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Breast cancer therapy has undergone a series of evolutionary (and sometimes revolutionary) steps, a process that has accelerated in the past two decades as our understanding of breast cancer biology has steadily improved. This chapter, and indeed this book, outline some of these changes and attempt to place them in the context of breast cancer biology.

It is important to recognize that breast cancer therapy, from its earliest days in the modern scientific period of medicine, has always had both a strong theoretical as well as a pragmatic and empirical basis. If one begins with the last years of the nineteenth century, two theories of breast cancer biology were already being examined for their therapeutic benefit.

First, and the dominant strand for over half a century, was the work of Halsted and colleagues, who posited that breast cancer was a disease with a logical basis of metastasis via direct extension from the breast to the regional lymph nodes to distant sites via the lymphatic system. This theoretical conception of breast cancer biology implied the necessity for complete removal of all local-regional disease, and served as the basis for both breast cancer surgery and radiation therapy as potentially curative modalities.

The second strand, and ultimately the most important one for our purposes, was the recognition by Sir George Beatson that many breast cancers, though not all, were under the control of the ovaries in premenopausal women, and that breast cancers (both in the breast and at distant sites) could regress if the ovaries were resected [1]. This deep insight was ignored and forgotten for many years, but eventually served as the basis for our modern understanding of breast cancer biology.


The modern synthesis of breast cancer biology began with the discovery of the estrogen receptor (ER) in the 1960s, and the recognition by the mid-1970s that the ER could be measured in human breast cancers and predicted therapeutic response to manipulations of the internal hormonal milieu [2]. The recognition that the ER played a key role in many breast cancers also led to the development of numerous agents targeting either the ER or its ligand, estrogen.

These agents included, famously, the selective ER modulator tamoxifen, an agent which perhaps represented the first real molecularly-targeted therapy in all of oncology, and to this day the agent that has arguably saved more lives than any other in all of oncology.

Tamoxifen was followed by numerous other agents (e.g. aromatase inhibitors, LHRH agonists, fulvestrant; and steroidal agents in the progesterone, androgen, and estrogen families), but serves as an excellent example of targeted therapy. First, measure the target (in this case, the ER, though the progesterone receptor was soon added as a measure of an intact ER pathway); then use the target ...

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