Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms
Abstract Background Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of r...
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| creator | Johnson, Douglas B Menzies, Alexander M Zimmer, Lisa Eroglu, Zeynep Ye, Fei Zhao, Shilin Rizos, Helen Sucker, Antje Scolyer, Richard A Gutzmer, Ralf Gogas, Helen Kefford, Richard F Thompson, John F Becker, Jürgen C Berking, Carola Egberts, Friederike Loquai, Carmen Goldinger, Simone M Pupo, Gulietta M Hugo, Willy Kong, Xiangju Garraway, Levi A Sosman, Jeffrey A Ribas, Antoni Lo, Roger S Long, Georgina V Schadendorf, Dirk |
| description | Abstract Background Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. Methods We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing. Results Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF V600E/K amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms. Conclusions This is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF -mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement. |
| doi_str_mv | 10.1016/j.ejca.2015.08.022 |
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| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4666799</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0959804915008217</els_id><sourcerecordid>1738480592</sourcerecordid><originalsourceid>FETCH-LOGICAL-c678t-f4c0c3ebea1cdb9a68ff6f93395112da43d78e007a089b2dcdc7ebb0189e21a83</originalsourceid><addsrcrecordid>eNp9kk1v1DAQhiMEokvhD3BAPnJolrHzZSNUaakoIFVC4uNsOc6EeEnsre2stD-Jf4nTbcvHgZMP8847nveZLHtOYU2B1q-2a9xqtWZAqzXwNTD2IFtR3ogceMUeZisQlcg5lOIkexLCFgAaXsLj7ITVNXDKYJX93Ojr2XjsyNvPm0ti7GBaE50nHoMJUVmNr8mGTPMYjUYb0ZMJo8qVVeMhKYjrSRyQhB3q6OeJKNuR3uP1jFYbDGdEj8YarUbS4qD2xs3-7Ea0G9C6eNgZTVQIThsVjbM3hr9np2F6UNaEKTzNHvVqDPjs9j3Nvl2--3rxIb_69P7jxeYq13XDY96XGnSBLSqqu1aomvd93YuiEBWlrFNl0TUcUxIKuGhZpzvdYNsC5QIZVbw4zc6Pvru5nbBblvZqlDtvJuUP0ikj_65YM8jvbi_Luq4bIZLBy1sD71IMIcrJBI3jqCy6OUjaFLzkUAmWpOwo1d6F4LG_H0NBLozlVi6M5cJYApeJcWp68ecH71vuoCbBm6MAU0x7g16GhCKl2SXQOsrOmf_7n__TfofwBx4wbBPBBD_tIQOTIL8sV7YcGa0AOEvb_QKgeNNB</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1738480592</pqid></control><display><type>article</type><title>Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms</title><source>MEDLINE</source><source>Access via ScienceDirect (Elsevier)</source><creator>Johnson, Douglas B ; Menzies, Alexander M ; Zimmer, Lisa ; Eroglu, Zeynep ; Ye, Fei ; Zhao, Shilin ; Rizos, Helen ; Sucker, Antje ; Scolyer, Richard A ; Gutzmer, Ralf ; Gogas, Helen ; Kefford, Richard F ; Thompson, John F ; Becker, Jürgen C ; Berking, Carola ; Egberts, Friederike ; Loquai, Carmen ; Goldinger, Simone M ; Pupo, Gulietta M ; Hugo, Willy ; Kong, Xiangju ; Garraway, Levi A ; Sosman, Jeffrey A ; Ribas, Antoni ; Lo, Roger S ; Long, Georgina V ; Schadendorf, Dirk</creator><creatorcontrib>Johnson, Douglas B ; Menzies, Alexander M ; Zimmer, Lisa ; Eroglu, Zeynep ; Ye, Fei ; Zhao, Shilin ; Rizos, Helen ; Sucker, Antje ; Scolyer, Richard A ; Gutzmer, Ralf ; Gogas, Helen ; Kefford, Richard F ; Thompson, John F ; Becker, Jürgen C ; Berking, Carola ; Egberts, Friederike ; Loquai, Carmen ; Goldinger, Simone M ; Pupo, Gulietta M ; Hugo, Willy ; Kong, Xiangju ; Garraway, Levi A ; Sosman, Jeffrey A ; Ribas, Antoni ; Lo, Roger S ; Long, Georgina V ; Schadendorf, Dirk</creatorcontrib><description>Abstract Background Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. Methods We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing. Results Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF V600E/K amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms. Conclusions This is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF -mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.