What influence does mammographic density have on breast cancer occurrence?

KEYWORDS:

• BMI
• mammographic density
• BI-RADS
• parity
• mutagens
• stem cells

1. Introduction

Breast cancer is now the most commonly diagnosed cancer worldwide, and despite the constant progress in early detection and treatments, it remains one of the leading causes of cancer-associated death [1].

Breast tissue comprises lobules and ducts composed of epithelial cells, surrounded by stromal and adipose tissue. The proportion of radiographically dense areas composed of epithelial and stromal tissues over adipose tissue determines mammographic density. Breast cancers emerge from epithelial cells, and it is hypothesized that the probability of transformation of a normal epithelial cell into a malignant one is associated with the density of the mammographic area [2]. Mammographic density is one of the established independent risk factors for familial and non-familial breast cancer, with a four to six-fold risk increase for the densest (≥75%) when compared to the less dense breast tissue (<5%) for non-familial cases [3]. High mammographic density is associated with both luminal A and triple-negative breast cancer subtypes but not luminal B and HER2 subtypes [4].

The Breast Imaging-Reporting and Data System (BI-RADS), developed by the American College of Radiology, is commonly used in the clinic to classify mammographic density and to minimize the variability in the interpretation of mammograms [5]. The BI-RADS divides mammographic density into four categories; the first two BI-RADS categories a and b group breast tissues are composed essentially of adipose tissue and scattered patterns of dense tissues, respectively. Category c describes breast tissue that is heterogeneously dense, while breasts with an extreme mammographic density constitute category d [6]. The prevalence of dense breast tissues (categories c and d) is approximately 50% among women aged between 40 to 74 years living in the US; a trend similarly observed in Europe and countries of European ancestry, Asia including the Middle East region, but more contrasted in Africa [5].

The mammogram sensitivity for breast cancer detection varies from 80 to 90% for BI-RADS a and b, pending the study [7]. As the density of the breast increases, the sensitivity drops to 60–70% for the BI-RADS c and less than 60% (30 to 64%) for highly dense breast tissue [7].

2. Influence of the mammographic density on the risk of developing breast cancer

The mechanisms by which mammographic density influence the risk of developing breast cancers remain poorly understood. Multiple hypotheses have been formulated and relate to the abundance of dense tissue. One hypothesis implies that the higher number of stem cells and progenitor cells observed in dense mammary tissue is sufficient to influence the risk of breast cancer. The dysregulation of mammary stem cells or progenitor cells is one of the two main assumptions to explain the origin of breast cancers [8]. However, despite the demonstration that the dense mammary tissues harbor more stem cells and progenitor cells than less dense areas, there is no evidence of their influence on the association between mammographic density and risk of breast cancer [9]. Another hypothesis postulates that the increased mitogenic activity in dense tissue areas combined with the potential genetic damage to proliferating cells by mutagens may influence the risk of breast cancer [10]. Cell proliferation is associated with reactive oxygen species (ROS) production, promoting lipid peroxidation and genomic instability [10].

The genes involved in developing and maintaining mammographic density are poorly understood. The heredity of mammographic density has been demonstrated in twin studies. The percentage of dense breast tissue had a correlation coefficient of 0.61 and 0.67 for monozygotic pairs and 0.25 and 0.27 for dizygotic pairs in Australia and North America, respectively, for women aged 40 to 70 years. A total of 46 mammographic density loci were identified by genome-wide association, including 17 linked to breast cancer [11]. Identifying the genes critical for mammographic density development will be essential to understand its impact as a breast cancer risk factor.

Similar to breast tissue aging and breast epithelium involution, mammographic density is influenced by many factors such as age, menopause, parity, and others. The age-dependent lobular involution initiated in the premenopausal phase continues after menopause and is associated with mammographic density reduction [12]. The decline is approximately 11% over a decade after the age of 50 and is similar for normal and dense breast tissues [13]. The delay in breast involution and high mammographic density are independent breast cancer risk factors and are associated with an increased risk of breast cancer. However, a more recent study showed that the decline in mammographic density observed with aging does not modify the risk of developing breast cancer [14].

The circulating levels of sex hormones and mammographic density are independent breast cancer risk factors for postmenopausal women [15]; however, sex hormone levels influence the basal mammographic density. The levels of estrogen, progesterone, corticosteroids, prolactin, and sex hormone-binding globulin (SHBG) are linked to the development and density of breast tissue. The elevated endogenous level of estrogens and androgens in postmenopausal women are known risk factors for the development of breast cancers. However, it remains unclear to which extent these risk factors are associated with mammographic density [15]. A high progesterone level is strongly associated with a high mammographic density in premenopausal women but not following menopause [16]. Postmenopausal women with high circulating testosterone have a smaller annual decrease of their mammographic density [16].

Another critical parameter influencing mammographic density is body mass index (BMI). BMI and mammographic density are inversely related [3]. Obesity is a prevalent risk factor for breast cancer in postmenopausal women but reduces the risk of breast cancer in premenopausal women [17]. A higher BMI also influences the circulatory levels of sex hormones. Obese women have a higher aromatase activity leading to increased estrogens, lower SHBG, and increased androgens (for review, see [15]). A high BMI with elevated sex hormone levels and high mammographic density are independent breast cancer risk factors in postmenopausal women [15]. However, a high BMI combined with a high mammographic density is associated with a higher risk of developing ER-negative breast cancer subtypes in premenopausal women [18].

Parity is also a modifier of mammographic density. It is hypothesized that the undifferentiated epithelium in nulliparous women with a high mammographic density may increase the susceptibility to mutagens and elevate the risk of breast cancer. However, studies did not support the hypothesis that parity modified the influence of mammographic density on breast cancer risk [19].

3. Conclusion

Breast tissue is a dynamic structure that is often overlooked in postmenopausal women and ignored before menopause. Identifying early markers associated with the development of dense tissue may facilitate the emergence of new therapeutic approaches for preventing breast cancers and the understanding of their potential relationship to other known independent risk factors. Mammographic density cannot be considered an independent marker in diseases as complex as breast cancers.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

The authors have no funding to report.