Combinations of endocrine and biological agents: present status of therapeutic and presurgical investigations.

There is an increasing rationale to develop effective combinations of endocrine agents with novel therapeutics that target aberrant signal transduction pathways in estrogen receptor-positive breast cancer. Acquired resistance to endocrine therapy is associated with an increase in peptide growth factor signaling that results in crosstalk activation of estrogen receptor, and various signal transduction inhibitors (STI) can target these pathways to inhibit hormone-resistant growth. In experimental models of hormone-sensitive breast cancer, combinations of endocrine agents with STIs provide significantly greater growth inhibition than either alone, delaying the emergence of resistance. There are now several trials assessing the efficacy of combinations of tyrosine kinase inhibitors with various endocrine agents in the tamoxifen-resistant/second-line setting, together with five randomized phase II/III trials in the first-line setting. Similar work is ongoing with both farnesyltransferase inhibitors and mTOR antagonists where there are strong preclinical data to suggest additive or synergistic effects for either of these agents in combination with tamoxifen or estrogen deprivation therapies. More recently, presurgical studies with biological primary end points are being utilized as an alternative approach to investigate whether combined endocrine/STI therapy is a more effective strategy than endocrine therapy alone. This article reviews the rationale and current status of clinical trials in this area as well as the challenges that lie ahead for the development of these therapeutic combinations for breast cancer.