DIALOGUES IN ONCOLOGY Breast Cancer Prevention Richard R. Love University of Wisconsin Medical School, Madison, Wisconsin, USA Correspondence: Richard R. Love, M.D., M.S., University of Wisconsin Medical School, 610 Walnut Street, 256 WARF, Madison, Wisconsin 53705-2397, USA. Telephone: 608-263-7066; Fax: 608-263-4497. Dr. Trevor Powles' review [1] of current results from clinical trials of agents that may prevent breast cancer from ever beginning or suppress preclinical disease touches on several issues critical in interpreting our understanding of this subject and on translating this understanding into evidence-based clinical practice. This commentary restates, emphasizes, and expands on the most important issues. THE ABSENCE OF A COMPREHENSIVE MODEL OF BREAST CANCER DEVELOPMENT While there is no doubt that estrogen plays a significant role in breast cancer development, we currently have no satisfying models that explain, well and completely, identified epidemiologic risk factors for this disease. Which hormones are most critical? What is the role of progestogens? When in women's lives are hormonal effects on the breast most critical; in particular, how important are in utero and congenital hormonal exposures? Such questions emphasize some important aspects of hormonal "prevention:" complexity, effects of hormones over long periods of time, and the multiorgan system nature of the particular hormonal biology focused on here. Before addressing the broad clinical issues Powles' data review raises, these biological uncertainties demand our consideration. Subject in point: the role of antiestrogen treatment in high-risk, presumed genetic-familial risk, women. Such women, BCRA1-presumptive or -proven carriers for example, have been considered a most important group to target for chemoprevention, and Powles correctly highlights our uncertainty about the results and role of tamoxifen in these women. On the one hand, clonic tumors from BCRA1 and BCRA2 mutation carriers are more likely to be hormone receptor-negative [2], and in an early analysis of small numbers of BCRA1 mutation carriers in the National Surgical Adjuvant Breast and Bowel Project breast cancer prevention trial, NSABP P-1, King has reported that tamoxifen was not associated with reduced numbers of breast cancers, while the opposite was true in BCRA2 mutation carriers [3]. These observations suggest that a hormonal treatment is not likely to prevent or suppress breast cancer in these BCRA1 women. On the other hand, Rebbeck found that prophylactic oophorectomy in BCRA1 mutation carriers was associated with decreased risk of later breast cancer [4]. One can argue that the absence of a testable model of breast cancer prevention is likely to make interpretation of clinical trials of prevention difficult, if not impossible. THE NUMBERS GAME IN PREVENTION The focus in breast cancer prevention trials has been on "high-risk" women for two broad reasons: to increase the numbers of events likely (i.e., cancers), and to increase the benefit:risk ratio. The general difficulty is that with the exception of laboratory-confirmed gene mutation carriers and women with lobular carcinoma in situ, other high-risk populations are small and have low absolute risks of developing breast cancer in the next 5-10 years [5, 6]. Thus, in the larger broad "high-risk" trials Powles discusses, the intervention can, in the best of circumstances, benefit only a minority of women, while any side effects accrue to the entire treated group. Quantifying the short-term benefits is not as difficult as quantifying the spectrum of risks. This is particularly a challenge in trials where healthy volunteers participate, a circumstance that makes generalization of results to broader populations difficult. The Oncologist, 4/02 The Oncologist, 4/02 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.