Breast Cancer Patients Who Are Obese at Diagnosis: Alea Iacta Est? or "Is the Die Cast?"

Obesity rates in the United States have increased twofold in adults and threefold in children during the past 30 years.[1] Beyond its detrimental effects on cardiovascular health, obesity increases the risk of several cancers, including postmenopausal breast cancer,[2] and it is also associated with a higher risk of recurrence and death in those who develop breast cancer.[3] Understanding the details of these relationships is important not only because of their public health implications, but also because they may point to potential behavioral and molecular interventions to reduce breast cancer mortality. In this issue of ONCOLOGY, Dr. Jennifer Ligibel provides a comprehensive yet concise overview of this subject. Her review raises three key questions that merit further discussion:

What is the biologic basis for the association between obesity and breast cancer?

Epidemiologic data have provided strong evidence regarding endogenous estrogen levels and risk of postmenopausal breast cancer,[4,5] including several studies suggesting that high estrogen levels partly explain the relationship between obesity and cancer risk.[5,6] Furthermore, estrogens and/or their metabolites may be carcinogenic by exerting mitogenic, anti-apoptotic, and mutagenic effects.[7] While the relationship between estrogen levels and breast cancer risk is less established in premenopausal women,[8,9] the importance of limiting estrogen signaling in the prevention of breast cancer recurrence is well established.[7]

Obesity is associated with hyperinsulinemia, and higher fasting insulin levels have been associated with increased breast cancer risk[10] and with recurrence in those who develop breast cancer.[11-13] One report indicated that although estradiol was independently associated with breast cancer risk, adjustment for fasting insulin levels best explained the relationship between obesity and breast cancer.[14] Insulin shares substantial amino acid sequence homology, downstream signaling pathways, and mitogenic/anti-apoptotic activity with insulin-like growth factor (IGF)-1, a peptide hormone that mediates many of the growth effects of growth hormone. Insulin receptors are expressed at high levels in breast cancer cell lines[15] and human breast cancer specimens.[16] Insulin decreases levels of sex hormone binding globulin (thereby increasing levels of free estradiol),[17] upregulates androgen secretion by the ovaries,[18] increases hormone receptor (HR) expression and binding capacity,[19] and induces proliferation in normal and dysplastic breast epithelial cells.[19,20] Moreover, higher expression of activated IGF-1/insulin receptors has been associated with a higher risk of breast cancer recurrence,[21] and IGF signaling has been associated with resistance to paclitaxel.[22] The IGF-axis also includes IGF-2, a related growth factor, and six IGF binding proteins (IGFBPs) that have both IGF-dependent and IGF-independent effects. In addition to their levels in circulation, IGF-axis proteins are produced locally in tissues with autocrine and paracrine activity.

There is also compelling evidence that obesity produces a systemic inflammatory state,[23] which in some settings may promote neoplastic transformation or growth.[24] In both dietary and mouse genetic models of obesity, necrotic adipocytes surrounded by macrophages form crown-like structures (CLS) in the mammary glands and visceral fat, and are associated with activation of NF-kappaB, proinflammatory mediators, and elevated levels of aromatase.[25] Indeed, in the ATAC trial it was shown that the relative benefit of the aromatase inhibitor (AI) anastrozole (Arimidex) vs tamoxifen tends to be better in leaner than in overweight women.[26] It is conceivable, therefore, that CLS may serve as biomarker for AI resistance, and patients with this biomarker may require tamoxifen or higher than conventional levels of AI dosing in order to adequately suppress the estrogen signaling.

Given the significant role of each of these elements, it will therefore be important in future studies to concurrently assess each of these interrelated pathways in a comprehensive manner, including evaluation of estrogens and their metabolites, multiple components of the insulin/IGF-axis ligand and receptor levels in circulation and in tissues, and inflammatory biomarkers.

Are all obese subjects at risk of increased recurrence, or only a subset?

