The 38th David A. Karnofsky Lecture: The Paradoxical Actions of Estrogen in Breast Cancer—Survival or Death?

During the first David A. Karnofsky Award lecture entitled "Thoughts on Chemical Therapy" in 1970, Sir Alexander Haddow commented about the dramatic regressions observed with estrogen in some breast cancers in postmenopausal women, but regrettably the mechanism was unknown. He was concerned that a cancer-specific target would remain elusive, without tests to predict response to therapy. At that time, I was conducting research for my PhD on an obscure group of estrogen derivatives called nonsteroidal antiestrogens. Antiestrogens had failed to fulfill their promise as postcoital contraceptives and were unlikely to be developed further by the pharmaceutical industry. In 1972, that perspective started to change and ICI 46,474 was subsequently reinvented as the first targeted therapy for breast cancer. The scientific strategy of targeting the estrogen receptor (ER) in the tumor, treating patients with long-term adjuvant therapy, examining active metabolites, and considering chemoprevention all translated through clinical trials to clinical practice during the next 35 years. Hundreds of thousands of women now have enhanced survivorship after their diagnosis of ER-positive breast cancer. However, it was the recognition of selective ER modulation (SERM) that created a new dimension in therapeutics. Nonsteroidal antiestrogens selectively turn on or turn off estrogen target tissues throughout the body. Patient care was immediately affected by the recognition in the laboratory that tamoxifen would potentially increase the growth of endometrial cancer during long-term adjuvant therapy. At that time, a failed breast cancer drug, keoxifene, was found to maintain bone density of rats (estrogenic action) while simultaneously preventing mammary carcinogenesis (antiestrogenic action). Perhaps a SERM used to prevent osteoporosis could simultaneously prevent breast cancer? Keoxifene was renamed raloxifene and became the first SERM for the treatment and prevention of osteoporosis as well as the prevention of breast cancer, but without an increase in endometrial cancer. There the story might have ended had the study of antihormone resistance not revealed a vulnerability of cancer cells that could be exploited in the clinic. The evolution of antihormone resistance over years of therapy reconfigures the survival mechanism of the breast cancer cell, so estrogen no longer is a survival signal but a death signal. Remarkably, remaining tumor tissue is again responsive to continuing antihormone therapy. This new discovery is currently being evaluated in clinical trials but it also solves the mystery mechanism of chemical therapy with estrogen noted by Haddow in the first Karnofsky lecture.