Breast cancer is considered one of the most common causes of cancer-related deaths in women worldwide.¹ Over the last few decades, much research has been conducted to understand breast cancer pathology, clinical behavior, biological features, early detection, and treatment outcomes. Shifting the focus from treatment to the detection of breast cancer has significantly advanced the field of breast pathology. This progress has necessitated improvements in three key areas: women's awareness programs, screening protocols, and breast cancer screening tools.²

In 1966, Shapiro et al. described the possibility of detecting early breast cancer by understanding the process of breast cancer, risk factors, and different patterns of presentation. Since then, the mammogram has been used as the tool of choice for screening and evaluating breast masses among women.³

In 1976, Wolfe et al. published a study about mammographic breast density and breast cancer.⁴ Since then, breast parenchymal characteristics, such as breast density, have become a major focus of research, where associations between breast density and other variables such as age, gender, and tumor hormonal receptors have been investigated.⁵

Mammographic breast density (MBD) is defined as the relative amount of radiologically dense stromal and epithelial tissue in relation to radiolucent adipose tissue, and it has been accepted as an independent risk factor for breast cancer.⁶

Studies of primarily Western populations have suggested that elevated MBD is considered a general marker of breast cancer risk, irrespective of breast cancer molecular subtypes.⁷

MBD is adversely related to breast tumor clinical characteristics, including larger tumor size, nodal involvement, and advanced stage at diagnosis.^5,6,8 According to the American College of Radiology (ACR), mammographic breast density is classified into four categories: A (fatty), B (scattered), C (heterogeneously dense), and D (dense).⁹

Patients with higher breast density are at higher risk of missing small cancers, as mammograms have lower sensitivity in those groups.¹⁰ Among the western population, mammographic breast density (MBD) has been extensively investigated. While MBD is considered a high-risk factor for breast cancer^6,8,11,12, its reporting based on the Breast Imaging Reporting and Data System (BI-RADS) is considered subjective and prone to suboptimal reproducibility.^13-15

In contrast to the western population, MBD has not been seriously investigated among Arab women except for a few reports from Jordan and Lebanon, which linked MBD to women's age and breast cancer risk, respectively.^16,17

In this study, we aimed to assess MBD in women with a recent diagnosis of breast cancer with respect to their breast cancer biology, specifically with progesterone (PR), estrogen receptors (ER), and the human epidermal growth factor receptor 2 (HER2/neu). To the best of our knowledge, this is the first paper discussing the correlation between breast biology and MBD in Jordan.

Mammographic breast density is considered an important topic in the medical literature because of its association with the risk of breast carcinoma as well as its impact on screening strategies.¹⁵ It has been reported that women with extremely dense breasts are at a 3-fold higher risk of developing breast cancer in comparison to those with fatty breasts, and this is considered a general risk that is not limited to the breast side.^15,19 In addition, the literature shows lower sensitivity of 2D mammography in women with dense breasts in comparison to those with non-dense breasts (67.9% vs 89.2%) (20), which could result in higher rates of interval cancers that limit the efficacy of breast screening programs.^20,21

Previous studies describing the association between MBD and molecular/biological subtype or receptor status have reported conflicting results.^22-25 Regarding the association between MBD and ER/PR expression, our results have shown a significant inverse relationship (i.e., higher MBD in ER/PR negative tumors), which was similar to results reported by Yaghjyan et al., and Sartor et al.^26,27 On the contrary, Ding et al. and Conroy et al. described a positive correlation between MBD and ER expression^28,29, while other studies failed to demonstrate an association between them, which is against our findings.^19,30-33 A meta-analysis in 2012 has found conflicting results in this association. Antoni et al. have explained the heterogeneity in previous studies by proposing that this association is underestimated by the effect of masking bias at screening.⁷ Similar to hormone receptor expression, results regarding the association between MBD and HER2 expression are also conflicting. Multiple studies have shown no association between MBD and the expression of HER in breast cancer cells, a finding consistent with our results.^26,32 An association between increased MBD and HER2 expression was reported by Edwards et al.³⁴ and Park et al. in Korean postmenopausal women only.³⁵

As a result, legislative changes in 39 states and the District of Columbia now require some level of notification about breast density following a mammogram. Radiologists must inform their patients about their breast density based on the mammogram results and may also recommend additional screening methods, such as digital breast tomosynthesis, whole-breast ultrasonography, and gadolinium-enhanced magnetic resonance imaging for women with dense breasts.^15,40 To date, much of the literature investigating MBD has focused on Western populations with few reports from other regions. This study is the first among women with breast cancer in Jordan, aiming to investigate the association between mammographic breast density and breast cancer biology.

Results from twin studies suggest that breast density is primarily determined genetically; however, it may also vary due to endogenous or external factors.³⁶ Reproductive hormones decline with normal aging, which is linked to terminal duct unit involution. Likewise, natural aging tends to reduce women’s breast density.^37,38

In this study, approximately 60.7% of breast cancer patients had low MBD on their diagnostic mammogram (ACR BI-RADS A or B). This figure is higher than what was previously reported from a study among Jordanian women who had their mammograms for screening (29.9%).¹⁶ Also, we demonstrated a significant inverse relationship between MBD and patient age (i.e., higher MBD in younger women), which is consistent with previously reported data from Jordan and Western countries.^16,39

This study is the first to describe MBD in breast cancer patients in the context of biological subtypes in Jordan. The assessment of MBD was performed blindly by two expert radiologists in reporting breast mammograms.

Similar to many previously published studies in this field, we relied on the BI-RADS density category classification, which is known to be subjective with only moderate inter- and intra-reader agreement. The occurrence of inter-reader variability was reported in approximately 15% of the cases, which was solved blindly by a 3rd opinion from an expert breast surgeon.

There is a need to establish a national database for breast cancer patients to perform a comprehensive assessment of MBD among breast cancer patients and to evaluate its association with tumor biological features as well as other demographics, including patients’ weight, menopausal status, hormonal treatment, and parity.

Mammographic breast density is recognized as an independent risk factor for breast cancer and a strong predictor of mammographic screening failure, although its association with breast cancer biology remains unclear. Our study found that women with low breast density were more likely to have positive expression of estrogen and progesterone receptors, with no correlation observed with HER2 status. Further research is needed to validate these findings.

The statement of ethical approval was obtained from the Institutional Review Board (IRB) committee at the Hashemite University and Prince Hamza Hospital. Informed consent was waived by the IRB committee due to the retrospective nature of the study. Patients’ data were anonymized and maintained with complete confidentiality.