Women's Intervention Nutrition Study Research Articles

Abstract S5-08: Final survival analysis from the randomized Women's Intervention Nutrition Study (WINS) evaluating dietary intervention as adjuvant breast cancer therapy

Abstract Between 1994 and 2001, 2,437 women between 48-79 years of age with early-stage breast cancer (73% node negative, 79% estrogen receptor positive, 70% = or < 2 cm) receiving standard cancer management (endocrine therapy +/- chemotherapy if hormone receptor positive or chemotherapy if hormone receptor negative plus radiation therapy if clinically indicated) were randomized, within 6 months of diagnosis, to a dietary intervention or control group from 39 US centers participating in the Women’s Intervention Nutrition Study (WINS). The dietary intervention, targeting fat intake reduction while maintaining nutritional adequacy, was initiated during 8 biweekly individual counseling sessions by centrally trained registered dieticians implementing a previously developed low-fat eating plan with subsequent every 3 month dietician contacts. During 5 years (median) intervention, fat intake was significantly reduced (from 29.2% to 20.3% of calories, P< 0.0001) as was body weight (-2.7 kg, P=0.005) in the dietary intervention group but not in the control group. Relapse-free survival, the primary study endpoint, was favorably impacted in the dietary intervention compared to the control group (9.8% vs 12.4% with events, respectively, HR 0.78 95% CI 0.60-0.98, P = 0.03 from adjusted Cox model) (J Natl Cancer Inst 2006:98;1767). Exploratory analyses suggested a greater dietary effect on women with hormone receptor negative cancers.When intervention ended after 5 years median follow-up with a total of 171 deaths, there were somewhat fewer deaths in the intervention group (6.6% vs 7.3%, HR 0.89 95% CI 0.65-1.21). In the last WINS update, based on national death registry information after 8.1 years median follow-up with a total of 251deaths, while there were fewer deaths in the intervention compared to the control group (9.1% vs 11.1%), the difference was again not statistically significant (HR 0.78 95% CI 0.59-1.03) (J Clin Oncol 2008:26;522). With this as background, the primary study objective is to determine, with updated survival information after now 15 years median follow-up, whether a lifestyle intervention targeting fat intake reduction associated with significant weight loss will improve overall survival in early stage breast cancer patients receiving standard breast cancer management. Information on survival is being obtained regarding the status of the 2,081 WINS study participants last known to be alive using the National Death Registry identified through DOBsearch.com. It is anticipated that there will now be a total of approximately 430 deaths in the trial. The new information will be incorporated in updated survival analyses, using time-to-event methods based on intention-to-treat principles, for the overall population and for subgroups of interest. Results will be presented as a late breaking abstract. Citation Format: Rowan T Chlebowski, George L Blackburn. Final survival analysis from the randomized Women's Intervention Nutrition Study (WINS) evaluating dietary intervention as adjuvant breast cancer therapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S5-08.

Nutrition and physical activity influence on breast cancer incidence and outcome

Introduction and aimsTo provide a current perspective on nutrition and physical activity influence on breast cancer. Methods and resultsA comprehensive literature review was conducted and selective presentation of findings follows. While some observational studies have associated higher dietary fat intake with higher breast cancer incidence, two full-scale randomized, clinical trials of dietary fat intake reduction programs were negative. However, a lifestyle intervention targeting fat intake reduction in the Women's Intervention Nutrition Study (WINS), resulted in weight loss and also reduced breast cancer recurrences in women with early stage disease. Observational studies evaluating specific nutrient intakes and dietary supplements have provided mixed results. Several observational studies find women with early stage breast cancer with lower 25-hydroxyvitamin D levels at higher recurrence risk, a finding requiring cautious interpretation. The lifestyle factor most strongly and consistently associated with both breast cancer incidence and breast cancer recurrence risk is physical activity. A meta-analyses of observational studies supports the concept that moderate recreational physical activity (about 3–4 h walking per week) may reduce breast cancer incidence and that women with early stage breast cancer who increased or maintain their physical activity may have lower recurrence risk as well. Feasibility of achieving increased physical activity and weight loss in women with early-stage breast cancer has been established. Two full-scale randomized clinical trials are evaluating weight loss/maintenance and increased physical activity in relation to recurrence risk in women with early-stage, resected breast cancer. Discussion/conclusionsDietary intake may influence breast cancer but influence is difficult to separate from influence of body weight. A consistent body of observational study evidence suggests higher physical activity has favorable influence on breast cancer incidence and outcome. While awaiting definitive evidence from ongoing randomized trials, breast cancer patients can reasonably be counseled to avoid weight gain and reduce body weight if overweight or obese and increase or maintain a moderate level of physical activity.

