Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in Non–Small-Cell Lung Cancer
Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non–small-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expressi...
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| creator | Cappuzzo, Federico Hirsch, Fred R. Rossi, Elisa Bartolini, Stefania Ceresoli, Giovanni L. Bemis, Lynne Haney, Jerry Witta, Samir Danenberg, Kathleen Domenichini, Irene Ludovini, Vienna Magrini, Elisabetta Gregorc, Vanesa Doglioni, Claudio Sidoni, Angelo Tonato, Maurizio Franklin, Wilbur A. Crino, Lucio Bunn, Paul A. Varella-Garcia, Marileila |
| description | Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non–small-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt [P-Akt]) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the Kaplan–Meier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P |
| doi_str_mv | 10.1093/jnci/dji112 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_67793480</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>67793480</sourcerecordid><originalsourceid>FETCH-LOGICAL-c516t-df2b2904642129ca7615bf8d3876bf695ee25eaf8bdd9a5aade1e36e2b24fe773</originalsourceid><addsrcrecordid>eNqFkc1uEzEUhS0EomlhxR5ZSHSDhvrfM8s2alKkUBAFqWJjeWauwenEE-yZlu76Dn1DngSHRFRigzc-0v18r889CL2g5C0lFT9ahsYftUtPKXuEJlQoUjBK5GM0IYTpoiy12EP7KS1JPhUTT9EelaUmgssJujpd-xbiynZ4Hvub4Tue2WboI_4EDaw3Yg4BsA0t_hj7AXz4o-fg_OCDr_EFhJTltR9ucS6e9-HX3f1F7tcVU-g6vBjDNzy1oYH4DD1xtkvwfHcfoC-z08_Ts2LxYf5uerwoGknVULSO1awiQglGWdVYraisXdnyUqvaqUoCMAnWlXXbVlZa2wIFriC_Eg605gfocNt3HfsfI6TBrHxq8mdsgH5MRmldcVGS_4JUc66qkmXw1T_gsh9jyCYMy7tmktDN2DdbqIl9ShGcWUe_svHWUGI2SZlNUmabVKZf7lqO9QraB3YXTQZe7wCbGtu5mHfo0wOnymxB8cwVW86nAX7-rdt4lY1yLc3Z5Vcj1PuTSzE7Nyf8N29zrLU</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>221025017</pqid></control><display><type>article</type><title>Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in Non–Small-Cell Lung Cancer</title><source>Oxford University Press Journals All Titles (1996-Current)</source><source>MEDLINE</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Cappuzzo, Federico ; Hirsch, Fred R. ; Rossi, Elisa ; Bartolini, Stefania ; Ceresoli, Giovanni L. ; Bemis, Lynne ; Haney, Jerry ; Witta, Samir ; Danenberg, Kathleen ; Domenichini, Irene ; Ludovini, Vienna ; Magrini, Elisabetta ; Gregorc, Vanesa ; Doglioni, Claudio ; Sidoni, Angelo ; Tonato, Maurizio ; Franklin, Wilbur A. ; Crino, Lucio ; Bunn, Paul A. ; Varella-Garcia, Marileila</creator><creatorcontrib>Cappuzzo, Federico ; Hirsch, Fred R. ; Rossi, Elisa ; Bartolini, Stefania ; Ceresoli, Giovanni L. ; Bemis, Lynne ; Haney, Jerry ; Witta, Samir ; Danenberg, Kathleen ; Domenichini, Irene ; Ludovini, Vienna ; Magrini, Elisabetta ; Gregorc, Vanesa ; Doglioni, Claudio ; Sidoni, Angelo ; Tonato, Maurizio ; Franklin, Wilbur A. ; Crino, Lucio ; Bunn, Paul A. ; Varella-Garcia, Marileila</creatorcontrib><description>Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non–small-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt [P-Akt]) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the Kaplan–Meier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P<.001), disease control rate (67% versus 26%, mean difference = 40.6%, 95% CI = 21.5 to 59.7; P<.001), time to progression (9.0 versus 2.5 months, mean difference = 6.5 months, 95% CI = 2.8 to 10.3; P<.001), and survival (18.7 versus 7.0 months, mean difference = 11.7 months, 95% CI = 2.1 to 21.4; P = .03). EGFR mutations (seen in 15 of 89 patients) were also statistically significantly related to response and time to progression, but the association with survival was not statistically significant, and 40% of the patients with mutation had progressive disease. In multivariable analysis, only high EGFR gene copy number remained statistically significantly associated with better survival (hazard ratio = 0.44, 95% CI = 0.23 to 0.82). Independent of EGFR assessment method, EGFR+/P-Akt+ patients had a statistically significantly better outcome than EGFR−, P-Akt−, or EGFR+/P-Akt− patients. Conclusions: High EGFR gene copy number identified by FISH may be an effective molecular predictor for gefitinib efficacy in advanced NSCLC.