, Christopher G" uniqKey="Smith C" first="Christopher G" last="Smith">Christopher G. Smith</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Chandrananda, Dineika" sort="Chandrananda, Dineika" uniqKey="Chandrananda D" first="Dineika" last="Chandrananda">Dineika Chandrananda</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Soo, Ross A" sort="Soo, Ross A" uniqKey="Soo R" first="Ross A" last="Soo">Ross A. Soo</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Lim, Hong Liang" sort="Lim, Hong Liang" uniqKey="Lim H" first="Hong Liang" last="Lim">Hong Liang Lim</name><affiliation wicri:level="1"><nlm:affiliation>Parkway Cancer Center, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Parkway Cancer Center, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Goh, Boon Cher" sort="Goh, Boon Cher" uniqKey="Goh B" first="Boon Cher" last="Goh">Boon Cher Goh</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.</nlm:affiliation><country xml:lang="fr">Singapour</country><wicri:regionArea>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Caldas, Carlos" sort="Caldas, Carlos" uniqKey="Caldas C" first="Carlos" last="Caldas">Carlos Caldas</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Forshew, Tim" sort="Forshew, Tim" uniqKey="Forshew T" first="Tim" last="Forshew">Tim Forshew</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Gale, Davina" sort="Gale, Davina" uniqKey="Gale D" first="Davina" last="Gale">Davina Gale</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Liu, Wei" sort="Liu, Wei" uniqKey="Liu W" first="Wei" last="Liu">Wei Liu</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Morris, James" sort="Morris, James" uniqKey="Morris J" first="James" last="Morris">James Morris</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Marass, Francesco" sort="Marass, Francesco" uniqKey="Marass F" first="Francesco" last="Marass">Francesco Marass</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Eisen, Tim" sort="Eisen, Tim" uniqKey="Eisen T" first="Tim" last="Eisen">Tim Eisen</name><affiliation wicri:level="4"><nlm:affiliation>Department of Oncology, University of Cambridge, Cambridge, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Department of Oncology, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author><author><name sortKey="Chin, Tan Min" sort="Chin, Tan Min" uniqKey="Chin T" first="Tan Min" last="Chin">Tan Min Chin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore csictm@nus.edu.sg nitzan.rosenfeld@cruk.cam.ac.uk.</nlm:affiliation><country wicri:rule="url">Singapour</country><wicri:regionArea>Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore</wicri:regionArea><wicri:noRegion>Singapore</wicri:noRegion></affiliation></author><author><name sortKey="Rosenfeld, Nitzan" sort="Rosenfeld, Nitzan" uniqKey="Rosenfeld N" first="Nitzan" last="Rosenfeld">Nitzan Rosenfeld</name><affiliation wicri:level="4"><nlm:affiliation>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK csictm@nus.edu.sg nitzan.rosenfeld@cruk.cam.ac.uk.</nlm:affiliation><country wicri:rule="url">Singapour</country><wicri:regionArea>Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge</wicri:regionArea><orgName type="university">Université de Cambridge</orgName><placeName><settlement type="city">Cambridge</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Angleterre de l'Est</region></placeName></affiliation></author></analytic><series><title level="j">EMBO molecular medicine</title><idno type="eISSN">1757-4684</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic Agents (therapeutic use)</term><term>Carcinoma, Non-Small-Cell Lung (drug therapy)</term><term>Carcinoma, Non-Small-Cell Lung (genetics)</term><term>Carcinoma, Non-Small-Cell Lung (pathology)</term><term>DNA Copy Number Variations</term><term>DNA Mutational Analysis</term><term>DNA, Neoplasm (blood)</term><term>Drug Resistance, Neoplasm (genetics)</term><term>ErbB Receptors (genetics)</term><term>Gefitinib (therapeutic use)</term><term>Humans</term><term>Hydroxychloroquine (therapeutic use)</term><term>Longitudinal Studies</term><term>Lung Neoplasms (drug therapy)</term><term>Lung Neoplasms (genetics)</term><term>Lung Neoplasms (pathology)</term><term>Mutation</term><term>Prognosis</term><term>Survival Analysis</term><term>Treatment Outcome</term><term>Tumor Suppressor Protein p53 (chemistry)</term><term>Tumor Suppressor Protein p53 (genetics)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ADN tumoral (sang)</term><term>Analyse de mutations d'ADN</term><term>Analyse de survie</term><term>Antinéoplasiques (usage thérapeutique)</term><term>Carcinome pulmonaire non à petites cellules (anatomopathologie)</term><term>Carcinome pulmonaire non à petites cellules (génétique)</term><term>Carcinome pulmonaire non à petites cellules (traitement médicamenteux)</term><term>Humains</term><term>Hydroxychloroquine (usage thérapeutique)</term><term>Mutation</term><term>Pronostic</term><term>Protéine p53 suppresseur de tumeur ()</term><term>Protéine p53 suppresseur de tumeur (génétique)</term><term>Récepteurs ErbB (génétique)</term><term>Résistance aux médicaments antinéoplasiques (génétique)</term><term>Résultat thérapeutique</term><term>Tumeurs