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.
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.
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, 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 vs 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.
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 Exercise and Breast Cancer Outcomes
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).
Evidence Linking Obesity and Breast Cancer Prognosis
Despite the large number of observational studies demonstrating an association between increased weight at diagnosis and poor prognosis in patients with early breast cancer, there is no direct evidence that weight loss decreases risk of breast cancer recurrence. A growing number of small studies are investigating the feasibility of a variety of weight-loss interventions in breast cancer survivors. Most of these studies have enrolled fewer than 100 patients and have been conducted at a single institution. A few of these pilot studies have led to larger-scale trials, most of which are ongoing. A comprehensive review of these studies is beyond the scope of this article, but selected representative interventions, including those now being tested in larger populations, are described here.
Goodwin and colleagues performed a single-arm trial assessing the ability of a weight-management intervention, which incorporated support-group-provided diet-and-exercise counseling, to help patients lose weight or avoid weight gain during adjuvant chemotherapy. The investigators reported that 70% of participants met the weight goals over the course of the study. In another report, Shaw and colleagues performed a randomized pilot study in 64 obese women with early-stage breast cancer and demonstrated that participants randomized to low-fat and low-calorie diets experienced significant weight loss and a reduction in body fat, compared with controls (P = .006 and .008, respectively). Another small study randomized 48 obese breast cancer survivors to one of three dietary intervention arms (a Weight Watchers program, individualized dietary counseling, or both interventions combined), or to a control group. Women assigned to the combination-intervention group lost significantly more weight than controls by 3 months and maintained this weight loss throughout the 12-month study. Women assigned to the individualized counseling group also lost a significant amount of weight by the end of the study, but the group assigned to Weight Watchers alone did not experience significant weight loss.
In one example of a pilot study leading to a larger weight-loss trial, Mefferd and colleagues performed a single-arm trial of a cognitive behavioral therapy (CBT) weight-loss intervention in 85 overweight breast cancer survivors and demonstrated significant reductions in body weight, body fat, and lipid levels following the 16-week intervention (P = .05). The group then randomized 68 breast cancer survivors to the CBT weight-loss intervention or usual care control group and demonstrated that the CBT group lost significantly more weight at 16 weeks than the control group (5.7 kg vs 0.2 kg, P < .001). This work led to development of the Exercise and Nutrition to Enhance Recovery and Good Health for You (ENERGY) trial (PI, Cheryl Rock, PhD, RD, School of Medicine, University of California at San Diego), in which the ability of a CBT weight-loss intervention to lead to weight loss and improvements in quality of life will be tested in 800 breast cancer survivors.
Thomson and colleagues have also recently launched a moderate-sized weight-loss trial that developed from a small weight-loss pilot study. In a 2010 report, these investigators demonstrated an average 6.1-kg weight loss among 40 breast cancer survivors taking part in two dietary weight-loss interventions, one focusing on a low-fat diet and the other on a low-carbohydrate diet. Both intervention groups experienced a decrease in cholesterol and improvements in insulin sensitivity. The investigators are now conducting the CHOICE study, which will randomize approximately 370 long-term breast cancer survivors to low-fat and low-carbohydrate dietary interventions, to determine which approach has a greater impact on biomarkers linked to breast cancer prognosis. These two ongoing studies will provide additional information about the feasibility of weight loss in large groups of breast cancer survivors, the impact of weight loss on quality of life, and the biological mechanisms through which weight loss could affect breast cancer outcomes.
In addition to the many small studies such as those described above demonstrating that weight-loss interventions are feasible in breast cancer populations, one study has demonstrated sustained weight loss in a larger group of survivors. The Lifestyle Intervention Study for Adjuvant Treatment of Early Breast Cancer (LISA), randomized 338 postmenopausal women with hormone receptor–positive breast cancer to an educational control group or to a 2-year, telephone-based weight-loss intervention, modeled on the Diabetes Prevention Project. The weight loss intervention focused on calorie restriction, a low-fat diet, and increased physical activity. Participants randomized to the intervention received 19 telephone calls, as well as mailings and a participant manual. Intervention participants lost approximately 4.5 kg more weight than the control group at 6, 12, and 18 months, and they reported a significant improvement in physical functioning scores compared with control participants. Additional follow-up is ongoing.
