A positive association between obesity and the risk of incident postmenopausal breast cancer has been consistently observed in epidemiologic studies. Although most studies of premenopausal women have not found a similar relationship between breast cancer and obesity, the prognosis for both pre- and postmenopausal breast cancer is substantially worse among obese than normal-weight individuals. Increasing evidence suggests that these associations may be mechanistically related to sex hormones, insulin, and certain adipokines. Insulin, for example, has important mitogenic/antiapoptotic activity in addition to its metabolic effects, and many breast tumors express high levels of the insulin receptor (IR)-A isoform. Further, the use of metformin, a diabetes medication that reduces insulin levels, has been epidemiologically associated with reduced breast cancer risk among patients with diabetes, and a recent observational study found a higher rate of pathologic complete responses among patients with diabetes and breast cancer who were using metformin. Formal clinical trials of metformin as adjuvant breast cancer therapy have been initiated and are ongoing. Similarly, the effect of lifestyle changes on breast cancer outcomes is actively being investigated. Several lifestyle intervention studies have demonstrated that weight loss, increased physical activity, and dietary changes are feasible in breast cancer populations, and that individuals who make lifestyle changes after breast cancer diagnosis experience several physical and psychologic benefits. In this article, the authors review the evidence linking obesity with breast cancer risk and outcomes and provide an overview of lifestyle intervention studies in patients with breast cancer.
The prevalence of obesity among U.S. women has more than doubled since the late 1970s, with 34% of women above 20 years of age currently estimated to be obese, and an additional 27% considered overweight (Fig. 1).1,2 Although the prevalence of obese and overweight women has, in recent years, stabilized at this high level, certain risk groups have especially high prevalence of excess adiposity, including women of black or Hispanic race/ethnicity, and those of lower social economic status.1,2 Obesity is a well-established risk factor for several common conditions including diabetes, cardiovascular disease, stroke, renal disease, nonalcoholic fatty liver disease/hepatic fibrosis, and disability. It is also significantly associated with overall mortality.3
Prevalence of obesity among women in the U.S. by (a) calendar time (1971 to 2004), and (b) race/ethnicity (average obesity prevalence during 1999 to 2004). Overweight was defined as a body mass index (BMI) of 25 to < 30 kg/m2, obese ≥ 30 kg/m2, and extreme obesity as ≥ 40 kg/m2. (Adapted from Ogden and colleagues.2)
More recently, obesity has been associated with cancer risk and mortality.3,4 Although data suggesting this association goes back to the 1990s and earlier, it is only in the past few years that the evidence has reached a point that the obesity-cancer relationship can be said to be well-established and broadly accepted. This change in perspective reflects not only the growing number of large, well-conducted prospective investigations regarding obesity and cancer, but also the growing number of laboratory and molecular epidemiologic studies that have helped demonstrate biologic plausibility. Table 1 shows a list of the cancers reported to have a significant positive association with obesity in women.4 In addition to breast cancer, these tumors include endometrial, gallbladder, esophageal adenocarcinoma, renal, leukemia, thyroid, pancreas, multiple myeloma, colon, non-Hodgkin lymphoma, rectal, and possibly ovarian cancers.3,4
TABLE 1. Cancers Associated with Obesity According to Meta-analysis Studies
*Adapted from Renehan et al, 20084
The review that follows provides an overview of the evidence relating obesity with breast cancer by subtype, including the associations of obesity with cancer incidence, recurrence, and survival. The laboratory and clinical/epidemiologic data that implicate specific signaling pathways in the obesity–breast cancer relationship are also discussed, and the authors review both published and ongoing interventional studies being conducted to target these pathways. Although there are currently no randomized trials testing the effect of purposeful weight loss after diagnosis on breast cancer prognosis, dozens of smaller-scale lifestyle intervention studies have been conducted in patients with breast cancer. This review provides an overview of the growing literature on lifestyle intervention studies in breast cancer.
