Postmenopausal mammographic breast density and subsequent breast cancer risk according to selected tissue markers

Background: This study aimed to determine if associations of pre-diagnostic percent breast density, absolute dense area, and non-dense area with subsequent breast cancer risk differ by the tumour's molecular marker status. Methods: We included 1010 postmenopausal women with breast cancer and 2077 matched controls from the Nurses' Health Study (NHS) and the Nurses' Health Study II (NHS II) cohorts. Breast density was estimated from digitised film mammograms using computer-assisted thresholding techniques. Information on breast cancer risk factors was obtained prospectively from biennial questionnaires. Polychotomous logistic regression was used to assess associations of breast density measures with tumour subtypes by the status of selected tissue markers. All tests of statistical significance were two sided. Results: The association of percent density with breast cancer risk appeared to be stronger in ER - as compared with ER + tumours, but the difference did not reach statistical significance (density >= 50% vs <10% odds ratio (OR) = 3.06, 95% confidence interval (CI) 2.17-4.32 for ER+; OR = 4.61, 95% CI 2.36-9.03 for ER -, P-heterogeneity = 0.08). Stronger positive associations were found for absolute dense area and CK5/6 - and EGFR- as compared with respective marker-positive tumours (P-heterogeneity = 0.002 and 0.001, respectively). Stronger inverse associations of non-dense area with breast cancer risk were found for ER - as compared with ER + tumours (P-heterogeneity = 0.0001) and for AR+, CK5/6+, and EGFR+ as compared with respective marker-negative tumours (P-heterogeneity = 0.03, 0.005, and 0.009, respectively). The associations of density measures with breast cancer did not differ by progesterone receptor and human epidermal growth factor receptor 2 status. Conclusions: Breast density influences the risk of breast cancer subtypes by potentially different mechanisms.