Changes in mammographic density and breast cancer risk

Breast cancer is the most frequently occurring cancer among women worldwide. One of the most important risk factors for breast cancer is high mammographic density. Mammographic density represents the amount of fibroglandular tissue relative to the fat tissue in the breast. Women with >75% of their breast composed of dense tissue have a three to six fold increase in breast cancer risk. Mammographic density usually decreases with increasing age. Especially after menopause, mammographic density declines rapidly in some women, although not all women do show such a decline. In this thesis it was investigated if women with a more rapid decline in mammographic density have a lower breast cancer risk than women who show a slower decline in mammographic density. Although we found that women with high mammographic density have an increased breast cancer risk, we did not find that the average decline in mammographic density was different for those who developed and those who did not develop breast cancer. However, we found some indication that very large declines in density do lower breast cancer risk. In this thesis we also had a closer look at the effect of the fatty breast tissue on breast cancer risk. Although the role of the fat breast tissue has not often been studied, there are indications that in postmenopausal women the fat tissue in general can play an important role in breast cancer risk. In our studies we found that women who had a large amount of fat breast tissue in combination with a large amount of dense tissue had the largest breast cancer risk. This does not necessarily imply that women with larger breasts have a higher breast cancer risk, as we also found in our studies that women with larger breasts often have less dense breast tissue, not only on a relative scale but also on an absolute scale. The risk increasing effect of the fatty breast tissue, can be explained by the fact that in the fat tissue androgens are being converted to estrogens, that have a carcinogenic effect. Endogenous sex hormone levels in the blood and reproductive factors are known to be associated with breast cancer risk. In this thesis we describe that these effects were independent of mammographic density. In addition we found that high mammographic density and being nulliparous work synergistically; the harmful effect on breast cancer risk of being nulliparous was stronger among women with high mammographic density than among women with low mammographic density. In this thesis we also evaluated new methods for measuring mammographic density. The replacement of the conventional film-screen mammography by full-field digital mammography in the last ten years, has provided opportunities to measure not only the two-dimensional area of the dense tissue but also its volume. Despite its alleged higher precision, the volumetric method was not more strongly related to breast cancer risk factors. However, the definitive relationship between volumetric density and breast cancer risk still needs to be investigated.