ASSOCIATIONS OF OBESITY WITH INCIDENT BREAST CANCER BY SUBTYPE
Postmenopausal Compared with Premenopausal
There is a substantial body of research showing that postmenopausal women who are overweight or obese have increased risk of breast cancer compared with normal weight individuals. Although the effect of obesity estimated by recent meta-analyses is modest, a relative risk of approximately 1.15,4,5 these types of studies often lack pertinent data to control for relevant cofactors or conduct subset analyses. As an important example, a prospective study in the Women's Health Initiative found that excluding the 53% of women who were using hormone therapy (HT) increased the association of obesity and postmenopausal breast cancer from a hazard ratio [HR] of 1.13 (95% confidence interval [CI]: 0.83–1.55) to a HR of 1.91 (95% CI: 1.11–3.27).6 Similar results were reported in the Nurses' Health Study7 and in other cohorts.8 The effect of HT use likely reflects the strong first-pass effect of oral estrogens on the liver, which alters hepatic protein production and processing, including proteins related to glucose metabolism such as insulin and other hormones6; a frequent consideration in interpreting the obesity and breast cancer literature.
In contrast, studies of obesity and premenopausal breast cancer have had conflicting findings. Most studies have reported either an inverse association4 or no association between obesity and cancer risk among menstruating women,5 although a few studies found a positive association.4 Hypotheses to explain the possible protective effect of obesity on premenopausal breast cancer risk have largely focused on the relation of obesity with irregular or long menstrual cycles and anovulatory infertility, as having fewer ovulations is thought to correlate with reduced estrogen exposure.9
Estrogen Receptor (ER) and Progesterone Receptor (PR) Expression
Multiple studies of postmenopausal women have shown strong associations between obesity and the risk of ER+/PR+ breast cancer but not other breast cancer subtypes.10,11 For example, a meta-analysis of nine cohorts and 22 case-control studies found that each five unit change in BMI was associated with a 33% increased risk of ER+/PR+ postmenopausal breast cancer and a 10% decreased risk in ER+/PR+ premenopausal breast cancer, whereas no associations were observed for ER-/PR- or ER+/PR-.11 Although this study could not address use of HT in postmenopausal women, a large case-control study found a similar positive association of obesity with all ER+/PR+ postmenopausal breast cancer (OR = 1.3; 95% CI: 1.0–1.7) that was nearly two-fold higher for obesity when HT users were excluded (OR = 2.3; 95% CI:1.3–3.8).10 A meta-analysis that specifically addressed “triple negative tumors” (i.e., ER-/PR-/HER2-) found positive associations with obesity but only among premenopausal women,12 although that study could not account for HT use in postmenopausal women.
POSSIBLE MECHANISMS UNDERLYING THE OBESITY–BREAST CANCER ASSOCIATION
Most hypotheses regarding the biologic pathways that may underlie the relation of obesity with breast cancer focus on three areas: sex hormones, including both estrogens and androgens; the insulin/insulin-like growth factor (IGF)-axis; and adipocytokines, including both metabolic and inflammatory factors.
High endogenous serum estrogen levels have been consistently associated with breast cancer risk in postmenopausal women6,9,13 and are, on average, higher in overweight and obese women than in normal-weight women, likely due the activity of aromatase in adipose tissue.9 Estrogens are reported to be carcinogenic through at least two pathways, namely, the mitogenic/antiapoptotic activity of estrogens in the breast as well as other tissues, and the possibly mutagenic effects of estrogen metabolites. Postmenopausal breast cancer risk has additionally been associated with endogenous androgens, including testosterone, DHEAS, and androstenedion,14 which may reflect the conversion of androgens to estrogens by aromotase. Serum androgen levels are, like estrogen levels, correlated with adiposity. Recent prospective data suggest that the associations with estrogens and androgens may be specific, or at least strongest, for ER+/PR+ tumors.13
Obese women have high rates of impaired fasting glucose and diabetes, often accompanied by high circulating levels of insulin. In addition to insulin's well-known metabolic activity, it is also an important growth factor for a wide range of tissues and plays a substantial role in normal organogenesis. Indeed, insulin shares 40% amino acid sequence homology with insulin-like growth factor (IGF)-I, the primary mediator of the effects of growth hormone, and also shares mitogenic/antiapoptotic activity and downstream signaling pathways with IGF-I.15