</description><identifier>ISSN: 0027-8874</identifier><identifier>EISSN: 1460-2105</identifier><identifier>DOI: 10.1093/jnci/dji112</identifier><identifier>PMID: 15870435</identifier><identifier>CODEN: JNCIEQ</identifier><language>eng</language><publisher>Cary, NC: Oxford University Press</publisher><subject>Adult ; Aged ; Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Biomarkers, Tumor - metabolism ; Carcinoma, Non-Small-Cell Lung - drug therapy ; Carcinoma, Non-Small-Cell Lung - metabolism ; Chemotherapy ; Clinical trials ; Disease-Free Survival ; Female ; Gene expression ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Inhibitor drugs ; Lung cancer ; Lung Neoplasms - drug therapy ; Lung Neoplasms - metabolism ; Male ; Medical sciences ; Middle Aged ; Multivariate Analysis ; Pharmacology. Drug treatments ; Predictive Value of Tests ; Proportional Hazards Models ; Protein Kinase Inhibitors - pharmacology ; Protein-Serine-Threonine Kinases - drug effects ; Protein-Serine-Threonine Kinases - metabolism ; Proteins ; Proto-Oncogene Proteins - drug effects ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt ; Quinazolines - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - genetics ; Research Design ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Analysis, DNA ; Survival Analysis ; Tumors</subject><ispartof>JNCI : Journal of the National Cancer Institute, 2005-05, Vol.97 (9), p.643-655</ispartof><rights>2005 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) May 4, 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c516t-df2b2904642129ca7615bf8d3876bf695ee25eaf8bdd9a5aade1e36e2b24fe773</citedby><cites>FETCH-LOGICAL-c516t-df2b2904642129ca7615bf8d3876bf695ee25eaf8bdd9a5aade1e36e2b24fe773</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16848063$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15870435$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cappuzzo, Federico</creatorcontrib><creatorcontrib>Hirsch, Fred R.</creatorcontrib><creatorcontrib>Rossi, Elisa</creatorcontrib><creatorcontrib>Bartolini, Stefania</creatorcontrib><creatorcontrib>Ceresoli, Giovanni L.</creatorcontrib><creatorcontrib>Bemis, Lynne</creatorcontrib><creatorcontrib>Haney, Jerry</creatorcontrib><creatorcontrib>Witta, Samir</creatorcontrib><creatorcontrib>Danenberg, Kathleen</creatorcontrib><creatorcontrib>Domenichini, Irene</creatorcontrib><creatorcontrib>Ludovini, Vienna</creatorcontrib><creatorcontrib>Magrini, Elisabetta</creatorcontrib><creatorcontrib>Gregorc, Vanesa</creatorcontrib><creatorcontrib>Doglioni, Claudio</creatorcontrib><creatorcontrib>Sidoni, Angelo</creatorcontrib><creatorcontrib>Tonato, Maurizio</creatorcontrib><creatorcontrib>Franklin, Wilbur A.</creatorcontrib><creatorcontrib>Crino, Lucio</creatorcontrib><creatorcontrib>Bunn, Paul A.