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Originally published as JCO Early Release 10.1200/JCO.2008.20.1624 on January 26 2009 © 2009 American Society of Clinical Oncology.
In ReplyDepartment of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX We would like to thank Dr Daniell for his interest in our article,1 and would like to address the two potential prognostic factors mentioned in his letter. Lifestyle factors have been frequently linked to poorer survival. Overweight status and tobacco consumption are associated with poorer prognosis in several types of cancer. Obesity is a recognized risk factor for the development of postmenopausal breast cancer, and has been shown to adversely affect prognosis in both premenopausal and postmenopausal breast cancer.2,3 Increased body weight or body mass index (BMI) has been found to be inversely associated with disease-free and overall survival in both premenopausal and postmenopausal women, although the evidence is not entirely consistent.4 In a review of 34 studies, a statistically significant association between obesity and recurrence or decreased survival in patients with breast cancer was found to have been reported in 26 studies, whereas eight studies indicated no association.5 Evidence suggests that weight gain after diagnosis of breast cancer is also associated with poorer overall and disease-free survival.6 The Women's Interventional Nutritional Study reported improved event-free survival in women randomly assigned to a reduced-fat diet and who experienced weight loss.7 In a recent study of 1,169 patients with breast cancer receiving neoadjuvant chemotherapy, Litton et al8 investigated the relationship between BMI and pathologic response rates. Increased BMI was associated with significantly more advanced disease and a higher rate of estrogen receptor–negative tumors. In addition, lower pathologic complete response rates were reported among overweight and obese women. Multiple factors contribute to the unfavorable survival rates in obese patients with breast cancer, including a higher likelihood of comorbid conditions, a higher likelihood of unfavorable tumor characteristics, decreased levels of sex hormone–binding globulin, increased levels of insulin and insulin-like growth factors, and systematic underdosing of chemotherapy.9–11 The complex endocrinology of obesity and the related factors that may contribute to breast cancer risk are largely unknown. Estradiol (E2) can potentially mediate carcinogenesis via two separate pathways. One pathway involves receptor-mediated stimulation of biologic events, and the other involves the metabolism of E2 to toxic compounds resulting in DNA damage. It is likely that these mechanisms work in either an additive or synergistic manner. It is speculated that the genetic mutations induced specifically by depurinating adducts and generally by oxidative DNA damage are propagated by the genomic effects of E2 on cellular proliferation. Furthermore, E2 can modulate immune responses occurring in the course of an inflammatory process, which can predispose one to cancer.11 Few epidemiologic studies have evaluated the relationship between tobacco and breast cancer prognosis. The results of these limited studies are largely inconsistent, and the small number of patients included is a major limitation.12–14 An inverse relationship between smoking and breast cancer survival has been reported,15 but is not supported by the results of other studies. In fact, an overview of studies of smoking and breast cancer indicates smoking has a neutral effect on the incidence of the disease. In a large epidemiologic study, tobacco was not associated with increased risk of breast cancer recurrence.16 Several mechanisms have been proposed to explain the adverse effect of smoking on prognosis, including increased levels of DNA adducts induced by tobacco carcinogens in women with breast cancer who smoke.17 However, the existing evidence regarding the effect of smoking on survival is still inconclusive. We need to evaluate the functional, endocrinologic, molecular, and immunologic end points associated with lifestyle modifications and the effects of such modifications on response to therapy in breast cancer trials. We also need to analyze whether environmental or lifestyle susceptibility factors that control the tissue-specific balance within cells are associated with overall outcome. There is much room for well-designed and well-powered epidemiologic studies and behavioral interventions in the effort to fully understand the effects of smoking and being overweight on the prognosis of patients with breast cancer. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Andreopoulou E, Hortobagyi G: Prognostic factors in metastatic breast cancer: Successes and challenges toward individualized therapy. J Clin Oncol 26:3660–3662, 2008. 2. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638, 2003. 3. Griggs JJ, Sabel MS: Obesity and cancer treatment: Weighing the evidence. J Clin Oncol 26:4060–4062, 2008. 4. Rock CL, Demark-Wahnefried W: Nutrition and survival after the diagnosis of breast cancer: A review of the evidence. J Clin Oncol 20:3302–3316, 2002. 5. Chlebowski RT, Aiello E, McTiernan A: Weight loss in breast cancer patient management. J Clin Oncol 20:1128–1143, 2002. 6. Kroenke CH, Chen WY, Rosner B, et al: Weight, weight gain, and survival after breast cancer diagnosis. J Clin Oncol 23:1370–1378, 2005. 7. 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. 8. Litton JK, Gonzalez-Angulo AM, Warneke CL, et al: Relationship between obesity and pathologic response to neoadjuvant chemotherapy among women with operable breast cancer. J Clin Oncol 26:4072–4077, 2008. 9. Creighton CJ, Casa A, Lazard Z, et al: Insulin-like growth factor-I activates gene transcription programs strongly associated with poor breast cancer prognosis. J Clin Oncol 26:4078–4085, 2008. 10. Griggs JJ, Sorbero ME, Lyman GH: Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 165:1267–1273, 2005. 11. Cavalieri E, Frenkel K, Liehr JG, et al: Estrogens as endogenous genotoxic agents: DNA adducts and mutations. J Natl Cancer Inst Monogr 27:75–93, 2000. 12. Daniell HW: Host factors in breast cancer recurrence. J Clin Oncol 10:1817–1819, 1992. 13. Holmes MD, Murin S, Chen WY, et al: Smoking and survival after breast cancer diagnosis. Int J Cancer 120:2672–2677, 2007.[CrossRef][Medline] 14. Sagiv SK, Gaudet MM, Eng SM, et al: Active and passive cigarette smoke and breast cancer survival. Ann Epidemiol 17:385–393, 2007.[CrossRef][Medline] 15. Calle EE, Miracle-McMahill HL, Thun MJ, et al: Cigarette smoking and risk of fatal breast cancer. Am J Epidemiol 139:1001–1007, 1994. 16. Brewster AM, Do KA, Thompson PA, et al: Relationship between epidemiologic risk factors and breast cancer recurrence. J Clin Oncol 25:4438–4444, 2007. 17. Faraglia B, Chen SY, Gammon MD, et al: Evaluation of 4-aminobiphenyl-DNA adducts in human breast cancer: The influence of tobacco smoke. Carcinogenesis 24:719–725, 2003.
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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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