Towards precision oncology for HER2 blockade in gastroesophageal adenocarcinoma.

Gastroesophageal adenocarcinoma (GEA) represents a very heterogeneous disease and patients in advanced stages have a very poor prognosis. Although several molecular classifications have been proposed, precision medicine for HER2-amplified GEA patients still represents a challenge. Despite improvement in clinical outcomes obtained by adding trastuzumab to first-line platinum-based chemotherapy, no other anti-HER2 agents used first-line or beyond progression have demonstrated any benefit. Several factors contribute to this failure. Among them, variable HER2 amplification assessment, tumour heterogeneity, molecular mechanisms of resistance and microenvironmental factors could limit the effectiveness of anti-HER2 blockade. Identifying the factors responsible for both primary and acquired resistance is a priority for providing an improved, personalised approach. In this review, we examine current treatments for HER2-amplified GEA, their potential mechanisms of resistance and the ways to overcome them, investigating the most relevant translational studies with anti-HER2 agents in GEA, as well as novel agents under development in this field.