HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma

Harry H Yoon, William R. Sukov, Qian D Shi, Christopher A. Sattler, Anne E. Wiktor, Robert B Diasio, Tsung Teh Wu, Robert Brian Jenkins, Frank A Sinicrope

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background Human epidermal growth factor receptor 2 (HER2) is a therapeutic target in patients with esophageal adenocarcinoma (EAC), with gene amplification used as a selection criterion for treatment, although to the authors' knowledge the concordance between amplification and HER2 protein expression remains undefined in EAC. Furthermore, the association between HER2 and its interacting partner, human epidermal growth factor receptor 3 (HER3), is unknown yet appears to be of potential therapeutic relevance. Methods Patients with untreated EACs (N = 673) were analyzed for HER2 amplification and polysomy 17 by fluorescence in situ hybridization in parallel with immunohistochemistry (IHC) (IHC scores of 0-1+, 2+, and 3+). Amplification was defined as HER2/CEP17 ≥ 2. HER3 expression by IHC was analyzed in randomly selected cases (n = 224). IHC and fluorescence in situ hybridization results were compared using least squares linear regression. Results Overall, 17% of the EACs (116 of 673 EACs) were HER2-amplified with an amplification frequency that was highest among IHC3+ cases (89%) and declined among IHC2+ cases (13%) and IHC0 to IHC1+ cases (4%). Among HER2-amplified cases, the level of amplification increased linearly with HER2 membranous expression (HER2/CEP17 ratio: 7.9 in IHC3+ and 5.5 in IHC2+ vs 2.8 in IHC0 to IHC1+ [P <.0001]), with 14% of amplified tumors demonstrating absent/faint expression (IHC0 to IHC1+). Polysomy 17 was not found to be associated with HER2 expression. Cytoplasmic HER3 expression was detected in 87% of tumors (195 of 224 tumors) and was found to be significantly associated with better differentiation (P <.0001). Stepwise increases in HER3 expression were associated with higher HER2 expression levels (P =.0019). Conclusions Levels of HER2 protein expression and amplification were found to be linearly associated and highly concordant. Among amplified tumors with absent/faint expression, the level of amplification was low. Frequent expression of HER3 suggests its relevance as a therapeutic target, and its significant association with HER2 supports ongoing efforts to inhibit HER2/HER3 in patients with EAC.

Original languageEnglish (US)
Pages (from-to)415-424
Number of pages10
JournalCancer
Volume120
Issue number3
DOIs
StatePublished - Feb 1 2014

Fingerprint

erbB-2 Genes
Gene Amplification
Epidermal Growth Factor Receptor
Adenocarcinoma
Proteins
Immunohistochemistry
human ERBB2 protein
Fluorescence In Situ Hybridization
Patient Selection
Neoplasms
Least-Squares Analysis

Keywords

  • concordance
  • ERBB2
  • esophageal adenocarcinoma
  • esophageal cancer
  • esophagogastric cancer
  • fluorescence in situ hybridization
  • HER2 expression
  • HER2 gene amplification
  • HER3/ERBB3
  • human epidermal growth factor receptor 2 (HER2)

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma. / Yoon, Harry H; Sukov, William R.; Shi, Qian D; Sattler, Christopher A.; Wiktor, Anne E.; Diasio, Robert B; Wu, Tsung Teh; Jenkins, Robert Brian; Sinicrope, Frank A.

In: Cancer, Vol. 120, No. 3, 01.02.2014, p. 415-424.

Research output: Contribution to journalArticle

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title = "HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma",
abstract = "Background Human epidermal growth factor receptor 2 (HER2) is a therapeutic target in patients with esophageal adenocarcinoma (EAC), with gene amplification used as a selection criterion for treatment, although to the authors' knowledge the concordance between amplification and HER2 protein expression remains undefined in EAC. Furthermore, the association between HER2 and its interacting partner, human epidermal growth factor receptor 3 (HER3), is unknown yet appears to be of potential therapeutic relevance. Methods Patients with untreated EACs (N = 673) were analyzed for HER2 amplification and polysomy 17 by fluorescence in situ hybridization in parallel with immunohistochemistry (IHC) (IHC scores of 0-1+, 2+, and 3+). Amplification was defined as HER2/CEP17 ≥ 2. HER3 expression by IHC was analyzed in randomly selected cases (n = 224). IHC and fluorescence in situ hybridization results were compared using least squares linear regression. Results Overall, 17{\%} of the EACs (116 of 673 EACs) were HER2-amplified with an amplification frequency that was highest among IHC3+ cases (89{\%}) and declined among IHC2+ cases (13{\%}) and IHC0 to IHC1+ cases (4{\%}). Among HER2-amplified cases, the level of amplification increased linearly with HER2 membranous expression (HER2/CEP17 ratio: 7.9 in IHC3+ and 5.5 in IHC2+ vs 2.8 in IHC0 to IHC1+ [P <.0001]), with 14{\%} of amplified tumors demonstrating absent/faint expression (IHC0 to IHC1+). Polysomy 17 was not found to be associated with HER2 expression. Cytoplasmic HER3 expression was detected in 87{\%} of tumors (195 of 224 tumors) and was found to be significantly associated with better differentiation (P <.0001). Stepwise increases in HER3 expression were associated with higher HER2 expression levels (P =.0019). Conclusions Levels of HER2 protein expression and amplification were found to be linearly associated and highly concordant. Among amplified tumors with absent/faint expression, the level of amplification was low. Frequent expression of HER3 suggests its relevance as a therapeutic target, and its significant association with HER2 supports ongoing efforts to inhibit HER2/HER3 in patients with EAC.",
keywords = "concordance, ERBB2, esophageal adenocarcinoma, esophageal cancer, esophagogastric cancer, fluorescence in situ hybridization, HER2 expression, HER2 gene amplification, HER3/ERBB3, human epidermal growth factor receptor 2 (HER2)",
author = "Yoon, {Harry H} and Sukov, {William R.} and Shi, {Qian D} and Sattler, {Christopher A.} and Wiktor, {Anne E.} and Diasio, {Robert B} and Wu, {Tsung Teh} and Jenkins, {Robert Brian} and Sinicrope, {Frank A}",
year = "2014",
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doi = "10.1002/cncr.28435",
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pages = "415--424",
journal = "Cancer",
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T1 - HER-2/neu gene amplification in relation to expression of HER2 and HER3 proteins in patients with esophageal adenocarcinoma

