Breast cancer is one of the most frequently diagnosed malignancies among women1, for which death rates have largely decreased by utilizing screening programs. Mammography is a widely accepted screening modality, even though it is limited by low detection rates.2,3 Mammographic density, referred to as the percentage of dense tissue associated with stromal and epithelial proliferation of the entire breast tissue, is considered a known risk factor for the development of breast cancer. Accordingly, women who possess mammographically dense breasts are at a three-to-five-fold heightened risk of developing breast cancer than that of women with mammographically fatty breasts.4–6

This phenomenon may be related to microenvironmental factors of the tumor and stroma.7 In addition, sensitivity in detecting malignant lesions and microcalcifications is reduced in mammograms of dense breasts2,8, causing delayed diagnoses, and revealing cancer at more advanced stages, i.e., larger tumors and nodal involvement.7,9–11

HER2 amplification, which is present in about 15% of breast cancer patients, is a negative prognostic factor. Lack of HER2 overexpression is detected by an immunohistochemistry score of either 0 or 1+, considered as negative. However, HER2 0 tumors may be biologically distinct from 1+ tumors since new HER2 targets have shown efficacy in low positivity of 1+ or 2+ unamplified HER2.12

This cross-sectional study was conducted on all women who underwent diagnostic mammography at the Shafa Imaging Center, Isfahan, Iran, between 2016 to 2019. We evaluated breast density using the American College of Radiology (ACR) breast composition classification: a) fatty; b) scattered densities; c) heterogeneously dense; and d) extremely dense.2,13

Medical records were studied to obtain information regarding histological tumor type, grade, and ER, PR, and HER2 status. Negative tumors were grouped as negative (IHC 0) and compared to otherwise (IHC 1+, 2+, 3+).11,12

Among 129 cases, the mean age was 52.86 years. In the density categories a, b, c, and d, there were 7, 47, 41, and 34 patients, respectively. Significant differences in mass density (χ²=11.6), mass morphology (χ²=8.5), and HER2 status (χ²=13.1) were observed.

In this retrospective study, results suggest a positive association between breast density and HER2-expressing breast tumors. Apart from age, which is a known negative confounding factor affecting breast density7, regarding ER/PR status, no difference was observed between groups, in contrast to studies showing a positive relation.14–17

Consistent with some studies, we found no obvious relation between density and specific intrinsic molecular subtypes, ER, PR, or Ki67.18–20 Inconsistency in findings may reflect different research populations or assessment methods.23 Breast density is a risk factor for all breast cancer subtypes.24,15 Higher density might contribute to the heightened incidence of HER2-positive subtypes among Asian women.25,26 Higher density and HER2-positive status show an increase in the STAT3 signaling pathway.28,29

Newer targets of this receptor show efficacy in weak HER2 expression.12,30 Some studies have suggested a link between density and adverse characteristics like larger tumor size.31,32

Mammographic dense breast may be associated with HER2-positive breast cancer.