The Obesity and Breast Cancer Connection: Advancing the Agenda

The review by Jennifer Ligibel, MD, approaches a topic of increasing importance-namely the role of obesity in breast cancer incidence and clinical outcome-in a comprehensive and up-to-date fashion, focusing on obesity and its influence on breast cancer recurrence and associated survival. This commentary will provide additional thoughts and clarifications.

In the cited meta-analysis by Protani and colleagues of 45 studies relating obesity at diagnosis to breast cancer-related mortality and overall mortality, a 30% higher risk was seen when obese women were compared with leaner women.[1] Importantly, only one of these studies was adjusted for diabetes. The impact of diabetes and diabetes therapy (insulin vs metformin) on breast cancer risk is an area that has received recent attention. A meta-analysis of older studies found that patients with breast cancer and diabetes presented at a later stage and had a greater risk of death compared with patients who did not have diabetes.[2] Based on mechanism of action and preclinical results, the influence of metformin on breast cancer outcomes has been more recently examined. In a retrospective neoadjuvant therapy analysis, breast cancer patients with diabetes had a higher complete response frequency if they were using metformin, compared with diabetic patients not using metformin and those without diabetes.[3] We recently presented analyses of a cohort of Women's Health Initiative trial participants in which women with diabetes who were using metformin had a lower incidence of breast cancer positive for both estrogen receptors and progesterone receptors (hazard ratio [HR] = 0.62; 95% confidence interval [CI], 0.44-0.87) compared with women without diabetes, whereas women with diabetes who were taking medications other than metformin had a slightly higher breast cancer incidence.[4] These distinctions will receive increasing focused attention in the future, in both observational and prospective clinical studies.

The Danish Breast Cancer Cooperative Group has published information on body mass index (BMI) and frequency and timing of recurrence risk (distant and locoregional) in a population of 18,967 women with early-stage breast cancer receiving adjuvant chemotherapy. In multivariate-adjusted analyses, women with a BMI greater than 25 had a substantially increased risk of recurrence vs women with lower BMIs. The influence was only seen after more than 5 years of follow-up, however, and it only correlated with distant, not locoregional, recurrences.[5] If these data can be confirmed, many reports of associations will need to be revisited, as follow-up in most reports is of a shorter duration than 10 years.

When one reviews the extensive body of observational studies that strongly associate obesity with a negative impact on breast cancer recurrence and survival, as well as the increasing number of moderately sized feasibility studies indicating that weight loss can be achieved in a clinical trial setting, one wonders why no full-scale lifestyle-intervention clinical trials targeting weight loss have gone forward.[6] This is especially puzzling in light of the strong signal described by Dr. Ligibel from the full-scale Women's Intervention Nutrition Study (WINS), in which a lifestyle intervention targeting fat-intake reduction also resulted in a 5- to 6-lb, statistically significant weight loss in the intervention group, with an associated statistically significant improvement in relapse-free survival in patients with early-stage breast cancer.[7] The Lifestyle Intervention Study for Adjuvant Treatment of Early Breast Cancer (LISA),[8] also described by Dr. Ligibel in detail, was originally designed as a full-scale intervention trial but will not progress beyond a successful feasibility stage.

There is one randomized prospective clinical trial going forward that is likely to provide definitive assessment of the influence of weight loss on breast cancer recurrence risk. The SUCCESS C Study is a European trial designed to include 3547 women with early-stage, HER2-negative breast cancer. Participants undergo an initial randomization to one of two taxane-containing chemotherapy regimens. In addition, a second step includes randomization of patients with BMIs of 24 to 40 to receive either a telephone-based lifestyle intervention program targeting moderate weight loss or a control condition involving general recommendations for a healthy lifestyle.[9] The recruitment status was described in a presentation at the 2010 CTRC-AACR San Antonio Breast Cancer Symposium, in which through November 2010 a total of 2310 patients had been recruited, with recruitment continuing at target rates.[10] This intervention was informed by the success of the WINS trial[7] and the design of LISA,[8] but it reflects an independently generated intervention plan. Results describing the impact of this randomized, controlled lifestyle-intervention program on disease-free survival of breast cancer are highly anticipated.

Finally, there is one relevant correction. Dr. Ligibel refers to the Austrian Breast Cancer Study Group 12 (ABCSG-12) study as comparing anastrozole to tamoxifen in premenopausal women treated with ovarian ablation.[11] Generally, ovarian ablation refers to oophorectomy, whereas ABCSG-12 participants received ovarian suppression with goserelin (Zoladex). Thus, in addition to obesity-related factors, some of the differential findings regarding anastrozole vs tamoxifen may represent the influence of incomplete ovarian suppression by goserelin. The potential for incomplete estrogen suppression with goserelin would not be an issue with tamoxifen therapy, which has been demonstrated to function in both low and high estrogen environments.[12]

In summary, a body of evidence strongly supports the concept that obesity is associated with adverse breast cancer outcome. Ongoing observational studies are now attempting to parse effects of obesity from diabetes and specific diabetes therapies. At least one full-scale clinical trial is moving forward to provide definitive assessment of moderate weight loss on breast cancer recurrence.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES

1. Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat. 2010;123:627-35.

2. Peairs KS, Barone BB, Snyder CF, et al. Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J Clin Oncol. 2011;29:40-6.

3. Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27:3297-302.

4. Chlebowski RT, McTiernan A, Aragaki AK, et al. Metformin and breast cancer incidence in postmenopausal diabetic women in the Women's Health Initiative (WHI). J Clin Oncol. 2011;29(suppl): abstract 1503.

5. Ewertz M , Jensen MB, Gunnarsdóttir KÁ, et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol. 2011;29:25-31.

6. Chlebowski RT. Lifestyle and breast cancer risk: the way forward. J Clin Oncol. 2010;28:1445-7.

7. Chlebowski RT, Blackburn G, Thomson CA, et al: Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women's Intervention Nutrition Study (WINS). J Natl Cancer Inst. 2006;98:1767-76.

8. Segal R, Pond G, Vallis M, et al. Randomized trial of a lifestyle intervention for women with early-stage breast cancer (BC) receiving adjuvant hormone therapy: initial results. J Clin Oncol. 2011;29: abstract 512.

9. Rack B, Andergassen U, Neugebauer J, et al. The German SUCCESS C Study-the first European lifestyle study on breast cancer. Breast Care. 2010;5:395-400.

10. Hepp P, Rack B, Annecke K, et al. Multivariate analysis of obesity and disease free survival in patients with nodal positive primary breast cancer– the ADEBAR trial (abstract S2-2). Presented at the CTRC-AACR San Antonio Breast Cancer Symposium. San Antonio, Texas, December 6-10, 2010.

11. Sestak I, Distler W, Forbes JF, et al. Effect of body mass index on recurrences in tamoxifen and anastrozole treated women: an exploratory analysis from the ATAC trial. J Clin Oncol. 2010;28:3411-5.

12. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomized trials. Lancet. 2011;378:771-84.