In a retrospective review of the large North American Breast Cancer Group trial E1199, which included patients with stage I to III breast cancer treated with contemporary chemotherapy, we found a statistically significant interaction between obesity and recurrence by breast cancer subtype; an increased risk of recurrence and death was evident only in patients with HR-positive disease. In addition, increasing body mass index (BMI) within the overweight range was also associated with increased recurrence risk in patients with HR-positive disease but not other subtypes.[27] Two prior reports have found a similar association.[28,29] HR-positive breast cancers exhibit significantly higher gene expression of the IGF pathway.[30] Widespread gene expression alterations have been described in breast tumors from obese patients as compared to other tumor types, which resulted in identification of a 662-gene signature; this signature correlated in publicly available datasets with a gene signature for IGF signaling, and in one cohort was associated with a shorter time to breast cancer recurrence.[31]

The relationship between obesity and insulin resistance, metabolic syndrome, and cardiovascular disease has been shown to vary. The concept of the "healthy obese"-a subset of patients who demonstrate few pernicious effects related to their obesity-has been described and is increasingly studied.[32] This concept also could apply to cancer risk in obese patients. Thus, risk stratification by relevant biomarkers could potentially be important in identifying which obese patients are at increased risk of recurrence and would therefore benefit from specific interventions.

Alea iacta est-"Is the die cast"-at diagnosis?

Can any intervention beyond standard adjuvant therapy reduce breast cancer risk in obese subjects with operable breast cancer? Julius Caesar is believed to have uttered the phrase "Alea iacta est" ("The die has been cast") as he led his forces across the Rubicon river into Roman territory. The phrase is still used today to indicate that events have passed a point of no return. Can anything be done after diagnosis to reduce the heightened risk associated with obesity, or has the cancer already been hard-wired to recur? The results of the WINS study suggest that dietary interventions resulting in weight loss could have a meaningful effect. Two major clinical trials will shed further light on this subject. The first is North American Breast Cancer Group trial MA32 (NCT01101438), a randomized investigation of the role of a 5-year course of metformin, an oral antidiabetic agent that reduces insulin levels by about 20%, in patients with operable breast cancer.[33,34] Although patients are not selected for enrollment based on BMI at diagnosis or breast cancer subtype, prespecified subgroup analyses may serve to identify which patients benefit from therapy. A second trial being developed by Dr. Ligibel and her colleagues will prospectively evaluate whether a dietary and exercise intervention further reduces the risk of recurrence in addition to standard adjuvant therapy in overweight or obese women. Embedded in these trials and others are correlative studies evaluating additional components of the insulin/IGF-axis, and investigating cross-talk with other hormonal and inflammatory factors, which may identify other possible targets for therapeutic intervention. In the meantime, referral of obese and overweight patients with operable breast cancer for nutritional counseling and weight loss seems like a reasonable option to consider, and an approach that may yield secondary health benefits.

The writing of this commentary was supported in part by grants from the Department of Health and Human Services and the National Institutes of Health P30-13330 to the Albert Einstein College of Medicine Cancer Center, Bronx, New York.

Financial Disclosure:The authors have 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. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999-2008. JAMA. 2010;303:235-41.

2. Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569-78.

3. 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.

4. Key T, Appleby P, Barnes I, et al. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94:606-16.

5. Key TJ, Appleby PN, Reeves GK, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst. 2003;95:1218-26.

6. Rinaldi S, Key TJ, Peeters PH, et al. Anthropometric measures, endogenous sex steroids and breast cancer risk in postmenopausal women: a study within the EPIC cohort. Int J Cancer. 2006;118:2832-9.

7. Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med. 2006;354:270-82.

8. Kaaks R, Berrino F, Key T, et al. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst. 2005;97:755-65.

9. Ziegler RG, Faupel-Badger JM, Sue LY, et al. A new approach to measuring estrogen exposure and metabolism in epidemiologic studies. J Steroid Biochem Mol Biol. 2010;121:538-45.

10. Kabat GC, Kim M, Caan BJ, et al. Repeated measures of serum glucose and insulin in relation to postmenopausal breast cancer. Int J Cancer. 2009;125:2704-10.