The biologic mechanisms underlying the relationship between lifestyle factors and breast cancer are not well understood. In post-menopausal women, obesity is associated with higher estrone and estradiol levels due to increased peripheral aromatization of adrenal androgens in adipose tissue. Obesity also leads to lower levels of sex-hormone-binding globulin, resulting in higher levels of free estradiol in circulation. In premenopausal women, however, pre-operative estradiol levels are not related to risk of breast cancer recurrence or death, suggesting that obesity must affect prognosis through mechanisms other than estradiol levels in this population.
Selected Studies of Insulin (and Related Factors) and Breast Cancer Prognosis
Studies have demonstrated that obesity, especially abdominal adiposity, is associated with higher levels of insulin and other metabolic hormones in both pre- and postmenopausal women.[27,28] Elevated insulin levels have been linked to an increased risk of breast cancer, and several recent reports have demonstrated that women with higher levels of insulin or related proteins at the time of breast cancer diagnosis are at increased risk of cancer recurrence and death (Table 3). For example, Goodwin and colleagues demonstrated a twofold increase in the risk of cancer recurrence and a threefold risk of death in patients with the highest vs the lowest quartile of fasting insulin levels, and another recent study demonstrated that women with high levels of c-peptide, a breakdown product of insulin production, at the time of breast cancer diagnosis were found to have a higher risk of breast cancer–specific and overall death vs women with lower levels of c-peptide.
Preclinical and epidemiologic studies also suggest that other metabolic hormones may play a role in the relationship between obesity and breast cancer recurrence. Observational studies show that premenopausal women with high levels of insulin-like growth factor-1 (IGF-1) are at increased risk of developing breast cancer, and in vitro data also suggest that IGF-1 signaling plays a central role in the development and progression of breast cancer.[32,33] Epidemiologic studies also suggest that leptin and adiponectin, metabolic hormones produced by adipose cells that modulate insulin sensitivity, are associated with breast cancer risk.[34,35] Leptin and hepatocyte growth factor have been shown to stimulate growth of breast cancer cells lines in vitro,[36,37] providing support for the hypothesis that insulin and related metabolic hormones may mediate, at least in part, the relationship between obesity and breast cancer prognosis.
Recent data have also suggested that chronic inflammation, associated with obesity, diabetes, and several other disease states, may also play a role in breast cancer risk and prognosis. It has long been known that chronic inflammation from conditions such as inflammatory bowel disease, infection with Heliobacter pylori, and hepatitis can lead to increased risk of cancer. Recent preclinical data also demonstrate that increased levels or genetic alterations in inflammatory biomarkers such as TNFÎ± and IL-2 can lead to increased risk of breast cancer, and cohort studies have demonstrated that higher levels of inflammatory biomarkers such as c-reactive protein and IL-6 are associated with poor prognosis in early-stage breast cancer.
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A number of small studies in breast cancer and at-risk populations have demonstrated that lifestyle interventions can decrease visceral body fat, improve insulin sensitivity, and lead to alterations in other metabolic hormones. One study demonstrated that participation in a mixed strength and aerobic exercise intervention led to a 28% decrease in fasting insulin levels in a group of overweight breast cancer survivors, and other reports demonstrate that participation in weight loss and physical activity interventions can impact other metabolic and inflammatory hormones linked to breast cancer risk and outcomes.[41-43] Data from large-scale lifestyle interventions are limited, however, and no clear intermediate markers of breast cancer prognosis have been established.
Obesity is a growing problem in the United States and may be especially problematic for breast cancer survivors. Dozens of studies have suggested that obesity at diagnosis is associated with poor outcomes in women with early-stage breast cancer. Recent observations confirm that this relationship persists in women treated with modern adjuvant therapy regimens. Data regarding the relationship between weight change after breast cancer diagnosis and prognosis are limited, but some reports suggest that women who gain significant amounts of weight after diagnosis could have a poor prognosis as well. The WINS study showed that women who were randomized to a low fat dietary intervention, and who lost an average of 6 lbs as a result of participation in the intervention, experienced a lower rate of breast cancer recurrence. However, no study has tested the impact of purposeful weight loss on disease outcomes in women with early breast cancer. A number of small weight-loss-intervention studies, as well as one larger-scale trial, have been performed in breast cancer populations. These trials demonstrate that weight loss is feasible after breast cancer diagnosis, and that women who lose weight experience improvements in quality of life and favorable alterations in serum biomarkers that are linked to breast cancer prognosis. More work is needed to determine whether weight loss after breast cancer diagnosis will lead to improvements in disease-free and overall-survival outcomes in women with early-stage disease.
Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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