Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression
Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggest...
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| Veröffentlicht in: | PloS one 2009-05, Vol.4 (5), p.e5133-e5133 |
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| creator | Rosell, Rafael Perez-Roca, Laia Sanchez, Jose Javier Cobo, Manuel Moran, Teresa Chaib, Imane Provencio, Mariano Domine, Manuel Sala, Maria Angeles Jimenez, Ulpiano Diz, Pilar Barneto, Isidoro Macias, Jose Antonio de Las Peñas, Ramon Catot, Silvia Isla, Dolores Sanchez, Jose Miguel Ibeas, Rafael Lopez-Vivanco, Guillermo Oramas, Juana Mendez, Pedro Reguart, Noemi Blanco, Remei Taron, Miquel |
| description | Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.
We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05).
Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.
(ClinicalTrials.gov) NCT00883480. |
| doi_str_mv | 10.1371/journal.pone.0005133 |
| format | Article |
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We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05).
Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.
(ClinicalTrials.gov) NCT00883480.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0005133</identifier><identifier>PMID: 19415121</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aged ; Analysis ; BRCA1 protein ; BRCA1 Protein - genetics ; Breast cancer ; Cancer ; Cancer genetics ; Cancer metastasis ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - mortality ; Carrier Proteins - genetics ; Cell Biology/Gene Expression ; Cell survival ; Chemotherapy ; Cisplatin ; Cisplatin - administration & dosage ; Customization ; Deoxycytidine - administration & dosage ; Deoxycytidine - analogs & derivatives ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA-Binding Proteins ; Docetaxel ; Drug Dosage Calculations ; Drug Resistance, Neoplasm - genetics ; Epidermal growth factor receptors ; ErbB Receptors - genetics ; Female ; Gefitinib ; Gemcitabine ; Gene expression ; Genetic aspects ; Histone Chaperones ; Humans ; Kinases ; Lung cancer ; Lung carcinoma ; Lung diseases ; Male ; Messenger RNA ; Metastases ; Middle Aged ; Mutation ; Non-small cell lung cancer ; Non-small cell lung carcinoma ; Nuclear Proteins - genetics ; Oncology ; Oncology/Lung Cancer ; Ovarian cancer ; Paraffin ; Patients ; Pharmacogenetics - methods ; Platinum ; Proteins ; Ribonucleic acid ; RNA ; RNA, Messenger - analysis ; RNA, Neoplasm - analysis ; Rodents ; Sensitivity enhancement ; Survival ; Survival Rate ; Taxoids - administration & dosage ; Treatment Outcome</subject><ispartof>PloS one, 2009-05, Vol.4 (5), p.e5133-e5133</ispartof><rights>COPYRIGHT 2009 Public Library of Science</rights><rights>2009 Rosell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Rosell et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c759t-60d0f25461a6504a1c3b0fc454f8668577ff90adc1ecf5487f17f3c3b7aae8c23</citedby><cites>FETCH-LOGICAL-c759t-60d0f25461a6504a1c3b0fc454f8668577ff90adc1ecf5487f17f3c3b7aae8c23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673583/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673583/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19415121$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rosell, Rafael</creatorcontrib><creatorcontrib>Perez-Roca, Laia</creatorcontrib><creatorcontrib>Sanchez, Jose Javier</creatorcontrib><creatorcontrib>Cobo, Manuel</creatorcontrib><creatorcontrib>Moran, Teresa</creatorcontrib><creatorcontrib>Chaib, Imane</creatorcontrib><creatorcontrib>Provencio, Mariano</creatorcontrib><creatorcontrib>Domine, Manuel</creatorcontrib><creatorcontrib>Sala, Maria Angeles</creatorcontrib><creatorcontrib>Jimenez, Ulpiano</creatorcontrib><creatorcontrib>Diz, Pilar</creatorcontrib><creatorcontrib>Barneto, Isidoro</creatorcontrib><creatorcontrib>Macias, Jose Antonio</creatorcontrib><creatorcontrib>de Las Peñas, Ramon</creatorcontrib><creatorcontrib>Catot, Silvia</creatorcontrib><creatorcontrib>Isla, Dolores</creatorcontrib><creatorcontrib>Sanchez, Jose Miguel</creatorcontrib><creatorcontrib>Ibeas, Rafael</creatorcontrib><creatorcontrib>Lopez-Vivanco, Guillermo</creatorcontrib><creatorcontrib>Oramas, Juana</creatorcontrib><creatorcontrib>Mendez, Pedro</creatorcontrib><creatorcontrib>Reguart, Noemi</creatorcontrib><creatorcontrib>Blanco, Remei</creatorcontrib><creatorcontrib>Taron, Miquel</creatorcontrib><title>Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.
