Toward optimizing outcomes in Her2-positive gastric cancer: timing and genomic context matter

In 2010, the ToGA trial demonstrated a 2.7-month improvement in overall survival (OS) with the addition of the anti-HER2 monoclonal antibody trastuzumab to platinum-5-FU in first-line treatment of advanced HER2-positive gastric cancer [1]. Subsequent attempts to address HER2-directed therapies in first and second lines have been met with largely disappointing results [2–5]. In the phase III LOGiC trial, the addition of the small molecule HER2-inhibitor lapatinib to first-line CapeOx failed to improve OS in the primary efficacy population (12.2 versus 10.5, Hazard Ratio (HR) 0.91, P = 0.35), though preplanned subset analysis suggested a benefit with the addition of lapatinib in Asian patients (HR 0.68) and patients < 60 years old (HR 0.69) [2]. There was no correlation between Immunohistochemistry (IHC)-status and OS benefit in the study population, which were all amplified by FISH. Contemporary with the LOGiC trial was several publications associating magnitude of HER2 amplification with degree of benefit from trastuzumab, as well as the recognition that HER2-positive gastric cancer is a highly heterogeneous disease complicated by chronologic HER2 changes, and inter- and intratumoral variations in molecular features [6–9]. The incorporation of cell-free DNA (cfDNA) has allowed for perhaps more representative sampling of global tumor makeup, potentially facilitating identification of patient subsets with better or worse outcomes though limited prospective data exist in esophagogastric cancers [10].