The usefulness of mutation-specific antibodies in detecting epidermal growth factor receptor mutations and in predicting response to tyrosine kinase inhibitor therapy in lung adenocarcinoma

Yoshiki Kozu, Koji Tsuta, Takashi Kohno, Ikuo Sekine, Akihiko Yoshida, Shunichi Watanabe, Tomohide Tamura, Jun Yokota, Kenji Suzuki, Hisao Asamura, Koh Furuta, Hitoshi Tsuda

Research output: Contribution to journalArticle

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Abstract

Introduction: Among the mutations of epidermal growth factor receptor (EGFR), deletions in exon 19 (DEL), and point mutations in exon 21 (L858R) predict the response to EGFR-tyrosine kinase inhibitors (TKIs) in primary lung adenocarcinoma. The ability to detecting such mutations using immunohistochemistry (IHC) would be advantageous. Methods: The molecular-based and IHC-based EGFR mutations were analyzed in 577 lung adenocarcinomas using high resolution melting analysis (HRMA) and 2 mutation-specific antibodies, respectively. Results: In the molecular-based analyses, DEL was detected in 135 cases (23%), and L858R was detected in 172 cases (30%). In the IHC-based analyses, a positive reaction was detected in 59 cases (10%) for the DEL-specific antibody, and in 139 cases (24%) for the L858R-specific antibody. With the molecular-based results set as the gold standard, the sensitivity and specificity of the DEL-specific antibody were 42.2% and 99.5%, respectively, while the sensitivity and specificity of the L858R-specific antibody were 75.6% and 97.8%, respectively. The antibody specificities improved when the threshold for the mutation-positive reactions was set as >50% of immunopositive tumor cells. The significant predictors of the clinical response to EGFR-TKI were molecular-based EGFR mutations (p< 0.001) and IHC-based EGFR mutations (p = 0.001). However, a multivariate analysis revealed that only molecular-based EGFR mutations were significantly correlated with the clinical response (p< 0.001). Conclusions: Mutation-specific antibodies demonstrated extremely high specificities, but their sensitivities were not higher than those of molecular-based analyses. However, IHC should be performed before a molecular-based analysis, because it is more cost-effective and can effectively select candidates for EGFR-TKI therapy.

Original languageEnglish
Pages (from-to)45-50
Number of pages6
JournalLung Cancer
Volume73
Issue number1
DOIs
Publication statusPublished - 2011 Jul
Externally publishedYes

Fingerprint

Epidermal Growth Factor Receptor
Protein-Tyrosine Kinases
Mutation
Antibodies
Immunohistochemistry
Therapeutics
Sensitivity and Specificity
Exons
Adenocarcinoma of lung
Antibody Specificity
Point Mutation
Freezing
Multivariate Analysis
Costs and Cost Analysis

Keywords

  • Epidermal growth factor receptor
  • High specificity
  • Immunohistochemistry
  • Lung adenocarcinoma
  • Mutation
  • Mutation-specific antibody
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

The usefulness of mutation-specific antibodies in detecting epidermal growth factor receptor mutations and in predicting response to tyrosine kinase inhibitor therapy in lung adenocarcinoma. / Kozu, Yoshiki; Tsuta, Koji; Kohno, Takashi; Sekine, Ikuo; Yoshida, Akihiko; Watanabe, Shunichi; Tamura, Tomohide; Yokota, Jun; Suzuki, Kenji; Asamura, Hisao; Furuta, Koh; Tsuda, Hitoshi.

In: Lung Cancer, Vol. 73, No. 1, 07.2011, p. 45-50.

Research output: Contribution to journalArticle

Kozu, Yoshiki ; Tsuta, Koji ; Kohno, Takashi ; Sekine, Ikuo ; Yoshida, Akihiko ; Watanabe, Shunichi ; Tamura, Tomohide ; Yokota, Jun ; Suzuki, Kenji ; Asamura, Hisao ; Furuta, Koh ; Tsuda, Hitoshi. / The usefulness of mutation-specific antibodies in detecting epidermal growth factor receptor mutations and in predicting response to tyrosine kinase inhibitor therapy in lung adenocarcinoma. In: Lung Cancer. 2011 ; Vol. 73, No. 1. pp. 45-50.
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T1 - The usefulness of mutation-specific antibodies in detecting epidermal growth factor receptor mutations and in predicting response to tyrosine kinase inhibitor therapy in lung adenocarcinoma

