Evidence is lacking that a dietary pattern high in vegetables, fruit, and fiber and low in total fat can influence breast cancer recurrence or survival.
To assess whether a major increase in vegetable, fruit, and fiber intake and a decrease in dietary fat intake reduces the risk of recurrent and new primary breast cancer and all-cause mortality among women with previously treated early stage breast cancer.
Design, Setting, and Participants
Multi-institutional randomized controlled trial of dietary change in 3088 women previously treated for early stage breast cancer who were 18 to 70 years old at diagnosis. Women were enrolled between 1995 and 2000 and followed up through June 1, 2006.
The intervention group (n=1537) was randomly assigned to receive a telephone counseling program supplemented with cooking classes and newsletters that promoted daily targets of 5 vegetable servings plus 16 oz of vegetable juice; 3 fruit servings; 30 g of fiber; and 15% to 20% of energy intake from fat. The comparison group (n=1551) was provided with print materials describing the "5-A-Day" dietary guidelines.
Main Outcome Measures
Invasive breast cancer event (recurrence or new primary) or death from any cause.
From comparable dietary patterns at baseline, a conservative imputation analysis showed that the intervention group achieved and maintained the following statistically significant differences vs the comparison group through 4 years: servings of vegetables, +65%; fruit, +25%; fiber, +30%, and energy intake from fat, −13%. Plasma carotenoid concentrations validated changes in fruit and vegetable intake. Throughout the study, women in both groups received similar clinical care. Over the mean 7.3-year follow-up, 256 women in the intervention group (16.7%) vs 262 in the comparison group (16.9%) experienced an invasive breast cancer event (adjusted hazard ratio, 0.96; 95% confidence interval, 0.80–1.14; P=.63), and 155 intervention group women (10.1%) vs 160 comparison group women (10.3%) died (adjusted hazard ratio, 0.91; 95% confidence interval, 0.72–1.15; P=.43). No significant interactions were observed between diet group and baseline demographics, characteristics of the original tumor, baseline dietary pattern, or breast cancer treatment.
Among survivors of early stage breast cancer, adoption of a diet that was very high in vegetables, fruit, and fiber and low in fat did not reduce additional breast cancer events or mortality during a 7.3-year follow-up period.
clinicaltrials.gov Identifier: NCT00003787
Considerable evidence from preclinical studies indicates that plant-derived foods contain anticarcinogens.1A comprehensive review of the literature found that a diet high in vegetables and fruit probably decreases breast cancer risk and that a diet high in total fat possibly increases risk.2 However, evidence of an association between a diet high in vegetables and fruit and low in total fat and prevention of cancer progression has been mixed in epidemiological studies.3–17 An interim analysis of data from the Women’s Intervention Nutrition Study (WINS), which assessed the effect of a dietary intervention designed to reduce fat intake on relapse-free survival in breast cancer patients,18 found that the intervention was associated with a marginally statistically significant improvement in relapse-free survival. To our knowledge, no other clinical trials investigating dietary change and breast cancer survival have been reported.
The Women’s Healthy Eating and Living (WHEL) Study was a randomized trial assessing whether a dietary pattern very high in vegetables, fruit, and fiber and low in fat reduces the risks of recurrent and new primary breast cancer and all-cause mortality among women with previously treated early stage breast cancer. The study was based on the recommendations of a national committee of experts called to respond to a 1993 challenge grant from a private philanthropist who believed that the role of diet in preventing cancer progression deserved scientific study to enable cancer survivors to make decisions without having “to rely on folklore, rumor and hearsay.”19
Details of the study design, eligibility criteria, randomization procedures, and dietary intervention have been reported previously.20,21 In brief, we compared 2 dietary patterns: an intervention group that was intensively counseled to adopt a dietary pattern very high in vegetables, fruit, and fiber and low in fat21and a comparison group advised to follow the 5-A-Day diet.22,23 The study tested primary hypotheses of whether the intervention dietary pattern was associated with (1) a longer breast cancer event–free interval and (2) increased overall survival among women previously treated for early stage breast cancer. Based on the 6 epidemiological studies that had been published at the time of the trial design, we estimated the likely effect size of this multicomponent diet.20 Following Lachin and Foulkes,24 we determined that a sample size of 3000 would have 82% power to detect a 19% reduction in additional breast cancer events in the intervention group (expected comparison group rate=24%) and a 24% reduction in all cause mortality (expected comparison group rate=15%).
Participants were enrolled at 7 study sites between 1995 and 2000. Eligibility criteria included diagnosis of a primary operable invasive breast carcinoma categorized using American Joint Committee on Cancer (edition IV) criteria as stage I (≥1 cm), stage II, or stage IIIA within the past 4 years; age at diagnosis between 18 and 70 years; treatment with axillary dissection and total mastectomy or lumpectomy followed by primary breast radiation; no current or planned chemotherapy; no evidence of recurrent disease or new breast cancer since completion of initial local treatment; and no other cancer in the past 10 years. Eligible women were randomly assigned to either the study dietary pattern or the comparison group (FIGURE 1). The institutional review boards at the 7 clinical sites approved the study protocol and consent forms, and all participants provided written informed consent.
The intensive intervention was delivered primarily by telephone counseling, supplemented with 12 cooking classes in the first year and monthly newsletters throughout the study. Trained counselors21 followed a computer-assisted protocol that was based on social cognitive theory25 and had 3 phases of decreasing intensity. During the first phase (3–8 calls in 4–6 weeks), counselors focused on building self-efficacy to implement the study targets, which consisted of daily intake of 5 vegetable servings plus 16 oz of vegetable juice, 3 fruit servings, 30 g of fiber, and 15% to 20% of energy intake from fat. Phase 2 (through 5 months) focused on self-monitoring and dealt with barriers to adherence. Phase 3 (through study completion) focused on retaining motivation for the study dietary pattern and preventing setbacks. During the first year of the intervention, participants received an average of 18 counseling calls, attended an average of 4 of 12 offered cooking classes, and received 12 study newsletters. By 4 years, a key point for assessing long-term effect, these participants had received an average of 31 calls and 48 newsletters.
