When Hofmann et al. [55] pooled data from 16 different studies (3264 tumor samples), a mean value of 18% of HER-2 Atezolizumab in vitro immunopositivity was obtained, and nine studies (from 1232 tumors) showed a mean value of 19% of HER-2 amplified cases using either fluorescence or chromogen in situ hybridization (HER-2/CEN-17≥2). These values are well in the range reported for HER-2 amplification in breast cancer (15–25%). In several studies, intestinal-type GCs were shown to express HER-2 more frequently (16–34%) than the diffuse-type tumors
(2–7%). Probably because of this association with intestinal type histology, HER-2 expression is higher in gastroesophageal junction carcinomas when compared to conventional (corpus and antrum) GC (24–32% vs 10–18%), Tanespimycin mouse because the intestinal type is more frequent in the proximal location. The role of HER-2 as a prognostic factor in GC is somewhat controversial, because several studies have failed to show any role in prognosis, while others have indicated that HER-2 is an independent prognostic factor in GC [48,49,56–59]. A randomized multicenter phase III trial (ToGa study) has shown that first-line treatment with trastuzumab in combination with either
cisplatin and 5-fluorouracil or cabecitapin is effective against metastatic gastric adenocarcinoma [60]. Median survival was improved (from 11.1 to 13.8 months; n = 584) in patients receiving trastuzumab in Phosphoglycerate kinase combination with cytostatic drugs, which was even more impressive in the subgroup of the HER-2 immunohistochemistry 3+ and 2+ with amplification positivity (median survival 11.8 vs. 16.0 months; n = 446). No major safety issues were reported between the two treatment arms. Consistent with earlier data, HER-2 was
more frequently positive in intestinal (32%) than in diffuse-type tumors (6%), and in gastroesophageal junctional cancers (33%) when compared to those in the stomach (21%). Overall rate of HER-2 positivity was 22% (immunohistochemistry 3+ or amplification positive) [61]. Based on these data, trastuzumab has been approved by the EMEA for metastatic GC and adenocarcinoma of the gastroesophageal junction. Assessment of HER-2 positivity in GC has become increasingly important because of the results of the ToGa study. Earlier studies have shown only modest concordance between HER-2 immunopositivity and amplification rates [48], but more recent studies have indicated that a much higher (over 90%) concordance between immunohistochemistry positivity and amplification can be obtained [55]. In the ToGa trial, a 87.5% concordance was reported [61]. This suggests that similarly to breast cancer also in GC the major mechanism for overexpression of the protein is the amplification of the gene.