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To determine the association of dietary patterns with cancer recurrence and mortality of early-stage breast cancer survivors.
Patients included 1,901 Life After Cancer Epidemiology Study participants diagnosed with early-stage breast cancer between 1997 and 2000 and recruited primarily from the Kaiser Permanente Northern California Cancer Registry. Diet was assessed at cohort entry using a food frequency questionnaire. Two dietary patterns were identified: prudent (high intakes of fruits, vegetables, whole grains, and poultry) and Western (high intakes of red and processed meats and refined grains). Two hundred sixty-eight breast cancer recurrences and 226 all-cause deaths (128 attributable to breast cancer) were ascertained. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs.
Increasing adherence to a prudent dietary pattern was associated with a statistically significant decreasing risk of overall death (P trend = .02; HR for highest quartile = 0.57; 95% CI, 0.36 to 0.90) and death from non–breast cancer causes (P trend = .003; HR for highest quartile = 0.35; 95% CI, 0.17 to 0.73). In contrast, increasing consumption of a Western dietary pattern was related to an increasing risk of overall death (P trend = .05) and death from non–breast cancer causes (P = .02). Neither dietary pattern was associated with risk of breast cancer recurrence or death from breast cancer. These observations were generally not modified by physical activity, being overweight, or smoking.
Women diagnosed with early-stage breast cancer might improve overall prognosis and survival by adopting more healthful dietary patterns.
The influence of diet on breast cancer prognosis has been explored in previous studies demonstrating inconsistent results with fat intake1–6 and modest inverse associations4,5,7,8 with fruit and vegetable consumption.4–8 Notably, two randomized dietary intervention trials among women with breast cancer reported contrasting findings. The Women's Intervention Nutrition Study found that a low-fat diet reduced breast cancer recurrence,1 whereas the Women's Health Eating and Lifestyle Study reported that a diet high in vegetables, fruits, and fiber and low in total fat did not reduce recurrence or mortality.6
Although focusing on specific nutrients or foods may be warranted based on interests in biologic mechanisms, foods are not consumed in isolation, but rather as part of an overall dietary pattern.9–11 Thus, in epidemiologic studies, there is growing interest in the exploration of dietary patterns and their associations with disease.12–18 For example, food intake patterns that have been characterized as Western (high intakes of meat, refined grains, and high-fat foods) tend to be associated with increased risk of coronary heart disease,12,15 stroke,14,19 diabetes,18,19 and colon cancer,11,13,20–22 whereas prudent dietary patterns (high intakes of fruits and vegetables and whole grains) tend to be associated with decreased risk of these diseases.
To our knowledge, only one study has examined the role of dietary patterns in breast cancer survival.23 Using data from the Nurses' Health Study (NHS), Kroenke et al23 reported that higher intake of the prudent pattern and lower intake of the Western pattern was associated with decreased mortality from causes other than breast cancer but not with death from breast cancer or all-cause death. Therefore, we undertook an analysis of dietary patterns and breast cancer prognosis among 1,901 participants in the Life After Cancer Epidemiology (LACE) Study, a prospective cohort study of long-term survival after breast cancer diagnosis.
The LACE cohort consists of 2,280 women diagnosed with invasive breast cancer between 1997 and 2000 and recruited primarily from the Kaiser Permanente Northern California (KPNC) Cancer Registry (82%) and the Utah Cancer Registry (12%). Further details on the cohort are provided elsewhere.24
In brief, eligibility criteria included age between 18 and 79 years old at enrollment; a diagnosis of early-stage primary breast cancer (stage I ≥ 1 cm, stage II, or stage IIIA); enrollment between 11 and 39 months after diagnosis; completion of breast cancer treatment (except for adjuvant hormonal therapy); free of recurrence; and no history of other cancers in the 5 years before enrollment.
Between January 2000 and April 2002, 5,656 women who initially met the LACE eligibility criteria were sent a recruitment package. Of these, 2,614 women (46%) agreed to participate and completed the questionnaires. Subsequent medical record review to confirm eligibility resulted in 334 exclusions. Reasons for exclusion were breast cancer recurrence, new primary breast cancer, or death between diagnosis and 3 months after study enrollment (37%); incorrect stage (34%); other cancer within 5 years before enrollment (10%); prior breast cancer (6%); more than 39 months since diagnosis (6%); incomplete demographic and medical data (3%); receiving treatment (2%); and language difficulty (2%). The remaining 2,280 women constitute the LACE cohort. Differences between KPNC participants and nonparticipants were compared,24 and both groups were similar in terms of cancer severity (stage and number of positive nodes) and treatment (chemotherapy and type of surgery). The only significant differences were that women approached within 15 months of diagnosis were more likely to enroll than those approached later, and women less than 50 years old were less likely to enroll than older women. This analysis was restricted to 1,901 women (83%) who completed a dietary questionnaire at baseline, as described in the following section. The study was approved by the institutional review boards of KPNC and the University of Utah (Salt Lake City, UT).
