Abstract P1-06-03: Validating the link between obesity and breast inflammation in women with breast cancer (BC)
Authors: Iyengar NM , Morris PG , Zhou XK , Giri DD , Harbus MD , Falcone DJ , Gucalp A , Morrow M , Hudis CA , Dannenberg AJ 
Published: August 2014

Abstract
Background: In post-menopausal women, obesity is a risk factor for the development of BC that expresses the estrogen and progesterone receptors (ER/PR). In mouse models of obesity, we previously described crown-like structures (CLS), consisting of macrophages surrounding dead adipocytes in white adipose tissue (WAT) of the mammary gland, which were associated with increased levels of proinflammatory mediators known to be involved in carcinogenesis. We translated these findings to women (n = 30), and provided the first evidence of CLS in the human breast (CLS-B). The presence and severity of CLS-B (CLS-B index) correlated with elevated body mass index (BMI), increased adipocyte size, activation of NF-κB, and increased levels of proinflammatory mediators (TNF-α, IL-1β, COX-2 and PGE2) and aromatase. We expanded our population to prospectively validate these preliminary findings.
Methods: We prospectively collected WAT from women undergoing breast and reconstructive surgery. WAT was subjected to immunohistochemistry for CD68, a macrophage marker, to detect CLS-B by light microscopy. Adipocyte diameter was measured on photomicrographs using the Canvas 11 Software. Endpoints were 1) CLS-B presence/absence and 2) CLS-B index (proportion of slides with CLS-B). Associations between CLS-B and clinicopathologic features were analyzed using logistic regression and Fisher's exact test.
Results: From 04/2010-02/2012, WAT (100 mastectomy and 5 abdominal reconstructions) was obtained from 101 women; median age 49 (range 26-80). CLS-B were found in 54 (53%) patients (pts). CLS-B were seen in 9/37 (24%) normal weight pts (BMI &lt;25), 23/39 (59%) overweight pts (BMI 25-29.9), and 22/25 (88%) obese pts (BMI ≥30). Pts with CLS-B had significantly larger average adipocyte diameter (106.5 +/- 11.5 microns) compared to those without CLS-B (91.5 +/- 16.1 microns; p&lt;0.001). Consistently, CLS-B index correlated with BMI (p&lt;0.001) and adipocyte size (p&lt;0.001). Breast inflammation was seen in pts with all tumor phenotypes: CLS-B were seen in 24/41 (59%) pts with ER/PR+, HER2- tumors; 7/16 (44%) pts with HER2+ tumors; and 3/10 (30%) pts with ER/PR/HER2- tumors. A higher CLS-B index was seen in WAT from ER+ tumors, but this was not statistically significant (p = 0.08). Regular use of nonsteroidal antiinflammatory drugs was protective against CLS-B (p = 0.17 for association with CLS-B, and p = 0.04 for association with CLS-B index in multivariable analyses). Among 25 pts with bilateral breast WAT, concordant CLS-B findings (+/-) were found in 20 (80%) pts. Among pts with paired breast and abdominal WAT, concordant findings were seen in 4/5 (80%) pts.
Conclusions: Findings from this prospective study, the largest reported to date, extend our previous observation that CLS-B are associated with BMI and adipocyte size. These results provide a plausible pathophysiological link between obesity and BC. Breast inflammation occurs in association with all BC phenotypes. Preliminary data suggest concordance between breasts and between abdominal and breast WAT. Hence, abdominal WAT may prove useful as a surrogate for breast WAT; biopsies of abdominal subcutaneous WAT are more easily done, which could prove useful in developing interventions to attenuate WAT inflammation.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-06-03.