A culturally specific dietary plan to manage weight gain among African American breast cancer survivors

Breast cancer survival rates are lower in African Americans (AAs) than in Caucasians, owing in part to a higher prevalence of obesity in the former, which increases the risk of recurrence and mortality. The Women's Intervention Nutrition Study (WINS) found that Caucasian women who followed a low-fat eating plan experienced a lower rate of cancer recurrence than women who maintained their usual diets. The purpose of this study was to test the feasibility of a WINS plan tailored to the cultural needs of AA breast cancer survivors. This feasibility pilot study was conducted at a university National Cancer Institute-designated comprehensive cancer center outpatient clinic with AA breast cancer survivors. The culturally specific WINS (WINS-c) plan included eight individual counseling sessions, five educational group meetings, and follow-up telephone calls over a 1-year period. Outcome measures included dietary fat, triglyceride, insulin and glucose levels, and fruit and vegetable intake. Participants (n = 8) had a mean age of 61.1 years (standard error of the mean (SEM) 3.1 years) and a mean BMI of 32 kg/m(2) (SEM 4.25 kg/m)(2). Baseline daily fat consumption decreased from 64.6g (range 36.8-119.6g) to 44.0g (21.6-73.4g) at 52 weeks (p = 0.07). Mean daily consumption of fruits and vegetables increased by 36% and 15%, respectively. Mean triglyceride levels decreased at 12 months (p < 0.05). Sustained hyperinsulinemia was noted in most participants, including those without diabetes. Mean calcium and vitamin D consumption decreased over the 1-year study period. In AA breast cancer survivors, the WINS-c program resulted in a trend toward reduced fat consumption and may represent a sustainable approach in this population for improvement of diet quality after breast cancer.

An overview of the European Society of Medical Oncology (ESMO) Symposium on Cancer and Nutrition 2009: from cancer prevention to nutrition support to alleviating suffering in patients with advanced cancer

The European Society of Medical Oncology Symposium (ESMO) on Cancer and Nutrition convened on March 20– 21, 2009, in Zurich, Switzerland. Welcoming 172 participants from 32 countries and from 4 different continents, this symposium was designed to address issues directly relevant to the interface between clinical nutrition and cancer. Was there truly a need for such a conference? The organizers of this meeting contend that the answer is “yes” and cite the following salient examples to show that nutrition really does impact cancer and cancer patients and that focusing a symposium on the interface between nutrition and cancer holds merit. Firstly, it behooves us to always test assumptions of efficacy and safety, particularly with nutritional interventions which are often assumed to be safe. Rates of vitamin/ nutritional supplementation vary dramatically throughout the world, but, in some populations, as many as 80% of individuals are taking them [15, 27]. Despite this high prevalence, only a few studies have demonstrated that supplements prevent cancer, and such studies suggest benefits are confined to nutrient-depleted populations [17]. For example, when one considers the plethora of epidemiologic data that points to an association between beta carotene-rich fruits and vegetables and a diminished risk of lung cancer, it is tempting to conclude—albeit prematurely and unwisely—that beta carotene supplementation is safe and even beneficial. Subsequent studies have nullified this conclusion. In the recent VITAL study that included 77,126 individuals, Satia and others reported that long-term use of patient-reported beta carotene (<10 years) was associated with a greater risk of lung cancer [21]. More importantly, two placebo-controlled, double-blinded randomized clinical trials tested β-carotene at doses of 30 mg in 18,314 individuals and 20 mg in 29,133 individuals all of whom were at high risk for lung cancer. Unexpectedly, both these trials demonstrated that the incidence of lung cancer increased by 28% or more and that, as a result, mortality was worse as a result of beta carotene supplementation. Yes, the unthinkable can happen, and therefore, rigorous testing with proof of safety and efficacy must be established prior to recommending any nutritional supplements, particularly those prescribed at “high” doses. Secondly, one might question whether diet itself has any favorable effect on cancer or cancer recurrence. The Women's Intervention Nutrition Study suggests that it does. A total of 2,437 early-stage breast cancer patients were F. Strasser (*) Oncological Palliative Medicine, Division of Oncology/Haematology, Department of Internal Medicine and Palliative Care Center, Cantonal Hospital, Rorschacherstrasse 95, CH-9007 St. Gallen, Switzerland e-mail: florian.strasser@kssg.ch

