Chemoprevention in the 21st Century: Is a Balance Best or Should Women Have No Estrogen at All?

Abstract

Twenty years ago, chemoprevention for cancer was a strategy conceived and proven in the laboratory and poised for clinical testing. Today, a selection of agents is now emerging that can reduce breast cancer risk so that remarkably, women will soon have choices in their health care needs. In this issue, I have invited Carol Fabian and Jack Cuzick to present overviews of progress in breast cancer risk reduction. Both individuals have been involved with the evolution of our concepts about hormones and cancer for the past 25 years, so they are well qualified to review their disciplines. This is an important time in health care delivery as there is a requirement not only for effective treatment of disease but also for an expectation of disease prevention (or deferment). Although there has been considerable progress in clinical chemoprevention, there are enormous challenges for the future. Whether these challenges can be resolved will ultimately decide the availability of the menu of medicines for women at risk. I strongly believe that there will be no single answer to chemoprevention in breast cancer. The reason for this statement is illustrated by the fact that two schools of thought have emerged. One choice is to use selective estrogen receptor modulators (SERMs) to prevent multiple diseases in women and the other is to use the aromatase inhibitors to reduce the risk of breast cancer by removing all estrogen. The goal with SERMs is to strike a balance for the patient. The idea that a medicine could be designed to reduce the risk of breast cancer in postmenopausal populations that are being treated for osteoporosis is now a reality. Raloxifene is available to treat and prevent osteoporosis with breast and endometrial safety. Nevertheless, the current scientific challenge with SERMs is to create a new targeted agent. In contrast, the strategy to remove all estrogen will provide optimal prevention of estrogen receptor–positive breast cancer and probably reduced risk of endometrial cancer and blood clots compared with tamoxifen. There is no doubt, based on current clinical experience with aromatase inhibitors, that this is possible. Nevertheless, the application of aromatase inhibitors in healthy women must be balanced against the potential to degrade other estrogen-dependant systems. The key role of estrogen in maintaining bone density is well recognized and can be addressed with prophylactic bisphosphonates, but the role of estrogen in maintaining neural integrity in the CNS may (or may not) accelerate dementia. Further progress in chemoprevention will be dependant upon recognizing the current shortcomings of both approaches. Chemoprevention must be advanced by the critical identification of select populations who really need the medication. We are currently embracing a targeted approach to breast cancer treatment, so why should high-risk populations of women accept anything less from chemoprevention? Regrettably, the two approaches to the chemoprevention of breast cancer have diverged, as there is a current reluctance to compare and contrast the SERM approach of ‘‘is a balance best’’ with the aromatase inhibitor approach of ‘‘no estrogen at all.’’ This may not be a bad thing, since the current SERMs, tamoxifen and raloxifene, are reinventions of older medicines, so the best of a new generation of SERMS needs to be pitted against the best aromatase inhibitor. Unfortunately, the genesis of drug development mandates that this process will take a couple of decades to achieve success. Indeed, the aromatase inhibitors have been used for three decades but only now are we VOLUME 23 d NUMBER 8 d MARCH 1