Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.
Identifieur interne : 000B84 ( Main/Exploration ); précédent : 000B83; suivant : 000B85Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.
Auteurs : Matthew J. Wongchenko [États-Unis] ; Grant A. Mcarthur [Australie] ; Brigitte Dréno [France] ; James Larkin [Royaume-Uni] ; Paolo A. Ascierto [Italie] ; Jeffrey Sosman [États-Unis] ; Luc Andries [Belgique] ; Mark Kockx [Belgique] ; Stephen D. Hurst [États-Unis] ; Ivor Caro [États-Unis] ; Isabelle Rooney [États-Unis] ; Priti S. Hegde [États-Unis] ; Luciana Molinero [États-Unis] ; Huibin Yue [États-Unis] ; Ilsung Chang [États-Unis] ; Lukas Amler [États-Unis] ; Yibing Yan [États-Unis] ; Antoni Ribas [États-Unis]Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research [ 1078-0432 ] ; 2017.
Abstract
Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF(V600)-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66).Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238-45. ©2017 AACR.
DOI: 10.1158/1078-0432.CCR-17-0172
PubMed: 28536307
Affiliations:
- Australie, Belgique, France, Italie, Royaume-Uni, États-Unis
- Angleterre, Californie, Grand Londres, Pays de la Loire, Tennessee, Victoria (État)
- Londres, Melbourne, Nantes
- Université de Melbourne
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Wongchenko</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California. wongchenko.matthew@gene.com.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name><affiliation wicri:level="4"><nlm:affiliation>Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia, and University of Melbourne, Parkville, Victoria, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia, and University of Melbourne, Parkville, Victoria</wicri:regionArea><orgName type="university">Université de Melbourne</orgName><placeName><settlement type="city">Melbourne</settlement><region type="état">Victoria (État)</region></placeName></affiliation></author><author><name sortKey="Dreno, Brigitte" sort="Dreno, Brigitte" uniqKey="Dreno B" first="Brigitte" last="Dréno">Brigitte Dréno</name><affiliation wicri:level="3"><nlm:affiliation>Nantes University, Nantes, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Nantes University, Nantes</wicri:regionArea><placeName><region type="region">Pays de la Loire</region><region type="old region">Pays de la Loire</region><settlement type="city">Nantes</settlement></placeName></affiliation></author><author><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name><affiliation wicri:level="3"><nlm:affiliation>The Royal Marsden NHS Foundation Trust, London, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>The Royal Marsden NHS Foundation Trust, London</wicri:regionArea><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Ascierto, Paolo A" sort="Ascierto, Paolo A" uniqKey="Ascierto P" first="Paolo A" last="Ascierto">Paolo A. Ascierto</name><affiliation wicri:level="1"><nlm:affiliation>Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy.</nlm:affiliation><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto Nazionale Tumori Fondazione G. Pascale, Naples</wicri:regionArea><wicri:noRegion>Naples</wicri:noRegion></affiliation></author><author><name sortKey="Sosman, Jeffrey" sort="Sosman, Jeffrey" uniqKey="Sosman J" first="Jeffrey" last="Sosman">Jeffrey Sosman</name><affiliation wicri:level="2"><nlm:affiliation>Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Tennessee</region></placeName><wicri:cityArea>Vanderbilt-Ingram Cancer Center, Nashville</wicri:cityArea></affiliation></author><author><name sortKey="Andries, Luc" sort="Andries, Luc" uniqKey="Andries L" first="Luc" last="Andries">Luc Andries</name><affiliation wicri:level="1"><nlm:affiliation>HistoGeneX, Antwerp, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>HistoGeneX, Antwerp</wicri:regionArea><wicri:noRegion>Antwerp</wicri:noRegion></affiliation></author><author><name sortKey="Kockx, Mark" sort="Kockx, Mark" uniqKey="Kockx M" first="Mark" last="Kockx">Mark Kockx</name><affiliation wicri:level="1"><nlm:affiliation>HistoGeneX, Antwerp, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>HistoGeneX, Antwerp</wicri:regionArea><wicri:noRegion>Antwerp</wicri:noRegion></affiliation></author><author><name sortKey="Hurst, Stephen D" sort="Hurst, Stephen D" uniqKey="Hurst S" first="Stephen D" last="Hurst">Stephen D. Hurst</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Caro, Ivor" sort="Caro, Ivor" uniqKey="Caro I" first="Ivor" last="Caro">Ivor Caro</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Rooney, Isabelle" sort="Rooney, Isabelle" uniqKey="Rooney I" first="Isabelle" last="Rooney">Isabelle Rooney</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Hegde, Priti S" sort="Hegde, Priti S" uniqKey="Hegde P" first="Priti S" last="Hegde">Priti S. Hegde</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Molinero, Luciana" sort="Molinero, Luciana" uniqKey="Molinero