Correlations of <it>EGFR </it>mutations and increases in <it>EGFR </it>and <it>HER2 </it>copy number to gefitinib response in a retrospective analysis of lung cancer patients
<p>Abstract</p> <p>Background</p> <p>Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (<it>EGFR</it>), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2007-07-01
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| Series: | BMC Cancer |
| Online Access: | http://www.biomedcentral.com/1471-2407/7/128 |
| _version_ | 1811293978368147456 |
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| author | English John Melosky Barbara Murray Nevin Ho Cheryl O'Connor Robert Salski Chris Fee John Sutcliffe Margaret Barclay Lorena Bebb Gwyn Pugh Trevor J Vielkind Jeurgen Horsman Doug Laskin Janessa J Marra Marco A |
| author_facet | English John Melosky Barbara Murray Nevin Ho Cheryl O'Connor Robert Salski Chris Fee John Sutcliffe Margaret Barclay Lorena Bebb Gwyn Pugh Trevor J Vielkind Jeurgen Horsman Doug Laskin Janessa J Marra Marco A |
| author_sort | English John |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (<it>EGFR</it>), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, <it>EGFR </it>and <it>HER2</it>, in 39 patients treated with gefitinib at the BC Cancer Agency.</p> <p>Methods</p> <p>Archival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18–24, coding for the tyrosine kinase domain of <it>EGFR</it>, were amplified by PCR and sequenced. <it>EGFR </it>and <it>HER2 </it>copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fisher's exact test.</p> <p>Results</p> <p>Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with <it>EGFR </it>amplification, three with <it>HER2 </it>amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and <it>EGFR </it>mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in <it>EGFR </it>or <it>HER2 </it>copy number (p = 0.552 and 0.437, respectively).</p> <p>Conclusion</p> <p>Neither mutation of <it>EGFR </it>nor increased copy number of <it>EGFR </it>or <it>HER2 </it>was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond <it>EGFR </it>status may be necessary to accurately predict treatment outcome.</p> |
| first_indexed | 2024-04-13T05:09:39Z |
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| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-13T05:09:39Z |
| publishDate | 2007-07-01 |
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| series | BMC Cancer |
| spelling | doaj.art-f603aa2f882142ae868167f8969568352022-12-22T03:01:04ZengBMCBMC Cancer1471-24072007-07-017112810.1186/1471-2407-7-128Correlations of <it>EGFR </it>mutations and increases in <it>EGFR </it>and <it>HER2 </it>copy number to gefitinib response in a retrospective analysis of lung cancer patientsEnglish JohnMelosky BarbaraMurray NevinHo CherylO'Connor RobertSalski ChrisFee JohnSutcliffe MargaretBarclay LorenaBebb GwynPugh Trevor JVielkind JeurgenHorsman DougLaskin Janessa JMarra Marco A<p>Abstract</p> <p>Background</p> <p>Gefitinib, a small molecule tyrosine kinase inhibitor of the Epidermal Growth Factor Receptor (<it>EGFR</it>), has shown limited efficacy in the treatment of lung cancer. Recognized clinical predictors of response to this drug, specifically female, non-smoker, Asian descent, and adenocarcinoma, together suggest a genetic basis for drug response. Recent studies have addressed the relationship between response and either sequence mutations or increased copy number of specific receptor tyrosine kinases. We set out to examine the relationship between response and the molecular status of two such kinases, <it>EGFR </it>and <it>HER2</it>, in 39 patients treated with gefitinib at the BC Cancer Agency.</p> <p>Methods</p> <p>Archival patient material was reviewed by a pathologist and malignant cells were selectively isolated by laser microdissection or manual recovery of cells from microscope slides. Genomic DNA was extracted from 37 such patient samples and exons 18–24, coding for the tyrosine kinase domain of <it>EGFR</it>, were amplified by PCR and sequenced. <it>EGFR </it>and <it>HER2 </it>copy number status were also assessed using FISH in 26 samples. Correlations between molecular features and drug response were assessed using the two-sided Fisher's exact test.</p> <p>Results</p> <p>Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours, seven with <it>EGFR </it>amplification, three with <it>HER2 </it>amplification, and three with amplification of both genes. In our study cohort, a correlation was not observed between response and <it>EGFR </it>mutations (exon 19 deletion p = 0.0889, we observed a single exon 21 mutation in a non-responder) or increases in <it>EGFR </it>or <it>HER2 </it>copy number (p = 0.552 and 0.437, respectively).</p> <p>Conclusion</p> <p>Neither mutation of <it>EGFR </it>nor increased copy number of <it>EGFR </it>or <it>HER2 </it>was diagnostic of response to gefitinib in this cohort. However, validation of these features in a larger sample set is appropriate. Identification of additional predictive biomarkers beyond <it>EGFR </it>status may be necessary to accurately predict treatment outcome.</p>http://www.biomedcentral.com/1471-2407/7/128 |
| spellingShingle | English John Melosky Barbara Murray Nevin Ho Cheryl O'Connor Robert Salski Chris Fee John Sutcliffe Margaret Barclay Lorena Bebb Gwyn Pugh Trevor J Vielkind Jeurgen Horsman Doug Laskin Janessa J Marra Marco A Correlations of <it>EGFR </it>mutations and increases in <it>EGFR </it>and <it>HER2 </it>copy number to gefitinib response in a retrospective analysis of lung cancer patients BMC Cancer |
| title | Correlations of <it>EGFR </it>mutations and increases in <it>EGFR </it>and <it>HER2 </it>copy number to gefitinib response in a retrospective analysis of lung cancer patients |
| title_full | Correlations of <it>EGFR </it>mutations and increases in <it>EGFR </it>and <it>HER2 </it>copy number to gefitinib response in a retrospective analysis of lung cancer patients |
| title_fullStr | Correlations of <it>EGFR </it>mutations and increases in <it>EGFR </it>and <it>HER2 </it>copy number to gefitinib response in a retrospective analysis of lung cancer patients |
| title_full_unstemmed | Correlations of <it>EGFR </it>mutations and increases in <it>EGFR </it>and <it>HER2 </it>copy number to gefitinib response in a retrospective analysis of lung cancer patients |
| title_short | Correlations of <it>EGFR </it>mutations and increases in <it>EGFR </it>and <it>HER2 </it>copy number to gefitinib response in a retrospective analysis of lung cancer patients |
| title_sort | correlations of it egfr it mutations and increases in it egfr it and it her2 it copy number to gefitinib response in a retrospective analysis of lung cancer patients |
| url | http://www.biomedcentral.com/1471-2407/7/128 |
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