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


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).


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/gastric-cancer/erbb2/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

HER2 (ERBB2) in Gastric Cancer

In various studies, 8–53% of gastric cancers have been shown to exhibit HER2 gene amplification or overexpression (Gravalos and Jimeno 2008; Hofmann et al. 2008; Tanner et al. 2005). A weighted mean for 24 studies reporting prevalence of HER2 amplification in gastric cancer is 19.0% (Jorgensen 2010), on par with prevalence estimates for HER2-positive breast cancer. HER2 mutations have not been described in upper gastrointestinal malignancies.

HER2 testing

There are two FDA approved testing methods for HER2: immunohistochemistry (IHC) for protein expression and fluorescence in situ hybridization (FISH) for gene amplification. There is controversy regarding the validity of HER2 testing in upper gastrointestinal malignancies because of high tumor heterogeneity (Bilous et al. 2010). In contrast to breast cancer, the distribution of HER2-positive gastric cancer cells in tissue is heterogeneous and frequently focal. In general, the ASCO/College of American Pathology (CAP) guidelines for HER2 IHC testing as used in breast cancer do not apply to upper gastrointestinal malignancies.

Interpreting the test

To establish a valid, accurate HER2 scoring system for gastric cancer, a panel of international oncology and pathology experts met to make specific recommendations regarding modifications to the Hercep-TestTM scoring system (Table 1; Hofmann et al. 2008). The IHC gastric cancer scoring system (GCSS) for surgical specimens and biopsies was used in a large trial ("ToGa") and is the currently accepted standard.

Based upon data from the ToGA trial, Bilous et al. (2010) made the following considerations for assessment of HER2 status in upper gastrointestinal malignancies:

  1. The levels of HER2 protein expression and gene amplification in upper GI malignancies are more heterogeneous than in breast cancers.
  2. A specific IHC scoring system proposed by Hofmann and Jimeno (2008) modifying the system utilized in breast cancer should be used for gastric cancers.
  3. A significant number of gastric cancers with HER2 protein at the 0–1+ level in IHC show gene amplification and should therefore be tested with FISH.
Table 1. Gastric Cancer Scoring System (GCSS) for Surgical Specimens and Biopsies, Modified Hercep-TestTM (Hofmann et al. 2008). 
Reactivity characteristics Score/classification
No reactivity or membranous reactivity in <10% of cells 0 ⁄ negative
Faint ⁄ barely perceptible membranous reactivity in >10% of cells; cells are reactive only in part of their membrane 1+ ⁄ negative
Weak to moderate complete or basolateral membranous reactivity in >10% of tumor cells 2+ ⁄ equivocal
Moderate to strong complete or basolateral membranous reactivity in >10% of tumor cells 3+ ⁄ positive
Biopsy (not surgery) samples with cohesive either IHC 3+ and⁄or FISH+ clones are considered positive irrespective of size, i.e., <10%  
NOTES: FISH = Fluorescence in situ hybridization; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry.

The interpretation of FISH results continues to follow the ASCO/CAP guidelines for breast cancer, summarized below:

  • FISH amplified includes HER2 to CEP17 ratio of >2.2 or average HER2 gene copy number >6 signals/nucleus for those test systems without an internal control probe.
  • Equivocal FISH for HER2 is defined as FISH ratio of 1.8–2.2 or average HER2 gene copy number 4 to 6 signals/nucleus for test systems without an internal control probe.
  • Negative for HER2 by FISH is defined as FISH ratio of <1.8 or average HER2 gene copy number of <4 signals/nucleus for test systems without an internal control probe.

An equivocal FISH for HER2 would require further testing. Additional cells should be counted for ratio confirmation. Otherwise, FISH must be repeated. Given the differences between the results in gastric cancer compared with breast cancer, both IHC and FISH testing should be used for the enrollment of gastric cancer patients in clinical trials of trastuzumab.

Who is a candidate for HER2 testing?

Where anti-HER2 targeted therapy is available for use in gastric/GEJ adenocarcinoma, HER2 testing should be considered for patients presenting with metastatic disease. Patients with localized disease or with esophageal cancer may also be tested, especially if they are candidates for clinical trials evaluating anti-HER2 targeted approaches. HER2 positivity in squamous cell carcinoma of the esophagus has been described (Maruyama 2010Mimura et al. 2005Sato-Kuwabara et al. 2009), but its clinical significance is less clear.




Contributors: Graham T. Watson, M.D., Laura W. Goff, M.D., Chanjuan Shi, M.D., Ph.D., Paula Pohlmann, M.D., Ph.D.

Suggested Citation: Watson, G., L. Goff, C. Shi, P. Pohlmann. 2015. HER2 (ERBB2) in Gastric Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/gastric-cancer/erbb2/ (Updated June 18).

Last Updated: June 18, 2015

HER2 (ERBB2) Amplification in Gastric Cancer

Location of mutation Not applicable
Frequency of HER2 amplification in gastric cancer 7–34% (Bang et al. 2010; Gravalos and Jimeno 2008; Hofmann et al. 2008; Tanner et al. 2005)
Implications for Targeted Therapeutics
Response to trastuzumab Confers increased sensitivity

A significant percentage of gastric cancers are shown to exhibit HER2 amplification (Gravalos and Jimeno 2008; Hofmann et al. 2008; Tanner et al. 2005). Based on this finding, the anti-HER2 monoclonal antibody trastuzumab was evaluated in a phase III study as treatment for HER2 positive gastric and gastroesophageal junction (GEJ) adenocarcinoma. In the ToGA trial (Bang et al. 2010), the addition of trastuzumab to chemotherapy produced a statistically significant benefit in terms of overall survival vs chemotherapy alone. Thus, trastuzumab became the first targeted therapy approved for use in gastric cancer.

Table 2. Main trial results.

Reference Study Type / Phase Line of Treatment Treatment Agent Mutation Status # patients in study Response Rate PFS (months) OS (months)
Bang et al. 2010 Phase III 1st line or greater Trastuzumab + chemotherapy All HER2 statuses 298 47% 6.7 13.8
High HER2a       16.0
Low HER2a       10.0
chemotherapy All HER2 statuses 296 35% 5.5 11.1
High HER2a       11.8
Low HER2a       8.7

NOTE: PFS = progression-free survival; OS = overall survival.
a High HER2 status includes IHC2+/FISH+ or IHC3+. Low HER2 status includes IHC0/FISH+ or IHC1+/FISH+.


Contributors: Graham T. Watson, M.D., Laura W. Goff, M.D., Chanjuan Shi, M.D., Ph.D., Paula Pohlmann, M.D., Ph.D.

Suggested Citation: Watson, G., L. Goff, C. Shi, P. Pohlmann. 2015. HER2 (ERBB2) Amplification in Gastric Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/gastric-cancer/erbb2/119/ (Updated June 18).

Last Updated: June 18, 2015

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