Combined targeted therapies in breast cancer


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Stephen Johnston

The Institute of Cancer Research, Royal Marsden Hospital, Sutton, UK

Abstract

Molecular targeted therapies for breast cancer are unlikely to be effective when given alone, and development of appropriate combinations is an active area of clinical and translational research.

HER2 targeted therapies (ie trastuzumab) have delivered significant improvements in disease-free and overall survival in early breast cancer. However, not all HER2 positive cancers respond to this therapy, and several strategies are now being developed to enhance blockade of HER2 signaling and overcome trastuzumab resistance. These include complete HER2 blockade by the addition of improved antibodies that target the dimerisation domain of HER2 (pertuzumab), or the addition of small molecule tyrosine kinase inhibitors that target both HER2 and EGFR (lapatinib, neratinib). Enhanced vertical blockade of HER2 signaling may be achieved by co-targeting downstream signaling pathways with either HSP90 inhibitors that interfere with client HER2 protein processing (tanespimycin), mTOR inhibitors (ie. everolimus), or anti-angiogenic therapies (bevacizumab, pazopanib).

Combined targeted therapies may also enhance the benefit of targeted endocrine therapy in ER+ breast cancer. Endocrine resistance is associated with EGFR / HER2 cross-talk with ER signaling, and Type I growth factor receptor inhibitors give additive / synergistic effects when combined with endocrine agents. Two randomised trials have reported that the addition of trastuzumab or lapatinib to an aromatase inhibitor significantly improved time to disease progression in ER+ HER2+ advanced breast cancer. Strategies to overcome or delay endocrine resistance in hormone sensitive ER+ disease have included adding either gefitinib, lapatinib or the mTOR inhibitors temsirolimus / everolimus to first-line endocrine therapy in either advanced or early stage breast cancer. Results to date have been mixed, although it is likely that small defined subgroups may derive added clinical benefit. Biomarker studies associated with these clinical trials remain critically important in attempting to select appropriate patients for whom the addition of these novel targeted agents is worthwhile.