As compared with insulin levels, however, levels of IGF-I in individuals with impaired fasting glucose and early diabetes are variable.16 Thus, it is insulin, and not IGF-I, that is increasingly thought to play a major role in the obesity-diabetes-cancer relationship. In animal models, high insulin levels have an independent mitogenic effect, and the insulin receptor (IR) is highly expressed in cancers of the breast.15 More specifically, tumors over-express the IR-A isoform, which is important in fetal development but does not have a primary role in metabolism; this observation may help explain increased cancer risk related to obesity, despite the presence of metabolic insulin resistance.15
Diabetes has been prospectively associated with postmenopausal breast cancer risk in many but not all studies.15 A meta-analysis found an overall relative risk (RR) of 1.20 (95% CI: 1.11–1.30) for the association of diabetes and breast cancer.17 This modest association could reflect the complicated relationship between diabetes and levels of insulin, as patients may use antidiabetic medications, and insulin levels may fall in advanced diabetes. Although few large prospective studies of insulin using fasting blood specimens have been reported, two of the three studies that addressed HT use found a strong relation of insulin levels with breast cancer among non-HT users.6,18 The largest of these studies measured fasting insulin, estradiol and IGF-I levels, and found that the highest compared with lowest insulin quartile was associated with a HR of 2.40 (95% CI: 1.30–4.41) in nondiabetic/non-HT users.6 In other recent studies, it was shown that patients with diabetes who used metformin, a medication that inhibits hepatic glucose production and reduces circulating insulin levels, had lower risk of postmenopausal breast cancer risk than patients with diabetes who did not use metformin.19
Leptin and adiponectin are the adipokines most extensively studied in relation to cancer.20 Obese individuals tend to have high levels of leptin, which has mitogenic/antiapoptotic activity, and low levels of adiponectin, which has antimitogenic/ pro-apoptotic activity. However there are only limited, conflicting epidemiologic data regarding the relation of adiponectin levels and breast cancer risk. For example, a cross-sectional study by Gaudet and colleagues (2010) failed to find associations between circulating adiponectin or other adipokines with postmenopausal breast cancer,21 whereas another cross-sectional study reported that the leptin/adiponectin ratio was increased in postmenopausal breast cancer cases relative controls.22 Overall, there is a paucity of relevant prospective cohort data regarding adipokines and breast cancer, and future studies will need to additionally control for both insulin and sex hormone levels.
RECURRENCE AND SURVIVAL
Obesity has been repeatedly shown to be a risk factor for breast cancer recurrence and poor survival. A meta-analysis of 43 studies, for example, found a HR of 1.33 (95% CI: 1.19–1.50) for breast cancer-related mortality and a similar HR for all-cause mortality, when contrasting obese and nonobese patients with breast cancer.23 These association did not differ by menopausal status,23 nor have results been found to differ by the ER status of tumors.23,24 Further, a recent study that accounted for use of screening, access to treatment, the type of treatment, use of adjuvant therapy, and tumor characteristics found a more than two-fold increased risk of recurrence (HR = 2.43; 95% CI: 1.34–4.41) and breast cancer-related death (HR = 2.41; 95% CI: 1.00–5.81) among obese patients compared with normal weight patients with breast cancer.24
Similarly, several studies found positive associations between high pretreatment insulin levels and poor prognosis.25,26 For example, in a recent study, those with high insulin levels had a two-fold worse distant disease-free survival (HR = 2.05; 95% CI: 1.16–3.62) and overall survival (HR = 2.57; 95% CI: 1.48–5.50) than other patients with breast cancer.25 Other studies have suggested that high leptin levels25 and low adiponectin levels were associated with poor prognosis.26 However, studies that concurrently address sex hormone, insulin, leptin, and adiponectin levels, before and after treatment, will be needed to comprehensively study these relationships with disease recurrence and survival.
