During the past two decades, the relationships between overall survival or recurrence and dietary intakes have been examined in 13 studies involving cohorts of women who had been diagnosed with breast cancer.19,25,36,78–87
The dietary factors examined in these studies were mainly those associated with breast cancer risk. These studies are summarized in . As noted in , most of these studies used dietary data collected at the time of diagnosis or soon thereafter.
Prospective Studies of Diet, Survival, and Recurrence After Breast Cancer Diagnosis
In these and other epidemiologic studies, food intake is self-reported and should be interpreted as estimates that may allow ranking rather than producing absolute values, even when the best-developed methodologies are used. Thus, a high risk for reporting bias and misclassification of subjects is inherent in this type of research. As noted in , several different methodologies were used to collect the dietary data in these studies, with self-administered food-frequency questionnaires being the most common method used. In the majority of the studies, dietary data were collected immediately after diagnosis, although the participants were often asked to report intake during the year preceding diagnosis. Associations between dietary factors, survival, and recurrence should ideally be adjusted for the effects of major nondietary determinants of survival, such as stage of cancer at diagnosis. This analysis strategy was used by some, but not all, of these studies. For the studies that analyzed associations with and without adjustment for stage and other possible influencing factors, the results summarized are the associations between dietary intake, survival, and recurrence adjusted for stage and other influencing factors.
The possible link between dietary fat and primary breast cancer risk has historically been the focus of more attention than other dietary factors, so fat intake (or selected high-fat foods) were examined in all of these studies. In addition to the general concerns described above, a major issue in the interpretation of the data relating dietary fat intake to breast cancer risk or progression is that fat intake and total energy consumption always covary (and also typically correlate with obesity), so an independent effect of total dietary fat per se is difficult to accurately assess unless the analysis is adjusted for these factors. Also, self-reported dietary assessment is known to underestimate energy intake, and this bias is most evident for high-fat foods.88,89
Underreporting affects the accuracy of dietary data more among women (v
men), those categorized as overweight, minority groups, and younger (v
Rates of underreporting of intake among breast cancer survivors are similar to rates in the general population, with obese women being twice as likely as nonobese women to underreport intake.91
To minimize the bias introduced by underreporting, particularly in the interpretation of data on fat intake, adjustment for energy intake is the accepted approach used in the analysis of associations between dietary fat and disease risk.92
Total dietary fat intake was significantly inversely associated with survival or treatment failure (described as recurrence or new cancer of the contralateral breast) in five of the 12 studies that examined this relationship,19,36,79,81,84
although the relationship with fat intake was unadjusted for energy intake in three of these five reports.19,79,81
In one of these studies, this relationship was seen only in women with estrogen receptor–positive (but not negative) tumors.84
A trend for this relationship was observed in another study.85
In two studies in which the investigators also analyzed fat intake as an energy-adjusted variable, adjusted fat intake was unrelated to survival.19,36
In a study in which the intakes of selected foods (rather than nutrients) were examined in relation to recurrence or risk for death,25
intakes of butter, margarine, and lard were directly associated with risk of recurrence but not with risk of death.
In 10 of these studies,19,36,78,80,81,83–87
intakes of various types of fat (in addition to total fat intake) were examined in the analysis. Studies in which total fat intake was not associated with survival or recurrence generally found no relationship between survival and intakes of various types of fat, with one exception. Jain et al78
found energy-adjusted saturated fat intake (but not total fat intake) to be significantly inversely associated with survival. In two of the studies in which total fat intake was associated with survival, intake of a fat subtype also was found to be similarly associated. Holm et al84
found both energy-adjusted total and saturated fat intakes to be directly associated with risk for recurrence or new cancer, and Zhang et al19
found monounsaturated fat intake (in addition to total fat intake), unadjusted for energy intake, to be inversely related to survival. In women with node-negative disease, a protective effect of omega-3 fatty acid intake was observed in one study.87
Thus, these studies do not provide strong support for a role for specific fat types in breast cancer progression.
Results of the analysis of associations between vegetable intake (or nutrients provided by vegetables and fruit, such as carotenoids and vitamin C) suggest a protective effect, although the strength of the association is modest. Of the eight studies that examined these dietary factors,19,36,78,82,84–87
three found a significant inverse association with risk of death,78,85,86
one found that risk of dying was nonsignificantly decreased in association with frequent vegetable consumption,82
and one found a significant inverse association in women with node-negative disease, who comprised 62% of that cohort (but not in the total group that included women at all stages of invasive breast cancer).87
In the studies that found an inverse relationship with survival and intakes of vegetables, fruit and related nutrients (beta-carotene, vitamin C), the magnitude of the protective effect was a 20% to 90% reduction in risk for death. Given that there is some variability in the findings and in the vegetable-related dietary factors that have been examined in these studies, these data do not provide conclusive evidence for a beneficial effect. Further research that examines the association between survival and intakes of vegetables and the various constituent phytochemicals would be useful.
The relationship between dietary fiber intake, survival, and recurrence was examined in seven of these cohorts of breast cancer survivors.19,36,78,84–87
None of these studies found a significant relationship in the total group under study, although the point estimates in one study suggest a trend for a protective effect.84
In four studies, intakes of selected high-fiber foods (ie, vegetables, fruits, cereal-grain products) were examined in relation to survival, recurrence, or both.36,82,86,87
As noted above, a significant protective effect of vegetables and fruit was found in one study,86
one found a trend for this relationship,82
and one found a protective relationship in women with node-negative disease.87
Bread and cereal intake was inversely associated with risk for recurrence in one of the three studies that specifically examined the relationship between survival and recurrence and this food type.36
Another dietary factor of interest in this patient population is alcohol, which has been consistently and positively associated with risk for primary breast cancer in epidemiologic studies.93
In the eight studies that examined the relationship between alcohol intake and survival in women who had been diagnosed with breast cancer,19,36,78,82,84–87
no significant associations were observed, although one of these studies reported that risk of dying was slightly (but not significantly) increased in association with frequent alcohol consumption.82
In the study involving the analysis of relationships that were based on selected foods rather than nutrients,25
the consumption of beer, but not wine or liquor, was inversely associated with risk of recurrence but was not associated with risk of death. These findings are fairly consistent and suggest that alcohol intake may not increase risk for recurrence or overall survival after the diagnosis of breast cancer.
