ABSTRACT: Obesity is a growing health problem in the United States and, increasingly, around the world. Excess body weight has been linked to an increased risk of postmenopausal breast cancer, and growing evidence also suggests that obesity is associated with poor prognosis in women diagnosed with early-stage breast cancer. Dozens of studies demonstrate that women who are overweight or obese at the time of breast cancer diagnosis are at increased risk of cancer recurrence and death compared with leaner women, and some evidence suggests that women who gain weight after breast cancer diagnosis may also be at increased risk of poor outcomes. In this review, we describe the evidence linking obesity to breast cancer recurrence, discuss the potential biological mechanisms through which weight could impact breast cancer prognosis, and review the weight-loss intervention studies that have been performed in breast cancer populations to date.
Observational Studies Linking Weight to Prognosis in Early Breast Cancer
Weight at diagnosis
In 1976, Abe et al reported the first study investigating the relationship between body weight and breast cancer recurrence. The study demonstrated that women who were overweight or obese had a 5-year survival rate of 55.6%, compared with a rate of 79.9% in leaner women. The study also showed that obese women were more likely to have larger tumors, with higher rates of lymphatic invasion and nodal involvement. Since this initial report, there have been more than 50 studies examining the relationship between body weight and breast cancer prognosis. A recent meta-analysis of 45 studies reported prior to 2005 demonstrated that women who are obese at diagnosis have a 30% higher risk of breast cancer–related and overall mortality, compared with leaner women. The authors also demonstrated that the relationship between obesity and poor prognosis was independent of menopausal status, type of study (observational vs treatment trial), year of study report (prior to or after 1995), and type of weight measurement (body mass index [BMI] vs weight).
Although these observational studies have consistently linked weight at diagnosis to breast cancer outcomes, there are still questions regarding the potential confounding of this relationship by treatment-related factors. In the past, obese patients were often treated with relatively lower doses of chemotherapy compared with leaner individuals. Common practices included dosing chemotherapy by ideal rather than actual body weight or capping the chemotherapy dosing at a body surface area (BSA) of 2 m2 in an effort to decrease toxicity. Treating obese patients with lower doses of chemotherapy was shown to be associated with an increased risk of cancer recurrence in Cancer and Leukemia Group B 8541, a randomized trial assessing the schedule and dose of adjuvant chemotherapy in women with lymph-node positive breast cancer. In this study, 23% of obese patients (defined in the study as patients with a BMI of 27.3 kg/m2 or greater rather than the modern definition of obesity as a BMI of at least 30 kg/m2) received less than 95% of the expected weight-based doses of chemotherapy drugs for their first cycle of therapy. These women had an increased risk of cancer recurrence compared with obese women who received the full weight-based doses of chemotherapy drugs (adjusted risk ratio [ARR], 0.73; 95% confidence interval [CI], 0.53 to 1.00). Obese women who were treated with chemotherapy dosed according to actual body weight had a risk of recurrence similar to that of leaner women (ARR, 1.02; 95% CI, 0.83-1.26).
Given this potential confounding effect of treatment factors, it is important that several more recent reports have demonstrated an increased risk of cancer recurrence in obese women in the setting of adjuvant treatment trials. Because these data were collected in the setting of clinical trials, the effect of chemotherapy dosing practices could be taken into account, and all patients received the same treatment. Patients in these studies were also treated with modern chemotherapy regimens and hormonal agents, making the results more relevant to current clinical practice. In the Anastrozole(Drug information on anastrozole), Tamoxifen(Drug information on tamoxifen), Alone or in Combination (ATAC) trial, postmenopausal women with hormone receptor–positive, stage I to III breast cancer were randomized to 5 years of tamoxifen, anastrozole (Arimidex), or the combination. Women who had a BMI of 35 kg/m2 or higher had an increased risk of recurrence vs women with a BMI less than 23 kg/m2 (hazard ratio [HR], 1.39; 95% CI, 1.06-1.82). The increased risk of recurrence in obese women was only seen among women treated with anastrozole and not those treated with tamoxifen; in all weight groups, however, the risk of recurrence was still greater in women treated with tamoxifen vs anastrozole. Obese premenopausal women treated with ovarian ablation and anastrozole in the Austrian Breast Cancer Study Group 12 study also had a higher risk of recurrence (HR, 1.60; 95% CI, 1.06-2.41) and death (HR, 2.14; 95% CI, 1.17-3.92) compared with normal weight women. Among overweight women in this study, the risk of cancer recurrence (HR, 1.49; 95% CI, 0.93-2.38) and death (HR, 3.03; 95% CI, 1.35-6.82) was higher in women treated with ovarian ablation and anastrozole, compared with those treated with ovarian ablation and tamoxifen, despite the fact that the two treatments were equivalent in the study population as a whole.