METFORMIN AND OTHER PHARMACOLOGIC INTERVENTIONS
Metformin is an oral medication for treatment of type II diabetes that acts by suppressing AMPK-mediated gluconeogenesis in the liver, and results in lower serum insulin levels. It is well tolerated and does not induce hypoglycemia in nondiabetics. Metformin may reduce the risk of breast cancer and its recurrence through several mechanisms. Most importantly, in addition to its effects on insulin levels, metformin may inhibit AMP-activated protein kinase activity in the mTOR cancer-related pathway.27
Meta-analyses have shown that metformin use in patients with diabetes is associated with reduced risk of postmenopausal breast cancer OR = 0.82; 95% CI: 0.71–0.97),19 and reduced breast cancer mortality (summary relative risk = 0.63; 95% CI: 0.40–0.99).28 This included improved overall survival in patients with diabetes with HER2+ tumors, and possibly distant metastasis free survival in patients with diabetes with triple-negative breast cancer.28 There are currently several clinical trials of metformin use as adjuvant therapy in the treatment of patients with breast cancer.27,29 In particular, there is a large phase III randomized clinical trial of 3,582 women with stage I-III breast cancer (NCIC MA.32)27, which is the only study with adequate sample size to assess the effect of metformin on breast cancer recurrence and mortality. Other pharmacologic regulators of AMPK are also being developed, as are methods to increase adiponectin levels and agents that directly target the IR-A and IR/IGF-IR hybrid receptors.
However, considerable effort is additionally being put toward the development of nonpharmacologic interventions. Given that obesity is a modifiable condition, behavioral interventions designed to change dietary and exercise practices in patients represent a major opportunity to reduce breast cancer risk and improve disease outcomes.
BEHAVIORAL INTERVENTIONS TARGETING OBESITY
Weight Loss Interventions in Breast Cancer Survivors
Until recently, there were relatively few studies evaluating the efficacy and potential benefits of weight loss interventions in patients with breast cancer. Many of the early studies of lifestyle change in breast cancer survivors focused on elements of weight maintenance, such as physical activity or dietary quality (described below), and did not include weight loss as an objective. However, as the evidence linking obesity to breast cancer recurrence and mortality has grown, along with the proportion of U.S. adults who are overweight and obese, the need to develop and test weight loss interventions in breast cancer populations has become more pressing.
Several small studies have evaluated different weight loss strategies in breast cancer survivors.30-34 Studies generally demonstrate that weight loss can be successfully implemented in this population through a variety of interventions. For example, Shaw and colleagues randomized 64 obese women with early stage breast cancer to a low-fat diet group, a low-calorie diet group, or a control group, and demonstrated that participants randomized to low-fat and low-calorie diets experienced significant weight loss and reductions in body fat as compared with controls (p = 0.006 and 0.008, respectively).33 Another small study randomized 48 obese breast cancer survivors to one of three dietary intervention arms (Weight Watchers, individualized dietary counseling, or a combination of the two) or to a control group31 and found that the individual counseling and combination groups lost significantly more weight than controls (p < 0.05 at 12 months for comparison of each group to control), whereas the Weight Watchers alone group did not experience significant weight loss.
Only one large-scale weight loss study has been reported to date in breast cancer survivors. The Lifestyle Intervention Study for Adjuvant Treatment of Early Breast Cancer (LISA)35 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 Program. The weight loss intervention focused on calorie reduction to attain a 500-1000 kcal per day deficit; reduction in fat intake to approximately 20% of calories; increased intake of fruits, vegetables, and grains; and increased physical activity to at least 150 minutes of moderate-intensity recreational activity per week. Intervention participants lost significantly more weight than control participants at 6, 12, 18, and 24 months (4.3 vs 0.6 kg, p < 0.001 at 6 months and 3.6 vs 0.3 kg, p < 0.001 at 24) and reported a significant improvement in physical functioning scores and higher levels of physical activity as compared with controls.35
Several other weight loss intervention studies are currently ongoing in breast cancer survivors (Table 2), although it is not clear that any of these will be adequately powered to test the effect of purposeful weight loss on the risk of breast cancer recurrence or mortality. These studies will compare the effects of different dietary interventions on weight change and biomarkers linked to breast cancer prognosis and will also evaluate the feasibility of in-person and distance-based weight loss interventions, thus providing information that will be essential in the design of future studies evaluating the impact of purposeful weight loss on disease outcomes in overweight and obese women with early breast cancer.
