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Originally published as JCO Early Release 10.1200/JCO.2005.10.949 on January 31 2005 © 2005 American Society of Clinical Oncology.
Obesity and Early-Stage Breast CancerLos Angeles Biomedical Research Institute, Torrance, CA The observation of Kroenke et al1 that weight and weight gain are associated with increased breast cancer recurrence and mortality, especially in never-smoking women, builds on a substantial body of evidence in this area and provides new information about obesity and breast cancer.2,3 Although tobacco use has not been linked historically to breast cancer, smoking has recently been associated with an increased risk of breast cancer development.4 In women with breast cancer, current smoking has also been linked with increased lung recurrence risk, as well.5,6 Taken together, these observations raise an intriguing hypothesis regarding interaction among smoking history, obesity, and the risk of breast cancer recurrence. The authors acknowledge that there are study limitations, including reliance on self-reported weight, a nonvalidated recurrence methodology, and a lack of information on adjuvant therapy. Body mass index (BMI) changes were calculated from a given height and the patient's self-reported weight, for which validity information is provided. However, issues related to reliable weight reporting during a period of weight change may differ from those in women with stable weight. A greater question is raised by the breast cancer recurrence methodology. Recurrence was determined using an innovative approach, which assumed that any new cancer in the lung, liver, bone, or brain represented breast cancer recurrence. Given that, for example, a smoker with a so-called lung cancer could potentially be misclassified, perhaps the study end point could be more accurately characterized as disease-free survival. Additional validation efforts to clarify this issue would be useful. Some of the identified design concerns, such as limited information on cancer therapy, have been addressed by retrospective analyses of data from randomized adjuvant therapy trials. In such studies, breast cancer stage is well characterized, comorbid condition influence is minimized by entry criteria, systemic treatment is defined bt the protocol, and recurrence is well characterized.7 The International Breast Cancer Study Group reported a cumulative experience involving 6,792 patients from randomized trials evaluating chemotherapy and endocrine therapy over a 15-year period.8 In this large population, patients with a normal BMI had significantly longer overall survival and disease-free survival than patients with intermediate or obese BMI. When adjusted for other factors, BMI significantly influenced overall survival (P = .03) but not disease-free survival (P = .12), with a greater effect seen in pre- and perimenopausal women. Dignam et al,9 analyzing results from a randomized trial evaluating tamoxifen in more than 3,500 women with negative lymph nodes and estrogen receptor–positive tumors, showed comparable findings. Although obesity had no significant effect on recurrence risk or tamoxifen efficacy, overall mortality was significantly greater for obese breast cancer patients compared with those of normal weight. Improved survival and quality of life are primary objectives of therapies provided to women with early-stage breast cancer. The observed influence of obesity on non-breast cancer–related survival will likely be of increasing importance in determining outcome of breast cancer patients in the future, given that breast cancers are now diagnosed at an earlier stage when other medical conditions represent substantial competing mortality risks. For example, in the Women's Health Initiative hormone trials, when postmenopausal women between the ages of 50 to 79 years had yearly mammography as a protocol requirement, breast cancers were diagnosed at an average size of 1.5 cm, and only 15% were lymph node-positive.10 In addition, mammographically detected tumors have a more favorable prognosis than tumors of similar size found outside of screening.11 Thus, attention to the morbidity and mortality consequences of obesity will likely play an increasing role in determining breast cancer patient outcome. Obese women are more likely to have lower physical activity