Past, present, and future challenges in breast cancer treatment.

The past half century—the lifetime of the American Society of Clinical Oncology—represents a historical watershed in the management of breast cancer, a period in which old dogmas were overthrown, to be replaced by biology-driven therapeutic approaches. These approaches transformed the disease from one where mutilating local therapy was followed by distant recurrence and death, to one where patients regularly choose local (and often minimal) therapy, then receive systemic therapies that are increasingly effective and progressively more targeted. Breast cancer, perhaps more than any other solid tumor, was transformed by the progressive application of clinical hypothesis testing of basic biologic concepts. The revolutionary overthrow of the Halstedian hypothesis, with its emphasis on the primacy of locoregional control through extensive surgery, led to changes both in locoregional therapy as well as providing the intellectual basis for adjuvant systemic therapies. And, at a time when systemic therapies were dominated by rank empiricism, breast cancer led the way in the application of targeted biologic therapy, long before targeted therapy became an oncologic mantra. This article will review a half-century of progress, focusing on the areas in which the greatest progress has been seen: the revolution in locoregional therapy; the application of cytotoxic chemotherapy in both local and advanced disease; the discovery and therapeutic exploitation of estrogen receptor biology; the use of estrogen receptor biology for breast cancer prevention; and the targeting of the human epidermal growth factor receptor complex. Collectively, these constitute a revolution in breast cancer therapeutics that has occurred within the lifetime of an organization. Finally, we will touch on the remaining therapeutic challenges for this disease. Locoregional Therapy The locoregional treatment of breast cancer has been transformed through changes in both the biologic understanding and the clinical presentation of the disease. Starting with the pivotal randomized clinical trials from the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Milan group, radical mastectomy was replaced by modified radical mastectomy and eventually breastconserving surgery, with breast radiation becoming the preferred