We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05).
Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.
(ClinicalTrials.gov) NCT00883480.</description><subject>Adult</subject><subject>Aged</subject><subject>Analysis</subject><subject>BRCA1 protein</subject><subject>BRCA1 Protein - genetics</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer genetics</subject><subject>Cancer metastasis</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - mortality</subject><subject>Carrier Proteins - genetics</subject><subject>Cell Biology/Gene Expression</subject><subject>Cell survival</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Cisplatin - administration & dosage</subject><subject>Customization</subject><subject>Deoxycytidine - administration & dosage</subject><subject>Deoxycytidine - analogs & derivatives</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA-Binding Proteins</subject><subject>Docetaxel</subject><subject>Drug Dosage Calculations</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Epidermal growth factor receptors</subject><subject>ErbB Receptors - genetics</subject><subject>Female</subject><subject>Gefitinib</subject><subject>Gemcitabine</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Histone Chaperones</subject><subject>Humans</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Lung carcinoma</subject><subject>Lung diseases</subject><subject>Male</subject><subject>Messenger RNA</subject><subject>Metastases</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Non-small cell lung cancer</subject><subject>Non-small cell lung carcinoma</subject><subject>Nuclear Proteins - genetics</subject><subject>Oncology</subject><subject>Oncology/Lung Cancer</subject><subject>Ovarian cancer</subject><subject>Paraffin</subject><subject>Patients</subject><subject>Pharmacogenetics - methods</subject><subject>Platinum</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Messenger - analysis</subject><subject>RNA, Neoplasm - analysis</subject><subject>Rodents</subject><subject>Sensitivity enhancement</subject><subject>Survival</subject><subject>Survival Rate</subject><subject>Taxoids - administration & dosage</subject><subject>Treatment Outcome</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl-L1DAUxYso7rr6DUQLwoIPHZMmadMXYRx214HFhfHPa7hNk5kuaTImqax-ejM7VWfEB8lDws3vnpscTpY9x2iGSY3f3LrRWzCzrbNqhhBimJAH2SluSFlUJSIPD84n2ZMQbhNDeFU9zk5wQzHDJT7NusUYohv6H6rLo1cQB2Vj3tvcOluEAYwppDImN6Nd5xKsVD5vISTa2fzi6nKVD2OE2DsbcrBd_m61mON8WH2Y5-pu61UI6epp9kiDCerZtJ9lny8vPi3eF9c3V8vF_LqQNWtiUaEO6ZLRCkPFEAUsSYu0pIzq9GzO6lrrBkEnsZKaUV5rXGuSoBpAcVmSs-zlXndrXBCTQUHgkjeYNgTxRCz3ROfgVmx9P4D_Lhz04r7g_FqAj700SvBOY57UpQZGS4ZbYBJxyVHLOJOtTlpvp2ljO6hOJuM8mCPR4xvbb8TafRNlVRPGSRI4nwS8-zqqEMXQh53bYJUbgyhRRTmvmgS--gv8999me2oN6fm91S5NlWl1auhlSonuU31Oa85LRDlNDa-PGhIT1V1cwxiCWH5c_T978-WYPT9gNwpM3ARnxvuUHIN0D0rvQvBK_zYPI7EL-a9_il3IxRTy1Pbi0Pg_TVOqyU_5nves</recordid><startdate>20090505</startdate><enddate>20090505</enddate><creator>Rosell, Rafael</creator><creator>Perez-Roca, Laia</creator><creator>Sanchez, Jose Javier</creator><creator>Cobo, Manuel</creator><creator>Moran, Teresa</creator><creator>Chaib, Imane</creator><creator>Provencio, Mariano</creator><creator>Domine, Manuel</creator><creator>Sala, Maria Angeles</creator><creator>Jimenez, Ulpiano</creator><creator>Diz, Pilar</creator><creator>Barneto, Isidoro</creator><creator>Macias, Jose Antonio</creator><creator>de Las Peñas, Ramon</creator><creator>Catot, Silvia</creator><creator>Isla, Dolores</creator><creator>Sanchez, Jose