TABLE 2. Select Ongoing Weight Loss Intervention Studies in Patients with Breast Cancer
|CHOICE50||370||- Postmenopausal breast cancer survivors||Participants are allowed to choose 1 of 3 arms:||-Primary: Change in C-reactive protein|
|-BMI 25–34.9kg/m2||-Control||-Secondary: Changes in other metabolic and inflammatory biomarkers linked to recurrence|
|-Low-fat diet + exercise|
|-Low carb diet + exercise|
|DIANA-551||1208–2000||-Stage I-III breast cancer within the past 5 yr||1:1 randomization:||-Primary: Breast cancer recurrence/new primary|
|-Age35–70||-Usual care control group||-Secondary:|
|-One of the following:||-“Mediterranean-Macrobiotic” lifestyle||· Biomarkers|
|· ER- tumor|| · Weight loss or maintenance||· Anthropometric measures|
|· Metabolic syndrome|| · Physical activity: 210 min/wk|
|· High serum insulin or testosterone|| · Modest calorie restriction|
|· Reduction in intake of foods with high glycemic index|
|ENERGY||800||-Stage I-III breast cancer||1:1 randomization:||-Primary: weight loss|
|-BMI 25–45kg/m2||-Usual care control group||-Secondary:|
|-Supervised weight loss intervention||· Quality of life|
| · Calorie restriction||· Serum biomarkers|
| · Increased physical activity|
| · Behavioral strategies & social support|
|SUCCESS-C52||̀1200*||-Newly diagnosed breast cancer:||Lifestyle randomization:||-Primary: Comparison of disease free survival between groups|
|· Node + OR||-Usual care control group|
|High risk node -: ER-, age ≤35, grade 3 tumor, T2–3||-Telephone-based lifestyle intervention|
|· BMI 24–40 kg/m2||· Calorie restriction|
|· Low fat diet|
|· Increased physical activity to 150–200 min/wk|
*Weight loss portion of the SUCCESS-C trial will include the subset of participants with BMI 24–40 kg/m2 in the parent adjuvant chemotherapy trial
Other Lifestyle Interventions in Breast Cancer Survivors
Many studies have looked at the feasibility and potential benefits of modifying two key components of weight control (dietary quality and physical activity patterns) after breast cancer diagnosis. The two largest lifestyle intervention studies in breast cancer survivors to date have been the Women's Interventional Nutrition Study (WINS)36 and the Women's Healthy Eating and Living (WHEL) study,37 which both looked at the impact of dietary interventions on disease recurrence in women with early-stage breast cancer. The WHEL study randomized 3,088 breast cancer survivors to a dietary intervention focused on increasing fruits, vegetables, and fiber and lowering fat intake, or to a usual care control group.37 Intervention participants substantially increased intake of fruits and vegetables and decreased percentage of dietary calories from fat. The diet was designed to be isocaloric with the baseline diet of study participants, and no weight loss was observed. There was no difference in recurrence rates in the diet and control groups (16.7 vs. 16.9%, p = 0.63). In contrast, the WINS randomized 2,437 women with early-stage breast cancer to a low-fat dietary intervention or to a usual care control group.36 Intervention participants substantially decreased dietary fat intake, lost approximately 6 pounds, and experienced significantly better disease free survival compared with controls (HR 0.76, 95% CI 0.60–0.98, p = 0.034). With further follow-up, these findings lost statistical significance, but an exploratory subgroup analysis demonstrated a significant survival benefit of the intervention in ER- patients (HR 0.41, p = 0.003).38 These findings have been interpreted as providing further support for the role of weight loss in breast cancer survivors.
A few recent studies have looked at the impact of increased physical activity and dietary change on quality of life and other outcomes in breast cancer survivors. The Reach Out to Enhance Wellness (RENEW) study randomized 641 survivors of breast, prostate, and colon cancers to a 1-year telephone- and print materials-based lifestyle intervention, designed to increase physical activity and improve dietary quality, or to a wait-list control group.39 The study demonstrated that participants randomized to the intervention group experienced significantly less decline in functional status, improvements in dietary quality, increased physical activity, and modest weight loss, as compared with control participants (all p < 0.05).39 The FRESH Start trial40 randomized 543 survivors of breast or prostate cancer to a 10-month tailored, mail-based intervention, designed to increase intake of fruit and vegetables, decrease fat intake, and increase exercise or to a control group who received nontailored materials about a healthy diet and exercise. Both groups significantly improved lifestyle behaviors (p < 0.05), but participants in the tailored intervention were more likely to improve two or more behaviors (34% vs.18%, p < 0.001), and also experienced modest weight loss and improvements in exercise patterns and dietary quality as compared with control participants.
