breast adipose inflammation: a silent killer · silent killer andrew j. dannenberg, m.d. november...
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Breast Adipose Inflammation: a Silent Killer
ANDREW J. DANNENBERG, M.D.November 17, 2017
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Obesity and Breast Cancer
• Risk factor for development of hormone receptor-positive breast cancer in postmenopausal women.
• Poor prognostic factor for breast cancer patients.
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Pathways Linking Obesity with Breast Cancer
Sinicrope FA & Dannenberg AJ. J Clin Oncol 2011
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Obesity Causes An Inflammatory State
Adapted from Olefsky & Glass. Annu. Rev. Physiol. 2010
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Objective
• To determine if CLS of the breast (CLS-B) exist in women and correlate with BMI.
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Study Design
• Breast tissue was obtained from women who underwent mastectomy.
• Routine H&E staining and CD68 IHC was performed.
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CLS-B are Common in the Breasts of Overweight and Obese Women
CD68 stain
H&E stain
Iyengar et al. Cancer Prev Res 2015Morris PG et al. Cancer Prev Res 2011
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Adipocyte Size Correlates with BMI and CLS-B Status
Iyengar et al. Cancer Prev Res 2015
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Objective
• To determine whether breast white adipose tissue inflammation (WATi) manifested as CLS-B is associated with shortened recurrence free survival in women who develop metastatic breast cancer.
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Clinicopathologic Characteristics in Patients with Recurrent Breast Cancer
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CLS-B and Distant Recurrence-free Survival
*adjusted for age, race, BMI, breast cancer subtype, grade, T stage, N stage, hyperlipidemia, hypertension, DM, NeoadjChemo, AdjChemo, AdjEndo, AdjTrast, AdjRT.
Iyengar NM et al. Clin. Cancer Res. 2016
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Conclusions
• Breast WAT inflammation is a/w metabolic syndrome.
• In patients who develop metastasis, WAT inflammation is associated with shortened distant recurrence free survival.
• Whether WAT inflammation promotes the progression of breast cancer via local effects, systemic mechanisms, e.g., hyperinsulinemia or both is uncertain.
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Is WATi a/w Local or Systemic Effects that Promote Breast Cancer?
• Assess CLS-B status in 100 women with varying BMI
• RNA-seq on nontumorous breast tissue
• Fasting serum/plasma used to quantify:
- hsCRP, IL-6, insulin, glucose
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Patient Characteristics by CLS-B Status
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Breast WATi is a/w Elevated hsCRP, IL-6, Insulin and Glucose
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Breast WAT Inflammation Occurs in Women with Normal BMI
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WAT Inflammation is a/w Breast Adipocyte Hypertrophy in Normal BMI Women
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Aromatase and the Local Production of Estrogens
aromatase
androgens
estrogens (incl. E2)
From Kristy Brown
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Aromatase Protein Levels and Activity are Increased in the Inflamed Breast Tissue of Normal Sized Women
Iyengar NM et al. Cancer Prev Res 2017
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Blood Variables Stratified by Inflammation
* P-values were obtained using linear regression adjusted for potential cohort differences.† Log-transformed data were used to ensure the underlying model assumptions were met.
Iyengar NM et al. Cancer Prev Res 2017
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Elevated Insulin Levels Are a/w Increased Breast Cancer Risk in Normal Weight Women
Gunter MJ et al. Cancer Res. 2015
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Conclusions
• WATi is a/w numerous changes in gene expression in the breast.
• WATi is a/w systemic changes that occur in the metabolic syndrome.
• WATi and its associated pathophysiology occur in a significant subset of normal BMI women.
• WATi is a potentially targetable process linking obesity to breast cancer.
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CONTRIBUTORS Weill Cornell • Kotha Subbaramaiah, PhD• Xi Kathy Zhou, PhD• Priya Bhardwaj, BA • Baoheng Du, MD• Domenick Falcone, PhD• Louise Howe, PhD• Kristy Brown, PhD• Nils Wendel, BS
McGill • Michael Pollak, MD
Funding• NIH/NCI• The Breast Cancer Research
Foundation• Prevent Cancer Foundation
MSKCC• Clifford Hudis, MD• Neil Iyengar, MD• Patrick Morris, MD• Monica Morrow, MD• Dilip Giri, MD• Ayca Gucalp, MD