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Originally published as JCO Early Release 10.1200/JCO.2008.19.7764 on December 15 2008 © 2009 American Society of Clinical Oncology.
Dietary Changes After Breast Cancer in Women Without Hot Flashes: A Simple and Inexpensive Way to Target Tumor and Host?
Medical Oncology Unit, Galliera Hospital; and Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy
Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy
Medical Oncology Unit, Galliera Hospital, Genoa; and Division of Cancer Prevention and Genetics, European Institute of Oncology, Milan, Italy One of the questions medical oncologists most frequently hear from patients recently diagnosed with breast cancer is whether dietary changes can help reduce the risk of disease recurrence. This is a pertinent question, and one that remains an unsettled scientific and clinical issue. The hypothesis of a negative influence of dietary fat and glucose load and of a beneficial effect of fiber, vegetable, and fruit consumption on breast cancer risk has existed for decades, even though epidemiologic evidence is not unanimous1 and a large primary prevention trial of a low-fat dietary modification has so far shown only a limited benefit.2 Likewise, observational studies of the influence of dietary fat on breast cancer recurrence have yielded mixed results,3-5 with some suggesting a direct association of higher fat intake with risk of recurrence in postmenopausal women.6,7 In this issue of Journal of Clinical Oncology, Gold et al8 demonstrate a disease-free survival advantage after dietary changes in women with early breast cancer without hot flashes at baseline. The article is a secondary analysis of the Women's Health Eating and Living study, a randomized trial testing whether a diet high in vegetables, fruit, and fiber and low in fat influenced prognosis in breast cancer survivors. The primary analysis of the trial did not reveal any disease-free survival benefit after the dietary pattern change.9 However, on the basis of subsequent findings of improved disease-free survival in women with hot flashes (HF+) undergoing tamoxifen treatment10 and higher circulating estradiol levels in patients without hot flashes (HF–),11 the authors conducted a secondary analysis to test whether the dietary intervention had a beneficial effect on breast cancer recurrence in the HF– subgroup (ie, those women with potentially higher estrogen levels and worse prognosis). Nearly 3,000 women 18 to 70 years of age with operable breast cancer were randomly assigned to a dietary intervention or comparison group within 4 years of diagnosis. Women were analyzed for this study if they had hot flash status ascertained at baseline (n = 2,967) with mean follow-up of 7.3 years. The intervention group underwent telephone counseling and attended cooking classes (approximately 1/month), whereas the control group was advised to eat five servings of fruit and vegetables daily. For women who were HF– at baseline, a similar proportion (approximately 35%) had received adjuvant chemotherapy in both arms, whereas more women randomly assigned to the dietary intervention had received adjuvant tamoxifen, had had a prior oophorectomy, and had prior menopause hormone therapy. Regardless of baseline hot flash status, the intervention group changed their dietary habits significantly. Although no weight loss was reported, fiber consumption rose by 33%, fruit servings by 20%, daily vegetable servings doubled, and energy from fat was reduced by 20%. After controlling for tumor characteristics and antiestrogen treatment, the HF– women assigned to the diet intervention arm were 31% less likely than the HF– women assigned to the control arm to have a breast cancer event (hazard ratio [HR] = 0.69; 95% CI, 0.51 to 0.93). There was no differential effect according to hormone receptor subtype. The diet intervention did not influence prognosis in HF+ women. Both the intervention and comparison arms in the HF+ group had a better prognosis than the HF– group. The conclusions drawn were as follows: a diet high in fiber, fruit, and vegetables, and with reduced fat improved recurrence-free survival in women without hot flashes at baseline and presumably with higher estrogen levels; and HF– women had a worse prognosis than HF+ patients, regardless of the dietary intervention arm. The study provides interesting findings on a thus far rather overlooked hormonal variable, namely the presence of hot flashes and its impact on the risk of breast cancer recurrence. Indeed, this vasomotor symptom may well turn out to be a significant prognostic and predictive factor for breast cancer, and possibly even a risk determinant for breast cancer in unaffected women. The study shows that a dietary intervention that curbed fat calories and increased vegetables, fruit, and fiber was effective in reducing recurrence by 30% overall and up to 47% in postmenopausal women, with a possible risk reduction of death from any cause in HF– women. In the era of molecular signatures and pathways, this simple, host-related natural symptom may provide a different paradigm for our breast cancer treatment and prevention strategies, through a proactive and inexpensive treatment method that includes, in addition to conventional targeted drug therapy, a holistic approach on the basis of healthier eating habits, weight loss, and increased physical activity.