A Culturally-Specific Dietary Plan To Manage Weight Gain among African American Breast Cancer Survivors: A Feasibility Study.

Abstract Background. African American (AA) women are less likely to survive for five years after a breast cancer diagnosis than Caucasian women. The higher prevalence of obesity in AA women may contribute to this disparity. Weight gain following breast cancer treatment is one of the few modifiable risk factors for breast cancer recurrence and mortality. AA breast cancer survivors face unique cultural and economic barriers to adopting diets which reduce the likelihood of weight gain.Objective. To determine the feasibility of adopting and maintaining a culturally-specific low-fat eating plan in a population of low to middle income AA breast cancer survivors.Participants. AA women recruited through urban medical centers who were between 30 to 75 years old, had a confirmed diagnosis of stage 0, I, II, III, or IIIA primary breast cancer, and had incomes &amp;lt; $50,000 per year.Methods. A culturally-specific dietary intervention was developed, based on the Women's Intervention Nutrition Study (WINS), to reduce consumption of dietary fat to 25% of total calories, while increasing fruits and vegetables.Eligible participants were enrolled in a one-year feasibility study. Participants received the Culturally-Specific WINS Low-Fat Eating Plan (WLEP) and 8 individual nutritional counseling sessions with a trained diet technician, to help reduce and maintain their fat intake to 25% of total calories. The intervention also included bi-monthly educational group meetings and follow-up telephone contacts with diet technicians.Study Measures. Dietary patterns were assessed with 3-day food records at baseline and follow-up. Compliance with the Culturally-Specific WLEP was defined as 1) dietary fat intake ≤ 25% of total calories; and 2) at least 6 to 7 servings of fruits and vegetables per day. Psychosocial factors and dietary biomarkers were also measured at baseline and follow-up to examine their association with study outcomes. Psychosocial factors included perceived susceptibility to recurrence, quality of life, and social support. Dietary biomarkers included weight, height, waist-hip circumference, blood pressure, lipids, serum fatty acid concentrations, insulin and insulin-like growth factors, glucose, and levels of sex hormone-binding globulins.Results. A total of 9 AA breast cancer survivors are enrolled and receiving the intervention. Baseline and six-month follow-up results for the psychosocial factors and dietary biomarkers associated with dietary compliance and weight maintenance will be reported in October 2009.Conclusions. A population of low to middle income AA breast cancer survivors with limited education and resources demonstrated compliance with the Culturally-Specific WLEP, thereby reducing their risk of cancer recurrence through diet. Procedures and data from this feasibility study will be used in a multi-center clinical trial of the Culturally-Specific WLEP. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1053.

Obesity, Insulin Resistance and Insulin.

