By Sara McKenna, Godalming, Surrey, UK
In this mini-symposium at the San Antonio Breast Cancer Symposium (SABCS) in December, three speakers addressed different aspects of the apparently increased risk of developing breast cancer that is associated with high breast tissue density, and also the clinical implications of this association.
Celine Vachon of the Mayo Clinic in Rochester first spoke of the genetics and epidemiology of breast tissue density. She observed that increased density was common, with 16-32% of women in general having more than 50% dense breast tissue, and that these women have a 3-5 fold increased risk of developing breast cancer compared to those with low or no breast density. Among women with breast cancer, up to one third are found in women with a density of over 50%.
Breast density decreases with age, with the greatest decline seen between ages 45-55. But Dr. Vachon also noted the protective value of fatty breast tissue in pre-menopausal women: the higher the amount of fatty breast tissue present in this group of women, the lower the overall density and risk of developing breast cancer.
As to why some women have more dense tissue that others, factors that seemed to be associated with higher density included pre-menopausal status, nulliparity, post-menopausal hormone use and alcohol intake. But Dr. Vachon pointed out that taken together, epidemiological risk factors account for only 20-30% of the variation in breast density in the general population. Genetics appeared to account for a higher percentage of the variance, with 30-60% of the variance attributed to inherited factors.
Norman Boyd of the Ontario Cancer Institute then looked at some of the clinical implications of the observed increased risk associated with high breast density.
With regard to breast cancer characteristics and clinical outcomes, he observed that those with 75% breast density had a 5-fold difference in risk compared to those with less than 10% density, and that extensive density was associated with an overall increased risk of developing both ER+ and ER- tumours, and of all “non-obligate” precursors of invasive tumours such as DCIS and ADH. It was also associated with larger tumours and higher histological grade. However, the risk from death did not appear to be increased.
The implications for screening were clear in that mammography is less effective for women with dense breast tissue, who would benefit from alternative screening modalities such as MRI or US. Conversely, women with translucent breast tissue were at lower risk and could therefore consider less frequent screening than is currently standard.
Dr. Boyd also addressed the issue of breast cancer prevention trials and pointed out that unlike most other risk factors for breast cancer, breast density can be changed. He suggested that breast density could be used as a surrogate marker for risk in such trials, which would allow the identification of a group at very high risk of developing breast cancer who might benefit from e.g., tamoxifen therapy, which is known to reduce breast tissue density. But validating breast density as a surrogate marker for risk would take time.
Overall, Dr. Boyd also reminded us that correlation does not prove causation: the apparent higher risk conferred on women with dense breast tissue could simply be down to chance, and the fact that these cancers are often found at a later stage compared to screen-detected tumours.
In the final presentation of the mini-symposium, Thea Tlsty of the University of California, San Francisco looked at the biological basis of breast density and cancer risk. She and her team had examined specifically the relationship between a higher amount of fatty tissue in the breast and lower breast density – also mentioned by Dr. Vachon in her presentation – and had identified a protein, CD36, which appears to modulate fatty tissue in the breast.
Dr. Tlsty and her team carried out both in vitro and in vivo (mouse model) experiments, which appear to show that CD36 protein levels are repressed in all stromal cells within tumour tissues compared to normal adjacent tissue, and that much higher levels of CD36 are found in normal breast tissue overall. So, measuring CD36 levels and finding a way of increasing them as necessary to produce a higher level of fatty breast tissue, could lead potentially to a reduction in the risk of developing breast cancer.
With reference to NBCC’s goals to end breast cancer by January 1, 2020 (Breast Cancer Deadline 2020®), any practical clinical application of Dr. Tlsty’s research seems unlikely to be ready by 2020. In the case of the overall increased risk that is associated with high density breast tissue, as discussed in this mini-symposium, even it could be proved beyond reasonable doubt that there is, in fact, a causal relationship between two, breast density is probably just one part of the jigsaw in any case.
Overall though, in looking at biological aspects of breast cancer risk, I think that Dr. Tlsty and her team’s work seems particularly promising, in that by arriving at a clearer understanding of the biology of breast cancer and the environment in which it develops, new approaches to prevention and intervention may be identified – all of which speaks to the deadline goals, even if not the timing.