Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.

2.50
Hdl Handle:
http://hdl.handle.net/10541/72621
Title:
Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.
Authors:
Hirsch, Fred R; Varella-Garcia, Marileila; Bunn, Paul A; Franklin, Wilbur A; Dziadziuszko, Rafal; Thatcher, Nick; Chang, Alex; Parikh, Purvish; Pereira, José Rodrigues; Ciuleanu, Tudor; Von Pawel, J; Watkins, Claire; Flannery, Angela; Ellison, Gillian; Donald, Emma; Knight, Lucy; Parums, Dinah V; Botwood, Nicholas; Holloway, Brian
Abstract:
PURPOSE: 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.
Affiliation:
University of Colorado Cancer Center, PO Box 6511, Mail Stop 8111, Aurora, CO 80045, USA. Fred.Hirsch@UCHSC.edu
Citation:
Molecular 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.
Journal:
Journal of Clinical Oncology
Issue Date:
1-Nov-2006
URI:
http://hdl.handle.net/10541/72621
DOI:
10.1200/JCO.2006.06.3958
PubMed ID:
17075123
Type:
Article
Language:
en
ISSN:
1527-7755
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
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.en
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

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