Abstract There is growing acceptance that overweight and obesity are associated with poor outcomes in early stage breast cancer. This effect has been reported in pre-and postmenopausal women, regardless of hormone receptor status. Postulated mechanisms have included presentation of cancer at a more advanced stage, underdosing of chemotherapy and higher levels of endogenous estrogens in overweight and obese women. Recent research has provided strong evidence that insulin may play a key role in mediating these prognostic effects. Overweight and obesity are associated with insulin resistance (and resulting hyperinsulinemia) in both the general population and in breast cancer patients; both insulin resistance and high insulin levels have been associated with increased risk of breast cancer recurrence or death, independent of traditional prognostic factors. Breast cancer cells commonly overexpress insulin receptors (frequently a fetal form of the receptor that may hybridize with the IGF-1 receptor), providing a biologic basis for a prognostic effect of insulin. These receptors are not downregulated by circulating insulin; as a result, cancer cell growth may be stimulated by high circulating insulin levels, leading to poor prognosis. Preclinical work provides strong evidence for a mitogenic role of insulin in breast cancer. Taken together, these observations have led to the development of lifestyle interventions targeting insulin and/or insulin resistance in breast cancer patients. Interventions include weight loss (which reduces insulin levels in the general population) and physical activity (which has been shown to reduce insulin in breast cancer patients). Randomized trials of weight loss are ongoing and planned. One completed trial (Women's Intervention Nutrition Study, J Natl Cancer Inst 2006;98:1767-1776) reported improved relapse free survival in breast cancer patients randomized to a reduced fat diet (that was associated with significant weight loss). Effects were greatest in hormone receptor negative breast cancer. Recent interest has focused on the use of metformin, a biguanide commonly used to treat type 2 diabetes. Metformin reduces insulin resistance and lowers insulin levels in many populations, including early stage breast cancer patients. In addition to this indirect (insulin lowering) effect, metformin may also exert direct anti-tumor effects via mTOR inhibition. Studies using metformin in the neoadjuvant setting in breast cancer are ongoing. The effect of metformin on breast cancer outcomes (with embedded correlative studies that will examine direct and indirect effects of the drug) will be examined in NCIC MA.32, a randomized trial of metformin versus placebo involving 3582 women with early breast cancer that will be activated in early 2010. Together, these lifestyle and pharmacologic studies will provide important information on the effect of modification of a key host factor (obesity with associated hyperinsulinemia) on breast cancer outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr MS2-1.

Implementing a Low-Fat Eating Plan in the Women's Intervention Nutrition Study

The Women's Intervention Nutrition Study is a randomized clinical trial designed to evaluate if a lifestyle intervention targeting fat intake reduction influences breast cancer recurrence in women with early stage, resected disease receiving conventional cancer management. This report details the concept, content, and implementation of the low-fat eating plan used in the dietary intervention group of this trial. Intervention group participants were given a daily fat gram goal. The intervention was delivered by centrally trained, registered dietitians who applied behavioral, cognitive, and motivational counseling techniques. The low-fat eating plan was implemented in an intensive phase with eight biweekly (up to Month 4), individual counseling sessions followed by a maintenance phase (Month 5 up to and including Year 5) with registered dietitian visits every 3 months and optional monthly group sessions. Self-monitoring (daily fat gram counting and recording), goal setting, and motivational interviewing strategies were key components. Dietary fat intake was equivalent at baseline and consistently lower in the intervention compared with the control group at all time points (percent eneregy from fat at 60 months 23.2%±8.4% vs 31.2%±8.9%, respectively, P<0.0001) and was associated with mean 6.1 lb mean weight difference between groups ( P=0.005) at 5 years (baseline and 5 years, respectively: control 160.0±35.0 and 161.7±32.8 lb; intervention 160.2±35.1 and 155.6±32.1 lb). Together with previously reported efficacy results, this information suggests that a lifestyle intervention that reduces dietary fat intake and is associated with modest weight loss may favorably influence breast cancer recurrence. The Women's Intervention Nutrition Study low-fat eating plan can serve as a model for implementing such a long-term dietary intervention in clinical practice.

Diet and breast cancer prognosis: making sense of the Women's Healthy Eating and Living and Women's Intervention Nutrition Study trials.

To clarify the role of dietary pattern on prognosis in breast cancer survivors. Observational trials show mixed results that do not strongly support an independent role for dietary pattern in prognosis. Women's Intervention Nutrition Study and Women's Healthy Eating and Living (WHEL) are two large randomized controlled trials that address this question. The interventions from both studies achieved significant reductions in energy from fat, and the WHEL Study achieved large increases in vegetables, fruit and fiber. Women's Intervention Nutrition Study examined postmenopausal women only and reported a not-quite-significant improved prognosis for women in the intervention group, with the benefit focused on ipsilateral localized recurrences, but little improvement in the more important distal recurrences. This review considers only WHEL postmenopausal women to aid a direct comparison with Women's Intervention Nutrition Study. The WHEL Study reported a convincing lack of association between diet and prognosis. However, a secondary analysis suggests that the dietary intervention reduced distal recurrences among the subgroup without hot flashes at baseline. There is no convincing evidence that changing dietary pattern following breast cancer diagnosis will improve prognosis for most women with early stage breast cancer. However, it would appear to be important for some subgroups. Further investigation of mechanisms for such selective action is needed.

