Mammographic Density Change and Risk of Breast Cancer

Shadi Azam; Mikael Eriksson; Arvid Sjölander; Roxanna Hellgren; Marike Gabrielson; Kamila Czene; Per Hall


J Natl Cancer Inst. 2020;112(4):391-399. 

In This Article


Using a large prospective cohort, we found no evidence for an association between annual MDC and risk of BC. Furthermore, MDC did not seem to influence the association between baseline MD and BC risk. Our results suggest that risk of BC is dependent on baseline MD, with no additional value of adding MDC. Our results on association between established risk factors and BC risk were as expected and in line with previous studies,[21–25] except that, among postmenopausal women, we did not see an increased risk in women with higher BMI.

The association between a single measure of MD and BC risk has been investigated extensively, and we confirmed that high MD at baseline is associated with an increased BC risk.[2,10,14,26] In contrast, studies of how MDC over time influences BC risk have been conflicting.[10–14] The results from prior studies, which used the contralateral breast for cases, are in agreement with our findings that MDC does not influence the risk of BC.[11–13] Maskarinec et al. and Vachon et al. who conducted case-control study designs with sufficient sample sizes and appropriate quantitative MD measurements did not observe any associations between percent MDC and risk of BC.[11,12] In agreement, Lokate et al. and van Gils et al. both observed a weak but statistically nonsignificant association between MDC and BC risk.[10,13] Finally, in a large prospective cohort of more than 300 000 women, Kerlikowske et al. found that women who did not decrease in MD over time had a higher BC risk compared with women who decreased.[14] A major limitation of that study was that MD was measured and compared only at two time points using the BIRADS score, which is a qualitative and rather crude measurement of MD. Another limitation of that study was an inability to adjust for BMI due to missing data. We previously showed that BMI is an important determinant of MDC.[9] However, in line with our findings, the highest BC risk was observed for women who had the highest MD at first mammogram, regardless of whether MD decreased at the last mammogram.[14]

To our knowledge, this is the first large population-based study examining not only the association between annual MDC and risk of BC but also investigating if adding MDC to a single baseline measure of MD improves BC risk prediction. Strengths of our study are the prospective population-based design, detailed information on the established BC risk factors, access to mammograms from two or more examinations for each of the participants, and repeated and longitudinal measurement of MD after aligning images using the fully automated STRATUS tool.[15]

The study had a number of limitations. Information on BC risk factors was based on a self-reported questionnaire and therefore is prone to information bias. However, a substantial differential misclassification is unlikely because women were not aware of their MD or the potential association between BC risk factors and MDC. Furthermore, answers were given before diagnosis. We lacked longitudinal information on established BC risk factors. All information on covariates was collected at baseline or at the date of the first mammogram. Repeated measures of BMI were only available for a subset of women (n = 7837). During the average follow-up of 5.4 years, BMI changed very little, on average 0.02 kg/m2/y. We did not expect dramatic changes in most of the risk factors, including reproductive history, given the mean age of 53.7 years for the cohort members. Only approximately 3% of the participants used MHT, and it is therefore not likely that changes in use of MHT would substantially affect our findings. Another limitation of this study is that participants of the KARMA cohort were screening attendants and are highly educated and tend to have a healthier lifestyle than the participants of most studies. This may explain the weak and statistically nonsignificant association of BMI and postmenopausal BC risk.

Previous studies, which did not find any evidence of association between MDC and risk of BC, suggested that reductions in density may occur at a young age, especially around menopause. Thus, perimenopausal age may be the critical period to investigate the association of MDC and risk of BC.[10,12] However, these researchers could not investigate the association between MDC and risk of BC among premenopausal women, because BC screening programs in most countries start at the age of 50 years.[10–12] One of the earlier small studies, composed of mostly premenopausal women, found a twofold increase in risk for women who persisted at high categories of density based on the Wolf density category.[27] This is in agreement with our results showing that perimenopausal women (age 40–49 years) who did not decrease in MD by more than 10% per year had a statistically nonsignificant higher risk of BC compared with perimenopausal women who decreased in MD.

We observed that, at fixed levels of baseline MD, the risk of BC did not seem to be influenced by MDC. An explanation could be that baseline MD is a strong risk factor, primarily based on the cumulative exposure to female sex hormones during the premenopausal part of life, and is not influenced by the subsequent rate of density change. The vast majority of women experience involution, that is, the process by which the breast epithelial tissue is gradually converted to fatty tissue. Whether this conversion is seen at more or less than 10% per year is of lesser importance from a risk point of view compared with the baseline MD.

As a conclusion, we found no evidence on the association between MDC and risk of BC. Also, adding MDC to baseline MD did not seem to strengthen the association between baseline MD and risk of BC in our dataset. However, in line with previous studies, we observed a weak and statistically nonsignificant association between MDC and risk of BC among perimenopausal women (age 40–49 years), which indicates that change in MD at a younger age might be of importance.