AU - Yoon, Harry H

AU - Sukov, William R.

AU - Shi, Qian D

AU - Sattler, Christopher A.

AU - Wiktor, Anne E.

AU - Diasio, Robert B

AU - Wu, Tsung Teh

AU - Jenkins, Robert Brian

AU - Sinicrope, Frank A

PY - 2014/2/1

Y1 - 2014/2/1

N2 - Background Human epidermal growth factor receptor 2 (HER2) is a therapeutic target in patients with esophageal adenocarcinoma (EAC), with gene amplification used as a selection criterion for treatment, although to the authors' knowledge the concordance between amplification and HER2 protein expression remains undefined in EAC. Furthermore, the association between HER2 and its interacting partner, human epidermal growth factor receptor 3 (HER3), is unknown yet appears to be of potential therapeutic relevance. Methods Patients with untreated EACs (N = 673) were analyzed for HER2 amplification and polysomy 17 by fluorescence in situ hybridization in parallel with immunohistochemistry (IHC) (IHC scores of 0-1+, 2+, and 3+). Amplification was defined as HER2/CEP17 ≥ 2. HER3 expression by IHC was analyzed in randomly selected cases (n = 224). IHC and fluorescence in situ hybridization results were compared using least squares linear regression. Results Overall, 17% of the EACs (116 of 673 EACs) were HER2-amplified with an amplification frequency that was highest among IHC3+ cases (89%) and declined among IHC2+ cases (13%) and IHC0 to IHC1+ cases (4%). Among HER2-amplified cases, the level of amplification increased linearly with HER2 membranous expression (HER2/CEP17 ratio: 7.9 in IHC3+ and 5.5 in IHC2+ vs 2.8 in IHC0 to IHC1+ [P <.0001]), with 14% of amplified tumors demonstrating absent/faint expression (IHC0 to IHC1+). Polysomy 17 was not found to be associated with HER2 expression. Cytoplasmic HER3 expression was detected in 87% of tumors (195 of 224 tumors) and was found to be significantly associated with better differentiation (P <.0001). Stepwise increases in HER3 expression were associated with higher HER2 expression levels (P =.0019). Conclusions Levels of HER2 protein expression and amplification were found to be linearly associated and highly concordant. Among amplified tumors with absent/faint expression, the level of amplification was low. Frequent expression of HER3 suggests its relevance as a therapeutic target, and its significant association with HER2 supports ongoing efforts to inhibit HER2/HER3 in patients with EAC.

AB - Background Human epidermal growth factor receptor 2 (HER2) is a therapeutic target in patients with esophageal adenocarcinoma (EAC), with gene amplification used as a selection criterion for treatment, although to the authors' knowledge the concordance between amplification and HER2 protein expression remains undefined in EAC. Furthermore, the association between HER2 and its interacting partner, human epidermal growth factor receptor 3 (HER3), is unknown yet appears to be of potential therapeutic relevance. Methods Patients with untreated EACs (N = 673) were analyzed for HER2 amplification and polysomy 17 by fluorescence in situ hybridization in parallel with immunohistochemistry (IHC) (IHC scores of 0-1+, 2+, and 3+). Amplification was defined as HER2/CEP17 ≥ 2. HER3 expression by IHC was analyzed in randomly selected cases (n = 224). IHC and fluorescence in situ hybridization results were compared using least squares linear regression. Results Overall, 17% of the EACs (116 of 673 EACs) were HER2-amplified with an amplification frequency that was highest among IHC3+ cases (89%) and declined among IHC2+ cases (13%) and IHC0 to IHC1+ cases (4%). Among HER2-amplified cases, the level of amplification increased linearly with HER2 membranous expression (HER2/CEP17 ratio: 7.9 in IHC3+ and 5.5 in IHC2+ vs 2.8 in IHC0 to IHC1+ [P <.0001]), with 14% of amplified tumors demonstrating absent/faint expression (IHC0 to IHC1+). Polysomy 17 was not found to be associated with HER2 expression. Cytoplasmic HER3 expression was detected in 87% of tumors (195 of 224 tumors) and was found to be significantly associated with better differentiation (P <.0001). Stepwise increases in HER3 expression were associated with higher HER2 expression levels (P =.0019). Conclusions Levels of HER2 protein expression and amplification were found to be linearly associated and highly concordant. Among amplified tumors with absent/faint expression, the level of amplification was low. Frequent expression of HER3 suggests its relevance as a therapeutic target, and its significant association with HER2 supports ongoing efforts to inhibit HER2/HER3 in patients with EAC.

KW - concordance

KW - ERBB2

KW - esophageal adenocarcinoma

KW - esophageal cancer

KW - esophagogastric cancer

KW - fluorescence in situ hybridization

KW - HER2 expression

KW - HER2 gene amplification

KW - HER3/ERBB3

KW - human epidermal growth factor receptor 2 (HER2)

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