Diabetes, obesity, and survival in a large cohort of early-stage breast cancer patients

Reporter: Samuel Swisher-McClure, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 6, 2010

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Presenter: S. H. Giordano, University of Texas M. D. Anderson Cancer Center, Houston, TX

Background

  • Diabetes and obesity are very prevalent in the US population and the incidence of these disorders continues to rise.
    • The National Institute of Health estimated that in 2007, 7.8% of Americans had either diagnosed or undiagnosed Diabetes Mellitus ( http://www.nih.gov)
    • In 2008 an estimated 1/3rd of Americans were reported as obese, which is defined as a Body Mass Index (BMI) ? 30 (Flegal et al. JAMA, 2010).
  • Obesity is associated with increased risk of breast cancer in post-menopausal women (van de Brandt et al. Am J Epidemiol, 2000).
    • Increased serum estrogen levels as a result of aromatase activity within adipose tissue are thought to contribute to this association (Key et al. JNCI, 2003).
  • Both obesity and diabetes, which share overlapping etiologies, have been associated with adverse breast cancer (BC) outcomes.
    • Retrospective data have suggested a 2-3 fold increase in breast cancer related mortality among obese patients when compared to their non-obese counterparts (Enger et al. Arch Surg, 2004).
    • Elevated fasting insulin levels have also been associated with increased risk of breast cancer related mortality. There is a growing body of evidence that the mitogenic effects of insulin play an important role in breast cancer (Goodwin et al. JCO 2002).
  • The authors sought to further characterize these clinical issues by examining the relationship between diabetes, body mass index (BMI), and survival in a large cohort of early-stage BC patients.

Methods

  • This study was a retrospective cohort study of early stage breast cancer patients treated at M.D. Anderson Cancer Center (MDACC) from 1996-2005.
  • Inclusion criteria:
    • Women with Stage I-III Breast Cancer treated at MDACC from 1996-2005
  • Exclusion Criteria:
    • Male patients with breast cancer
    • Diagnosis of inflammatory breast cancer
    • Multiple episodes of breast cancer
    • Receipt of neoadjuvant chemotherapy/endocrine therapy
  • For comparison, the patients were divided into diabetic (DM) and non-diabetic (ND) groups and into 3 BMI classes: normal or underweight (N, BMI < 25), overweight (Ov, BMI 25-30), and obese (Ob, BMI ? 30).
  • Recurrence-free survival (RFS), disease specific survival (DSS), and overall survival (OS) were estimated by the Kaplan-Meier product and compared among groups via the log-rank test.
  • Categorical variables which were compared by chi-squared tests
  • Multivariate analysis was conducted via Cox proportional hazards models, which were adjusted for covariates including: DM status, BMI, age, stage, grade, hormone receptor (HR) status, receipt of adjuvant chemotherapy, and Charlson comorbidity index.

Results

  • There were 6,342 patients included in the analysis.
    • Median age was 53 years (range 19 - 91).
    • 93% had stage I-II disease, 7% had stage III disease.
    • 77% were hormone-receptor (HR) positive, 21% HER2-positive.
    • 56% of patients received adjuvant chemotherapy.
    • 497 patients had DM (7.8%).
    • Distribution of patient’s calculated BMI were categorized as follows : N 40%, Ov 30%, Ob 30%.
  • The median follow-up was 5.4 years, with 488 recurrences and 921 deaths noted at that time.
  • Diabetes was associated with increasing age, stage, and BMI. DM patients were less likely to receive adjuvant chemotherapy compared to ND patients
  • Elevated BMI was associated with increasing age, stage, grade, and diabetes.
  • RFS and OS were both significantly worse in DM vs. ND patients (p < 0.001 and p < 0.001, respectively) and in the high vs. low BMI groups (p = 0.01 and p = 0.0008, respectively).
  • On multivariate analysis:
    • DM patients had decreased RFS (hazard ratio [hr], 1.20; 95% CI = 0.99,1.50; p = 0.08) and OS (hr, 1.38; 1.11,1.78; p = 0.008).
    • Ob vs N patients had decreased RFS (hr, 1.15; 0.99,1.33; p = 0.065) and OS (hr, 1.26; 1.06,1.50; p = 0.010).
    • Ob vs N patients also had significant inferior DSS (hr, 1.25 ; p = 0.036). However, DM vs. ND patients had no significant differences in DSS ( hr, 1.05 ; p = 0.763).

Authors’ Conclusions

  • In this large cohort of early-stage BC patients, diabetes and obesity each correlated with a significant decrease in OS, as well as a borderline significant decrease in RFS, after adjustment for DM status, BMI, age, stage, grade, HR status, Charlson comorbidity index, and adjuvant chemotherapy administration.
  • Further studies to discover the reasons for these adverse outcomes in diabetic and obese breast cancer patients are underway.

Clinical Implications

  • Diabetes and obesity are extremely common in the US and in some studies have been associated with adverse breast cancer related outcomes
  • This study provides further evidence that diabetes and obesity are associated with inferior cancer related outcomes as measured in overall survival, relapse free survival, and disease specific survival.
  • The current study, along with previously conducted work mentioned above, identifies two important prognostic factors for patients with early stage breast cancer.
  • There is ongoing work to further characterize the underlying mechanisms that can explain these observed associations.
  • The study was a large retrospective cohort study with a well-designed statistical analysis to control for potential confounding covariates in the patient groups.
  • Potential limitations of the study include those common to most retrospective analyses in that there may be potential unknown confounding factors that are not included in the multivariate model and for which the results of the analysis are not adjusted.
    • For example, the authors did not include race or socioeconomic status in the multivariate analysis conducted here.
  • This and other studies suggest that adequate control of obesity and diabetes may be important in improving breast cancer related outcomes. These topics should be addressed with patients as they may significantly impact survival.
  • Currently ongoing trials such as the Women's Health Initiative Dietary Modification Study and the Women's Healthy Eating and Lifestyle study may provide further information regarding potential benefit of weight loss interventions in breast cancer survivors.



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