Hitting multiple targets in HER2-positive breast cancer: proof of principle or therapeutic opportunity?

Importance of the field: Pharmacological targeting of the tyrosine kinase receptor HER2 with the monoclonal antibody trastuzumab has dramatically changed the outlook of HER2-positive breast cancer patients. However, HER2 is part of a more complex biological network that, when deregulated, plays a central role in sustaining the cancer phenotype. These interactions account for primary or acquired resistance to drugs that hit a single biological target, like trastuzumab. Several preclinical models suggest that simultaneous targeting of crucial metabolic pathways has the potential to circumvent or delay the onset of resistance phenomena in HER2-positive breast cancer cells. Areas covered in this review: This review will describe the rationale and results of clinical trials using biologically targeted agents in HER2-positive breast cancer patients. Either single drugs that hit multiple targets or cocktails of biologically targeted agents will be considered, whereas combinations with chemotherapy will not be addressed. What will the reader gain: The reader will have an overview on the most promising strategies to increase the efficacy of HER2-targeting using biological agents. Take home message: Most of the studies using biological agents to hit multiple targets in HER2-positive breast cancer patients confirm that resistance to single-agent HER2-targeting can be overcome. Further developments will include combination of multi-targeting strategies with chemotherapy in patients with earlier-stage disease. In addition, it is possible that newer molecular predictive factors may allow a more rationale choice of the most appropriate targeting for each individual patient.