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Journal of Clinical Oncology, Vol 26, No 25 (September 1), 2008: pp. 4072-4077 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.4527
Relationship Between Obesity and Pathologic Response to Neoadjuvant Chemotherapy Among Women With Operable Breast Cancer
From the Departments of Breast Medical Oncology, Epidemiology, and Clinical Cancer Prevention and Division of Quantitative Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, TX Corresponding author: Abenaa M. Brewster MD, MHS, PO Box 301439, Houston, TX 77230-1439; e-mail: abrewster{at}mdanderson.org
Purpose To understand the mechanism through which obesity in breast cancer patients is associated with poorer outcome, we evaluated body mass index (BMI) and response to neoadjuvant chemotherapy (NC) in women with operable breast cancer.
Patients and Methods From May 1990 to July 2004, 1,169 patients were diagnosed with invasive breast cancer at M. D. Anderson Cancer Center and received NC before surgery. Patients were categorized as obese (BMI Results Median age was 50 years; 30% of patients were obese, 32% were overweight, and 38% were normal or underweight. In multivariate analysis, there was no significant difference in pCR for obese compared with normal weight patients (odds ratio [OR] = 0.78; 95% CI, 0.49 to 1.26). Overweight and the combination of overweight and obese patients were significantly less likely to have a pCR (OR = 0.59; 95% CI, 0.37 to 0.95; and OR = 0.67; 95% CI, 0.45 to 0.99, respectively). Obese patients were more likely to have hormone-negative tumors (P < .01), stage III tumors (P < .01), and worse overall survival (P = .006) at a median follow-up time of 4.1 years. Conclusion Higher BMI was associated with worse pCR to NC. In addition, its association with worse overall survival suggests that greater attention should be focused on this risk factor to optimize the care of breast cancer patients.
Obesity as measured using body mass index (BMI) is generally regarded as a poor prognostic factor for breast cancer;1-5 however, there is inconsistency in the literature.6 Conflicting reports on the prognostic role of obesity have been attributed to variations in chemotherapy dosing of obese patients7,8 and failure to adjust for treatment and tumor characteristics that strongly predict for clinical outcome.9 In addition, the biologic mechanism of action through which obesity may contribute to breast cancer prognosis remains unclear. It has been proposed that obesity influences breast cancer prognosis by increasing circulating plasma levels of estrogen, insulin, insulin-like growth factor, and other hormonal factors that act to promote the growth of occult metastatic disease.10,11 It is also possible that obesity may affect response to chemotherapy because the conversion to active metabolite and/or clearance of cytotoxic drugs such as doxorubicin and cyclophosphamide may be altered by higher body weight without a corresponding increase in toxicity.12,13 An assessment of tumor response to neoadjuvant chemotherapy (NC) may serve as a surrogate measure for understanding how obesity influences breast cancer prognosis. There is a lack of studies that have examined the influence of obesity on response to NC for the treatment of primary breast tumors. Therefore, we used a cohort of 1,169 patients with operable breast cancer treated with NC at The University of Texas M. D. Anderson Cancer Center (MDACC) to evaluate the relationship between BMI at diagnosis and the end points of pathologic complete response (pCR) and breast cancer–specific and progression-free survival. Because pCR to NC is considered a marker of improved progression-free survival,14,15 we hypothesized that decreased rates of pCR among obese patients should also predict for worse progression-free survival. Understanding the specific biologic mechanisms through which being overweight or obese contributes to breast cancer prognosis is essential for individualizing care for improving outcomes among overweight and obese breast cancer patients.
Patient Selection The Breast Cancer Management System database of MDACC was searched to identify women with nonmetastatic, primary invasive ductal or lobular noninflammatory breast cancer who were treated with NC before being eligible for surgical treatment at MDACC between May 1990 and July 2004. The database contains detailed information on patient (race, age, and menopausal status at start of NC), clinical (height and weight at start of NC, chemotherapy and endocrine treatment, surgery type, and assessment of pathologic response in the breast and axilla), and tumor (clinical stage, estrogen receptor [ER] and progesterone receptor [PR] status, histologic grade, and HER-2/neu status) characteristics at diagnosis and has been previously described.15 Follow-up information for patients in the Breast Cancer Management System database is obtained every 2 years by direct review of the medical records and linkage to the MDACC Tumor Registry, which mails annual follow-up letters to each patient registered at MDACC known to be alive to determine the patient's clinical status. The MDACC Tumor Registry checks the Social Security Death Index and the Texas Bureau of Vital Statistics for the status of patients who do not respond to the letters. One thousand one hundred ninety-three patients were identified who met study criteria. Twenty-four patients were excluded for the following reasons: partial surgery before receiving NC (n = 21); patient refused surgery after NC (n = 1); concomitant pregnancy (n = 1); and time between NC and response assessment of more than 1 year (n = 1). The final study population consisted of 1,169 breast cancer patients.