Miguel</creator><creator>Ibeas, Rafael</creator><creator>Lopez-Vivanco, Guillermo</creator><creator>Oramas, Juana</creator><creator>Mendez, Pedro</creator><creator>Reguart, Noemi</creator><creator>Blanco, Remei</creator><creator>Taron, Miquel</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20090505</creationdate><title>Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression</title><author>Rosell, Rafael ; Perez-Roca, Laia ; Sanchez, Jose Javier ; Cobo, Manuel ; Moran, Teresa ; Chaib, Imane ; Provencio, Mariano ; Domine, Manuel ; Sala, Maria Angeles ; Jimenez, Ulpiano ; Diz, Pilar ; Barneto, Isidoro ; Macias, Jose Antonio ; de Las Peñas, Ramon ; Catot, Silvia ; Isla, Dolores ; Sanchez, Jose Miguel ; Ibeas, Rafael ; Lopez-Vivanco, Guillermo ; Oramas, Juana ; Mendez, Pedro ; Reguart, Noemi ; Blanco, Remei ; Taron, Miquel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c759t-60d0f25461a6504a1c3b0fc454f8668577ff90adc1ecf5487f17f3c3b7aae8c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Analysis</topic><topic>BRCA1 protein</topic><topic>BRCA1 Protein - genetics</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer genetics</topic><topic>Cancer metastasis</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - mortality</topic><topic>Carrier Proteins - genetics</topic><topic>Cell Biology/Gene Expression</topic><topic>Cell survival</topic><topic>Chemotherapy</topic><topic>Cisplatin</topic><topic>Cisplatin - administration & dosage</topic><topic>Customization</topic><topic>Deoxycytidine - administration & dosage</topic><topic>Deoxycytidine - analogs & derivatives</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA-Binding Proteins</topic><topic>Docetaxel</topic><topic>Drug Dosage Calculations</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>Epidermal growth factor receptors</topic><topic>ErbB Receptors - genetics</topic><topic>Female</topic><topic>Gefitinib</topic><topic>Gemcitabine</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Histone Chaperones</topic><topic>Humans</topic><topic>Kinases</topic><topic>Lung cancer</topic><topic>Lung carcinoma</topic><topic>Lung diseases</topic><topic>Male</topic><topic>Messenger RNA</topic><topic>Metastases</topic><topic>Middle Aged</topic><topic>Mutation</topic><topic>Non-small cell lung cancer</topic><topic>Non-small cell lung carcinoma</topic><topic>Nuclear Proteins - genetics</topic><topic>Oncology</topic><topic>Oncology/Lung Cancer</topic><topic>Ovarian cancer</topic><topic>Paraffin</topic><topic>Patients</topic><topic>Pharmacogenetics - methods</topic><topic>Platinum</topic><topic>Proteins</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Messenger - analysis</topic><topic>RNA, Neoplasm - analysis</topic><topic>Rodents</topic><topic>Sensitivity enhancement</topic><topic>Survival</topic><topic>Survival Rate</topic><topic>Taxoids - administration & dosage</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rosell, Rafael</creatorcontrib><creatorcontrib>Perez-Roca, Laia</creatorcontrib><creatorcontrib>Sanchez, Jose Javier</creatorcontrib><creatorcontrib>Cobo, Manuel</creatorcontrib><creatorcontrib>Moran, Teresa</creatorcontrib><creatorcontrib>Chaib, Imane</creatorcontrib><creatorcontrib>Provencio, Mariano</creatorcontrib><creatorcontrib>Domine, Manuel</creatorcontrib><creatorcontrib>Sala, Maria Angeles</creatorcontrib><creatorcontrib>Jimenez, Ulpiano</creatorcontrib><creatorcontrib>Diz, Pilar</creatorcontrib><creatorcontrib>Barneto, Isidoro</creatorcontrib><creatorcontrib>Macias, Jose Antonio</creatorcontrib><creatorcontrib>de Las