and higher caloric and fat intakes when compared with nonobese women, with all three factors—at least in some reports—associated with increased breast cancer recurrence risk.12-15 Obesity is associated with higher grade breast cancers, especially in black women.16 In addition, obesity affects changes in hormones, which influence breast cancer growth, including estrogens, androgens, insulin-like growth factors, and insulin.3 Although attention has been reasonably focused on estrogen as a potential mediator of the obesity influence on breast cancer,17 emerging evidence suggests that insulin levels also could play a role. Both higher fasting insulin levels and obesity independently predict a significantly increased risk of recurrence and decreased survival in a breast cancer cohort.18 This has been recently confirmed in a separate breast cancer population in which high levels of fasting insulin were also significantly associated with decreased survival.19 In addition, a recent report found obesity was most strongly related to mortality in women with estrogen receptor–negative breast cancers, suggesting that factors other than estrogen mediate the effect.20 The issues raised by the potential for interaction among smoking and obesity with factors that influence breast cancer outcome suggest that observational studies are unlikely to provide definitive information on the relationships among obesity, weight change after diagnosis, and breast cancer outcome. Randomized trials in other than cancer settings have identified a strategy that achieves moderate long-term weight reduction, and incorporates dietary counseling, increased physical activity, behavioral therapy, and ongoing medical supervision.21 There are currently no full-scale outcome studies evaluating weight loss or weight maintenance as potential adjuvant breast cancer interventions. However, weight loss interventions have been successfully piloted in breast cancer survivors.22 In addition, there are three randomized clinical trials evaluating dietary lifestyle interventions that may indirectly address some aspects of the weight issue. All three completed trials incorporate fat intake reduction and, to a greater or lesser degree, fruit and vegetable increase without specifically targeting weight change. The Women's Intervention Nutrition Study is evaluating a reduced fat intake intervention among 2,437 postmenopausal women, 48 years of age or older, with early-stage breast cancer.23,24 The Women's Healthy Eating and Lifestyle study is evaluating a reduced fat and increased fruit and vegetable, high-fiber intervention among both pre- and postmenopausal women with early-stage breast cancer,25 and the Women's Health Initiative Dietary Modification is evaluating a dietary intervention incorporating fat, fruit, and vegetable change in more than 48,000 cancer-free postmenopausal women as primary breast cancer prevention.26 Modest, but statistically significant, weight loss has been reported in at least one of these studies,27 and all three trials are scheduled to provide other outcome information in the near future. In summary, body weight and weight gain after a diagnosis of breast cancer may adversely affect outcome in subpopulations of patients with resected breast cancer. Intervention strategies have been developed that have successfully led to weight loss in other settings. Evidence from observational studies and retrospective analyses of randomized trials is now sufficient to support clinical trials of lifestyle interventions with an anticipated improvement in survival comparable to that seen for many current systemic adjuvant treatments. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devised used in a study if they are not being evaluated as part of the investigation. Research Funding: Rowan T. Chlebowski, National Cancer Institute. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. REFERENCES 1. Kroenke CH, Chen WY, Rosner B, et al: Weight, weight gain and survival after breast cancer diagnosis. J Clin Oncol 23:10.1200/JCO.2005.01.079 2. Goodwin PJ, Boyd NF: Body size and breast cancer prognosis: A critical review of the evidence. Breast Cancer Res Treat 16:205-214, 1990[CrossRef][Medline]
3. Chlebowski RT, Aiello E, McTiernan A: Weight loss in breast cancer patient management. J Clin Oncol 20:1128-1143, 2002
