Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A southwest oncology group study

Fred R. Hirsch, Marileila Varella-Garcia, Jason McCoy, Howard West, Ana Carolina Xavier, Paul Gumerlock, Paul A. Bunn, Wilbur A. Franklin, John Crowley, David R Gandara

Research output: Contribution to journalArticle

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Abstract

Purpose: Bronchioloalveolar carcinoma (BAC) and adenocarcinomas with BAC features seem to be increasing in incidence, particularly in younger, never-smoking women. Epidermal growth factor receptor (EGFR) inhibitors demonstrated response rates of 20% to 30% in patients with advanced BAC subtypes, but selection methods for patient therapy are not established. Patients and Methods: EGFR and HER2 gene copy numbers were assessed by fluorescence in situ hybridization (FISH) in 81 patients treated with gefitinib 500 mg/d (Southwest Oncology Group protocol S0126) and were correlated to treatment outcome. Tumors were classified into two main strata: FISH-positive (high polysomy/gene amplification) and FISH-negative (disomy/low polysomy). Results: In 81 patients, the median survival time for EGFR/FISH-negative patients was 8 months and not yet reached for FISH-positive patients (but approaching 18 months; hazard ratio [HR] = 2.02; P = .042). Median progression-free survival time for EGFR/FISH-positive patients was 9 months versus 4 months for the FISH-negative patients (HR = 1.67; P = .072). In multivariate analysis, EGFR copy number by FISH remained a significant predictive factor for survival after accounting for smoking status, sex, histology, and performance status. Fifty-five patients were evaluated for response using Response Evaluation Criteria in Solid Tumors Group, and 12 of 19 EGFR/FISH-positive patients (63%) demonstrated disease control versus 14 (39%) of 36 patients in the FISH-negative group (P = .087). No association was found between HER2 gene copy number and response (n = 39 patients) or survival (n = 56 patients; P > .10). Conclusion: Increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced BAC, suggesting FISH methodology can be used to assess survival potential in patients treated with EGFR tyrosine kinase inhibitors.

Original languageEnglish (US)
Pages (from-to)6838-6845
Number of pages8
JournalJournal of Clinical Oncology
Volume23
Issue number28
DOIs
StatePublished - 2005

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Bronchiolo-Alveolar Adenocarcinoma
erbB-1 Genes
Gene Dosage
Fluorescence In Situ Hybridization
Epidermal Growth Factor Receptor
Survival
erbB-2 Genes
gefitinib
Smoking
Gene Amplification

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes : A southwest oncology group study. / Hirsch, Fred R.; Varella-Garcia, Marileila; McCoy, Jason; West, Howard; Xavier, Ana Carolina; Gumerlock, Paul; Bunn, Paul A.; Franklin, Wilbur A.; Crowley, John; Gandara, David R.

In: Journal of Clinical Oncology, Vol. 23, No. 28, 2005, p. 6838-6845.

Research output: Contribution to journalArticle

Hirsch, Fred R. ; Varella-Garcia, Marileila ; McCoy, Jason ; West, Howard ; Xavier, Ana Carolina ; Gumerlock, Paul ; Bunn, Paul A. ; Franklin, Wilbur A. ; Crowley, John ; Gandara, David R. / Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes : A southwest oncology group study. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 28. pp. 6838-6845.
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abstract = "Purpose: Bronchioloalveolar carcinoma (BAC) and adenocarcinomas with BAC features seem to be increasing in incidence, particularly in younger, never-smoking women. Epidermal growth factor receptor (EGFR) inhibitors demonstrated response rates of 20{\%} to 30{\%} in patients with advanced BAC subtypes, but selection methods for patient therapy are not established. Patients and Methods: EGFR and HER2 gene copy numbers were assessed by fluorescence in situ hybridization (FISH) in 81 patients treated with gefitinib 500 mg/d (Southwest Oncology Group protocol S0126) and were correlated to treatment outcome. Tumors were classified into two main strata: FISH-positive (high polysomy/gene amplification) and FISH-negative (disomy/low polysomy). Results: In 81 patients, the median survival time for EGFR/FISH-negative patients was 8 months and not yet reached for FISH-positive patients (but approaching 18 months; hazard ratio [HR] = 2.02; P = .042). Median progression-free survival time for EGFR/FISH-positive patients was 9 months versus 4 months for the FISH-negative patients (HR = 1.67; P = .072). In multivariate analysis, EGFR copy number by FISH remained a significant predictive factor for survival after accounting for smoking status, sex, histology, and performance status. Fifty-five patients were evaluated for response using Response Evaluation Criteria in Solid Tumors Group, and 12 of 19 EGFR/FISH-positive patients (63{\%}) demonstrated disease control versus 14 (39{\%}) of 36 patients in the FISH-negative group (P = .087). No association was found between HER2 gene copy number and response (n = 39 patients) or survival (n = 56 patients; P > .10). Conclusion: Increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced BAC, suggesting FISH methodology can be used to assess survival potential in patients treated with EGFR tyrosine kinase inhibitors.",
author = "Hirsch, {Fred R.} and Marileila Varella-Garcia and Jason McCoy and Howard West and Xavier, {Ana Carolina} and Paul Gumerlock and Bunn, {Paul A.} and Franklin, {Wilbur A.} and John Crowley and Gandara, {David R}",
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T1 - Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes

T2 - A southwest oncology group study

AU - Hirsch, Fred R.

AU - Varella-Garcia, Marileila

AU - McCoy, Jason

AU - West, Howard

AU - Xavier, Ana Carolina

AU - Gumerlock, Paul

AU - Bunn, Paul A.

AU - Franklin, Wilbur A.

AU - Crowley, John

AU - Gandara, David R

PY - 2005

Y1 - 2005

N2 - Purpose: Bronchioloalveolar carcinoma (BAC) and adenocarcinomas with BAC features seem to be increasing in incidence, particularly in younger, never-smoking women. Epidermal growth factor receptor (EGFR) inhibitors demonstrated response rates of 20% to 30% in patients with advanced BAC subtypes, but selection methods for patient therapy are not established. Patients and Methods: EGFR and HER2 gene copy numbers were assessed by fluorescence in situ hybridization (FISH) in 81 patients treated with gefitinib 500 mg/d (Southwest Oncology Group protocol S0126) and were correlated to treatment outcome. Tumors were classified into two main strata: FISH-positive (high polysomy/gene amplification) and FISH-negative (disomy/low polysomy). Results: In 81 patients, the median survival time for EGFR/FISH-negative patients was 8 months and not yet reached for FISH-positive patients (but approaching 18 months; hazard ratio [HR] = 2.02; P = .042). Median progression-free survival time for EGFR/FISH-positive patients was 9 months versus 4 months for the FISH-negative patients (HR = 1.67; P = .072). In multivariate analysis, EGFR copy number by FISH remained a significant predictive factor for survival after accounting for smoking status, sex, histology, and performance status. Fifty-five patients were evaluated for response using Response Evaluation Criteria in Solid Tumors Group, and 12 of 19 EGFR/FISH-positive patients (63%) demonstrated disease control versus 14 (39%) of 36 patients in the FISH-negative group (P = .087). No association was found between HER2 gene copy number and response (n = 39 patients) or survival (n = 56 patients; P > .10). Conclusion: Increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced BAC, suggesting FISH methodology can be used to assess survival potential in patients treated with EGFR tyrosine kinase inhibitors.

AB - Purpose: Bronchioloalveolar carcinoma (BAC) and adenocarcinomas with BAC features seem to be increasing in incidence, particularly in younger, never-smoking women. Epidermal growth factor receptor (EGFR) inhibitors demonstrated response rates of 20% to 30% in patients with advanced BAC subtypes, but selection methods for patient therapy are not established. Patients and Methods: EGFR and HER2 gene copy numbers were assessed by fluorescence in situ hybridization (FISH) in 81 patients treated with gefitinib 500 mg/d (Southwest Oncology Group protocol S0126) and were correlated to treatment outcome. Tumors were classified into two main strata: FISH-positive (high polysomy/gene amplification) and FISH-negative (disomy/low polysomy). Results: In 81 patients, the median survival time for EGFR/FISH-negative patients was 8 months and not yet reached for FISH-positive patients (but approaching 18 months; hazard ratio [HR] = 2.02; P = .042). Median progression-free survival time for EGFR/FISH-positive patients was 9 months versus 4 months for the FISH-negative patients (HR = 1.67; P = .072). In multivariate analysis, EGFR copy number by FISH remained a significant predictive factor for survival after accounting for smoking status, sex, histology, and performance status. Fifty-five patients were evaluated for response using Response Evaluation Criteria in Solid Tumors Group, and 12 of 19 EGFR/FISH-positive patients (63%) demonstrated disease control versus 14 (39%) of 36 patients in the FISH-negative group (P = .087). No association was found between HER2 gene copy number and response (n = 39 patients) or survival (n = 56 patients; P > .10). Conclusion: Increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced BAC, suggesting FISH methodology can be used to assess survival potential in patients treated with EGFR tyrosine kinase inhibitors.

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