Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials

Daphne W. Bell, Thomas J. Lynch, Sara M. Haserlat, Patricia L. Harris, Ross A. Okimoto, Brian W. Brannigan, Dennis C. Sgroi, Beth Muir, Markus J. Riemenschneider, Renee Bailey Iacona, Annetta D. Krebs, David H. Johnson, Giuseppe Giaccone, Roy S. Herbst, Christian Manegold, Masahiro Fukuoka, Mark G. Kris, José Baselga, Judith S. Ochs, Daniel A. Haber

Research output: Contribution to journalArticle

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Abstract

Purpose: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. Patients and Methods: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. Results: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFf? genotype. Conclusion: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

Original languageEnglish (US)
Pages (from-to)8081-8092
Number of pages12
JournalJournal of Clinical Oncology
Volume23
Issue number31
DOIs
StatePublished - 2005

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erbB-1 Genes
Gene Amplification
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Mutation
Neoplasms
Drug Therapy
Survival
gefitinib
Lung Neoplasms
Histology
Adenocarcinoma
Smoking
History
Genotype
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer : Molecular analysis of the IDEAL/INTACT gefitinib trials. / Bell, Daphne W.; Lynch, Thomas J.; Haserlat, Sara M.; Harris, Patricia L.; Okimoto, Ross A.; Brannigan, Brian W.; Sgroi, Dennis C.; Muir, Beth; Riemenschneider, Markus J.; Iacona, Renee Bailey; Krebs, Annetta D.; Johnson, David H.; Giaccone, Giuseppe; Herbst, Roy S.; Manegold, Christian; Fukuoka, Masahiro; Kris, Mark G.; Baselga, José; Ochs, Judith S.; Haber, Daniel A.

In: Journal of Clinical Oncology, Vol. 23, No. 31, 2005, p. 8081-8092.

Research output: Contribution to journalArticle

Bell, DW, Lynch, TJ, Haserlat, SM, Harris, PL, Okimoto, RA, Brannigan, BW, Sgroi, DC, Muir, B, Riemenschneider, MJ, Iacona, RB, Krebs, AD, Johnson, DH, Giaccone, G, Herbst, RS, Manegold, C, Fukuoka, M, Kris, MG, Baselga, J, Ochs, JS & Haber, DA 2005, 'Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials', Journal of Clinical Oncology, vol. 23, no. 31, pp. 8081-8092. https://doi.org/10.1200/JCO.2005.02.7078
Bell, Daphne W. ; Lynch, Thomas J. ; Haserlat, Sara M. ; Harris, Patricia L. ; Okimoto, Ross A. ; Brannigan, Brian W. ; Sgroi, Dennis C. ; Muir, Beth ; Riemenschneider, Markus J. ; Iacona, Renee Bailey ; Krebs, Annetta D. ; Johnson, David H. ; Giaccone, Giuseppe ; Herbst, Roy S. ; Manegold, Christian ; Fukuoka, Masahiro ; Kris, Mark G. ; Baselga, José ; Ochs, Judith S. ; Haber, Daniel A. / Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer : Molecular analysis of the IDEAL/INTACT gefitinib trials. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 31. pp. 8081-8092.
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abstract = "Purpose: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. Patients and Methods: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. Results: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46{\%}) with an EGFR mutation, two of seven tumors (29{\%}) with amplification, and five of 56 tumors (9{\%}) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFf? genotype. Conclusion: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.",
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T1 - Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer

T2 - Molecular analysis of the IDEAL/INTACT gefitinib trials

AU - Bell, Daphne W.

AU - Lynch, Thomas J.

AU - Haserlat, Sara M.

AU - Harris, Patricia L.

AU - Okimoto, Ross A.

AU - Brannigan, Brian W.

AU - Sgroi, Dennis C.

AU - Muir, Beth

AU - Riemenschneider, Markus J.

AU - Iacona, Renee Bailey

AU - Krebs, Annetta D.

AU - Johnson, David H.

AU - Giaccone, Giuseppe

AU - Herbst, Roy S.

AU - Manegold, Christian

AU - Fukuoka, Masahiro

AU - Kris, Mark G.

AU - Baselga, José

AU - Ochs, Judith S.

AU - Haber, Daniel A.

PY - 2005

Y1 - 2005

N2 - Purpose: Most cases of non-small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib. Patients and Methods: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC. Results: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFf? genotype. Conclusion: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

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