Do Flavonoid Intakes of Postmenopausal Women With Breast Cancer Vary on Very Low Fat Diets?

In the Women's Intervention Nutrition Study (WINS), a very low-fat eating pattern decreased breast cancer recurrence. We assessed whether the women's flavonoid intakes varied on the very low fat diet. A total of 550 randomly selected WINS participants who had been treated with conventional therapy (surgery, chemotherapy, and/or radiation) for primary breast cancer were randomized to either a very low fat diet (15% of calories from fat, N = 218) or their usual diets (30% calories from fat, N = 332). We compared their intakes of total flavonoids and 6 flavonoid classes (isoflavones, flavones, flavanones, flavonols, flavan-3-ols, and anthocyanins) for these 2 groups using the U.S. Department of Agriculture food flavonoid database and a flavonoid dietary supplement database on three 24-h dietary recalls at baseline and 12 mo after randomization. At baseline, neither mean fat intakes (31.7% ± 6.8 SD of calories, n = 332 in the usual diet group and 31.6% ± 6.8 SD of calories, n = 218 in the very low fat diet group; P = NS) nor flavonoid intakes (218 ± 283 SD mg/day, n = 332 in the usual diet group and 236 ± 393 SD mg/day, n = 218 in the very low fat diet group; P = NS) differed. Over half of the women's flavonoid intakes were from the flavan-3-ols. After 12 months of intervention, with 39 participants lost to follow-up, dietary fat intakes were 30.7 ± 8.4 SD calories (n = 316) among those on their usual diets but were significantly lower among those on the very low fat diet intervention: 21.4 ± 8.3 SD calories (n = 195), P = < 0.05. However, flavonoid intakes remained similar in both groups (201 ± 252 SD mg/day, n = 316 in the usual diet group vs. 235 ± 425 SD mg/day, n = 195 in the very low fat group; P = NS). In this random sample of WINS participants, neither total flavonoid intakes nor intakes of subclasses of flavonoids differed between those who had dramatically decreased their fat intakes and those who had not. Flavonoid intakes are therefore unlikely to account for WINS results on differences between the groups in cancer recurrence.

Survival analyses from the Women's Intervention Nutrition Study (WINS) evaluating dietary fat reduction and breast cancer outcome

522 Background: We previously reported five year results with follow up through October, 2003 of a phase III randomized trial where a dietary intervention targeting fat intake reduction, associated with significant weight loss, improved relapse-free survival compared to control in women with resected, early stage breast cancer receiving conventional cancer management (RR 0.79, P=0.034) (JNCI 2006;98:1767- 76). After initiating the dietary intervention with 16 visits over 8 weeks, ongoing adherence was addressed by q 3 month nutritionist contacts. Active dietary intervention and contacts with nutritionists ended in May, 2004. We now report a protocol-mandated survival analysis update. Methods: Updated survival information was obtained through October, 2007 largely through national death registries and randomization group survival differences were examined using Cox proportional hazards models in intention-to-treat analyses. Exploratory analyses examined survival by hormone receptor subgroups and active dietary intervention status. Results: Although fewer deaths were seen in the intervention group (9.1% vs. 11.1% cumulative mortality, RR 0.83) the difference was not statistically significant (P=0.146). In the 362 women with ER- and PR- disease, a significant overall survival benefit was seen for intervention group participants (7.5% vs. 18.1%, cumulative mortality, RR 0.41, P=0.003). The influence of ongoing active dietary intervention was examined by analyses censored six months after contact with nutritionists ended (for survival before and after 12/31/04). Conclusions: A dietary intervention targeting fat intake reduction did not significantly increase overall survival of women with resected breast cancer receiving conventional cancer management. Exploratory analyses suggest dietary intervention influence on survival may be greater in hormone receptor negative subgroups and during the period of active dietary intervention. Dietary Intervention Effect on Survival By Receptor Status and Active Dietary Intervention Interval Patient Group # entered Entire Period During Intervention After Intervention Ended # Deaths RR P value # Death RR P Value # Death RR P value All 2437 251 0.83 0.146 208 0.78 0.068 43 1.15 0.217 ER + 1959 183 0.88 0.146 147 0.85 0.459 36 1.08 0.221 ER − 478 68 0.68 0.059 61 0.60 0.049 7 1.57 0.599 No significant financial relationships to disclose.

