Dual Blockade of HER2 - Twice as Good or Twice as Toxic?

With about 20% of breast cancers overexpressing HER2, the implementation of trastuzumab and, more recently, lapatinib has revolutionised the care of these patients. Despite these successes, de novo and acquired resistance to these agents represent significant barriers that need to be overcome if further progress is to be achieved. Given that resistance can involve interplay between different members of the HER family multi-targeted inhibition of HER receptors represents an interesting therapeutic strategy. To date, clinical trials have shown that a number of targeted drugs can be combined with trastuzumab and lead to improved overall response rates and potentially also survival. However, such progress leads to an increased burden of toxicity. This review will discuss the mechanisms behind HER2 resistance, the preclinical basis for combining different agents with trastuzumab and the available results from clinical studies evaluating these combinations.