</creatorcontrib><creatorcontrib>Varella-Garcia, Marileila</creatorcontrib><title>Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in Non–Small-Cell Lung Cancer</title><title>JNCI : Journal of the National Cancer Institute</title><addtitle>JNCI J Natl Cancer Inst</addtitle><description>Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non–small-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt [P-Akt]) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the Kaplan–Meier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P<.001), disease control rate (67% versus 26%, mean difference = 40.6%, 95% CI = 21.5 to 59.7; P<.001), time to progression (9.0 versus 2.5 months, mean difference = 6.5 months, 95% CI = 2.8 to 10.3; P<.001), and survival (18.7 versus 7.0 months, mean difference = 11.7 months, 95% CI = 2.1 to 21.4; P = .03). EGFR mutations (seen in 15 of 89 patients) were also statistically significantly related to response and time to progression, but the association with survival was not statistically significant, and 40% of the patients with mutation had progressive disease. In multivariable analysis, only high EGFR gene copy number remained statistically significantly associated with better survival (hazard ratio = 0.44, 95% CI = 0.23 to 0.82). Independent of EGFR assessment method, EGFR+/P-Akt+ patients had a statistically significantly better outcome than EGFR−, P-Akt−, or EGFR+/P-Akt− patients. Conclusions: High EGFR gene copy number identified by FISH may be an effective molecular predictor for gefitinib efficacy in advanced NSCLC.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - drug therapy</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Chemotherapy</subject><subject>Clinical trials</subject><subject>Disease-Free Survival</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Enzymologic</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>Inhibitor drugs</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - metabolism</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Multivariate Analysis</subject><subject>Pharmacology. Drug treatments</subject><subject>Predictive Value of Tests</subject><subject>Proportional Hazards Models</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein-Serine-Threonine Kinases - drug effects</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - drug effects</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Quinazolines - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Receptor, Epidermal Growth Factor - genetics</subject><subject>Research Design</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Sequence Analysis, DNA</subject><subject>Survival Analysis</subject><subject>Tumors</subject><issn>0027-8874</issn><issn>1460-2105</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1uEzEUhS0EomlhxR5ZSHSDhvrfM8s2alKkUBAFqWJjeWauwenEE-yZlu76Dn1DngSHRFRigzc-0v18r889CL2g5C0lFT9ahsYftUtPKXuEJlQoUjBK5GM0IYTpoiy12EP7KS1JPhUTT9EelaUmgssJujpd-xbiynZ4Hvub4Tue2WboI_4EDaw3Yg4BsA0t_hj7AXz4o-fg_OCDr_EFhJTltR9ucS6e9-HX3f1F7tcVU-g6vBjDNzy1oYH4DD1xtkvwfHcfoC-z08_Ts2LxYf5uerwoGknVULSO1awiQglGWdVYraisXdnyUqvaqUoCMAnWlXXbVlZa2wIFriC_Eg605gfocNt3HfsfI6TBrHxq8mdsgH5MRmldcVGS_4JUc66qkmXw1T_gsh9jyCYMy7tmktDN2DdbqIl9ShGcWUe_svHWUGI2SZlNUmabVKZf7lqO9QraB3YXTQZe7wCbGtu5mHfo0wOnymxB8cwVW86nAX7-rdt4lY1yLc3Z5Vcj1PuTSzE7Nyf8N29zrLU</recordid><startdate>20050504</startdate><enddate>20050504</enddate><creator>Cappuzzo, Federico</creator><creator>Hirsch, Fred R.</creator><creator>Rossi, Elisa</creator><creator>Bartolini, Stefania</creator><creator>Ceresoli, Giovanni L.</creator><creator>Bemis, Lynne</creator><creator>Haney, Jerry</creator><creator>Witta, Samir</creator><creator>Danenberg, Kathleen</creator><creator>Domenichini, Irene</creator><creator>Ludovini, Vienna</creator><creator>Magrini, Elisabetta</creator><creator>Gregorc, Vanesa</creator><creator>Doglioni, Claudio</creator><creator>Sidoni, Angelo</creator><creator>Tonato, Maurizio</creator><creator>Franklin, Wilbur A.</creator><creator>Crino, Lucio</creator><creator>Bunn, Paul A.