Breast density and cancer risk—more than meets the eye

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Breast density and cancer risk—more than meets the eye

Density increases breast cancer risk due to both masking and physiology.

Breast density arises as a result of an increased proportion of the breast being composed of fibroglandular tissue. Women in the top category of density are routinely described as being at 4-6 times higher risk of breast cancer than women in the lowest category [1]. As both fibroglandular tissue and tumours attenuate X-rays and appear white on the mammogram, high density poses a masking risk during breast cancer screening. This concept is easy to grasp and is well-supported by research. For instance, women with more than 75% breast density are at 17-fold increased risk of being diagnosed with a breast cancer within twelve months after a negative breast screen (referred to as an interval cancer), compared to women with less than 10% density [2]. Furthermore, the top density category (according to ACR BI-RADS or Volpara Density Grades) corresponds to 26% lower sensitivity than the least dense category [3-5]. However, masking is not all there is to the picture. Breast density produces a double blow in the fight against breast cancer, as it not only makes cancer harder to find but also constitutes an independent risk of developing the cancer in the first place.

 The increase in risk is clearly illustrated by a case-studies performed in the Breast Cancer Detection Demonstration Project and the Canadian Breast Screening Program [2, 6]. Women with more than 75% density had more than three and a half times the risk of having screen-detected breast cancer, relative to women with the most fatty breasts. Furthermore, the risk associated with density remained elevated even up to ten years after the initial determination of density (for both screen-detected and interval cancers). This cannot be explained solely by the masking risk posed by density.  High density is also associated with developing ductal carcinoma in situ (DCIS) as well as a number of pre-cancerous histological abnormalities such as hyperplasia (both atypical and without atypia) and columnar cell lesions [7]. Finally, sub-regions of the breast where lesions arise have increased localized density (prior to lesion development) relative to the breast overall [8, 9].

How does dense breast tissue pose a risk in terms of future cancer? Firstly, the vast majority of breast cancers are carcinomas—this means they arise from the epithelial layer of cells. These are the cells that line the ducts and lobules that constitute the glandular part of the breast (Figure) [10]. Glandular tissue is one of the components of mammographic density [11, 12] and high density corresponds to more sites for cancer to arise. Another substituent of density is the breast stroma—the connective tissue that supports and maintains the functional glands of the breast. Increased density is linked with increased amounts a class of molecules called proteoglycans, as well an increased abundance and organization of collagen. These two molecule types are the major components of the breast stroma. They can interact with a number of other cellular components to ultimately encourage the growth and migration of epithelial cells and thus can promote tumour initiation and development [12-16].

Physiological aspects of density5

Most breast cancers arise as a result of abnormal proliferation of cells in the epithelial layer that lines the glandular portion of the breast. In situ disease is confined within the ducts and lobules; once the proliferation extends beyond the basement membrane layer of the gland, it is known as invasive.

 Breast density constitutes a multifaceted problem for fighting breast cancer. The development of new technologies, such as 3D tomosynthesis or molecular breast imaging is a considerable boon in reducing the masking risk for a lot of women [17, 18]. However, it does not obliterate the promoting effect density has for cancer development. This independent risk needs to be fully understood and addressed if we hope to win the aforementioned fight.

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2. Boyd , N.F., et al., Mammographic Density and the Risk and Detection of Breast Cancer. New England Journal of Medicine, 2007. 356(3): p. 227-236.

3. Carney, P.A., et al., Individual and combined effects of age, breast density, and hormone replacement therapy use on the accuracy of screening mammography. Ann Intern Med, 2003. 138(3): p. 168-75.

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10. Blanpain, C., Tracing the cellular origin of cancer. Nat Cell Biol, 2013. 15(2): p. 126-134.

11. Li, T., et al., The association of measured breast tissue characteristics with mammographic density and other risk factors for breast cancer. Cancer Epidemiol Biomarkers Prev, 2005. 14(2): p. 343-9.

12. Huo, C.W., et al., High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium. Breast Cancer Res, 2015. 17: p. 79.

13. Alowami, S., et al., Mammographic density is related to stroma and stromal proteoglycan expression. Breast Cancer Research : BCR, 2003. 5(5): p. R129-R135.

14. Guo, Y.P., et al., Growth factors and stromal matrix proteins associated with mammographic densities. Cancer Epidemiol Biomarkers Prev, 2001. 10(3): p. 243-8.

15. Vachon, C.M., et al., Aromatase immunoreactivity is increased in mammographically dense regions of the breast. Breast Cancer Res Treat, 2011. 125(1): p. 243-52.

16. Provenzano, P.P., et al., Collagen density promotes mammary tumor initiation and progression. BMC Med, 2008. 6: p. 11.

17. Rafferty, E.A., et al., Breast cancer screening using tomosynthesis and digital mammography in dense and nondense breasts. JAMA, 2016. 315(16): p. 1784-1786.

18. Shermis, R.B., et al., Supplemental Breast Cancer Screening With Molecular Breast Imaging for Women With Dense Breast Tissue. American Journal of Roentgenology, 2016. 207(2): p. 450-457.


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