Association between mammographic density and tumor marker-defined breast cancer subtypes: a case-control study

High mammographic density (MD) is the most important risk factor for breast cancer. This study aimed to clarify the relationship between MD and breast cancer subtypes defined by tumor markers. We enrolled 642 women with breast cancer (69% premenopausal) and 1241 controls matched for age and menopausal status. Absolute mammographic dense area (ADA), percent mammographic dense area (PDA), and nondense area were assessed using a computer-assisted thresholding technique. We classified breast cancer cases into four subtypes using information on tumor marker expression such as estrogen receptor (ER), progesterone receptor (PR), and Cerb2 receptor (HER2); luminal A (ER+ and/or PR+, HER2-), luminal B (ER+ and/or PR+, HER2+), HER2-overexpressing (ER-, PR-, and HER2+), and triple-negative (ER-, PR-, and HER2-). Analysis was carried out using a conditional logistic regression model with adjustment for covariates. ADA and PDA were associated positively with the risk of breast cancer overall. Both ADA and PDA tended to have a positive association with breast cancer with any ER, any PR, or HER2-, but not for HER2+. The risk of luminal A breast cancer increased significantly 1.11 times (95% confidence interval: 1.01-1.23) for ADA and 1.12 times (95% confidence interval: 1.01-1.24) for PDA, estimated per 1 SD of the age and BMI-adjusted MD. However, the risk of breast cancer with luminal B, HER2-overexpressing, and triple-negative subtypes did not differ (P>0.10). Differential associations between MD measures and breast cancer by tumor marker status or tumor marker-defined subtypes were not detected. These findings suggested that the association between MD and breast cancer subtype may be because of other causal pathways.