Abstract CN06-02: Fitness versus fatness in breast cancer risk and prognosis
Authors: McTiernan Anne 
Published: May 2012

Abstract
CN06-02
Breast cancer prevention and survivorship have several common modalities. Lifestyle factors such as increased physical activity and maintenance of normal weight, are associated with reduced risk of breast cancer, and are also associated with improved prognosis in breast cancer patients and survivors. The International Agency for Research on Cancer (IARC) estimates that 25% of breast cancer cases worldwide are due to overweight/obesity and a sedentary lifestyle (1). Several observational and intervention studies suggest that the greatest benefit from physical activity is seen in individuals who are normal weight or, in intervention studies, in persons who exercise at high enough levels to lose body fat. These lifestyle patterns may increase breast cancer risk and reduce prognosis by several mechanisms including, but not limited to, increased estrogens, testosterone, and prolactin; hyperinsulinemia, insulin resistance, and hyperglycemia; and increased inflammation (1).
This talk will review human observational and experimental studies including: 1) the Women’s Health Initiative (WHI) Observational Study; the WHI Dietary Modification Trial; 3) a randomized controlled trial testing exercise effect on breast cancer biomarkers; and 4) a cohort study of breast cancer survivors.
The WHI Observational Study includes over 92,000 postmenopausal women aged 50-75 years recruited through 40 clinical centers across the U.S. We ascertained physical activity habits at study entry, including vigorous, moderate, and light activities, and walking for transportation or recreation, and created composite variables weighting for intensity (METS) (2). After a mean follow-up of 4.7 years, we found a statistically significant reduction in risk of breast cancer with increasing MET-hours/week (p trend = 0.02). Women who engaged in the equivalent of 1.25-2.5 hours per week of brisk walking had an 18% decreased risk of breast cancer (RR 0.82, 95% CI 0.68-0.97), compared with inactive women. Slightly greater reduction in risk was observed for women who engaged in the equivalent of 10 hours or more per week of brisk walking. The effect of exercise was most pronounced in women in the lowest tertile of body mass index (BMI) (&lt; 24.1), but was also observed for women in the middle tertile of BMI (24.1-28.4).
Baseline data from a WHI Dietary Modification sub-sample indicate that obese, sedentary postmenopausal women have the greatest blood levels of estrogens compared with lighter-weight, more active women (3). In multiple regression analyses on log-transformed hormones, BMI was positively and statistically significantly associated with concentrations of estrone (β=0.031, p&lt;0.001), estradiol (β=0.048, p&lt;0.001), free estradiol (β=0.062, p&lt;0.001), free testosterone level ( β=0.017, p=0.02), prolactin (β=0.012, p=0.02), and negatively associated with SHBG (β=-0.02, p=0.001). Total physical activity (METs/week) was negatively and significantly associated with concentrations of estrone, estradiol, and androstenedione (estimated β= -0.006, -0.007, and -0.005 respectively, all p &lt; 0.05). Using a composite variable of BMI and physical activity dichotomized by median values, women with high BMI/low physical activity had a mean estrone concentration of 28.8 pg/mL, compared with 24.1, 19.9, and 18.4 pg/mL for women with high BMI/high physical activity, low BMI/high physical activity, and low BMI/high physical activity, respectively (p trend &lt;0.001). Similar statistically significant trends were observed for estradiol and free estradiol, and, in inverse, for SHBG.
We examined the effects of a 12-month moderate-intensity exercise intervention on serum estrogens (4). We randomly assigned 173 sedentary, overweight (body mass index &gt; 24.0 kg/m2, body fat &gt; 33%), postmenopausal women, ages 50 to 75 years, not using hormone therapy. The exercise intervention included facility and home-based exercise (45 minutes, 5 days/week moderate intensity sports/recreational exercise). 170 (98.3%) women completed the study with exercisers averaging 171 minutes per week of exercise. After three months, exercisers experienced declines in estrone, estradiol, and free estradiol of 3.8%, 7.7%, and 8.2%, respectively, vs. no change or increased concentrations in controls (p = 0.03, 0.07, 0.02, respectively). At 12 months, the direction of effect remained the same, although the differences were no longer statistically significant. The effect was limited to women who lost body fat: women whose percent body fat (by DEXA) decreased by 2% or greater had statistically significant (comparing exercisers vs. controls) decreases at 12 months of 11.9%, 13.7%, and 16.7% for serum estrone, estradiol, and free estradiol, respectively. Similar findings were observed for androgens (5). In particular, serum testosterone and free testosterone significantly decreased with increasing loss of body fat in exercisers vs. controls.
In a population-based multi-race/ethnic cohort study of 1183 Stage 0-3a breast cancer patients followed for up to 10 years, we are assessing the effects of obesity, physical activity, and related metabolic factors on prognosis. In baseline cross-sectional analyses among postmenopausal patients, we found that increasing adiposity was positively associated with serum estrogens and testosterone, regardless of tamoxifen use (6). In prospective analyses in women with Stage I-IIIa breast cancer, the multivariable hazard ratio for total deaths for women expending at least 9 metabolic equivalent hours per week two years after diagnosis (approximately 2 to 3 h/wk of brisk walking) was 0.33 (95% CI, 0.15 to 0.73; P = .046) vs. inactive women (7).
These studies support associations of maintenance of normal weight and an active lifestyle with reduced risk of breast cancer occurrence, and improved prognosis for women with breast cancer. Future research directions will also be outlined in this talk.
Citation Information: Cancer Prev Res 2008;1(7 Suppl):CN06-02.