L" first="Luciana" last="Molinero">Luciana Molinero</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Yue, Huibin" sort="Yue, Huibin" uniqKey="Yue H" first="Huibin" last="Yue">Huibin Yue</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Chang, Ilsung" sort="Chang, Ilsung" uniqKey="Chang I" first="Ilsung" last="Chang">Ilsung Chang</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Amler, Lukas" sort="Amler, Lukas" uniqKey="Amler L" first="Lukas" last="Amler">Lukas Amler</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Yan, Yibing" sort="Yan, Yibing" uniqKey="Yan Y" first="Yibing" last="Yan">Yibing Yan</name><affiliation wicri:level="2"><nlm:affiliation>Genentech, Inc., South San Francisco, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Genentech, Inc., South San Francisco</wicri:cityArea></affiliation></author><author><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><affiliation wicri:level="2"><nlm:affiliation>Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles, California.</nlm:affiliation><country>États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles</wicri:cityArea></affiliation></author></analytic><series><title level="j">Clinical cancer research : an official journal of the American Association for Cancer Research</title><idno type="ISSN">1078-0432</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF(V600)-mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated.Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS (P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures.Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 (n = 63) and the vemurafenib arm of BRIM-3 (n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set (n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib (n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66).Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238-45. ©2017 AACR.</div></front></TEI><affiliations><list><country><li>Australie</li><li>Belgique</li><li>France</li><li>Italie</li><li>Royaume-Uni</li><li>États-Unis</li></country><region><li>Angleterre</li><li>Californie</li><li>Grand Londres</li><li>Pays de la Loire</li><li>Tennessee</li><li>Victoria (État)</li></region><settlement><li>Londres</li><li>Melbourne</li><li>Nantes</li></settlement><orgName><li>Université de Melbourne</li></orgName></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Wongchenko, Matthew J" sort="Wongchenko, Matthew J" uniqKey="Wongchenko M" first="Matthew J" last="Wongchenko">Matthew J. Wongchenko</name></region><name sortKey="Amler, Lukas" sort="Amler, Lukas" uniqKey="Amler L" first="Lukas" last="Amler">Lukas Amler</name><name sortKey="Caro, Ivor" sort="Caro, Ivor" uniqKey="Caro I" first="Ivor" last="Caro">Ivor Caro</name><name sortKey="Chang, Ilsung" sort="Chang, Ilsung" uniqKey="Chang I" first="Ilsung" last="Chang">Ilsung Chang</name><name sortKey="Hegde, Priti S" sort="Hegde, Priti S" uniqKey="Hegde P" first="Priti S" last="Hegde">Priti S. Hegde</name><name sortKey="Hurst, Stephen D" sort="Hurst, Stephen D" uniqKey="Hurst S" first="Stephen D" last="Hurst">Stephen D. Hurst</name><name sortKey="Molinero, Luciana" sort="Molinero, Luciana" uniqKey="Molinero L" first="Luciana" last="Molinero">Luciana Molinero</name><name sortKey="Ribas, Antoni" sort="Ribas, Antoni" uniqKey="Ribas A" first="Antoni" last="Ribas">Antoni Ribas</name><name sortKey="Rooney, Isabelle" sort="Rooney, Isabelle" uniqKey="Rooney I" first="Isabelle" last="Rooney">Isabelle Rooney</name><name sortKey="Sosman, Jeffrey" sort="Sosman, Jeffrey" uniqKey="Sosman J" first="Jeffrey" last="Sosman">Jeffrey Sosman</name><name sortKey="Yan, Yibing" sort="Yan, Yibing" uniqKey="Yan Y" first="Yibing" last="Yan">Yibing Yan</name><name sortKey="Yue, Huibin" sort="Yue, Huibin" uniqKey="Yue H" first="Huibin" last="Yue">Huibin Yue</name></country><country name="Australie"><region name="Victoria (État)"><name sortKey="Mcarthur, Grant A" sort="Mcarthur, Grant A" uniqKey="Mcarthur G" first="Grant A" last="Mcarthur">Grant A. Mcarthur</name></region></country><country name="France"><region name="Pays de la Loire"><name sortKey="Dreno, Brigitte" sort="Dreno, Brigitte" uniqKey="Dreno B" first="Brigitte" last="Dréno">Brigitte Dréno</name></region></country><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Larkin, James" sort="Larkin, James" uniqKey="Larkin J" first="James" last="Larkin">James Larkin</name></region></country><country name="Italie"><noRegion><name sortKey="Ascierto, Paolo A" sort="Ascierto, Paolo A" uniqKey="Ascierto P" first="Paolo A" last="Ascierto">Paolo A. Ascierto</name></noRegion></country><country name="Belgique"><noRegion><name sortKey="Andries, Luc" sort="Andries, Luc" uniqKey="Andries L" first="Luc" last="Andries">Luc Andries</name></noRegion><name sortKey="Kockx, Mark" sort="Kockx, Mark" uniqKey="Kockx M" first="Mark" last="Kockx">Mark Kockx</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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