ASTRO keynote address “Progress in targeted therapies for breast cancer (BC)”

Abstract

Optimal treatment of BC includes cytotoxic and endocrine therapies, in addition to surgery and radiotherapy. Combined modality strategies have improved survival, are safe with a modest rate of long-term serious adverse events. Research into the biological behavior of BC uncovered a number of molecular signaling processes involved in growth, proliferation, invasion and metastasis. Progress in our understanding of steroid hormone biology facilitated the development of novel endocrine agents. The discovery and identification of the estrogen receptor represented the watershed event in endocrine therapy. Thus, endocrine interventions became the prototype for “targeted therapy” for BC. Important lessons learned in endocrine therapy were that identification of the molecular target was critical to determine the population likely to benefit from this therapy, expanded understanding of the role of various co-factors (co-activators and co-repressors) in determining the specificity and direction of the signal, identification of structure-function interactions in the binding pocket of the receptor and the development of selective estrogen receptor modulators (SERMs) and selective estrogen receptor downregulators (SERDs). Tamoxifen, the first SERM became the endocrine treatment of choice for all stages of hormone receptor-positive breast cancer, and the first agent with demonstrated effect of chemoprevention of breast cancer. Recent research highlighted the critical role of estrogen deprivation (ovarian suppression/ablation and the use of selective aromatase inhibitors) as a form of endocrine therapy. The differential effects of genomic and non-genomic functions of the estrogen receptor led to better understanding of complex cross-talk functions between steroid hormone receptors and other growth factor receptors in proliferation, survival and apoptosis of breast cancer cells. Such expanded understanding led to increasing interest in combining highly targeted molecular therapeutics to more fully interrupt critical drivers of intracellular signaling.