Women randomized to the comparison group were provided with print materials (from the US Department of Agriculture26 and the National Cancer Institute22,23) describing a diet with a recommended daily intake of 5 servings of vegetables and fruit, more than 20 g of fiber, and less than 30% total energy intake from fat. The comparison group attended an average of 1 of 4 offered cooking classes in the first year and received 24 newsletters tailored to the comparison group during the first 4 years.
Dietary intake was assessed by sets of 4 prescheduled 24-hour dietary recalls conducted by telephone on random days over a 3-week period, stratified for weekend vs weekdays.20These dietary recalls were scheduled for all participants at baseline, 1 year, 4 years, and 6 years and on 50% random samples at 6, 24, and 36 months. We report data for participants completing follow-up assessments. We also conducted additional analyses as follows: for participants who did not complete follow-up assessments we imputed estimates by assuming that they changed dietary intake in a manner similar to comparison group respondents, using the expectation maximization algorithm in SAS software, version 9.1 (SAS Institute Inc, Cary, North Carolina).27As previously described,20 dietary assessors completed a training program and used the multipass software-driven recall protocol of the Nutritional Data System software (NDS-R, 1994–2006, University of Minnesota, Minneapolis). To assess overall adherence, we developed an adherence score.20 A completely adherent participant would score 600 points: 300 points reflected vegetable consumption and the remaining 300 points were divided equally among fiber, fruit, and energy from fat.
Other Data Collection
We collected a detailed family history of cancer at baseline and used the mutation prevalence tables from Myriad Genetic Laboratories (Salt Lake City, Utah)28 to classify families with at least a 10% risk of a BRCA1/2 mutation as high-risk. Clinic visits conducted at baseline, 1 year, 2 or 3 years (randomly determined), 4 years, and 6 years included measured weight and venipuncture. Separated blood samples were stored in cryovials in −80°C freezers for later analysis. Participants were mailed a set of study questionnaires to complete and bring to each clinic visit, including a health status questionnaire with questions on recent physician visits and 2 questionnaires used in the Women’s Health Initiative: the Personal Habits Questionnaire,29 which included a 9-item measure of physical activity validated for our study30 and from which we calculated metabolic equivalent task minutes per week,31 and the Thoughts and Feelings Questionnaire,32 which included measures of psychosocial functioning. Each participant self-reported race/ethnicity as 1 of 8 categories.
Assessment of Study Outcomes
Primary study end points were (1) the combined outcome of invasive breast cancer recurrence or new primary breast cancer and (2) death due to any cause. Recurrences were further classified as local/regional or distant metastasis. Carcinoma in situ was not counted as a study outcome. The breast cancer event–free interval was defined as the time from date of enrollment to development of a new breast cancer event. Follow-up time was censored at the time of the participant’s death, at the last documented staff contact date, or at the study completion date (June 1, 2006).
During semiannual telephone interviews, clinical site staff queried study participants regarding the occurrence of outcome events, any hospitalization, or new or existing medical diagnoses. Any report of a breast cancer event or death triggered a confirmation interview and collection of medical records and/or death certificates. Two independent oncologists reviewed the medical records (pathology reports and physician notes) to confirm reported recurrences. In cases of disagreement, the coordinating center pathologist adjudicated the outcome. Finally, we searched the National Death Index using Social Security number, name, and date of birth.
Participants were randomly assigned to the intervention or comparison group using a random permuted-block design stratified by tumor stage, age, and clinical site. The allocation of participants was conducted by the clinical site coordinator running the study’s randomization computer program, which automatically stamped the assigned study group in the database. An independent data and safety monitoring committee conducted a blind review of potential post-randomization exclusions.20
Baseline group comparisons of demographic, anthropometric, clinical, and dietary measures were conducted with 2-sided t tests, rank-sum tests, or χ² tests. We based the primary analysis of disease-free survival on the intention-to-treat principle using time-to-event methods. A 2-sided log-rank test was performed with P<.041 considered statistically significant (to account for interim analyses undertaken at the request of the data and safety monitoring committee). Both unadjusted and adjusted hazard ratios were computed. We fit a Cox model stratified by stage, age, and clinical site.
The frequencies of antiestrogen therapy use and bilateral oophorectomies differed marginally between study groups at baseline; therefore, these covariates were also included in the model. However, the antiestrogen therapy variable did not satisfy the proportional hazards assumption; hence, the analysis was stratified by this covariate.33 Thus, the final model was stratified by stage of initial tumor, age at randomization, clinical site, and antiestrogen use and was adjusted for oophorectomy status.
The a priori analysis plan20 included fitting a Cox proportional hazards model to evaluate the effect of the intervention on key covariates. These included stage of disease (classified as I, II, or III), age at randomization (<55 years vs ≥55 years), hormone receptor characteristics of initial tumor, body mass index, and years from diagnosis to randomization. Product terms between randomization assignment and indicator variables for covariate categories were included in Cox regression models. Interactions between randomization group and each covariate were formally tested for significance with likelihood ratio tests. The results are presented as hazard ratios and 95% confidence intervals.
In additional analyses, we examined possible interactions between study group and the baseline dietary factors targeted by the intervention (vegetable, fruit, fiber, and fat intakes) to address whether the effects of the dietary intervention might vary by baseline intake level.
Analyses were conducted in the statistics software package R, version 2.3.1 (R Foundation, Vienna, Austria; http://www.r-project.org) or SAS, version 9.1.