The pathophysiology of hot flashes is complex and poorly understood. Although lower estrogen concentrations after lower fat intake and higher fiber intake may be partly responsible for the beneficial effect of dietary changes on prognosis, the finding that women taking aromatase inhibitors have fewer hot flashes than those taking tamoxifen despite much lower estrogen levels12 indicates that the interactions between vasomotor symptoms, estrogen concentrations, and antiestrogen intervention are quite complex and cannot be explained by hormone levels alone. Women who report hot flashes during menopause are at higher risk of complaining about tamoxifen-associated symptoms than other women,13 suggesting that genetic factors in the estrogen receptor signaling pathway may influence the likelihood of experiencing hot flashes. An association has been reported between hot flashes during natural menopause and polymorphisms in the estrogen receptor The study by Gold et al8 has some important limitations. First, it is an unplanned, subgroup analysis, in which, moreover, the diet intervention arm comprised a significantly higher proportion of women undergoing different hormonal treatments, including tamoxifen, oophorectomy, and prior menopause hormone therapy, compared with the control arm, particularly in the HF– group. Although the authors separated the women who had completed tamoxifen treatment from those who had dropped out because of hot flashes—a putative reason for drug interruption in extensive tamoxifen metabolizers21 and a predictor of tamoxifen efficacy18—the continuous adjustment added complexity to data interpretation. Second, there was no weight reduction in the intervention arm, indicating that the total energy balance was unaffected by the dietary pattern. Given the growing body of evidence implicating glycemic load in the promotion of breast carcinogenesis,22 it is possible that a compensatory increase in glucose consumption partly hampered the protective effect of reducing fat intake. Moreover, long-term compliance to a modified diet was low, inasmuch as the average percentage of fat intake was higher than baseline at year 4 in the intervention arm. Also, data collection is questionable, given that total daily caloric intake was reported to be lower than baseline, notwithstanding the lack of weight decrease. Clearly, the findings by Gold et al are intriguing, but they need to be replicated in a prospective trial before any dietary guidelines can be recommended to women for the prevention of breast cancer recurrence. How does the study fit into what we already know? The Women's Intervention Nutrition Study,23 another low-fat diet intervention trial in women with early breast cancer, provides important clues as to whether a change in dietary pattern may become an essential component in the medical oncologist's treatment armamentarium. This trial, which enrolled nearly 2,400 women with stages I to IIIA breast cancer within 1 year of diagnosis, was designed specifically to assess whether a low-fat diet (15% of total calories) affects breast cancer recurrence or survival. Interim results23 indicated a significant benefit (HR = 0.76; 95% CI, 0.60 to 0.98) for relapse-free survival after a median of 5 years in women randomly assigned to the low-fat dietary intervention group compared with control group patients, who received minimal dietary guideline information. Exploratory analysis reveals that the beneficial effect might be restricted to women with estrogen receptor–negative/progesterone receptor–negative breast cancers. Interestingly, a recent survival analysis update24 showed that fat intake reduction did not significantly increase overall survival (HR = 0.82; 95% CI, 0.64 to 1.07), but exploratory analyses showed a greater reduction of overall mortality (HR = 0.36; 95% CI, 0.18 to 0.74) in the estrogen receptor–negative/progesterone receptor–negative subgroup. These results are particularly encouraging because they offer a potentially effective treatment alternative in women who cannot benefit from endocrine therapy after completion of adjuvant chemotherapy. Although differences in dietary pattern changes and energy balance have been noted that might explain the different results between the two trials,25 the results of these secondary analyses strongly suggest that reducing fat intake and increasing fruit, vegetable, and fiber consumption may improve breast cancer prognosis, at least in selected subgroups of women. Additional research in the area of diet and lifestyle changes must be pursued to unequivocally confirm these exploratory findings. At present, the available evidence already urges medical oncologists to incorporate counseling about dietary habits and lifestyle attitudes as a prominent component of their breast cancer adjuvant treatment strategy. A not-only-drug approach to the science and practice of medical oncology has come of age. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Andrea Decensi Financial support: Andrea Decensi Administrative support: Matteo Puntoni, Andrea Decensi Provision of study materials or patients: Matteo Puntoni, Andrea Decensi Collection and assembly of data: Matteo Puntoni, Andrea Decensi Data analysis and interpretation: Matteo Puntoni, Bernardo Bonanni, Andrea Decensi Manuscript writing: Matteo Puntoni, Bernardo Bonanni, Andrea Decensi Final approval of manuscript: Matteo Puntoni, Bernardo Bonanni, Andrea Decensi NOTES published online ahead of print at www.jco.org on December 15, 2008 REFERENCES 1. Boyd NF, Stone J, Vogt KN, et al: Dietary fat and breast cancer risk revisited: A meta-analysis of the published literature. Br J Cancer 89:1672-1685, 2003[CrossRef][Medline] 2. Prentice RL, Caan B, Chlebowski RT, et al: Low-fat dietary pattern and risk of invasive breast cancer: The Women's Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 295:629-642, 2006 3. Mai V, Kant AK, Flood A, et al: Diet quality and subsequent cancer incidence and mortality in a prospective cohort of women. Int J Epidemiol 34:54-60, 2005 4. Kroenke CH, Fung TT, Hu FB, et al: Dietary patterns and survival after breast cancer diagnosis. J Clin Oncol 23:9295-9303, 2005 5. Rock CL, Flatt SW, Natarajan L, et al: Plasma carotenoids and recurrence-free survival in women with a history of breast cancer. J Clin Oncol 23:6631-6638, 2005 6. Pierce JP, Stefanick ML, Flatt SW, et al: Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol 25:2345-2351, 2007 7. McEligot AJ, Largent J, Ziogas A, et al: Dietary fat, fiber, vegetable, and micronutrients are associated with overall survival in postmenopausal women diagnosed with breast cancer. Nutr Cancer 55:132-140, 2006[CrossRef][Medline] 8. Gold EB, Pierce JP, Natarajan L, et al: Dietary pattern influences breast cancer prognosis in women without hot flashes: The Women's Healthy Eating and Living Trial. J Clin Oncol doi:10.1200/JCO.2008.16.1067 [epub ahead of print on December 15, 2008] 9. Pierce JP, Natarajan L, Caan BJ, et al: Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: The Women's Healthy Eating and Living (WHEL) randomized trial. JAMA 298:289-298, 2007 10. Mortimer JE, Flatt SW, Parker BA, et al: Tamoxifen, hot flashes and recurrence in breast cancer. Breast Cancer Res Treat 108:421-426, 2008[CrossRef][Medline] 11. Rock CL, Flatt SW, Laughlin GA, et al: Reproductive steroid hormones and recurrence-free survival in women with a history of breast cancer. Cancer Epidemiol Biomarkers Prev 17:614-620, 2008 12. Baum M, Budzar AU, Cuzick J, et al: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 13. Loprinzi CL, Zahasky KM, Sloan JA, et al: Tamoxifen-induced hot flashes. Clin Breast Cancer 1:52-56, 2000[Medline] 14. Malacara JM, Perez-Luque EL, Martinez-Garza S, et al: The relationship of estrogen receptor-[alpha] polymorphism with symptoms and other characteristics in postmenopausal women women. Maturitas 49:163-169, 2004[CrossRef][Medline] 15. Cai Q, Shu XO, Jin F, et al: Genetic polymorphisms in the estrogen receptor alpha gene and risk of breast cancer: Results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev 12:853-859, 2003 16. Boyapati SM, Shu XO, Ruan ZX, et al: Polymorphisms in ER-alpha gene interact with estrogen receptor status in breast cancer survival. Clin Cancer Res 11:1093-1098, 2005 17. Ntukidem NI, Nguyen AT, Stearns V, et al: Estrogen receptor genotypes, menopausal status, and the lipid effects of tamoxifen. Clin Pharmacol Ther 83:702-710, 2008[CrossRef][Medline] 18. Goetz MP, Rae JM, Suman VJ, et al: Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol 23:9312-9318, 2005 19. Bonanni B, Macis D, Maisonneuve P, et al: Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: Data from the Italian Tamoxifen Trial. J Clin Oncol 24:3708-3709, 2006 20. Cuzick J: Hot flushes and the risk of recurrence - retrospective, exploratory results from the ATAC trial. Presented at 30th San Antonio Breast Cancer Symposium, San Antonio, TX, December 13-16, 2007 (abstr 2069) 21. Rae JM, Sikora MJ, Henry NL, et al: Cytochrome P450 2D6 activity predicts adherence to tamoxifen therapy. Presented at 30th San Antonio Breast Cancer Symposium, San Antonio, TX, December 13-16, 2007 (abstr 77) 22. Barclay AW, Petocz P, McMillan-Price J, et al: Glycemic index, glycemic load, and chronic disease risk: A meta-analysis of observational studies. Am J Clin Nutr 87:627-637, 2008 23. Chlebowski RT, Blackburn GL, Thomson CA, et al: Dietary fat reduction and breast cancer outcome: Interim efficacy results from the Women's Intervention Nutrition Study. J Natl Cancer Inst 98:1767-1776, 2006 24. Chlebowski RT, Blackburn GL, Hoy MK, et al: Survival analyses from the Women's Intervention Nutrition Study (WINS) evaluating dietary fat reduction and breast cancer outcome. J Clin Oncol 26:12s, 2008 (suppl; abstr 522). 25. Gapstur SM, Khan S: Fat, fruits, vegetables, and breast cancer survivorship. JAMA 298:335-336, 2007
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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(ESR1) and estrogen receptor β (ESR2) genes.