</creator><creator>Varella-Garcia, Marileila</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</scope><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>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>20050504</creationdate><title>Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in Non–Small-Cell Lung Cancer</title><author>Cappuzzo, Federico ; Hirsch, Fred R. ; Rossi, Elisa ; Bartolini, Stefania ; Ceresoli, Giovanni L. ; Bemis, Lynne ; Haney, Jerry ; Witta, Samir ; Danenberg, Kathleen ; Domenichini, Irene ; Ludovini, Vienna ; Magrini, Elisabetta ; Gregorc, Vanesa ; Doglioni, Claudio ; Sidoni, Angelo ; Tonato, Maurizio ; Franklin, Wilbur A. ; Crino, Lucio ; Bunn, Paul A. ; Varella-Garcia, Marileila</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c516t-df2b2904642129ca7615bf8d3876bf695ee25eaf8bdd9a5aade1e36e2b24fe773</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - drug therapy</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Chemotherapy</topic><topic>Clinical trials</topic><topic>Disease-Free Survival</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Enzymologic</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>In Situ Hybridization, Fluorescence</topic><topic>Inhibitor drugs</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - metabolism</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Multivariate Analysis</topic><topic>Pharmacology. Drug treatments</topic><topic>Predictive Value of Tests</topic><topic>Proportional Hazards Models</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein-Serine-Threonine Kinases - drug effects</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins - drug effects</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Quinazolines - pharmacology</topic><topic>Receptor, Epidermal Growth Factor - antagonists & inhibitors</topic><topic>Receptor, Epidermal Growth Factor - genetics</topic><topic>Research Design</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Sequence Analysis, DNA</topic><topic>Survival Analysis</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cappuzzo, Federico</creatorcontrib><creatorcontrib>Hirsch, Fred R.</creatorcontrib><creatorcontrib>Rossi, Elisa</creatorcontrib><creatorcontrib>Bartolini, Stefania</creatorcontrib><creatorcontrib>Ceresoli, Giovanni L.</creatorcontrib><creatorcontrib>Bemis, Lynne</creatorcontrib><creatorcontrib>Haney, Jerry</creatorcontrib><creatorcontrib>Witta, Samir</creatorcontrib><creatorcontrib>Danenberg, Kathleen</creatorcontrib><creatorcontrib>Domenichini, Irene</creatorcontrib><creatorcontrib>Ludovini, Vienna</creatorcontrib><creatorcontrib>Magrini, Elisabetta</creatorcontrib><creatorcontrib>Gregorc, Vanesa</creatorcontrib><creatorcontrib>Doglioni, Claudio</creatorcontrib><creatorcontrib>Sidoni, Angelo</creatorcontrib><creatorcontrib>Tonato, Maurizio</creatorcontrib><creatorcontrib>Franklin, Wilbur A.</creatorcontrib><creatorcontrib>Crino, Lucio</creatorcontrib><creatorcontrib>Bunn, Paul A.</creatorcontrib><creatorcontrib>Varella-Garcia, Marileila</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>JNCI : Journal of the National Cancer Institute</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cappuzzo, Federico</au><au>Hirsch, Fred R.</au><au>Rossi, Elisa</au><au>Bartolini, Stefania</au><au>Ceresoli, Giovanni L.</au><au>Bemis, Lynne</au><au>Haney, Jerry</au><au>Witta, Samir</au><au>Danenberg, Kathleen</au><au>Domenichini, Irene</au><au>Ludovini, Vienna</au><au>Magrini, Elisabetta</au><au>Gregorc, Vanesa</au><au>Doglioni, Claudio</au><au>Sidoni, Angelo</au><au>Tonato, Maurizio</au><au>Franklin, Wilbur A.</au><au>Crino, Lucio</au><au>Bunn, Paul A.