Diet was assessed at cohort entry using the Fred Hutchinson Cancer Research Center Food Questionnaire (FHCRC-FQ), a self-administered, semiquantitative food frequency questionnaire with 122 food and beverage items.25,26 For each food or beverage, participants marked frequency of consumption over the last 12 months and indicated the associated serving size as small, medium, or large.
A total of 1,962 women completed the FHCRC-FQ at baseline. Participants with questionnaires indicating extremes of total energy intake (< 500 or > 4,000 kcal; n = 54) or an excessive number of skipped items (n = 7) were considered unreliable and were excluded, leaving 1,901 women for the current analyses. Servings per day were calculated by multiplying portion size by frequency of consumption of each food and beverage item, standardized to daily consumption. Food items were classified into 38 food groups based on nutrient profiles and/or culinary usage, which was similar to previous studies.16,21,23 Foods with unique nutrient profiles and/or culinary usage were maintained as individual categories (eg, fried chicken, fried potatoes, mayonnaise).
Information on clinical factors was obtained through electronic data sources available from KPNC or from medical chart review for the non-KPNC participants. Data included tumor size, number of positive lymph nodes, hormone receptor status, and treatments. Treatment data included surgical procedures and associated dates, as well as types and dates of chemotherapy, radiation therapy, and hormone therapy. Tumor stage was calculated according to criteria of the American Joint Committee on Cancer (third edition). Data on race, family history of breast cancer, menopausal status, and weight gain were obtained from the mailed baseline questionnaire at cohort entry. Physical activity was assessed (metabolic equivalent [MET] hours per week) from a mailed questionnaire modeled loosely on the Arizona Activity Frequency Questionnaire.27
Four prognostic outcomes were considered: new breast cancer event (hereafter referred to as recurrence), all-cause death, death from breast cancer, and death from causes other than breast cancer. Recurrence includes a local or regional cancer recurrence, distant recurrence or metastasis, and development of a contralateral breast primary. All-cause death includes death from any cause including breast cancer; death from breast cancer includes death attributable to breast cancer as a primary or underlying cause on the death certificate; and death from causes other than breast cancer includes all other deaths. A physician reviewer was consulted in the event a cause of death was unclear. Recurrences were ascertained by a mailed semi-annual (until April 2005) or annual (after April 2005) health status update questionnaire that asked participants to report any events occurring in the preceding 6 or 12 months, respectively. All nonrespondents to the health status questionnaire were called to complete the questionnaire by telephone. Participants receiving care outside of KPNC who reported any event were contacted to obtain permission to view their protected health information. Medical records were reviewed to verify reported outcomes.
Participant deaths were determined through KPNC electronic data sources, a family member responding to a mailed questionnaire, or a phone call. In the event of a long-term nonresponse, death certificates were requested from the county or state of last known residence. For all study participants who were known to have died, copies of death certificates were obtained from the same sources to confirm cause of death.
For these analyses, 268 breast cancer recurrences (of which 84.3% were distant metastases) and 226 deaths were ascertained through May 29, 2008. Among the 226 deaths, 128 (56.6%) were attributable to breast cancer, 17 (7.5%) were attributable to other cancers, 29 (12.9%) were attributable to cardiovascular causes, and 52 (23.0%) were attributable to other causes not related to cancer or cardiovascular disease (CVD; International Classification of Diseases, 9th revision).
To identify major dietary patterns, principal components analysis was used on the basis of the 38 predetermined food groups to identify factors that account for much of the variance in the variables.28,29 The food groups (factors) were rotated using an orthogonal transformation, resulting in uncorrelated, independent factors. Major factors were retained based on eigenvalue (> 1), Scree test, and factor interpretability. The factor score for each factor (pattern) was calculated by summing intakes of food groups weighted by factor loading, and each individual was assigned a score for each identified pattern. Individuals with a high score for a pattern compared with individuals with lower scores have a stronger tendency to follow that pattern. The scores were then categorized by quartiles. Comparisons of baseline cohort characteristics by category of dietary pattern were conducted using Pearson χ2, analysis of variance, and Kruskal-Wallis tests.
