A Weight Loss Trial for Breast Cancer Recurrence: Pre-Menopausal, Post-Menopausal, Both, or Neither?

Abstract

Because the link between adiposity (overweight and obesity) and breast cancer outcomes has been apparent for many years, it seems that a randomized controlled trial to test the effects of weight loss on breast cancer recurrence is long overdue. In this commentary we will review the rationale for such a trial and comment on how emerging changes in clinical practice and surprising observations from recent research would suggest that if we had already begun such a trial we might well have designed it incor? rectly. Perhaps, then, it is fortunate that such a large-scale trial has not yet been initiated. Our bottom line: whether such a trial should now be done among pre-menopausal breast cancer survivors, among post-menopausal survivors, among both, or perhaps among neither, is not clear. After menopause, adiposity is clearly associated with increased risk of incident breast cancer [1-4]. Adiposity has also been found to be associated with a higher risk of breast cancer recurrence and/or poorer survival among post-menopausal women, though the evidence for this is mixed [1, 5-8]. The confounding effects of tobacco smoking and treatment on the adiposity-outcome rela? tionships may account for variation across studies. After menopause, when estrogen levels predict risk of incident breast cancer, the principal pathway for estrogen produc? tion is via the enzyme aromatase, which converts andro gens to estrogens, mainly in adipose tissues [9-11]. The etiologic role of estrogen in post-menopausal breast cancer has been proven by large trials demonstrating that estrogen replacement therapy increases breast cancer incidence [12], and that estrogen receptor blockade lowers risk of both breast cancer incidence [13] and recurrence [14]. That adiposity affects breast cancer risk via an estrogen pathway is supported by the observations that adiposity is a signif? icant predictor of breast cancer risk only among post menopausal women who do not take hormone replacement supplements [IS], and when estrogen receptors are blocked with Tamoxifen, the adverse effect of adiposity on breast cancer recurrence is reduced [16]. Physical activity, a necessary element in long-term weight control, may also affect breast cancer recurrence via an estrogen pathway as physical activity is protective against breast cancer recur? rence among women who have had cancers positive for estrogen receptors but not among women with cancers negative for estrogen receptors [17]. A combination of both weight loss and increased physical activity reduce estrogen levels [18]. Whether weight loss could therefore reverse the adverse effects of adiposity on breast cancer is not certain. There is some observational evidence that is consistent with the idea that weight loss can reduce breast cancer risk [15, 19, 20]. Observational studies assessing the effects of weight loss on recurrence will always be difficult to interpret, though, due to a myriad of confounding factors associated with intentional weight loss and due to the effects of both breast cancer and its treatment on body weight [21]. In many ways, then, the rationale for a trial of weight loss to benefit breast cancer survival has seemed most compelling for post-menopausal women, in whom adi? posity increases risk of breast cancer incidence, is associ? ated with poorer disease-free survival, and causes increased levels of estrogens which are proven to directly affect breast cancer risk. However, the new standard of care for estrogen receptor positive breast cancer may soon elimi? nate the pathway whereby a weight loss trial could be T. Byers (E) ? R. L. Sedjo Department of Preventive Medicine and Biometrics, University of Colorado School of Medicine, 4200 East Ninth Avenue, Box B-119, Denver, CO 80262, USA e-mail: Tim.Byers@uchsc.edu