Obesity and Hormone Therapy in Breast Cancer: An Unfinished Puzzle

Abstract

The relationship between obesity and breast cancer is a complex one. 1 Obesity is associated with breast cancer risk in qualitatively different ways before and after menopause (with decreased risk in premenopausal women and increased risk in postmenopausal women), whereas similar associations of obesity with prognosis are seen in pre- and postmenopausal women (obese women in both groups experience poorer outcomes). This complexity likely reflects, atleastinpart,thevariablerelationshipsbetweenobesityandestrogen (a major contributor to the growth of hormone receptor‐positive breast cancer) before and after menopause. Before menopause, obesity may interfere with normal menstrual cycling, potentially leading to reductions in estrogen levels; after menopause, increased production of estrogen in excess adipose tissue in obese women is associated with higher estrogen levels. It is likely that the complexity of the relationshipbetweenobesityandbreastcanceralsoreflectsimportant contributions of obesity-related factors other than estrogen to both breast cancer risk and prognosis. 2 These factors include insulin, adipocytokines such as leptin, and adiponectin, as well as inflammatory markers such as C-reactive protein and interleukins. In this issue of Journal of Clinical Oncology, Sestak et al 3 report intriguingresultsofananalysisoftheimpactofobesityontheefficacy of tamoxifen and anastrozole in 5,172 postmenopausal women with hormone receptor‐positive breast cancer who participated in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trial. The population studied was predominantly overweight (body mass index [BMI] 25 to 30 kg/m 2 ; 36.7% of the study population) or obese (BMI 30 kg/m 2 ; 27.3% of the study population). This pattern of obesity is similar to that reported in many recent trials in early breast cancer. The authors reported a significant increase in risk of breast cancerrecurrenceanddeathafterbreastcancerrecurrenceforwomen with higher BMIs but not an increase in the risk of death without recurrence. The authors also demonstrated a significant interaction between treatment and obesity on risk of recurrence—there was a significantlygreaterriskofrecurrenceinoverweightwomenreceiving anastrozole but not in those receiving tamoxifen (Table 4 in Sestak et al 3 ). Furthermore, the relative reduction in risk of recurrence with anastrozole (v tamoxifen) was insignificantly smaller for heavier womenthanforlighterwomen(Fig2inSestaketal 3 ).Theseobserva