BMI was calculated as weight (kg) divided by height (m2), and groups were separated into obese (BMI
Pathology
Treatment
Statistical Methods Overall survival was calculated from the date of NC initiation to the date of death or last follow-up. Progression-free survival was calculated from the time of treatment initiation to the time of disease recurrence or metastasis or, if no recurrence or metastasis was recorded, to the time of last follow-up. Patients who had not experienced progression or died by the last follow-up were censored. To address whether BMI was associated with breast cancer–specific mortality, we used a classification system that has been used by other investigators21 with high concordance for documented cause of death. We classified deaths as caused by breast cancer if the death occurred after a report of a recurrence. Deaths were classified as not being breast cancer related if no recurrence was recorded before the death. Initially, univariate models were fit to evaluate the predictive effect of each factor alone, and then a backward selection procedure was used to determine the most parsimonious multivariate model. Variables considered in modeling of the probability of pCR to NC and the survival analyses included BMI, race, age at treatment start, menopausal status, ER status, PR status, HER-2/neu status, tumor histology, nuclear grade, clinical stage, lymphatic or vascular invasion, chemotherapy, and duration of NC. Number of positive nodes, number of nodes removed, adjuvant endocrine therapy, and pathologic response to NC were also considered in the survival analyses. All reported P values are two-sided, and P < .05 was considered statistically significant. Analyses were performed using SAS for Windows (release 9.1; SAS Institute, Cary, NC).
Relationship Between Patient and Tumor Characteristics and BMI Categories Table 1 lists the patient and tumor characteristics by BMI categories. African American race, older age, and postmenopausal status at start of NC were significantly associated with overweight and obese status. Obese patients had a higher percentage of tumors that were ER negative (46% in obese v 38% in overweight and 36% in normal/underweight patients; P = .01). A higher percentage of obese patients (41%) had stage III tumors compared with overweight (31%) or normal/underweight patients (28%; P < .01). Specifically, more obese patients (40%) had stage T3 or T4 tumors compared with overweight (31%) or normal/underweight patients (25%; P < .01). BMI did not show a significant association with tumor histology, PR status, HER-2 status, nuclear grade, lymph node involvement, and presence of vascular or lymphatic invasion. A subgroup analysis was performed to evaluate the distribution of BMI category among patients with triple-negative (ER, PR, and HER-2/neu negative) breast cancers (n = 208). There was a trend of a higher percentage of triple-negative breast cancers among overweight (23%) and obese (25%) patients compared with normal weight patients (18%; P = .05; data not shown).
BMI and pCR to NC The time from initiation of NC to definitive surgical management ranged from 1.7 to 11.8 months (median, 5.5 months). Approximately 15% (14.5%, n = 170) of patients had a pCR to NC. In the univariate model, there was no association between pCR and BMI as either a categoric or continuous variable. In the multivariate model, there was no significant difference in pCR to NC for obese compared with normal/underweight patients (odds ratio [OR] = 0.78; 95% CI, 0.49 to 1.26). However, overweight patients compared with normal/underweight patients were less likely to have a pCR to NC (OR = 0.59; 95% CI, 0.37 to 0.95; Table 2). When the overweight and obese groups were combined and compared with the normal/underweight group, there was a significant association with pCR (OR = 0.67; 95% CI, 0.45 to 0.99).
BMI and Progression-Free Survival Median time to progression was not attained in the follow-up of this study population. At 5 years, the estimated progression-free survival rate was 75% (95% CI, 72% to 77%). In multivariate analysis, progression-free survival was not associated with overweight or obese status (Table 3). The clinical factor most strongly related to an increased risk of progression was failure to obtain a pCR (hazard ratio = 4.76; 95% CI, 2.40 to 9.41; P < .001). Patients with a hormone receptor–positive tumor who received adjuvant endocrine therapy had a 66% reduced risk of progression compared with hormone receptor–negative patients (ER and PR negative; P < .001). Younger age at start of NC, clinical stage III at diagnosis, ER-negative status, nuclear grade 3, higher number of positive lymph nodes, and longer duration from start of neoadjuvant therapy to response assessment were all significantly associated with a decreased progression-free survival (Table 3).