Obesity at diagnosis has also been linked to a higher risk of recurrence in recent adjuvant chemotherapy trials. In the Adjuvant Docetaxel(Drug information on docetaxel) vs Epirubicin(Drug information on epirubicin) Based Regimen (ADEBAR) study, a randomized trial that assessed the value of adding a taxane to anthracycline-based chemotherapy in patients with involved lymph nodes, obese women had a significantly higher risk of cancer recurrence vs women with a BMI less than 25 (P = .007). A similar adjuvant study, the Eastern Cooperative Oncology Group (ECOG) 1199 trial, randomized women with lymph node–positive breast cancer to four different anthracycline- and taxane-containing adjuvant therapy regimens. Obese women with hormone receptor–positive tumors were found to have a higher risk of recurrence (HR, 1.23; 95% CI, 1.02-1.49) and death (HR, 1.46; 95% CI, 1.15-1.85), compared with leaner women. There was no relationship between obesity at diagnosis and outcomes in patients with hormone receptor–negative or HER2-positive cancers. These results were verified in the ECOG 5188 study, which enrolled 1502 premenopausal women with estrogen receptor–positive, node-positive cancers. In this study, obese women were found to have a 40% increase in the risk of cancer recurrence and a 50% increase in the risk of death compared with leaner women.
A few trials have also evaluated the association between weight gain after diagnosis and rates of recurrence, but the results have not been consistent. Four studies looked at recurrence and weight gain in small groups of patients treated with older chemotherapy regimens, which often incorporated significant doses of corticosteroids and therefore were associated with greater weight gain than is typically seen with modern chemotherapy regimens.[8-10] Three of these studies demonstrated an association between weight gain and increased risk of recurrence in at least a subset of patients, but many women in these studies gained 10 kg or more. Modern studies using shorter-course, often anthracycline-based chemotherapy, in which weight gain was less severe (often averaging less than 2 kg) have largely failed to identify a relationship between weight gain and poor prognosis. One notable exception is the Nurses' Health Study (NHS), in which investigators showed that non-smoking women who gained 0.5 to 2 kg/m2 (median weight gain, 6 lbs) after the diagnosis of breast cancer, as well as women who gained more than 2 kg/m2 (median weight gain, 17 lbs), had a significantly increased risk of breast cancer death compared with women who maintained a stable weight (risk reduction [RR] for breast cancer death 1.35, 95% CI 0.93-1.95 for weight gain 0.5 to 2 kg/m2; and RR for death 1.64, 95% CI 1.07-2.51 for weight gain of > 2 kg/m2). In contrast, Cann et al found no prognostic effect of obesity in women in the Life After Cancer Epidemiology (LACE) study cohort, even among those with extreme weight gain (greater than 10%). Finally, recent data from several clinical trials also did not show a consistent relationship between weight gain after diagnosis and breast cancer outcomes, although some individual studies reported an increased risk of cancer recurrence in women who gained weight. More work is needed to understand the relationship between post-diagnosis weight change and outcomes in women with early-stage breast cancer.
Weight Loss and Prognosis in Dietary Interventional Studies
Given that many women gain weight after breast cancer diagnosis, there are relatively few data from observational studies describing the relationship between weight loss after diagnosis and disease outcomes. There are also no studies examining the impact of purposeful weight loss on breast cancer prognosis. However, two randomized trials that assessed the impact of dietary modification on disease-free and overall survival in women with early stage breast cancer shed some light on this issue. The Women's Interventional Nutrition Study (WINS) randomized 2400 women to a low-fat dietary intervention or a usual-care control group. Patients assigned to the intervention group experienced a 6-lb weight loss and a 24% reduction in breast cancer recurrence vs control participants. In contrast, the Women's Healthy Eating and Living (WHEL) study randomized 3088 women to a high fruit and vegetable, low-fat diet. Participants in the intervention group did not lose weight, and there was no difference in rates of recurrence in the intervention and control groups. Although there were a number of other differences between the studies, the weight loss sustained by participants assigned to the dietary intervention in the WINS study has been suggested as one potential reason for the difference in the study outcomes. Further work is needed to test the impact of weight loss on the risk of recurrence in women with early breast cancer.
Observational Studies of Physical Activity and Prognosis in Early Breast Cancer
Observational data also suggest that physical activity, an important factor in maintaining a healthy weight, may yield beneficial effects on breast cancer outcomes. Several reports have demonstrated better breast cancer–specific and overall survival in individuals who are physically active after breast cancer diagnosis, compared with breast cancer survivors who were more sedentary, although the data are not entirely consistent (Table 1). For example, the NHS investigators looked at the relationship between physical activity after diagnosis and rates of breast cancer recurrence and death in a cohort of 2987 women diagnosed with stage I to IIIa breast cancer. After a median follow-up of 96 months, patients who engaged in more than 9 MET (metabolic equivalent of task) hours per week of physical activity, equivalent to walking at an average pace for 3 hours per week, had a 50% lower risk of breast cancer recurrence, breast cancer death, and all-cause mortality than women who were inactive (engaging in less than an hour of moderate-intensity recreational activity per week). This finding adds to the growing evidence that obesity and related factors could affect breast cancer prognosis (Table 2).