The Low-Fat Imperative

This issue of Obesity includes two studies that support reduced fat consumption, Donnelly et al. and Donahoo et al. Diets with less fat (∼20–25%) can reduce mean energy intake by 100 kcal/day—enough to stop the growing epidemic of overweight and obesity. Our task is not to debate whether low-fat diets work, but to find ways to increase adherence to them. Approximately two-thirds of the US adult population is overweight and one-third is obese.1 In 2002, obesity and obesity-related complications accounted for 9.1% of US health care expenditures (or more than $92 billion), and those numbers are rising.2 Cutting dietary fat is the most efficient way to stop the obesity epidemic. With 9 kcal/g, fat is the most energy-dense nutrient. Eating less fat, particularly less saturated and trans fat, easily reduces energy intake. This issue of Obesity includes two studies that support reduced fat consumption, Donnelly et al.3 and Donahoo et al.4 Each examines the typical range of western fat intake and suggests that eating more fat leads to increased energy intake and greater weight gain compared with reduced fat consumption. Diets with less fat (∼20–25%) can reduce mean energy intake by 100 kcal/day, or the equivalent, over the course of a year, of 10 lb—enough to stop the growing epidemic of overweight and obesity.5,6,7 Low-fat diets produce moderate weight loss, but questions remain as to whether such diets can be sustained. Long-term studies demonstrate that diets moderately low in fat can be maintained over time. In a 7-year follow-up, the Women's Health Initiative found that those who consumed less fat and more fruits, vegetables, and whole grains lost more weight than controls, and maintained their weight loss.8 The Framingham Study showed that over 40 years, a modest 5–7% decrease in dietary fat reduced total caloric intake by ∼150 kcal/day in men and 100 kcal/day in women.9,10 Health benefits from low-fat diets are not unimpressive. A 5-year study examining cancer patients in remission found that those who consumed the prototypical “Western Diet” (characterized by high intake of fat, red meat, refined grains, and desserts) showed a higher risk of recurrence than those who ate less of those foods.11 The recently completed Women's Intervention Nutrition Study found that a diet low in fat (33.3 g/day vs. 51.3 g/day) and higher in fiber, fruits, and vegetables produced greater weight loss over 5 years, and reduced breast cancer relapse rates by 24%.12 Unlike a diet high in carbohydrates and proteins, a high-fat diet works against the goals of healthy eating. Satiety hormones in the gut, e.g., cholecystokinin and peptide-YY, normally slow gastric emptying and promote satiety in response to nutrient stimulation. With long-term intake of a high-fat diet (i.e., 58% energy), these hormones become dysregulated.13 Hunger increases, as does energy intake required to achieve satiety. In turn, body weight also increases. The United States Department of Agriculture has been recommending moderate fat intake since it released its first set of nutritional guidelines in 1916.14 The American Dietetic Association,15 American Heart Association,16 National Heart, Lung, and Blood Institute,17 and the Institute of Medicine18 all recommend lifetime consumption of diets high in vegetables and moderately low in fat. Evolution favors such a diet. For nearly 2 million years, our predecessors consumed lean meat, fish, vegetables, fruits, and nuts—low-fat diets high in fiber, proteins, and essential fatty acids. Retrospective models of Paleolithic diets estimate macronutrient content at ∼62% carbohydrates, 24% fat, and 14% protein.19 Whole foods and moderately low-fat diets approximate this macronutrient content. As all macronutrient-based diets produce similar long-term weight loss, it does not matter which one people choose; the key is long-term adherence and maintenance of weight loss. Our task is not to debate whether low-fat diets work, but to find ways to increase adherence to them. We need to spread the message that moderate weight loss of 10% is an acceptable, healthy option for those who want to lose weight—an option easily achieved by cutting small amounts of fat out of each meal. This is a reasonable and realistic goal, one that can be achieved as well as sustained. The author is a co-primary investigator for the Women's Intervention Nutrition Study (grant number CA45504) and the Boston Obesity and Nutrition Research Center (grant number P30DK46200). Preparation of this manuscript was supported in part by the Center for Healthy Living at Harvard Medical School. The author thanks Shannon G. Fischer and Rita B. Buckley for technical and editorial support.

Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Dietary fat reduction and breast cancer outcome: results from the Women's Intervention Nutrition Study (WINS)

Given that existing epidemiologic data on the correlation between dietary fat and breast cancer have been mixed, the Women's Intervention Nutrition Study was launched in 1987. This randomized clinical trial of 2437 women between the ages of 48 and 79 y with early-stage breast cancer tested the hypothesis that dietary fat reduction would increase the relapse-free survival rate. The study determined that low-fat dietary interventions can influence body weight and decrease breast cancer recurrence. Results showing a differential effect of diet on hormone-receptor-positive and -negative disease suggest that metabolic mechanisms involving insulin and insulin-like growth factor-1 may be involved in tumorigenesis. The results of the Women's Intervention Nutrition Study may therefore contribute to knowledge of the role of insulin resistance in cancer risk.

Fat, Fruits, Vegetables, and Breast Cancer Survivorship

BREAST CANCER IS THE MOST COMMONLY DIAGNOSED CANcer and the second most common cause of cancer mortality among women in the United States. Advances in early detection, surgical treatment, and chemotherapy have led to significant improvements in breast cancer survival, particularly among women with early stage disease.Current estimates indicate that thereareat least2.4million women who are breast cancer survivors in the United States. Among these women, there is particular concern about the long-term risk of recurrence. Whether that risk might be modified through changes in lifestyle habits such as diet has been an important question for investigation. Results of observational epidemiologic studies on associations of dietary patterns high in fruits and vegetables, low in fat, or both with risk of recurrence or survival are inconsistent. Although it is not possible to draw firm conclusions about the potential benefits of such dietary patterns from the results of those studies, a growing body of evidence is emerging from randomized clinical trials designed specifically to examine the effects of dietary interventions on breast cancer prognosis. In this issue of JAMA, Pierce and colleagues report the results of the Women’s Healthy Eating and Living (WHEL) Study. The WHEL Study was a randomized controlled trial designed toassesswhetheran intensivedietary interventionaimed at increasing fruits to 3 servings/d, vegetables to 5 servings/d, and fiber to 30 g/d and decreasing fat intake to 15% to 20% of total calories would reduce the risk of recurrence, new primary invasive breast cancer, or mortality among survivors of early stage (stages I-IIIA) breast cancer. In this multicenter study, 3088 women who had diagnosis and treatment within the past 4 years were randomly assigned to either the intensive intervention group or a less-intensive comparison group that was advised to follow the 5-A-Day program. After an average follow-up period of 7.3 years, there were no differences in the risk of recurrence or incidence of a new primary breast cancer (P=.63) or in the risk of overall mortality (P=.43) between the 2 groups. Similarly, there were no between-group prognostic differences according to baseline demographic characteristics, including body mass index, or clinical characteristics, including tumor stage and hormone receptor status. Furthermore, the interventionshowednobenefit forwomenwhose diet at baseline was low in fruits, vegetables, or fiber or high in fat. The Women’s Intervention Nutrition Study (WINS) is another randomized clinical trial designed specifically to assess whether a low-fat diet (15% of total calories) affects breast cancer recurrence or survival. In that study, which enrolled 2437 women within 1 year of diagnosis of early stage breast cancer (stages I-IIIA), interim results showed a significant benefit (P=.03) on the hazard ratio for relapse-free survival after a median of 5 years of follow-up among women randomized to the low-fat dietary intervention group compared with the control group, which received minimal dietary guideline information. Results of an exploratory analysis suggested that the beneficial effect of the low-fat intervention might be isolated to women with estrogen and progesterone receptor–negative breast cancers. While there is debate regarding the differential effects of the low-fat intervention according to hormone receptor status and whether this difference could be explained by variation in the hazard rates for recurrences of hormone receptor–positive vs –negative breast cancers according to length of follow-up, a recent update and analysis of WINS data based on 8 years of follow-up demonstrated similar benefits in the low-fat diet group. These conflicting results from the WHEL Study and WINS regarding the potential benefits of a dietary modification on long-term breast cancer prognosis require careful consideration. In particular, a key issue is the difference in energy balance that was achieved between WINS and WHEL Study participants. In WINS, over the 5-year follow-up, there was a continuous increase in the difference in self-reported total energyintakebetweentheinterventionandcomparisongroups. Consequently, women randomized to the low-fat intervention experienced significant weight loss, with a 6-lb (2.7 kg) weight difference between intervention and control women at 5 years. Conversely, in the WHEL Study, self-reported total energy intake decreased to a comparable extent in both the interventionandcomparisongroups through6yearsof followup, and both groups experienced small weight gains (ie, 0.6 and 0.4 kg, respectively). It is unclear whether the difference inenergybalance,asreflectedbyweightchange,partlyaccounts

