Treatment of advanced HER2-positive breast cancer: 2018 and beyond.

In the 1980s the importance of HER2 signalling to the aberrant behaviour of a subset of breast cancer cells was recognized for the first time and, consequently, a hitherto unknown subtype of breast cancer - HER2-positive (HER2+) breast cancer was identified. The development of the anti-HER2 class of drugs, first with trastuzumab, followed closely by lapatinib, pertuzumab, and T-DM1, has improved outcomes dramatically. Nevertheless, metastatic HER2+ breast cancer remains an incurable disease and new therapeutic options are needed. Additionally, the rapid changes in treatment standards 5 years ago have left unanswered numerous questions, including the "real-life" benefit of pertuzumab and T-DM1, since both the CLEOPATRA and EMILIA trials were conducted in populations that no longer exist in practice and, moreover, on the role of endocrine therapy in HER2+ disease. Furthermore, despite significant research efforts, including translational efforts and new imaging techniques, no predictive biomarkers have been clinically validated and therefore a more refined approach to treatment tailoring remains beyond our reach. Finally, a better understanding of resistance to currently existing anti-HER2 agents and of the role played by the microenvironment (e.g. immune system) and of interconnected signalling pathways (e.g. PI3K-mTOR-AKT) is at the core of clinical trials exploring new drugs and new regimens. These include the combination of anti-HER2 agents and anti-PD-1/PDL-1, PI3K inhibitors and CDK 4/6 inhibitors, as well as a host of new panHER inhibitors, drug antibody conjugates and anti-HER antibodies, which may, in coming years further push the boundaries of what we can do for our patients.