</au><au>Varella-Garcia, Marileila</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in Non–Small-Cell Lung Cancer</atitle><jtitle>JNCI : Journal of the National Cancer Institute</jtitle><addtitle>JNCI J Natl Cancer Inst</addtitle><date>2005-05-04</date><risdate>2005</risdate><volume>97</volume><issue>9</issue><spage>643</spage><epage>655</epage><pages>643-655</pages><issn>0027-8874</issn><eissn>1460-2105</eissn><coden>JNCIEQ</coden><abstract>Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including non–small-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt [P-Akt]) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the Kaplan–Meier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P<.001), disease control rate (67% versus 26%, mean difference = 40.6%, 95% CI = 21.5 to 59.7; P<.001), time to progression (9.0 versus 2.5 months, mean difference = 6.5 months, 95% CI = 2.8 to 10.3; P<.001), and survival (18.7 versus 7.0 months, mean difference = 11.7 months, 95% CI = 2.1 to 21.4; P = .03). EGFR mutations (seen in 15 of 89 patients) were also statistically significantly related to response and time to progression, but the association with survival was not statistically significant, and 40% of the patients with mutation had progressive disease. In multivariable analysis, only high EGFR gene copy number remained statistically significantly associated with better survival (hazard ratio = 0.44, 95% CI = 0.23 to 0.82). Independent of EGFR assessment method, EGFR+/P-Akt+ patients had a statistically significantly better outcome than EGFR−, P-Akt−, or EGFR+/P-Akt− patients. Conclusions: High EGFR gene copy number identified by FISH may be an effective molecular predictor for gefitinib efficacy in advanced NSCLC.</abstract><cop>Cary, NC</cop><pub>Oxford University Press</pub><pmid>15870435</pmid><doi>10.1093/jnci/dji112</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | JNCI : Journal of the National Cancer Institute, 2005-05, Vol.97 (9), p.643-655 |
| issn | 0027-8874 1460-2105 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_67793480 |
| source | Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adult Aged Antineoplastic agents Antineoplastic Agents - pharmacology Biological and medical sciences Biomarkers, Tumor - metabolism Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - metabolism Chemotherapy Clinical trials Disease-Free Survival Female Gene expression Gene Expression Regulation, Enzymologic Gene Expression Regulation, Neoplastic Humans Immunohistochemistry In Situ Hybridization, Fluorescence Inhibitor drugs Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Male Medical sciences Middle Aged Multivariate Analysis Pharmacology. Drug treatments Predictive Value of Tests Proportional Hazards Models Protein Kinase Inhibitors - pharmacology Protein-Serine-Threonine Kinases - drug effects Protein-Serine-Threonine Kinases - metabolism Proteins Proto-Oncogene Proteins - drug effects Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Quinazolines - pharmacology Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - genetics Research Design Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis, DNA Survival Analysis Tumors |
| title | Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in Non–Small-Cell Lung Cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T03%3A18%3A08IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Epidermal%20Growth%20Factor%20Receptor%20Gene%20and%20Protein%20and%20Gefitinib%20Sensitivity%20in%20Non%E2%80%93Small-Cell%20Lung%20Cancer&rft.jtitle=JNCI%20:%20Journal%20of%20the%20National%20Cancer%20Institute&rft.au=Cappuzzo,%20Federico&rft.date=2005-05-04&rft.volume=97&rft.issue=9&rft.spage=643&rft.epage=655&rft.pages=643-655&rft.issn=0027-8874&rft.eissn=1460-2105&rft.coden=JNCIEQ&rft_id=info:doi/10.1093/jnci/dji112&rft_dat=%3Cproquest_cross%3E67793480%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=221025017&rft_id=info:pmid/15870435&rfr_iscdi=true |