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Chemoprevention in the 21st Century: Is a Balance Best or Should Women Have No Estrogen at All
http://www.100md.com 《临床肿瘤学》
     Fox Chase Cancer Center, Philadelphia, PA

    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 women1 and the other is to use the aromatase inhibitors to reduce the risk of breast cancer by removing all estrogen.2

    The goal with SERMs is to strike a balance for the patient. The idea3 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.4,5 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.6-8 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,9 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 testing a third generation of safer, more specific compounds. Tamoxifen is an agent originally developed for the "regulation of the sexual cycle" with the "possibility of use in the treatment of hormone dependent cancers."9 Raloxifene, under the name of keoxifene, is a reinvention of a failed breast cancer treatment.9 New SERMs are needed for a variety of applications. Indeed, the recent concern over the widespread use of hormone replacement therapy10 should act as an incentive to seek SERMs as multifunctional medicines.

    The story of chemoprevention for breast cancer is a tale of individuals proposing or creating the correct path to promote progress. The advantage that breast cancer has had over other solid tumors is the known link between estrogen and breast carcinogenesis. By necessity, progress has been advanced through laboratory research establishing scientific principles that support the feasibility of clinical testing.

    Professor Antoine Lacassagne,11 speaking before the members of the American Association for Cancer Research at their meeting in Boston in 1936, suggested that a therapeutic antagonist to estrogen should be developed to block estrogen-induced breast cancer. His conclusions were based on laboratory observations that early ovariectomy would prevent the appearance of mammary tumors in strains of mice with a high incidence of mammary cancer. It was obvious, however, that the random oophorectomy of teenage girls was an inappropriate prevention strategy! Fifty years later, tamoxifen, a nonsteroidal estrogen antagonist, was shown to be superior to ovariectomy in the same mouse model12 prior to Benard Fisher opening the National Surgical Adjuvant Breast and Bowel Project P-1 prevention trial testing the worth of tamoxifen to prevent primary breast cancer in high-risk pre- and postmenopausal women.13

    The term "chemoprevention" was first introduced by Michael Sporn14,15 to describe the application of drugs to slow or reverse the process of carcinogenesis. This definition contrasted with the use of the term "chemotherapy" by Professor Paul Ehrlich in the early 20th century to describe a synthetic agent employed to treat disease.16

    Tamoxifen, whether administered simultaneously17,18 or after19-21 a chemical carcinogen, almost completely prevents mammary carcinogenesis in rats. These scientific data, coupled with the observation that tamoxifen reduces the incidence of contralateral breast cancer,22 acted as a catalyst to take a bold step toward testing the safety of tamoxifen as a chemopreventive in high-risk women. In 1986, Trevor Powles initiated a vanguard study of tamoxifen to test the safety and acceptability of the medicine as a chemopreventive.23 The enormous amount of safety data, that was subsequently developed by the clinical community, presaged the pioneering study by Bernard Fisher and the National Surgical Adjuvant Breast and Bowel Project that resulted in the approval by the Food and Drug Association of the first agent to reduce the risk of breast cancer in high-risk pre- and postmenopausal women.13

    Now that we have started down the path to prevent cancer with chemicals, what are the challenges that must be overcome We need new SERMs for women's health to fill the void left by hormone replacement therapy. We need to target the correct populations rather than blanket treatments to help a few. This is what made the original SERM idea so attractive; prevent osteoporosis and coronary heart disease, and prevent breast cancer as a beneficial side effect.3 But there is another major challenge for the scientific community dedicated to advancing chemoprevention. The idea of developing SERMs focuses entirely on postmenopausal women. Aromatase inhibitors focus on postmenopausal women. In fact, most of the breast cancer that occurs in the 50- to 65-year age group has its genesis in the premenopausal years. In the future, we need to advance chemoprevention beyond the manipulation of hormones, while not creating a potential catastrophe for women of reproductive age.

    The challenge is to address agent safety and product liability satisfactorily. It is said that the major problem with the use of tamoxifen as a chemopreventive was that we knew too much about the problems with the medicine. It had become the most investigated drug for cancer but the strategy for testing it was again an old concept; estrogen is bad for breast cancer. The next advance can only be made if new ideas and new targets come from academic laboratories and are rapidly developed by partnerships with the pharmaceutical industry. It was done with tamoxifen and raloxifene, and it can be done again.

    Author's Disclosures of Potential Conflicts of Interest

    The author indicated no potential conflicts of interest.

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