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Very low breast density and worse prognosis for invasive breast cancer—what’s going on?

Christina Roberts – Published on July 10, 2016

Very low breast density is associated with more aggressive tumours and reduced survival.

A recent study by Amro Masarwah has investigated the relationship between breast density and the prognosis of invasive cancer, published in a doctoral thesis from the University of Eastern Finland and associated papers. While the association between breast density and the risk of future breast cancer is well established, the effect of density on cancer prognosis (that is, what happens after the disease is established) is not as thoroughly explored. Previous studies have provided a range of conclusions—some have established a direct relationship between increased density and poor prognosis, while others have established the two factors are unrelated or even have an inverse relationship. The wide array of density measurements and study techniques applied has further contributed to the confusion.

Masarwah’s study looked at the effect of density (measured visually on the Boyd six-point scale using diagnostic mammograms) and several markers of poor cancer prognosis—those being tumour aggressiveness (as measured by tumour grade) and survival (disease-free survival, overall survival and disease-specific survival). A 6.4-year follow-up of 270 women revealed that breast density had an inverse relationship with poor cancer prognosis (that is, apparently opposite to the direct relationship between density and breast cancer risk). Low density was associated with higher grade tumours. Furthermore, women with density ≤25% had significantly reduced cumulative survival (in all three survival measures examined) compared to women with higher breast density. Further sub-classification of these low-density women revealed that this reduced survival was only apparent in women with very low breast density (<10%).

Mixed density breasts (>25% density) Low density breasts (≤25% density) p-value
Overall survival 90.2% 75.3% 0.003
Disease-free survival 84.8% 74.4% 0.048
Disease-specific survival 75% 25% 0.021

What may account for these findings? One aspect to consider is that biological factors that are important for breast cancer risk may not be the same as those that determine breast cancer prognosis. Low density breasts have a higher proportion of fat cells—and fat cells have been described to have a proliferative effect on surrounding cells within the breast through the production of estrogen. This may result in encouraging the proliferation of cancer cells that have invaded the breast stroma. This study also illustrated the importance of a cellular component known as hyaluronan (HA) on poor prognosis in very low density breasts. Such poor prognostic findings were found to be limited only to women that had low breast density combined with high levels of HA. HA normally promotes cell proliferation and migration and its levels are inversely associated with density. It is hypothesised that HA may promote the migration of stem cells which lead to cancer recurrence; furthermore, the cellular migration promoted by HA may be more efficient in fatty breasts.

Study design factors may have also contributed to the findings from this study. It is possible that low density only has a significant relationship with cancer prognosis when one considers the diagnostic mammogram taken after cancer development; the selection of mammographic image (for instance, using the diagnostic mammogram as opposed to one taken from a previous screening round, prior to cancer development) may confound these results. The small and unusual subject population (a mere 270 women, of whom about 50% were HER2 positive) may have affected the outcomes. Additionally, it should be kept in mind that only patients with invasive cancer were examined; the same associations between prognosis and density may not be found when other patient groups are compared. Overall, this study raises interesting questions regarding breast density and cancer prognosis. However, considering the presence of conflicting findings in the literature and the small sample used, it would be worthwhile repeating such a study in a broader setting with more subjects before low density is used as a clinical indicator of poor cancer prognosis.