Follow-up began at date of study entry and ended at date of first confirmed cancer recurrence or date of death, depending on the specific analysis. Individuals who did not have an event were censored at date of last contact. Hazard ratios (HRs) and 95% CIs representing the association between a defined event and quartiles of a dietary pattern were computed adjusting for covariates using the delayed entry Cox proportional hazards model.30,31 Because women entered the cohort over an approximately 3-year period since diagnosis, the delayed entry model ensures that a woman who enrolled onto the study t years after her initial breast cancer diagnosis was not considered at risk for a possible outcome before t years. A linear test for trend was estimated by modeling the median value of each category on an ordinal scale. All models were adjusted for age at diagnosis (years) and total energy intake (kcal).
A priori confounders included race, body mass index (BMI) at enrollment, family history of breast cancer, menopausal status, total physical activity at baseline, weight change from before diagnosis to study entry, smoking status, stage of disease, hormone receptor status, surgery, tamoxifen use, treatment, positive lymph nodes, and tumor size ≥ 2 cm, as specified in Tables 2 and and33.
Covariates were retained in the final multivariable model if they were statistically significant (P < .05) when added individually to the model adjusted for age at diagnosis and total energy intake. We also examined whether the associations between dietary patterns and prognosis varied by total physical activity at baseline (> v < median MET-h/wk), BMI at enrollment (< 25 v ≥ 25 kg/m2), and smoking status (ever v never smoker) by first generating strata-specific estimates and then including interaction terms in the models to test for statistical significance. A sensitivity analysis was conducted by excluding women who experienced recurrence or died within the first year of entering the cohort to address the possibility that sick patients with underlying cancer recurrences and limited survival may have altered their diet.
The following two distinct dietary patterns were identified at baseline: prudent and Western. Table 1 lists the factor-loading matrix between the individual food groups and the two major dietary patterns such that a higher factor loading value is indicative of a stronger correlation between the specific food group and relevant dietary pattern.
Higher prudent pattern scores at baseline were observed for women who were more physically active (P < .0001) and gained less weight from 1 year before diagnosis to enrollment (P = .04; Table 2). Higher Western pattern scores at baseline were observed for women who were younger (P = .008), had higher BMI at enrollment (P < .0001), had ever smoked (P = .04), and gained more weight from 1 year before diagnosis to enrollment onto the study (P = .0002; Table 3). In addition, Asian women were less likely to follow the Western dietary pattern, whereas Hispanic women were more likely to follow the Western dietary pattern (P = .005).
Mean follow-up times from cohort entry until the end points of recurrence and death were 3.17 years (range, 0.27 to 8.20 years) and 4.20 years (range, 0.34 to 7.75 years), respectively. Overall, cohort members were observed 5.93 years from entry (range, 0.00 to 8.36 years). In both the age- and energy-adjusted only and full multivariable models adjusted for additional prognostic factors, increasing tendency to follow the prudent diet was associated with a lower risk of overall death and death from other causes aside from breast cancer (Table 4). The highest quartile of the prudent pattern was associated with a decreased risk of overall death (HR = 0.57; 95% CI, 0.36 to 0.90; P trend = .02) and death from non–breast cancer causes (HR = 0.35; 95% CI, 0.17 to 0.73; P trend = .003). Furthermore, in both the age- and energy-adjusted only and full multivariable models, increasing tendency to follow the Western pattern was associated with increased risk of overall death (HR for highest quartile = 1.53; 95% CI, 0.93 to 2.54; P trend = .05) and death from non–breast cancer causes (HR for highest quartile = 2.15; 95% CI, 0.97 to 4.77; P trend = .02; Table 4). No associations were observed between these dietary patterns and breast cancer recurrence or death from breast cancer. These results did not change after excluding the 35 women who experienced recurrence or died within 1 year of study enrollment.
In analyses of overall death stratified by total physical activity, BMI at enrollment, and smoking status, no significant interactions were observed (Table 5). For breast cancer recurrence, death from breast cancer, and death from other causes, the stratified analyses did not yield any significant differential effect of dietary patterns by these factors (data not shown).
In this prospective cohort study of early-stage breast cancer survivors, increasing adherence to a prudent dietary pattern, characterized by high intakes of fruits, vegetables, legumes, whole grains, low-fat dairy products, poultry, and fish, was associated with a decreasing risk of overall death and death from causes other than breast cancer. In a complementary trend, increasing consumption of a Western dietary pattern consisting of high intakes of red and processed meats, refined grains, sweets, high-fat dairy products, snacks, and butter was related to an increasing risk of overall death and death from causes other than breast cancer. In contrast, neither dietary pattern was associated with risk of breast cancer recurrence or death from breast cancer. Women who tended to follow the prudent dietary pattern were more physically active, whereas women who had greater adherence to the Western dietary pattern were more likely to be overweight or obese and gained more weight (on average, 6 lb) after diagnosis. The corresponding protective and deleterious effects of a prudent diet and Western diet, respectively, on survival did not vary markedly by these or other modifiable lifestyle factors.
