College of American Pathologists Guidelines for Reporting HER2 Test Results in Gastric Cancer

This is the authors' abstract. We don't add key points for this paper.

We read with interest the recently published “Template for Reporting Results of HER2 (ERBB2) Biomarker Testing of Specimens From Patients With Adenocarcinoma of the Stomach or Esophagogastric Junction”1 and do appreciate the efforts the College of American Pathologists is taking to standardize reporting of cancer specimens, including the results of biomarker testing. However, we take exception to one point made in the explanatory notes. In the trial of trastuzumab in gastric adenocarcinoma (ToGA), all patients were dual tested (ie, samples underwent both immunohistochemistry [IHC] and fluorescence in situ hybridization [FISH]) and if either was positive, they were eligible for randomization.2 It is true that in the updated survival analysis, when sorted by IHC results, the IHC-negative, FISH-positive cohort did not seem to derive a benefit from trastuzumab.3 However, this result did not reach statistical significance. Additionally, the overall survival of IHC-negative, FISH-positive patients receiving chemotherapy alone was 8.8 months, versus 13.2 months among the IHC-positive patients receiving chemotherapy alone. So perhaps the apparent lack of response to trastuzumab in IHC-negative, FISH-positive patients has nothing to do with trastuzumab but rather reflects a more aggressive tumor biology.No reference was provided for the following statement: “In the US, the FDA [Food and Drug Administration] has approved trastuzumab in association with chemotherapy for metastatic gastric cancer using the eligibility criteria of the ToGA trial, limited to patients with a score of IHC 3+ or 2+ and ISH [in situ hybridization] positivity.”1 During our review of the FDA Web site, we found several locations where they caution: “The study also demonstrated that gene amplification and protein expression (IHC) are not as correlated as with breast cancer, therefore a single method should not be used to determine HER2 status.”4We certainly think the utility of trastuzumab in patients with IHC-negative, FISH-positive tumors is worthy of additional study, but we believe it is too early to deny these patients therapy based on a retrospective analysis that did not reach statistical significance in a study that was not designed to assess outcome based on IHC result. Additionally, we would argue that the FDA has also cautioned about using a single testing modality to deem a patient ineligible for trastuzumab; we therefore believe statements advocating the use of IHC alone to exclude patients with gastric cancer from receiving trastuzumab is tenuous at best. It is the policy at our institution to perform FISH on all nonpositive IHC, and if the patient is found to be IHC-negative, FISH-positive, then the patient should be considered to be eligible for HER2-targeted therapy with trastuzumab.