HER2 heterogeneity in gastric/gastroesophageal cancers: From benchside to practice

Abstract

HER2 is overexpressed in approximately 10%-20% of gastric and gastroesophageal junction carcinomas. In these types of cancer, accurate assessment of HER2 status is mandatory, for selecting patients who may benefit from targeted therapies with anti-HER2 drugs such as Trastuzumab. This manuscript focuses on HER2 in gastric carcinogenesis, on optimal evaluation of HER2 and on the possible causes which may contribute to inaccurate HER2 evaluation. Similarly to breast cancer HER2 evaluation, standardization of HER2 testing in gastric cancer is necessary in diagnostic practice. The three principle aspects which require consideration are: (1) the choice of sample with regards to cancer morphology - intestinal vs diffuse areas; (2) the choice of scoring criteria - use of HER2 scoring criteria specific for gastric cancer; and (3) the choice of HER2 evaluation methods - use of an algorithm in which both immunohistochemistry and in situ hybridization play a role. Problematic issues include: (1) pre-analytic variables with particular emphasis on fixation; (2) recommended methodology for HER2 assessment (immunohistochemistry vs in situ hybridization); (3) HER2 heterogeneity both within the primary tumor and between primary tumor and metastases; (4) reliability of biopsies in HER 2 evaluation; and (5) quantity of sample (FFPE blocks from surgical specimens or endoscopic biopsies) necessary for an adequate assessment.

Keywords: FISH; Gastric cancer; HER2; Heterogeneity; Immunohistochemistry.

Figures

Figure 1

Diagnostic algorithm for HER2 status evaluation in gastric and gastroesophageal adenocarcinomas. Immunohistochemistry (IHC) represents the initial testing method. IHC score 0 and 1+ are considered negative while score 3+ cases are considered positive and do not need further testing. Fluorescence in situ hybridization testing is required only for equivocal IHC score 2+ cases. On the basis of HER2 (red spots): CEP 17 (green spots) ratio (< 2 vs ≥ 2) patients are eligible or not to anti-HER2 therapy.

Figure 2

Heterogeneity of HER2 expression in gastric and gastroesophageal cancer. A: Gastric carcinoma, intestinal type, with HER2 overexpression (score 3+; left side) vs HER2 negativity (score 0, right side). Magnification 10 x; B: Gastroesophageal carcinoma with HER2 equivocal positivity (score 2+; left side) vs negativity (score 1+; right side). Magnification x 25.