Although several studies have investigated the role of dietary patterns in relation to risk of primary breast cancer,17,32–38 to our knowledge, only the NHS23 has examined the impact of this measure of diet on breast cancer survival in a cohort of 2,619 women over a median follow-up time of 9 years since diagnosis. Our results agree with the NHS findings in that women who followed a more prudent diet had a decreased risk of death from causes other than breast cancer, whereas those who followed a more Western diet had an increased risk of death from causes other than breast cancer. Our death rates (56.6% as a result of breast cancer and 44.4% as a result of other causes after a median of 6.3 years of follow-up) were similar to those of the NHS (58.5% as a result of breast cancer and 41.5% as a result of other causes after a median of 9 years of follow-up). Among women who died of non–breast cancer causes in our study (n = 98), 29.6% died of CVD, 17.3% died of other cancers, and 53.1% died of causes aside from CVD and cancer, compared with rates of 22%, 45%, and 33%, respectively, in the NHS. Also similar to the NHS, we found no association between either of the dietary patterns and risk of death from breast cancer. Although the NHS did not observe an association between dietary patterns and risk of overall death, our study noted an inverse relationship of increasing adherence to the prudent dietary pattern and decreasing risk of all-cause mortality and a direct relationship of increasing adherence to the Western dietary pattern and increasing risk of all-cause mortality.
Our results are consistent with the NHS23 and studies of diet and cardiovascular disease12,15 and suggest that dietary patterns may represent a more important factor in the etiology of overall health and outcomes not related to breast cancer, as opposed to outcomes related to breast cancer. In fact, previous studies have reported somewhat modest and/or mixed associations of specific foods and/or food groups in relation to breast cancer prognosis.39 Furthermore, in another analysis from the LACE Study, no association was observed between postdiagnosis weight gain (which is strongly correlated with increasing adherence to the Western dietary pattern and weaker adherence to the prudent dietary pattern in the present study) and breast cancer–related outcomes.40
Strengths of the LACE study include being one of the few existing cohorts of early-stage breast cancer survivors and one of the first studies to comprehensively examine the association between dietary patterns and breast cancer recurrence and survival. Although our analyses rely on self-report of diet on the FHCRC-FQ, this questionnaire has been validated in the Women's Health Initiative.26,41 Cause-specific mortality may have been misclassified on death certificates from which we extracted cause of death information. Although misclassification of cause of death has been an issue in most studies of cause-specific mortality, it is somewhat reassuring that our findings regarding deaths not associated with breast cancer are consistent with results from the NHS.23 Because the LACE cohort consists of early-stage breast cancer survivors who were enrolled on average 2 years after diagnosis, we would not be able to detect associations with breast cancer death if the associations were only related to deaths that occurred in the immediate survivorship period (within 2 years) but not in the extended survivorship period (after 2 years). Finally, our results are not generalizable to women diagnosed with advanced-stage breast cancer and apply only to women who have survived, on average, 2 years since diagnosis.
In summary, we found that higher consumption of prudent and Western dietary patterns are associated with decreased and increased risks of overall death and death from causes other than breast cancer, respectively, but the patterns had no association with risk of breast cancer recurrence or breast cancer–related deaths. These results indicate that although dietary habits may not influence breast cancer–related outcomes for women diagnosed with breast cancer, they are nonetheless strong predictors of overall prognosis after breast cancer diagnosis. Consistent with dietary guidelines directed towards the general population for overall chronic disease or cancer prevention,42–44 women diagnosed with early-stage breast cancer may benefit from dietary patterns that include healthier foods such as fruits, vegetables, whole grains, and poultry and less consumption of red meat and refined foods.
We thank all Life After Cancer Epidemiology Study staff and participants.
Supported by National Cancer Institute Grant No. R01 CA80027 and by Utah Cancer Registry Grant No. N01 PC67000, with additional support from the State of Utah Department of Health.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
The author(s) indicated no potential conflicts of interest.
Conception and design: Marilyn L. Kwan, Lawrence H. Kushi, Martha L. Slattery, Bette J. Caan
Financial support: Bette J. Caan
Administrative support: Marilyn L. Kwan, Adrienne Castillo
Provision of study materials or patients: Adrienne Castillo
Collection and assembly of data: Erin Weltzien, Adrienne Castillo, Martha L. Slattery, Bette J. Caan
Data analysis and interpretation: Marilyn L. Kwan, Erin Weltzien, Lawrence H. Kushi, Martha L. Slattery, Bette J. Caan
Manuscript writing: Marilyn L. Kwan, Bette J. Caan
Final approval of manuscript: Marilyn L. Kwan, Erin Weltzien, Lawrence H. Kushi, Adrienne Castillo, Martha L. Slattery, Bette J. Caan