• What is ERBB2?
  • ERBB2 in Breast Cancer
  • HER2 Amplification
  • Clinical Trials

HER2 (ERBB2)

HER2 belongs to a family of receptor tyrosine kinases (RTKs) that includes EGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4. The gene for HER2 is located on chromosome 17 and has been found to be amplified with an increased copy number in several cancers (Jorgensen 2010). Amplification of HER2 has been found to promote tumorigenesis and to be involved in the pathogenesis of several human cancers (Moasser 2007).

To date, no ligand has been identified for HER2. However, HER2 appears to be the preferential dimerization partner for all members of the ERBB family (Graus-Porta et al. 1997). The binding of ligand followed by HER2 hetero-dimerization results in activation of HER2 tyrosine kinase activity. Activated HER2 then phosphorylates its substrates, leading to activation of multiple downstream pathways within the cell, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).

her2.png

Figure 1.
Schematic of HER2 signaling pathway. Growth factor binding results HER2 heterodimerization and activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Chanjuan Shi, M.D., Ph.D., Graham T. Watson, M.D., Leora Horn, M.D., M.Sc., Paula Pohlmann, M.D., Ph.D., Laura W. Goff, M.D.

Suggested Citation: Lovly, C., C. Shi, G. Watson, L. Horn, P. Pohlmann, L. Goff. 2015. HER2 (ERBB2). My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/erbb2/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

HER2 (ERBB2) in Breast Cancer

Human epidermal receptor growth factor 2 (HER2, ERBB2) overexpression occurs in 18–20% of breast cancer (Owens et al. 2004; Slamon et al. 1987; Yaziji et al. 2004). HER2 overexpression arises from multiple mechanisms; gene amplification is the most common. Overexpression in general is measured by IHC and gene amplification is measured by FISH methods. Activating mutations in HER2 are estimated to occur at a frequency of 1.6–2.0% in breast cancer (Bose et al. 2013; COSMIC).

HER2 overexpression in breast cancer carries prognostic and predictive significance. In the adjuvant setting, HER2 status is prognostic for outcomes and predictive for outcomes with HER2-targeting therapies such as trastuzumab- based therapy and with anthracycline-based therapies (NCCN 2012). In the metastatic setting, HER2 status predicts outcomes with trastuzumab and HER2-targeting agents (NCCN 2012).

Recently, in patients without HER2 gene amplification, activating HER2 mutations have also been identified (Bose et al. 2013). Preclinical studies have indicated that some HER2 mutations may result in sensitivity or resistance to trastuzumab, neratinib, or lapatinib, depending on the specific mutation (Bose et al. 2013).


Gene or Protein Invasive Breast Cancer Hormone Receptor Positive (ER+ and/or PR+) Invasive Breast Cancer HER2 positive Invasive Breast Cancer Triple-negative Invasive Breast Cancer
HER2 amplification 18% (Slamon et al. 1987) 18% (Slamon et al. 1987) 100% N/A
HER2 overexpression 18–20% (Owens et al. 2004Yaziji et al. 2004) 8% (Blows et al. 2011) 100% N/A
HER2 mutations 1.6–2.0% (25 cases reported in Bose et al. 2013; COSMIC) 8 cases reported (Bose et al. 2013) One case reported (Bose et al. 2013) No cases reported (Bose et al. 2013)
NOTE: ER = estrogen receptor; PR = progesterone receptor; N/A = not applicable
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Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2013. HER2 (ERBB2) in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/erbb2/ (Updated April 10).

Last Updated: April 10, 2013

HER2 (ERBB2) Amplification in Breast Cancer

Properties
Location of mutation Not applicable
Frequency of HER2 amplification in breast cancer 18% (Slamon et al. 1987)
Implications for Targeted Therapeutics
Response to trastuzumab Confers increased sensitivitya
Response to ado-trastuzumab emtansine Confers increased sensitivityb
Response to pertuzumab Confers increased sensitivityc
Response to lapatinib Confers increased sensitivityd
Response to neratinib Confers increased sensitivitye

Human epidermal receptor growth factor 2 (HER2, ERBB2) gene amplification is the primary mechanism for HER2 overexpression and occurs in 18–20% of breast cancer (Owens et al. 2004Slamon et al. 1987Yaziji et al. 2004). HER2 gene amplification test results are grouped into the three statuses shown in Table 2 (Wolff et al. 2007).


Table 2. HER2 Status by FISH (Wolff et al. 2007).

HER2 Status FISH HER2 Gene Amplification
Positive HER2/CEP17 ratio >2.2 or average HER2 gene copy number >6
Equivocal HER2/CEP17 ratio of 1.8–2.2 or average HER2 gene copy number 4–6
Negative HER2/CEP17 ratio <1.8 or average HER2 gene copy number <4

HER2 testing guidelines provided by the National Comprehensive Cancer Network (NCCN) state that initial IHC testing resulting in an equivocal status should be re-assessed by FISH methods (NCCN 2012). If IHC is equivocal and FISH results are >2, the patient should be treated as HER2 positive. Equivocal FISH results should be re-assessed by IHC methods, retested using FISH methods, or additional cells should be evaluated (NCCN 2012).

HER2 gene amplification is predictive for patient outcomes with HER2-targeting agents (Wolff et al. 2007). Several targeted agents are approved for the treatment of HER2 positive breast cancer.

a Trastuzumab is a HER2-targeting monoclonal antibody approved for the treatment of HER2 overexpressing breast cancer (FDA 1998).

b Ado-trastuzumab emtansine is a HER2-targeting monoclonal antibody and microtubule inhibitor conjugate approved for the treatment of HER2 overexpressing metastatic breast cancer after treatment with trastuzumab and a taxane (FDA 2013).

c Pertuzumab is a HER2 receptor antagonist approved in combination with trastuzumab and docetaxel for the treatment of HER2 overexpressing breast cancer (FDA 2012).

d Lapatinib is a small-molecule EGFR/HER2 inhibitor approved in combination with capecitabine or letrozole for types of HER2 overexpressing breast cancer (FDA 2007).

e In a phase II trial, first-line HER2 positive breast cancer patients treated with neratinib experienced a 56% response rate and a median progression-free survival of 39.6 months (Burstein et al. 2010). ​​​​

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Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2013. HER2 (ERBB2) Amplification in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/erbb2/119/ (Updated April 10).

Last Updated: April 10, 2013

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