Trastuzumab: a novel standard option for patients with HER-2-positive advanced gastric or gastro-oesophageal junction cancer

Abstract

Abstract:The human epidermal receptor-2 (HER-2) is amplified in up to 25% of patients with gastroesophageal adenocarcinomas. Although the presence of this amplification does not appear to confer a poor prognosis, it provides a valuable novel therapeutic target for this group of patients. Trastuzumab is a fully humanized monoclonal antibody directed at HER-2 which binds the external domain of the receptor and exerts its action via a combination of antibodydependent cytotoxicity, reduced shedding of the extracellular domain, inhibition of dimerization and possibly receptor downregulation. The ToGA trial was an international multicentre randomized phase III study which evaluated the addition of trastuzumab to a cisplatin plus fluoropyrimidine chemotherapy doublet in 594 patients with HER-2-positive advanced gastric or oesophagogastric junction adenocarcinoma. The combination of the antibody with chemotherapy significantly improved response rate, median progression-free survival and median overall survival without additional toxicity or adversely affecting quality of life. Accordingly, trastuzumab plus chemotherapy is now a standard first-line treatment option for patients with advanced HER-2-positive gastroesophageal cancer. Unfortunately, many patients with HER-2-positive cancer exhibit primary resistance to trastuzumab and the remainder will acquire resistance to the antibody; therefore, urgent investigation into novel agents which may circumvent resistance mechanisms is warranted. Small molecule inhibitors of HER-2, which commonly also target other members of the HER family of receptors, such as EGFR and HER-3, are currently undergoing evaluation in gastroesophageal cancer as first-line alternatives to trastuzumab and second-line salvage treatments for trastuzumab-resistant disease. Extrapolating the successful use of trastuzumab in the advanced disease setting, clinical trials are underway to assess the role of this antibody in the perioperative and adjuvant settings, where it is hoped that it will have a meaningful impact upon the currently poor survival rates.

Evaluation of the Expression of the Human Epithelial Receptor 2 (HER2) in Gastric Carcinoma

“…Its superexpression is generally associated with tumors of epithelial origin, but with much varied frequency; studies focusing on gastric cancer or esophagogastric transition found rates varying from 5 to 25% [6, 9]. We found positivity in 3.3%, a little under the literature data.…”

HER2 gene amplification in esophageal squamous cell carcinoma is less than in gastroesophageal junction and gastric adenocarcinoma

“…Differences in HER2 dysregulation in primary solid tumors and metastases may, at least partially, explain HER2-targeted therapeutic inconsistencies. Trastuzumab has been approved for the treatment of advanced gastric cancer (GC) and GEJAC (6–9). While, HER2 is overexpressed in a number of cancers, the rate of HER2 amplification is variable in esophageal cancer (10) and few studies have investigated the different features of HER2 gene amplification among ESCC, GEJAC and GC.…”

Is there an Increased Risk of Central Nervous System Metastasis in Cases with Gastric Cancer Showing Her2 Expression and Treated by Trastuzumab?

“…This study and other similar studies suggest that ERBB2 is an important therapeutic target in these cases. It can be said that 15-25% of the cases with gastroesophageal cancers show ERBB2 expression similar to the breast cancers and about one in five cases with breast cancer is candidate for anti-ERBB2 treatment modalities [13]. Our case had proximal cancer and he lived about 2 years and brain metastasis developed.…”

“…On the other hand it has been shown that lapatinib reverses irinotecan resistance in vitro and it is reasonable to combine lapatinib and irinotecan which is an active drug in second line treatment of gastric cancer [17]. Another choice may be the combination of capecitabine, lapatinib and oxaliplatin which this regimen will be tested in LOGiC trial [13]. Trastuzumab and lapatinib combination which has been found to be effective in metastatic breast cancer may be another option [18].…”