4. Reynolds P, Hurley S, Goldberg DE, et al: Active smoking, household passive smoking, and breast cancer: Evidence from the California Teachers Study. J Natl Cancer Inst 96:29-37, 2004 5. Scanlon FA, Suh O, Murthy SM, et al: Influence of smoking on the development of lung metastases from breast cancer. Cancer 75:2693-2699, 1995[CrossRef][Medline]
6. Murin S, Inciardi J: Cigarette smoking and the risk of pulmonary metastasis from breast cancer. Chest 119:1635-1640, 2001
7. Dignam JJ, Mamounas EP: Obesity and breast cancer prognosis: An expanding body of evidence. Ann Oncol 15:850-851, 2004
8. Berclaz G, Li S, Price KN, et al: Body mass index as a prognostic feature in operable breast cancer: The International Breast Cancer Study Group experience. Ann Oncol 15:875-884, 2004
9. Dignam JJ, Wieand K, Johnson K, et al: Obesity, tamoxifen use, and outcomes in women with estrogen receptor-positive early stage breast cancer. J Natl Cancer Inst 95:1467-1476, 2003
10. Chlebowski RT, Hendrix SL, Langer RD, et al: Estrogen plus progestin influence on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative Randomized Trial. JAMA 289:3243-3253, 2003
11. Joensuu H, Lehtimaki T, Holli K, et al: Risk for distant recurrence of breast cancer detected by mammography screening or other methods. JAMA 292:1064-1073, 2004
12. McTiernan A, Kooperberg C, White E, et al: Recreational physical activity and the risk of breast cancer in postmenopausal women: The Women's Health Initiative Cohort Study. JAMA 290:1331-1336, 2003
13. Michels KB, Ekbom A: Caloric restriction and incidence of breast cancer. JAMA 291:1226-1230, 2004
14. Jain M, Miller AB, To T: Premorbid diet and the prognosis of women with breast cancer. J Natl Cancer Inst 86:1390-1397, 1994 15. Zhang S, Folsom AR, Sellers TA, et al: Better breast cancer survival for postmenopausal women who are less overweight and eat less fat: The Iowa Women's Health Study. Cancer 76:275-283, 1995[CrossRef][Medline] 16. Chlebowski RT, Chen Z, Anderson G, et al: Ethnicity and breast cancer in the Women's Health Initiative: A unifying concept for unfavorable outcome in African American women. Proc Am Soc Clin Oncol 23:99s, 2004 (abstr 1008)
17. Key TJ, Applyby PN, Reeves GK, et al: Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95:1218-1226, 2003
18. Goodwin PJ, Ennis M, Pritchard KI, et al: Fasting insulin and outcome in early-stage breast cancer: Results of a prospective cohort study. J Clin Oncol 20:42-51, 2002
19. Borugian MJ, Shep SB, Kim-Sing C, et al: Insulin, macronutrient intake, and physical activity: A potential indicators of insulin resistance associated with mortality from breast cancer? Cancer Epidemiol Biomarkers Prev 13:1163-1172, 2004
20. Enger SM, Greif JM, Polikoff J, et al: Body weight correlates with mortality in early stage breast cancer. Arch Surg 139:954-960, 2004
21. McTigue KM, Harris R, Hemphill B, et al: Screening and interventions for obesity in adults: Summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 139:933-949, 2003 22. Dujuric Z, DuLaura NM, Jenkins I, et al: Combining weight-loss counseling with the Weight Watchers plan for obese breast cancer survivors. Obes Res 10:657-665, 2002[Medline]
23. Chlebowski RT, Blackburn GL, Buzzard IM, et al: Adherence to a dietary fat intake reduction program in postmenopausal women receiving therapy for early breast cancer. J Clin Oncol 11:2072-2080, 1993 24. Chlebowski RT, Blackburn G, Winters B, et al: Long term adherence to dietary fat reduction in the Women's Intervention Nutrition Study (WINS). Proc Am Soc Clin Oncol 19:78a, 2000 (abstr 302) 25. Pierce JP, Faerber S, Wright FA, et al: A randomized trial of the effect of a plant-based dietary pattern on additional breast cancer events and survival: The Women's Healthy Eating and Living (WHEL) Study. Control Clin Trials 23:728-756, 2002[CrossRef][Medline] 26. Ritenbaugh C, Patterson RE, Chlebowski RT, et al: The Women's Health Initiative Dietary Modification trial: Overview and baseline characteristics of participants. Ann Epidemiol 13:S87-S97, 2003[CrossRef][Medline] 27. Blackburn GL, Nixon D, Chlebowski RT, et al: Interim results reflect changes in fat intake an weight in the Women's Intervention Nutrition Study (WINS). Proc Am Assoc Cancer Res 44:171, 2003 (abstr 866)
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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