A personal account of the chemoprevention of breast cancer: Possible or not possible?

Abstract

Thirty-five years ago, the answer to the simple question "is the chemoprevention of breast cancer possible?" would have been "most unlikely." Thirty-five years ago, there was almost no constructive strategy to prevent breast cancer. This approach to cancer therapeutics was not considered necessary because combination cytotoxic chemotherapy was predicted to cure cancer. Regrettably, this clinical prophecy did not materialize. Nevertheless, the link between estrogen and the development and growth of breast cancer became an established fact throughout the early years of the 20th century. Beatson [1] and Boyd [2] demonstrated that some women with advanced breast cancer responded to oophorectomy but subsequent advances in laboratory investigations would create a new strategy that would transform an idea i.e., chemoprevention, into a practical reality for thousands of women at high risk for developing breast cancer. Lathrop and Loeb [3] used inbred strains of mice with a high incidence of mammary cancer to demonstrate that early oophorectomy would prevent carcinogenesis. Twenty years later in 1936, Lacassagne, in an address to the American Association for Cancer Research concluded that to prevent breast cancer "a therapeutic antagonist was necessary to stop the congestion of oestrone in the breast" [4]. However, there was no appreciation of a subcellular therapeutic target until Jensen identified the estrogen receptor (ER) [5] as the mediator of estrogen action in estrogen target tissues, including the breast [6]. The story of the practical application of chemoprevention for women at high risk would start with the assembly of apparently unrelated pieces of scientific evidence to develop not one, but ultimately two, approaches to reducing breast cancer incidence. But first, existing compounds needed to be taken from the shelves of the pharmaceutical industry where they had been placed. The so-called nonsteroidal antiestrogens, tamoxifen and raloxifene, were never intended by the pharmaceutical scientists to be chemopreventives, and both had failed in their initial applications. Only with the recognition of the potential of a new drug group, the selective estrogen receptor modulators or SERMs [7], would both tamoxifen and raloxifene be reinvented as the first agents to reduce the incidence of breast cancer in targeted populations of high-risk women. © 2008 Humana Press Inc.