du poumon (anatomopathologie)</term><term>Tumeurs du poumon (génétique)</term><term>Tumeurs du poumon (traitement médicamenteux)</term><term>Variations de nombre de copies de segment d'ADN</term><term>Études longitudinales</term></keywords><keywords scheme="MESH" type="chemical" qualifier="blood" xml:lang="en"><term>DNA, Neoplasm</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Tumor Suppressor Protein p53</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>ErbB Receptors</term><term>Tumor Suppressor Protein p53</term></keywords><keywords scheme="MESH" type="chemical" qualifier="therapeutic use" xml:lang="en"><term>Antineoplastic Agents</term><term>Gefitinib</term><term>Hydroxychloroquine</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Drug Resistance, Neoplasm</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Protéine p53 suppresseur de tumeur</term><term>Récepteurs ErbB</term><term>Résistance aux médicaments antinéoplasiques</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Carcinoma, Non-Small-Cell Lung</term><term>Lung Neoplasms</term></keywords><keywords scheme="MESH" qualifier="sang" xml:lang="fr"><term>ADN tumoral</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Carcinome pulmonaire non à petites cellules</term><term>Tumeurs du poumon</term></keywords><keywords scheme="MESH" qualifier="usage thérapeutique" xml:lang="fr"><term>Antinéoplasiques</term><term>Hydroxychloroquine</term></keywords><keywords scheme="MESH" xml:lang="en"><term>DNA Copy Number Variations</term><term>DNA Mutational Analysis</term><term>Humans</term><term>Longitudinal Studies</term><term>Mutation</term><term>Prognosis</term><term>Survival Analysis</term><term>Treatment Outcome</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Analyse de mutations d'ADN</term><term>Analyse de survie</term><term>Humains</term><term>Mutation</term><term>Pronostic</term><term>Protéine p53 suppresseur de tumeur</term><term>Résultat thérapeutique</term><term>Variations de nombre de copies de segment d'ADN</term><term>Études longitudinales</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 <i>EGFR</i>-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 <i>EGFR</i> T790M (31/50, 62%), <i>TP53</i> (23/50, 46%), <i>PIK3CA</i> (7/50, 14%) and <i>PTEN</i> (4/50, 8%). Patients with both <i>TP53</i> and <i>EGFR</i> mutations before treatment had worse overall survival than those with only <i>EGFR</i> 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 <i>TP53</i> 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.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li><li>Singapour</li></country><region><li>Angleterre</li><li>Angleterre de l'Est</li></region><settlement><li>Cambridge</li></settlement><orgName><li>Université de Cambridge</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Tsui, Dana Wai Yi" sort="Tsui, Dana Wai Yi" uniqKey="Tsui D" first="Dana Wai Yi" last="Tsui">Dana Wai Yi Tsui</name></region><name sortKey="Caldas, Carlos" sort="Caldas, Carlos" uniqKey="Caldas C" first="Carlos" last="Caldas">Carlos Caldas</name><name sortKey="Chandrananda, Dineika" sort="Chandrananda, Dineika" uniqKey="Chandrananda D" first="Dineika" last="Chandrananda">Dineika Chandrananda</name><name sortKey="Eisen, Tim" sort="Eisen, Tim" uniqKey="Eisen T" first="Tim" last="Eisen">Tim Eisen</name><name sortKey="Forshew, Tim" sort="Forshew, Tim" uniqKey="Forshew T" first="Tim" last="Forshew">Tim Forshew</name><name sortKey="Gale, Davina" sort="Gale, Davina" uniqKey="Gale D" first="Davina" last="Gale">Davina Gale</name><name sortKey="Liu, Wei" sort="Liu, Wei" uniqKey="Liu W" first="Wei" last="Liu">Wei Liu</name><name sortKey="Marass, Francesco" sort="Marass, Francesco" uniqKey="Marass F" first="Francesco" last="Marass">Francesco Marass</name><name sortKey="Morris, James" sort="Morris, James" uniqKey="Morris J" first="James" last="Morris">James Morris</name><name sortKey="Murtaza, Muhammed" sort="Murtaza, Muhammed" uniqKey="Murtaza M" first="Muhammed" last="Murtaza">Muhammed Murtaza</name><name sortKey="Rueda, Oscar M" sort="Rueda, Oscar M" uniqKey="Rueda O" first="Oscar M" last="Rueda">Oscar M. Rueda</name><name sortKey="Smith, Christopher G" sort="Smith, Christopher G" uniqKey="Smith C" first="Christopher G" last="Smith">Christopher G. Smith</name></country><country name="Singapour"><noRegion><name sortKey="Wong, Alvin Seng Cheong" sort="Wong, Alvin Seng Cheong" uniqKey="Wong A" first="Alvin Seng Cheong" last="Wong">Alvin Seng Cheong Wong</name></noRegion><name sortKey="Chin, Tan Min" sort="Chin, Tan Min" uniqKey="Chin T" first="Tan Min" last="Chin">Tan Min Chin</name><name sortKey="Goh, Boon Cher" sort="Goh, Boon Cher" uniqKey="Goh B" first="Boon Cher" last="Goh">Boon Cher Goh</name><name sortKey="Lim, Hong Liang" sort="Lim, Hong Liang" uniqKey="Lim H" first="Hong Liang" last="Lim">Hong Liang Lim</name><name sortKey="Rosenfeld, Nitzan" sort="Rosenfeld, Nitzan" uniqKey="Rosenfeld N" first="Nitzan" last="Rosenfeld">Nitzan Rosenfeld</name><name sortKey="Soo, Ross A" sort="Soo, Ross A" uniqKey="Soo R" first="Ross A" last="Soo">Ross A. Soo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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