Updates in HER2 Testing in Gastric Cancer

Gastric adenocarcinoma is a major cause of morbidity and mortality in the world with median overall survival being less than a year [1-4]. Advanced gastric adenocarcinoma is associated with a dismal prognosis, and increasing survival time, even by a few months, can be significant in this patient population [3,5,6]. Recently there was a major breakthrough in the treatment of gastric cancer, which arose by studying a therapy currently used for treatment of another solid tumor, HER2 positive breast carcinoma. Trastuzumab, a monoclonal antibody that targets the extracellular domain of the HER2 receptor, has become standard first-line treatment in this classification of breast carcinomas [7-10]. A recent clinical trial (ToGA) using trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2positive advanced gastric or gastro-esophageal junction cancer showed an increase in overall survival in advanced (inoperable locally advanced, recurrent, or metastatic) gastric cancer treated with chemotherapy plus trastuzumab versus chemotherapy alone [1]. This was the first time a biological therapeutic was proven to increase survival in gastric cancer. Critical to the ToGA trial was determining which patients would be eligible for randomization i.e. which patients had tumors that over-expressed HER2. Therefore, not only was trastuzumab shown to prolong survival in patients with advanced gastric cancer, but a protocol was proposed for HER2 testing in gastric cancer in a corollary study [11]. HER2 interpretation in gastric cancer is similar to, but slightly different than interpretation in breast cancer. Hofmann put forth an initial proposal, which was subsequently validated with minor clarifications added by Ruschoff [11,12]. The modifications in gastric cancer HER2 interpretation are related to heterogeneity (percentage of cells positive and different criteria in biopsies versus resections) and physiology (pattern of staining basolateral/lateral versus complete circumferential staining). The ToGA study established trastuzumab as a viable treatment option in advanced gastric cancer and led to approval by the Food and Drug Administration (FDA) and the European Union for its use in combination with chemotherapy in that setting [13,14]. The most recent National Comprehensive Cancer Network (NCCN) Guidelines recommend trastuzumab with chemotherapy for patients with advanced or metastatic cancer, if the tumor is HER2 positive as confirmed by immunohistochemistry (IHC 3+) or fluorescence in situ hybridization (FISH score ≥ 2 for IHC 2+ tumors).