To date, no epidemiologic or clinical studies have examined or reported the relationship between soy intake and survival in women who have been diagnosed with breast cancer. Also, studies conducted to date have not identified dietary supplement use as being protective against recurrence in breast cancer survivors.
Possible Mechanisms for Dietary Factors
Various mechanisms by which dietary fat may promote increased risk for and progression of breast cancer have been previously reviewed.94–96
In animal studies, diets that are rich in linoleic acid (an omega-6 fatty acid) have been observed to promote tumor development in rats exposed to a mammary chemical carcinogen, possibly by a mechanism that involves tumor cell eicosanoids.96
Free-radical mediated lipid peroxidation and DNA-adduct formation has also been suggested to be another mechanism by which dietary fat could promote carcinogenesis.94
Clinical studies have suggested that low-fat diets may decrease serum estrogen concentrations, as reviewed and summarized in a meta-analysis.97
However, significant weight loss also occurred in response to the low-fat diet modification in the majority of the studies in which serum estradiol was significantly reduced in response to a low-fat diet intervention, and an energy deficit and weight reduction would be expected to produce a reduction in serum gonadal hormone concentrations independent of diet composition. In fact, the promotion of weight loss is another proposed mechanism by which lower fat intake could influence the progression of breast cancer.95
Several biologically feasible mechanisms that might explain a protective effect of vegetables and fruits have been demonstrated in cell culture and animal studies. For example, carotenoids have retinoid-like effects on cellular differentiation and apoptosis and also exhibit inhibitory effects on mammary cell growth.98–100
Vegetables of the Brassica
genus, such as broccoli, demonstrate a favorable effect on estrogen metabolism via the induction of cytochrome P-450.101
In mammalian biologic systems, fiber binds estrogen in the enterohepatic circulation and interferes with reabsorption, thus reducing circulating estrogen concentrations.102,103
Diet Intervention Trials
Two large multicenter randomized controlled trials are examining whether diet modification can influence the risk for recurrence and survival after the diagnosis of early-stage breast cancer. In both of these studies, participants will be followed up for an average of at least 6 years, and results are anticipated after 2005.
The Women’s Intervention Nutrition Study (WINS) involves 2,500 postmenopausal women who were randomized within 12 months of primary surgery for breast cancer, and the goal of the intervention is a reduction in dietary fat intake (≤ 15% energy from fat). The rationale for the WINS is based on comparisons of survival of women diagnosed with breast cancer across countries with different fat consumption patterns and evidence from cell culture and laboratory animal studies suggesting that dietary fat may affect a variety of factors involved in the progression of breast cancer.94,104
The WINS pilot and feasibility studies demonstrated that women with postmenopausal breast cancer would adhere to a low-fat diet and suggest that hormonal factors may be responsive to the dietary change. In a 6-month feasibility study, 19 of 27 postmenopausal breast cancer survivors completed the counseling sessions, with average fat intake reduced from 34% to 22% of energy, body weight reduced by an average of 2.3 kg, and serum estradiol (but not estrone) reduced by 37%.105
In a report of data from 93 women enrolled onto the feasibility phase of WINS, the low-fat diet intervention was associated with a reduction in fat intake to 21% of energy, an average weight loss of 2 kg, and an average 20% reduction in serum estradiol concentrations in subjects with baseline serum estradiol ≥ 10 pg/mL at 6 months after randomization.106
Subjects with lower serum estradiol concentrations at baseline exhibited a significant increase in serum estradiol in response to the intervention, and serum estrone, estrone sulfate, and sex hormone– binding globulin concentrations did not change in that study. In another subset of 290 WINS feasibility study subjects, fat intake was significantly reduced in the intervention group versus the control group (averaging 20% v
32% of energy) at 3 months.107
In the Women’s Healthy Eating and Living (WHEL) study, the participants are 3,109 pre- and postmenopausal women who were enrolled onto the trial and randomized after completion of initial therapies and within 4 years of diagnosis.108
The primary emphasis of the WHEL study diet intervention is on increased vegetable and fruit intake, with daily dietary goals of five vegetable servings, 16 ounces of vegetable juice, three fruit servings, 15% to 20% energy from fat, and 30 g of dietary fiber. The rationale is that a high-vegetable, high-fiber diet may influence progression of breast cancer through several mechanisms. For example, this dietary pattern may exert beneficial effects on gonadal hormones, and increased intakes of carotenoids provided by vegetables and fruit may promote normal mammary cell growth regulation.98–100
Other biologic activities of phytochemicals, such as antioxidant activity, also are hypothesized to contribute to beneficial effects of a plant-based diet on risk for cancer progression.
In the WHEL feasibility study that involved 93 women, intervention group subjects increased vegetable intake more than two-fold, from 2.8 to 7.4 servings per day, at 12 months.109
These subjects also significantly increased mean intakes of fruit (from 2.9 to 4.0 servings per day) and fiber (from 12.8 to 21.0 g/1,000 kcal/d) and reduced fat intake from 29% to 20% of energy. Plasma carotenoids, a biomarker of the high vegetable and fruit intervention, were increased nearly two-fold in the first 12 months of the feasibility study and remained significantly higher in the intervention group versus comparison group at 3 years after randomization.110,111