BMI and Breast Cancer–Specific Survival We evaluated patients for disease-specific survival based on BMI categories. There was a total of 194 deaths. Deaths were classified as caused by breast cancer if the death occurred after a report of a recurrence (n = 167). There were 18 deaths from other causes, and the cause of death was unknown in nine patients. The unadjusted breast cancer–specific survival percentages at 10 years were 74% for normal/underweight patients, 67% for overweight patients, and 62% for obese patients (P = .048). Adjusting for prognostic factors, there was no significant association between obese or overweight status and breast cancer–specific survival.
BMI and Overall Survival
To our knowledge, this is the first study to evaluate the relationship between overweight and obese status and pathologic response to NC among patients with operable breast cancer. Patients with higher BMI were more likely to present with high-risk tumor characteristics and were less likely to obtain pCR to NC. Obese patients experienced a worse overall survival compared with normal or underweight patients, which is a consistent finding in the literature. Randomized studies have shown that pCR to NC is a predictor of overall survival in breast cancer patients.19,22 In our study, higher BMI was associated with decreased pCR to NC and worse overall survival, but there was no association of overweight and obesity with breast cancer–specific or progression-free survival, as has been observed in some studies.21,23,24 It is possible that our study was underpowered to detect any small impact of BMI on breast cancer–specific or progression-free survival. In addition, differences in lymph node involvement at diagnosis, use of adjuvant endocrine therapy, and intrinsic tumor biology have been speculated to contribute to the heterogeneity in the disease-free survival of breast cancer patients who do not obtain a pCR to NC.22 Obese and overweight patients were more likely to present at diagnosis with larger tumors and more advanced clinical stage at diagnosis than normal or underweight patients. This association has been observed in some studies25 but not in others,26,27 and the conflicting reports may be a result of differences in study populations and access to early diagnosis. Although it has been reported that obese women are more likely to have hormone receptor–positive tumors,28,29 subgroups of premenopausal and postmenopausal obese women have been demonstrated to have hormone-negative tumors, as also shown in our study.30 Obese and overweight patients were also more likely to present with triple-negative breast cancers, which tend to respond better to NC.31 Despite having these tumors, obese and overweight patients were less likely to achieve a pCR to NC, highlighting the significance of BMI in this study as a predictive factor for pCR. Several limitations of the study should be considered when interpreting the results. Although it is the standard of care at MDACC that breast cancer patients receive treatment according to their actual body weight, we were unable to verify the chemotherapy doses of the patients included in this study. Because clinicians tend to reduce doses in overweight and obese patients for fear of overdosing, this suggests that a less efficacious therapy would be more likely to be administered.7,8 Changes in chemotherapy dosing because of weight fluctuations or toxicities that occur during the course of NC treatments may also have influenced the study end points. We did not include data on clinical response to NC; however, all breast surgery after NC was performed at MDACC, and assessment of pathologic response was performed using uniform criteria. In conclusion, this large single-institution study of breast cancer patients treated with NC demonstrates that higher BMI is associated with lower pCR to NC. This finding may be attributed to the influence of BMI on the clinical effectiveness of chemotherapy or the underdosing of overweight and obese patients by clinicians because of fears of toxicity despite randomized studies that have demonstrated that this practice contributes to worse disease-free survival.7,21 Efforts are currently underway to identify tumor gene expression profiles to better predict pCR and outcome in patients who do not experience a pCR.21 Clinicians should be aware of higher BMI status as a host risk factor influencing pCR to NC and overall survival for which attention to chemotherapy dosing based on actual body weight, investigations into chemotherapy pharmacokinetics, and management of comorbidities may yield significant benefits in improving the outcome of breast cancer patients.
The author(s) indicated no potential conflicts of interest.