</description><identifier>ISSN: 0959-8049</identifier><identifier>EISSN: 1879-0852</identifier><identifier>DOI: 10.1016/j.ejca.2015.08.022</identifier><identifier>PMID: 26608120</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Acquired ; Antineoplastic Agents - therapeutic use ; Australia ; Biomarkers, Tumor - antagonists & inhibitors ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; BRAF ; Dabrafenib ; Disease Progression ; Disease-Free Survival ; DNA Mutational Analysis ; Drug Resistance, Neoplasm - genetics ; Europe ; Female ; Genetic Predisposition to Disease ; Hematology, Oncology and Palliative Medicine ; Humans ; Kaplan-Meier Estimate ; Male ; MAPK ; MEK1 ; Melanoma - drug therapy ; Melanoma - enzymology ; Melanoma - genetics ; Melanoma - mortality ; Melanoma - pathology ; Meta-analysis ; Middle Aged ; Mutation ; NRAS ; Phenotype ; Proportional Hazards Models ; Protein Kinase Inhibitors - therapeutic use ; Proto-Oncogene Proteins B-raf - antagonists & inhibitors ; Proto-Oncogene Proteins B-raf - genetics ; Proto-Oncogene Proteins B-raf - metabolism ; Resistance ; Risk Factors ; Signal Transduction - drug effects ; Skin Neoplasms - drug therapy ; Skin Neoplasms - enzymology ; Skin Neoplasms - genetics ; Skin Neoplasms - mortality ; Skin Neoplasms - pathology ; Splice ; Time Factors ; Treatment Outcome ; United States ; Vemurafenib</subject><ispartof>European journal of cancer (1990), 2015-12, Vol.51 (18), p.2792-2799</ispartof><rights>Elsevier Ltd</rights><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c678t-f4c0c3ebea1cdb9a68ff6f93395112da43d78e007a089b2dcdc7ebb0189e21a83</citedby><cites>FETCH-LOGICAL-c678t-f4c0c3ebea1cdb9a68ff6f93395112da43d78e007a089b2dcdc7ebb0189e21a83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ejca.2015.08.022$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,315,781,785,886,3551,27929,27930,46000</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26608120$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Johnson, Douglas B</creatorcontrib><creatorcontrib>Menzies, Alexander M</creatorcontrib><creatorcontrib>Zimmer, Lisa</creatorcontrib><creatorcontrib>Eroglu, Zeynep</creatorcontrib><creatorcontrib>Ye, Fei</creatorcontrib><creatorcontrib>Zhao, Shilin</creatorcontrib><creatorcontrib>Rizos, Helen</creatorcontrib><creatorcontrib>Sucker, Antje</creatorcontrib><creatorcontrib>Scolyer, Richard A</creatorcontrib><creatorcontrib>Gutzmer, Ralf</creatorcontrib><creatorcontrib>Gogas, Helen</creatorcontrib><creatorcontrib>Kefford, Richard F</creatorcontrib><creatorcontrib>Thompson, John F</creatorcontrib><creatorcontrib>Becker, Jürgen C</creatorcontrib><creatorcontrib>Berking, Carola</creatorcontrib><creatorcontrib>Egberts, Friederike</creatorcontrib><creatorcontrib>Loquai, Carmen</creatorcontrib><creatorcontrib>Goldinger, Simone M</creatorcontrib><creatorcontrib>Pupo, Gulietta M</creatorcontrib><creatorcontrib>Hugo, Willy</creatorcontrib><creatorcontrib>Kong, Xiangju</creatorcontrib><creatorcontrib>Garraway, Levi A</creatorcontrib><creatorcontrib>Sosman, Jeffrey A</creatorcontrib><creatorcontrib>Ribas, Antoni</creatorcontrib><creatorcontrib>Lo, Roger S</creatorcontrib><creatorcontrib>Long, Georgina V</creatorcontrib><creatorcontrib>Schadendorf, Dirk</creatorcontrib><title>Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms</title><title>European journal of cancer (1990)</title><addtitle>Eur J Cancer</addtitle><description>Abstract Background Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. Methods We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing. Results Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF V600E/K amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms. Conclusions This is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF -mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.