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.
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 2010; Mimura et al. 2005; Sato-Kuwabara et al. 2009), but its clinical significance is less clear.