Conception and design: Jennifer K. Litton, Ana M. Gonzalez-Angulo, Carla L. Warneke, Aman U. Buzdar, Melissa Bondy, Gabriel N. Hortobagyi, Abenaa M. Brewster Administrative support: Jennifer K. Litton, Shu-Wan Kau Provision of study materials or patients: Shu-Wan Kau Collection and assembly of data: Jennifer K. Litton, Ana M. Gonzalez-Angulo, Carla L. Warneke, Aman U. Buzdar, Shu-Wan Kau, Abenaa M. Brewster Data analysis and interpretation: Jennifer K. Litton, Carla L. Warneke, Abenaa M. Brewster Manuscript writing: Jennifer K. Litton, Ana M. Gonzalez-Angulo, Carla L. Warneke, Aman U. Buzdar, Melissa Bondy, Somdat Mahabir, Gabriel N. Hortobagyi, Abenaa M. Brewster Final approval of manuscript: Jennifer K. Litton, Ana M. Gonzalez-Angulo, Carla L. Warneke, Aman U. Buzdar, Melissa Bondy, Somdat Mahabir, Gabriel N. Hortobagyi, Abenaa M. Brewster
Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Obermair A, Kurz C, Hanzal E, et al: The influence of obesity on the disease-free survival in primary breast cancer. Anticancer Res 15:2265-2269, 1995[Medline] 7. Rosner GL, Hargis JB, Hollis DR, et al: Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: Results from Cancer and Leukemia Group B study 8541. J Clin Oncol 14:3000-3008, 1996[Abstract] 8. Madarnas Y, Sawka CA, Franssen E, et al: Are medical oncologists biased in their treatment of the large woman with breast cancer? Breast Cancer Res Treat 66:123-133, 2001[CrossRef][Medline] 9. Goodwin P: Body size and breast cancer prognosis: A critical review of the evidence. Breast Cancer Res Treat 16:205-214, 1990[CrossRef][Medline] 10. Modugno F, Kip K, Cochrane B, et al: Obesity, hormone therapy, estrogen metabolism and risk of postmenopausal breast cancer. Int J Cancer 118:1292-1301, 2006[CrossRef][Medline] 11. 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 12. Powis G, Reece P, Ahmann D, et al: Effect of body weight on the pharmacokinetics of cyclophosphamide in breast cancer patients. Cancer Chemother Pharmacol 20:219-222, 1987[CrossRef] 13. Rodvold K, Rushing D, Tewksbury D: Doxorubicin clearance in the obese. J Clin Oncol 6:1321-1327, 1988 14. Hennessy BT, Hortobagyi GN, Rouzier R, et al: Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol 23:9304-9311, 2005 15. Guarneri V, Broglio K, Kau S-W, et al: Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 24:1037-1044, 2006 16. National Institutes of Health/National Heart, Lung, and Blood Institute: Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View.ShowTOCrid=obesity.TOC 17. WHO: The World Health Organization Histological Typing of Breast Tumors–Second Edition. Am J Clin Pathol 78:806-816, 1982[Medline] 18. Black M, Speer F: Nuclear structure in cancer tissues. Surg Gynecol Obstet 105:97-102, 1957[Medline] 19. Mazouni C, Peintinger F, Wan-Kau S, et al: Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol 25:2650-2655, 2007 20. Bear HD, Anderson S, Smith RE, et al: Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 24:2019-2027, 2006 21. Dignam J, 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 22. Rastogi T, Devesa S, Mangtani P, et al: Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project protocols. J Clin Oncol 26:778-785, 2008 23. Dignam JJ, Wieand K, Johnson KA, et al: Effects of obesity and race on prognosis in lymph node-negative, estrogen receptor-negative breast cancer. Breast Cancer Res Treat 97:245-254, 2006[CrossRef][Medline] 24. 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 25. Moorman PG, Jones BA, Millikan RC, et al: Race, anthropometric factors, and stage at diagnosis of breast cancer. Am J Epidemiol 153:284-291, 2001 26. Wasserman L, Flatt SW, Natarajan L, et al: Correlates of obesity in postmenopausal women with breast cancer: Comparison of genetic, demographic, disease-related, life history and dietary factors. Int J Obes Relat Metab Disord 28:49-56, 2004[CrossRef][Medline] 27. Chagpar A, McMasters K, Saul J, et al: Body mass index influences palpability but not stage of breast cancer at diagnosis. Am Surg 73:555-560, 2007[Medline] 28. Enger SM, Ross RK, Paganini-Hill A, et al: Body size, physical activity, and breast cancer hormone receptor status: Results from two case-control studies. Cancer Epidemiol Biomarkers Prev 9:681-687, 2000 29. Huang Z, Hankinson SE, Colditz GA, et al: Dual effects of weight and weight gain on breast cancer risk. JAMA 278:1407-1411, 1997 30. Maehle BO, Tretli S, Skjaerven R, et al: Premorbid body weight and its relations to primary tumour diameter in breast cancer patients; its dependence on estrogen and progesterone receptor status. 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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
30 kg/m2), overweight (BMI of 25 to < 30 kg/m2), or normal/underweight (BMI < 25 kg/m2). Logistic regression was used to examine associations between BMI and pathologic complete response (pCR). Breast cancer–specific, progression-free, and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. All statistical tests were two-sided. 
2 test was used to compare groups with respect to categoric variables. The Wilcoxon rank sum test and Kruskal-Wallis test were used to examine associations between categoric and ordinal variables, and Spearman's correlation coefficient was used to test for associations between two ordinal variables. Associations between clinical factors at diagnosis and BMI were analyzed using logistic regression. Survival curves were constructed using the Kaplan-Meier product-limit method and compared between BMI groups with the log-rank test. Cox proportional hazards regression analysis was performed to calculate hazard ratios and 95% CIs for demographic and clinical characteristics and treatment variables. 
