HER2-positive breast cancer: cotargeting to overcome treatment resistance.

Abstract

The introduction in clinical practice of anti-HER2 agents changed the prognosis of patients with HER2-positive (HER2+) breast cancer in both metastatic and early setting. Although the incomparable results obtained in the last years with the approval of new drugs targeting HER2, not all patients derive benefit from these treatments, experiencing primary or secondary resistance. The aim of this article is to review the data about cotargeting HER2 with different pathways (or epitopes of receptors) involved in its oncogenic signaling, as a mechanism to overcome resistance to anti-HER2 agents. Concordantly to the knowledge of the HER2+ breast cancer heterogeneity as well as new drugs, novel predictive biomarkers of response to anti-HER2 treatments are always raised helping to define target to overcome resistance. Cotargeting HER2 and hormone receptors is the most well known mechanism to improve benefit in HER2+/HR+ breast cancer. Additional HER2-cotargeting, such as, with PI3K pathway, as well as different HERs receptors or immune-checkpoints revealed promising results. HER2+ breast cancer is an heterogenous disease. Cotargeting HER2 with other signaling pathways involved in its mechanism of resistance may improve patient outcomes. Research efforts will continue to investigate novel targets and combinations to create more effective treatment regimes.