Physical activity interventions.
Physical activity interventions.
Many studies have focused on the feasibility and potential benefits of physical activity in patients with breast cancer both during and after adjuvant therapy.41,42 Given that studies have shown that decreased physical activity in the adjuvant period is one of the strongest predictors of weight gain in patients with breast cancer,43 effective means of increasing physical activity may be especially important in breast cancer survivors. The American College of Sports Medicine performed a comprehensive review of exercise intervention studies of populations of patients with cancer, including data from 54 randomized controlled trials of exercise in breast cancer survivors.44 Studies evaluated a variety of exercise modalities including walking, cycling, yoga, strength training, and rowing. In both the adjuvant and post-treatment settings, the review found consistent evidence that physical activity interventions were safe and led to increased aerobic fitness and strength. Many studies also found that individuals who participated in physical activity interventions experienced improvements in quality of life, anxiety, depression, fatigue, body image, body size, and body composition, although not all studies were consistent in these findings.
Lifestyle Intervention Trials with Biologic Endpoints
Lifestyle intervention studies also provide the opportunity to learn more about the complex biologic mechanisms through which obesity and other lifestyle factors could impact breast cancer risk and outcomes. Evaluating the efficacy of lifestyle interventions in affecting changes in biomarkers linked to breast cancer risk and recurrence could help determine which interventions are most promising for further testing, as well as identifying the patient populations most likely to benefit from lifestyle change after breast cancer diagnosis. For example, the Nutrition and Exercise for Women (NEW) Trial evaluated the effect of different lifestyle interventions on biomarkers linked to breast cancer in 439 postmenopausal, sedentary, overweight women. Participants were randomized to one of four groups: dietary weight loss, exercise alone, dietary weight loss + exercise, or control. Women randomized to the weight loss groups, with or without exercise, experienced the most significant reductions in insulin, other metabolic hormones,45 sex steroids, and inflammatory mediators.46 Women randomized to exercise alone experienced smaller but significant changes in estrogen, testosterone and leptin levels (p < 0.001, p = 0.04, and p < 0.01, respectively), but no significant changes in other hormones.
Several studies have looked at the impact of exercise alone on biomarkers linked to cancer risk and outcomes in breast cancer survivors. For example, Ligibel and colleagues demonstrated a 28% decrease in insulin levels in a group of sedentary, overweight breast cancer survivors participating in a 16-week mixed strength-training and aerobic exercise intervention (p = 0.07)47; similar effects were reported by Irwin and colleagues.48 Individual studies have also demonstrated a favorable impact of exercise on IGF-I and other metabolic and inflammatory hormones,49 but data are too limited to draw firm conclusions. More work is needed to better understand the effect of lifestyle change on biologic mechanisms linked to breast cancer.
Obesity is associated with breast cancer incidence and prognosis, and increasing evidence implicates sex hormones, insulin, adipokines, and their inter-related biologic pathways as major factors underlying these relationships. More importantly, these hormones and biologic pathways represent important potential targets for primary and secondary breast cancer prevention. The MA-32 study, for example, is the first formal randomized clinical trial of metformin use and its effect on prognosis in early-stage breast cancer. However, there are additional potential biologic targets related to the implicated signaling pathways, and appropriate pharmacologic studies to assess these opportunities for cancer prevention and treatment are needed. Furthermore, the ability of purposeful weight loss to improve prognosis has not been tested in the setting of randomized trials. Several lifestyle intervention trials have been conducted in breast cancer survivors, demonstrating the feasibility of implementing weight loss and other interventions after cancer diagnosis. Data from two large-scale dietary intervention studies provide further evidence that dietary changes that produce weight loss may improve outcomes in breast cancer survivors, and other studies suggest that weight loss induces significant favorable changes in biomarkers linked to breast cancer risk and outcomes. Adequately powered adjuvant studies are needed to define the role of weight loss in the management of overweight and obese breast cancer survivors. Overall, the association of obesity with breast cancer incidence and prognosis represents a very significant, but still under-exploited opportunity to improve prognosis for patients with early-stage breast cancer.
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