</description><subject>Acquired</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Australia</subject><subject>Biomarkers, Tumor - antagonists & inhibitors</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>BRAF</subject><subject>Dabrafenib</subject><subject>Disease Progression</subject><subject>Disease-Free Survival</subject><subject>DNA Mutational Analysis</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Europe</subject><subject>Female</subject><subject>Genetic Predisposition to Disease</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Humans</subject><subject>Kaplan-Meier Estimate</subject><subject>Male</subject><subject>MAPK</subject><subject>MEK1</subject><subject>Melanoma - drug therapy</subject><subject>Melanoma - enzymology</subject><subject>Melanoma - genetics</subject><subject>Melanoma - mortality</subject><subject>Melanoma - pathology</subject><subject>Meta-analysis</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>NRAS</subject><subject>Phenotype</subject><subject>Proportional Hazards Models</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>Proto-Oncogene Proteins B-raf - metabolism</subject><subject>Resistance</subject><subject>Risk Factors</subject><subject>Signal Transduction - drug effects</subject><subject>Skin Neoplasms - drug therapy</subject><subject>Skin Neoplasms - enzymology</subject><subject>Skin Neoplasms - genetics</subject><subject>Skin Neoplasms - mortality</subject><subject>Skin Neoplasms - pathology</subject><subject>Splice</subject><subject>Time Factors</subject><subject>Treatment Outcome</subject><subject>United States</subject><subject>Vemurafenib</subject><issn>0959-8049</issn><issn>1879-0852</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kk1v1DAQhiMEokvhD3BAPnJolrHzZSNUaakoIFVC4uNsOc6EeEnsre2stD-Jf4nTbcvHgZMP8847nveZLHtOYU2B1q-2a9xqtWZAqzXwNTD2IFtR3ogceMUeZisQlcg5lOIkexLCFgAaXsLj7ITVNXDKYJX93Ojr2XjsyNvPm0ti7GBaE50nHoMJUVmNr8mGTPMYjUYb0ZMJo8qVVeMhKYjrSRyQhB3q6OeJKNuR3uP1jFYbDGdEj8YarUbS4qD2xs3-7Ea0G9C6eNgZTVQIThsVjbM3hr9np2F6UNaEKTzNHvVqDPjs9j3Nvl2--3rxIb_69P7jxeYq13XDY96XGnSBLSqqu1aomvd93YuiEBWlrFNl0TUcUxIKuGhZpzvdYNsC5QIZVbw4zc6Pvru5nbBblvZqlDtvJuUP0ikj_65YM8jvbi_Luq4bIZLBy1sD71IMIcrJBI3jqCy6OUjaFLzkUAmWpOwo1d6F4LG_H0NBLozlVi6M5cJYApeJcWp68ecH71vuoCbBm6MAU0x7g16GhCKl2SXQOsrOmf_7n__TfofwBx4wbBPBBD_tIQOTIL8sV7YcGa0AOEvb_QKgeNNB</recordid><startdate>20151201</startdate><enddate>20151201</enddate><creator>Johnson, Douglas B</creator><creator>Menzies, Alexander M</creator><creator>Zimmer, Lisa</creator><creator>Eroglu, Zeynep</creator><creator>Ye, Fei</creator><creator>Zhao, Shilin</creator><creator>Rizos, Helen</creator><creator>Sucker, Antje</creator><creator>Scolyer, Richard A</creator><creator>Gutzmer, Ralf</creator><creator>Gogas, Helen</creator><creator>Kefford, Richard F</creator><creator>Thompson, John F</creator><creator>Becker, Jürgen C</creator><creator>Berking, Carola</creator><creator>Egberts, Friederike</creator><creator>Loquai, Carmen</creator><creator>Goldinger, Simone M</creator><creator>Pupo, Gulietta M</creator><creator>Hugo, Willy</creator><creator>Kong, Xiangju</creator><creator>Garraway, Levi A</creator><creator>Sosman, Jeffrey A</creator><creator>Ribas, Antoni</creator><creator>Lo, Roger S</creator><creator>Long, Georgina V</creator><creator>Schadendorf, Dirk</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20151201</creationdate><title>Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms</title><author>Johnson, Douglas B ; Menzies, Alexander M ; Zimmer, Lisa ; Eroglu, Zeynep ; Ye, Fei ; Zhao, Shilin ; Rizos, Helen ; Sucker, Antje ; Scolyer, Richard A ; Gutzmer, Ralf ; Gogas, Helen ; Kefford, Richard F ; Thompson, John F ; Becker, Jürgen C ; Berking, Carola ; Egberts, Friederike ; Loquai, Carmen ; Goldinger, Simone M ; Pupo, Gulietta M ; Hugo, Willy ; Kong, Xiangju ; Garraway, Levi A ; Sosman, Jeffrey A ; Ribas, Antoni ; Lo, Roger S ; Long, Georgina V ; Schadendorf, Dirk</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c678t-f4c0c3ebea1cdb9a68ff6f93395112da43d78e007a089b2dcdc7ebb0189e21a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Acquired</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Australia</topic><topic>Biomarkers, Tumor - antagonists & inhibitors</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>BRAF</topic><topic>Dabrafenib</topic><topic>Disease Progression</topic><topic>Disease-Free Survival</topic><topic>DNA Mutational Analysis</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Europe</topic><topic>Female</topic><topic>Genetic Predisposition to Disease</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Humans</topic><topic>Kaplan-Meier Estimate</topic><topic>Male</topic><topic>MAPK</topic><topic>MEK1</topic><topic>Melanoma - drug therapy</topic><topic>Melanoma - enzymology</topic><topic>Melanoma - genetics</topic><topic>Melanoma - mortality</topic><topic>Melanoma - pathology</topic><topic>Meta-analysis</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>NRAS</topic><topic>Phenotype</topic><topic>Proportional Hazards Models</topic><topic>Protein Kinase Inhibitors - therapeutic use</topic><topic>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins B-raf - genetics</topic><topic>Proto-Oncogene Proteins B-raf - metabolism</topic><topic>Resistance</topic><topic>Risk Factors</topic><topic>Signal Transduction - drug effects</topic><topic>Skin Neoplasms - drug therapy</topic><topic>Skin Neoplasms - enzymology</topic><topic>Skin Neoplasms - genetics</topic><topic>Skin Neoplasms - mortality</topic><topic>Skin Neoplasms - pathology</topic><topic>Splice</topic><topic>Time Factors</topic><topic>Treatment Outcome</topic><topic>United States</topic><topic>Vemurafenib</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johnson, Douglas B</creatorcontrib><creatorcontrib>Menzies, Alexander M</creatorcontrib><creatorcontrib>Zimmer, Lisa</creatorcontrib><creatorcontrib>Eroglu, Zeynep</creatorcontrib><creatorcontrib>Ye, Fei</creatorcontrib><creatorcontrib>Zhao, Shilin</creatorcontrib><creatorcontrib>Rizos, Helen</creatorcontrib><creatorcontrib>Sucker, Antje</creatorcontrib><creatorcontrib>Scolyer, Richard A</creatorcontrib><creatorcontrib>Gutzmer, Ralf</creatorcontrib><creatorcontrib>Gogas, Helen</creatorcontrib><creatorcontrib>Kefford, Richard F</creatorcontrib><creatorcontrib>Thompson, John F</creatorcontrib><creatorcontrib>Becker, Jürgen C</creatorcontrib><creatorcontrib>Berking, Carola</creatorcontrib><creatorcontrib>Egberts, Friederike</creatorcontrib><creatorcontrib>Loquai, Carmen</creatorcontrib><creatorcontrib>Goldinger, Simone M</creatorcontrib><creatorcontrib>Pupo, Gulietta M</creatorcontrib><creatorcontrib>Hugo, Willy</creatorcontrib><creatorcontrib>Kong, Xiangju</creatorcontrib><creatorcontrib>Garraway, Levi A</creatorcontrib><creatorcontrib>Sosman, Jeffrey A</creatorcontrib><creatorcontrib>Ribas, Antoni</creatorcontrib><creatorcontrib>Lo, Roger S</creatorcontrib><creatorcontrib>Long, Georgina V</creatorcontrib><creatorcontrib>Schadendorf, Dirk</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>European journal of cancer (1990)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johnson, Douglas B</au><au>Menzies, Alexander M</au><au>Zimmer, Lisa</au><au>Eroglu, Zeynep</au><au>Ye, Fei</au><au>Zhao, Shilin</au><au>Rizos, Helen</au><au>Sucker, Antje</au><au>Scolyer, Richard A</au><au>Gutzmer, Ralf</au><au>Gogas, Helen</au><au>Kefford, Richard F</au><au>Thompson, John F</au><au>Becker, Jürgen C</au><au>Berking, Carola</au><au>Egberts, Friederike</au><au>Loquai, Carmen</au><au>Goldinger, Simone M</au><au>Pupo, Gulietta M</au><au>Hugo, Willy</au><au>Kong, Xiangju</au><au>Garraway, Levi A</au><au>Sosman, Jeffrey A</au><au>Ribas, Antoni</au><au>Lo, Roger S</au><au>Long, Georgina V</au><au>Schadendorf, Dirk</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms</atitle><jtitle>European journal of cancer (1990)</jtitle><addtitle>Eur J Cancer</addtitle><date>2015-12-01</date><risdate>2015</risdate><volume>51</volume><issue>18</issue><spage>2792</spage><epage>2799</epage><pages>2792-2799</pages><issn>0959-8049</issn><eissn>1879-0852</eissn><abstract>Abstract Background Acquired resistance to BRAF inhibitors (BRAFi) is a near-universal phenomenon caused by