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. 2002;20:42-51.

12. Duggan C, Irwin ML, Xiao L, et al. Associations of insulin resistance and adiponectin with mortality in women with breast cancer. J Clin Oncol. 2011;29:32-9.

13. Irwin ML, Duggan C, Wang CY, et al. Fasting C-peptide levels and death resulting from all causes and breast cancer: the health, eating, activity, and lifestyle study. J Clin Oncol. 2011;29:47-53

14. Gunter MJ, Hoover DR, Yu H, et al. Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 2009;101:48-60.

15. Milazzo G, Giorgino F, Damante G, et al. Insulin receptor expression and function in human breast cancer cell lines. Cancer Res. 1992;52:3924-30.

16. Frittitta L, Vigneri R, Papa V, et al. Structural and functional studies of insulin receptors in human breast cancer. Breast Cancer Res Treat. 1993;25:73-82.

17. Pugeat M, Crave JC, Elmidani M, et al. Pathophysiology of sex hormone binding globulin (SHBG): relation to insulin. J Steroid Biochem Mol Biol. 1991;40:841-9.

18. Barbieri RL, Smith S, Ryan KJ. The role of hyperinsulinemia in the pathogenesis of ovarian hyperandrogenism. Fertil Steril. 1988;50:197-212.

19. Panno ML, Salerno M, Pezzi V, et al. Effect of oestradiol and insulin on the proliferative pattern and on oestrogen and progesterone receptor contents in MCF-7 cells. J Cancer Res Clin Oncol. 1996;122:745-9.

20. Elias JJ, Armstrong RC. Brief communication: hyperplastic and metaplastic responses of human mammary fibroadenomas and dysplasias in organ culture. J Natl Cancer Inst. 1973;51:1341-3.

21. Law JH, Habibi G, Hu K, et al. Phosphorylated insulin-like growth factor-1/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res. 2008;68:10238-46.

22. Huang GS, Brouwer-Visser J, Ramirez MJ, et al. Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. Clin Cancer Res. 2010;16:2999-3010.

23. Sinicrope FA, Dannenberg AJ. Obesity and breast cancer prognosis: weight of the evidence. J Clin Oncol. 2011;29:4-7.

24. Wang T, Rohan TE, Gunter MJ, et al. A prospective study of inflammation markers and endometrial cancer risk in postmenopausal hormone nonusers. Cancer Epidemiol Biomarkers Prev. 2011;20:971-7.

25. Subbaramaiah K, Howe LR, Bhardwaj P, et al. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila). 2011;4:329-46.

26. 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.

27. Sparano J, Wang M, Martino S, et al. Obesity at diagnosis is associated with inferior outcomes in hormone receptor positive breast cancer (abstract S2-1). Presented at the CTRC-AACR San Antonio Breast Cancer Symposium. San Antonio, Texas, December 6-10, 2010.

28. de Azambuja E, McCaskill-Stevens W, Francis P, et al. The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial. Breast Cancer Res Treat. 2010;119:145-53.

29. Majed B, Moreau T, Senouci K, et al. Is obesity an independent prognosis factor in woman breast cancer? Breast Cancer Res Treat. 2008;111:329-42.

30. Sparano JA, Gray R, Goldstein LJ, et al. Gene expression profiling of phenotypically defined hormone-receptor positive breast cancer: evidence for increased transcriptional activity of the insulin growth factor receptor pathway and other pathways. Cancer Res. 2009;69(24 Suppl): abstract 5165.

31. Creighton CJ, Sada YH, Zhang Y, et al. A gene transcription signature of obesity in breast cancer. Breast Cancer Res Treat. 2011 Jul 13 [Epub ahead of print].

32. Wildman RP. Healthy obesity. Curr Opin Clin Nutr Metab Care. 2009;12:438-43.

33. Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action. J Clin Oncol. 2009;27:3271-3.

34. Goodwin PJ, Stambolic V, Lemieux J, et al. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat. 2011;126:215-20.