Targeting HER-2 in gastric cancer – incorporation of trastuzumab into the treatment of operable disease

Abstract:

Gastric cancer is the fourth most common malignancy and second leading cause of cancer death world-wide, and is therefore a significant global health problem. Radical surgery with a D2 lymph node dissection is an accepted standard approach, and is a key component of multimodality therapy. Perioperative chemotherapy significantly improves 5-year overall survival compared with surgery alone. A significant improvement in overall survival has also been demonstrated with postoperative 5-fluorouracil-based chemoradiotherapy and adjuvant oral S-1 chemotherapy; approaches commonly used widely in North America and Japan, respectively. Approximately 10% to 20% of gastric cancers and 20% to 30% of esophago-gastric junction cancers are HER-2 positive. The effect of HER-2 overexpression and HER-2 gene amplification on gastric cancer prognosis remains unresolved. The results of the first randomized phase III trial of trastuzumab, a monoclonal antibody directed at the HER-2 receptor, in patients with metastatic gastric cancer were reported recently. Response rate, median progression-free survival, and median overall survival were all significantly improved with the addition of trastuzumab to a cisplatin/fluoropyrimidine doublet. Evaluation of trastuzumab in HER-2 positive operable esophago-gastric cancer is now underway. Lapatinib, a small-molecule inhibitor targeting EGFR and HER-2 is well established in the treatment of trastuzumab-refractory HER-2 positive breast cancer and phase III trials in advanced esophago-gastric cancers are ongoing. Novel, small molecule pan-HER inhibitors have entered early phase evaluation and the antibody-drug conjugate, trastuzumab-DM1, and pertuzumab, a monoclonal antibody which prevents HER-2/HER-3 dimerization, are currently undergoing phase II/III evaluation in breast cancer. It is our hope that advances in the targeted treatment of HER-2 positive breast cancer will be replicated in HER-2 positive esophago-gastric cancers.

Keywords::

• gastric cancer
• adjuvant
• perioperative
• chemotherapy
• trastuzumab
• HER-2