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dc.contributor.authorHirsch, Fred R
dc.contributor.authorVarella-Garcia, Marileila
dc.contributor.authorBunn, Paul A
dc.contributor.authorFranklin, Wilbur A
dc.contributor.authorDziadziuszko, Rafal
dc.contributor.authorThatcher, Nick
dc.contributor.authorChang, Alex
dc.contributor.authorParikh, Purvish
dc.contributor.authorPereira, José Rodrigues
dc.contributor.authorCiuleanu, Tudor
dc.contributor.authorVon Pawel, J
dc.contributor.authorWatkins, Claire
dc.contributor.authorFlannery, Angela
dc.contributor.authorEllison, Gillian
dc.contributor.authorDonald, Emma
dc.contributor.authorKnight, Lucy
dc.contributor.authorParums, Dinah V
dc.contributor.authorBotwood, Nicholas
dc.contributor.authorHolloway, Brian
dc.date.accessioned2009-07-06T15:23:52Z
dc.date.available2009-07-06T15:23:52Z
dc.date.issued2006-11-01
dc.identifier.citationMolecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer. 2006, 24 (31):5034-42 J. Clin. Oncol.en
dc.identifier.issn1527-7755
dc.identifier.pmid17075123
dc.identifier.doi10.1200/JCO.2006.06.3958
dc.identifier.urihttp://hdl.handle.net/10541/72621
dc.description.abstractPURPOSE: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. METHODS: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). RESULTS: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. CONCLUSION: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.
dc.language.isoenen
dc.subjectLung Canceren
dc.subjectTumour Markersen
dc.subject.meshAdult
dc.subject.meshAged
dc.subject.meshAntineoplastic Agents
dc.subject.meshCarcinoma, Non-Small-Cell Lung
dc.subject.meshFemale
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshHumans
dc.subject.meshImmunohistochemistry
dc.subject.meshIn Situ Hybridization, Fluorescence
dc.subject.meshLung Neoplasms
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshMutation
dc.subject.meshPhosphorylation
dc.subject.meshPredictive Value of Tests
dc.subject.meshProto-Oncogene Proteins
dc.subject.meshProto-Oncogene Proteins B-raf
dc.subject.meshProto-Oncogene Proteins c-akt
dc.subject.meshQuinazolines
dc.subject.meshReceptor, Epidermal Growth Factor
dc.subject.meshSurvival Analysis
dc.subject.meshTreatment Outcome
dc.subject.meshTumor Markers, Biological
dc.subject.meshras Proteins
dc.titleMolecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.en
dc.typeArticleen
dc.contributor.departmentUniversity of Colorado Cancer Center, PO Box 6511, Mail Stop 8111, Aurora, CO 80045, USA. Fred.Hirsch@UCHSC.eduen
dc.identifier.journalJournal of Clinical Oncologyen
html.description.abstractPURPOSE: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. METHODS: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). RESULTS: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. CONCLUSION: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.


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