AU - Kozu, Yoshiki

AU - Tsuta, Koji

AU - Kohno, Takashi

AU - Sekine, Ikuo

AU - Yoshida, Akihiko

AU - Watanabe, Shunichi

AU - Tamura, Tomohide

AU - Yokota, Jun

AU - Suzuki, Kenji

AU - Asamura, Hisao

AU - Furuta, Koh

AU - Tsuda, Hitoshi

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N2 - Introduction: Among the mutations of epidermal growth factor receptor (EGFR), deletions in exon 19 (DEL), and point mutations in exon 21 (L858R) predict the response to EGFR-tyrosine kinase inhibitors (TKIs) in primary lung adenocarcinoma. The ability to detecting such mutations using immunohistochemistry (IHC) would be advantageous. Methods: The molecular-based and IHC-based EGFR mutations were analyzed in 577 lung adenocarcinomas using high resolution melting analysis (HRMA) and 2 mutation-specific antibodies, respectively. Results: In the molecular-based analyses, DEL was detected in 135 cases (23%), and L858R was detected in 172 cases (30%). In the IHC-based analyses, a positive reaction was detected in 59 cases (10%) for the DEL-specific antibody, and in 139 cases (24%) for the L858R-specific antibody. With the molecular-based results set as the gold standard, the sensitivity and specificity of the DEL-specific antibody were 42.2% and 99.5%, respectively, while the sensitivity and specificity of the L858R-specific antibody were 75.6% and 97.8%, respectively. The antibody specificities improved when the threshold for the mutation-positive reactions was set as >50% of immunopositive tumor cells. The significant predictors of the clinical response to EGFR-TKI were molecular-based EGFR mutations (p< 0.001) and IHC-based EGFR mutations (p = 0.001). However, a multivariate analysis revealed that only molecular-based EGFR mutations were significantly correlated with the clinical response (p< 0.001). Conclusions: Mutation-specific antibodies demonstrated extremely high specificities, but their sensitivities were not higher than those of molecular-based analyses. However, IHC should be performed before a molecular-based analysis, because it is more cost-effective and can effectively select candidates for EGFR-TKI therapy.

AB - Introduction: Among the mutations of epidermal growth factor receptor (EGFR), deletions in exon 19 (DEL), and point mutations in exon 21 (L858R) predict the response to EGFR-tyrosine kinase inhibitors (TKIs) in primary lung adenocarcinoma. The ability to detecting such mutations using immunohistochemistry (IHC) would be advantageous. Methods: The molecular-based and IHC-based EGFR mutations were analyzed in 577 lung adenocarcinomas using high resolution melting analysis (HRMA) and 2 mutation-specific antibodies, respectively. Results: In the molecular-based analyses, DEL was detected in 135 cases (23%), and L858R was detected in 172 cases (30%). In the IHC-based analyses, a positive reaction was detected in 59 cases (10%) for the DEL-specific antibody, and in 139 cases (24%) for the L858R-specific antibody. With the molecular-based results set as the gold standard, the sensitivity and specificity of the DEL-specific antibody were 42.2% and 99.5%, respectively, while the sensitivity and specificity of the L858R-specific antibody were 75.6% and 97.8%, respectively. The antibody specificities improved when the threshold for the mutation-positive reactions was set as >50% of immunopositive tumor cells. The significant predictors of the clinical response to EGFR-TKI were molecular-based EGFR mutations (p< 0.001) and IHC-based EGFR mutations (p = 0.001). However, a multivariate analysis revealed that only molecular-based EGFR mutations were significantly correlated with the clinical response (p< 0.001). Conclusions: Mutation-specific antibodies demonstrated extremely high specificities, but their sensitivities were not higher than those of molecular-based analyses. However, IHC should be performed before a molecular-based analysis, because it is more cost-effective and can effectively select candidates for EGFR-TKI therapy.

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KW - High specificity

KW - Immunohistochemistry

KW - Lung adenocarcinoma

KW - Mutation

KW - Mutation-specific antibody

KW - Tyrosine kinase inhibitor

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