numerous genetic and non-genetic alterations. In this study, we evaluated the spectrum, onset, pattern of progression, and subsequent clinical outcomes associated with specific mechanisms of resistance. Methods We compiled clinical and genetic data from 100 patients with 132 tissue samples obtained at progression on BRAFi therapy from 3 large, previously published studies of BRAFi resistance. These samples were subjected to whole-exome sequencing and/or polymerase chain reaction-based genetic testing. Results Among 132 samples, putative resistance mechanisms were identified in 58%, including NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF V600E/K amplifications (13%), MEK1/2 mutations (7%), and non-mitogen-activated protein kinase pathway alterations (11%). Marked heterogeneity was observed within tumors and patients; 18 of 19 patients (95%) with more than one progression biopsy had distinct/unknown drivers of resistance between samples. NRAS mutations were associated with vemurafenib use (p = 0.045) and intracranial metastases (p = 0.036), and MEK1/2 mutations correlated with hepatic progression (p = 0.011). Progression-free survival and overall survival were similar across resistance mechanisms. The median survival after disease progression was 6.9 months, and responses to subsequent BRAF and MEK inhibition were uncommon (2 of 15; 13%). Post-progression outcomes did not correlate with specific acquired BRAFi-resistance mechanisms. Conclusions This is the first study to systematically characterise the clinical implications of particular acquired BRAFi-resistance mechanisms in patients with BRAF -mutant melanoma largest study to compile the landscape of resistance. Despite marked heterogeneity of resistance mechanisms within patients, NRAS mutations correlated with vemurafenib use and intracranial disease involvement.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>26608120</pmid><doi>10.1016/j.ejca.2015.08.022</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | European journal of cancer (1990), 2015-12, Vol.51 (18), p.2792-2799 |
| issn | 0959-8049 1879-0852 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4666799 |
| source | MEDLINE; Access via ScienceDirect (Elsevier) |
| subjects | Acquired Antineoplastic Agents - therapeutic use Australia Biomarkers, Tumor - antagonists & inhibitors Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism BRAF Dabrafenib Disease Progression Disease-Free Survival DNA Mutational Analysis Drug Resistance, Neoplasm - genetics Europe Female Genetic Predisposition to Disease Hematology, Oncology and Palliative Medicine Humans Kaplan-Meier Estimate Male MAPK MEK1 Melanoma - drug therapy Melanoma - enzymology Melanoma - genetics Melanoma - mortality Melanoma - pathology Meta-analysis Middle Aged Mutation NRAS Phenotype Proportional Hazards Models Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins B-raf - metabolism Resistance Risk Factors Signal Transduction - drug effects Skin Neoplasms - drug therapy Skin Neoplasms - enzymology Skin Neoplasms - genetics Skin Neoplasms - mortality Skin Neoplasms - pathology Splice Time Factors Treatment Outcome United States Vemurafenib |
| title | Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-11T14%3A28%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Acquired%20BRAF%20inhibitor%20resistance:%20A%20multicenter%20meta-analysis%20of%20the%20spectrum%20and%20frequencies,%20clinical%20behaviour,%20and%20phenotypic%20associations%20of%20resistance%20mechanisms&rft.jtitle=European%20journal%20of%20cancer%20(1990)&rft.au=Johnson,%20Douglas%20B&rft.date=2015-12-01&rft.volume=51&rft.issue=18&rft.spage=2792&rft.epage=2799&rft.pages=2792-2799&rft.issn=0959-8049&rft.eissn=1879-0852&rft_id=info:doi/10.1016/j.ejca.2015.08.022&rft_dat=%3Cproquest_pubme%3E1738480592%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1738480592&rft_id=info:pmid/26608120&rft_els_id=S0959804915008217&rfr_iscdi=true |