Megan S Rice1, Rulla M Tamimi2,3, Kimberly A Bertrand4, Christopher G Scott5, Matthew R Jensen5, Aaron D Norman5, Daniel W Visscher6, Yunn-Yi Chen7, Kathleen R Brandt8, Fergus J Couch5, John A Shepherd9, Bo Fan9, Fang-Fang Wu5, Lin Ma10, Laura C Collins11, Steven R Cummings12, Karla Kerlikowske13, Celine M Vachon5. 1. Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital/Harvard Medical School, 55 Fruit Street, Bartlett 9, Boston, MA, 02116, USA. mrice1@mgh.harvard.edu. 2. Channing Division of Network Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA. 3. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 4. Slone Epidemiology Center, Boston University, Boston, MA, USA. 5. Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA. 6. Department of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA. 7. Department of Pathology, University of California, San Francisco, CA, USA. 8. Department of Radiology, Mayo Clinic, Rochester, MN, USA. 9. Department of Radiology, University of California, San Francisco, CA, USA. 10. Department of Medicine, University of California, San Francisco, CA, USA. 11. Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, USA. 12. San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA. 13. Departments of Epidemiology and Biostatistics and General Internal Medicine Section, Department of Veterans Affairs, University of California, San Francisco, CA, USA.
Abstract
BACKGROUND: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics. METHODS: Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women. RESULTS: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11-27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2- breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05). CONCLUSION: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.
BACKGROUND: Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics. METHODS: Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women. RESULTS: Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11-27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2- breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05). CONCLUSION: Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.
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