Peñas, Ramon</creatorcontrib><creatorcontrib>Catot, Silvia</creatorcontrib><creatorcontrib>Isla, Dolores</creatorcontrib><creatorcontrib>Sanchez, Jose Miguel</creatorcontrib><creatorcontrib>Ibeas, Rafael</creatorcontrib><creatorcontrib>Lopez-Vivanco, Guillermo</creatorcontrib><creatorcontrib>Oramas, Juana</creatorcontrib><creatorcontrib>Mendez, Pedro</creatorcontrib><creatorcontrib>Reguart, Noemi</creatorcontrib><creatorcontrib>Blanco, Remei</creatorcontrib><creatorcontrib>Taron, Miquel</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Opposing Viewpoints Resource Center</collection><collection>Science (Gale in Context)</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>ProQuest Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Database (1962 - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>Biological Sciences</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest advanced technologies & aerospace journals</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rosell, Rafael</au><au>Perez-Roca, Laia</au><au>Sanchez, Jose Javier</au><au>Cobo, Manuel</au><au>Moran, Teresa</au><au>Chaib, Imane</au><au>Provencio, Mariano</au><au>Domine, Manuel</au><au>Sala, Maria Angeles</au><au>Jimenez, Ulpiano</au><au>Diz, Pilar</au><au>Barneto, Isidoro</au><au>Macias, Jose Antonio</au><au>de Las Peñas, Ramon</au><au>Catot, Silvia</au><au>Isla, Dolores</au><au>Sanchez, Jose Miguel</au><au>Ibeas, Rafael</au><au>Lopez-Vivanco, Guillermo</au><au>Oramas, Juana</au><au>Mendez, Pedro</au><au>Reguart, Noemi</au><au>Blanco, Remei</au><au>Taron, Miquel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2009-05-05</date><risdate>2009</risdate><volume>4</volume><issue>5</issue><spage>e5133</spage><epage>e5133</epage><pages>e5133-e5133</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels.
We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05).
Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.
(ClinicalTrials.gov) NCT00883480.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>19415121</pmid><doi>10.1371/journal.pone.0005133</doi><tpages>e5133</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2009-05, Vol.4 (5), p.e5133-e5133 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1289149308 |
| source | MEDLINE; Public Library of Science; DOAJ Directory of Open Access Journals; PubMed Central; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Adult Aged Analysis BRCA1 protein BRCA1 Protein - genetics Breast cancer Cancer Cancer genetics Cancer metastasis Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - mortality Carrier Proteins - genetics Cell Biology/Gene Expression Cell survival Chemotherapy Cisplatin Cisplatin - administration & dosage Customization Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Deoxyribonucleic acid DNA DNA damage DNA-Binding Proteins Docetaxel Drug Dosage Calculations Drug Resistance, Neoplasm - genetics Epidermal growth factor receptors ErbB Receptors - genetics Female Gefitinib Gemcitabine Gene expression Genetic aspects Histone Chaperones Humans Kinases Lung cancer Lung carcinoma Lung diseases Male Messenger RNA Metastases Middle Aged Mutation Non-small cell lung cancer Non-small cell lung carcinoma Nuclear Proteins - genetics Oncology Oncology/Lung Cancer Ovarian cancer Paraffin Patients Pharmacogenetics - methods Platinum Proteins Ribonucleic acid RNA RNA, Messenger - analysis RNA, Neoplasm - analysis Rodents Sensitivity enhancement Survival Survival Rate Taxoids - administration & dosage Treatment Outcome |
| title | Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression |
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