2–2 Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

2–2 Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Re: Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Background: Preclinical and observational studies suggest a relationship between dietary fat intake and breast cancer, but the association remains controversial. We carried out a randomized, prospective, multicenter clinical trial to test the effect of a dietary intervention designed to reduce fat intake in women with resected, early-stage breast cancer receiving conventional cancer management. Methods: A total of 2437 women were randomly assigned between February 1994 and January 2001 in a ratio of 40 : 60 to dietary intervention (n = 975) or control (n = 1462) groups. An interim analysis was performed after a median follow-up of 60 months when funding for the intervention ceased. Mean differences between dietary intervention and control groups in nutrient intakes and anthropometric variables were compared with t tests. Relapse-free survival was examined using Kaplan-Meier analysis, stratified log-rank tests, and Cox proportional hazards models. Statistical tests were two-sided. Results: Dietary fat intake was lower in the intervention than in the control group (fat grams/day at 12 months, 33.3 [95% confidence interval {CI} = 32.2 to 34.5] versus 51.3 [95% CI = 50.0 to 52.7], respectively; P<.001), corresponding to a statistically significant (P =.005), 6-pound lower mean body weight in the intervention group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) have been reported in 96 of 975 (9.8%) women in the dietary group and 181 of 1462 (12.4%) women in the control group. The hazard ratio of relapse events in the intervention group compared with the control group was 0.76 (95% CI = 0.60 to 0.98, P =.077 for stratified log rank and P =.034 for adjusted Cox model analysis). Exploratory analyses suggested a differential effect of the dietary intervention based on hormonal receptor status. Conclusions: A lifestyle intervention reducing dietary fat intake, with modest influence on body weight, may improve relapse-free survival of breast cancer patients receiving conventional cancer management. Longer, ongoing nonintervention follow-up will address original protocol design plans, which called for 3 years of follow-up after completion of recruitment.

Re: Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Re: Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Response: Re: Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Response: Re: Dietary Fat Reduction and Breast Cancer Outcome: Interim Efficacy Results From the Women's Intervention Nutrition Study

Breast Cancer: Lower Fat Intake May Reduce Recurrence

pPostmenopausal women who’ve been treated for early-stage breast cancer might reduce their chances for recurrence or for a second breast cancer if they reduce their consumption of dietary fat, according to results from the Women’s Intervention Nutrition Study (WINS). The results, which are based on an interim analysis of the data, are reported in the Dec. 20, 2006 issue of the Journal of the National Cancer Institute. This study adds to evidence found in the Women’s Health Initiative (WHI), which last year examined the effect of a low-fat diet on breast cancer risk and showed a trend toward a modest benefi t of a reduced-fat diet on the incidence of invasive breast cancer. WINS enrolled 2,437 women between 1994 and 2001 who had been treated for early-stage breast cancer. The women, ages 48 to 79, were randomly assigned to a lower fat dietary intervention group or a control group who ate their regular diet. At the start of the study, both groups consumed similar amounts of calories from fat— about 57 g of fat per day or close to 30 percent of total daily caloric intake. At the end of the fi rst year of observation, the