Change in breast density as a biomarker of breast cancer risk reduction; results from IBIS-1.
Authors: Cuzick J , Warwick J , Pinney L , Warren R , Cawthorn S , Howell A , Duffy S 
Published: December 2010

Abstract #61

Background:&#x2028; Numerous studies have documented the importance of mammographic breast density as a risk factor for breast cancer. It has the highest attributable risk of all currently known risk factors, and is modifiable. For mammographic density to be considered a biomarker, however, one would have to demonstrate that the risk reduction induced by a preventive intervention can be predicted by change in density, and that those who experience the largest change are most likely to have benefited. In the IBIS-1 study, tamoxifen reduced the risk of breast cancer by about 40% (Cuzick, et al JNCI 2007). Here we focus on whether the change in breast density after 12-18 months of prophylactic treatment predicts the subsequent impact of tamoxifen on the development of breast cancer.&#x2028; Material and Methods:&#x2028; The entry and 12-18 month mammograms for 120 UK breast cancer cases and 943 controls (women who had not developed breast cancer) who were participants in IBIS-1 were retrieved and mammographic density visually assessed (as a percentage of the total breast area) by a consultant radiologist (RW) using a semi-continuous 21-point categorical scale (0,5, 10,…, 100). Using logistic regression we assessed the univariate and multivariate effects of treatment, mammographic density (change over the first 12-18 months on treatment and at entry), anthropometric, hormonal and familial factors on the risk of developing breast cancer. All analyses were unmatched but adjusted for age at entry to the study. Sub-analyses were performed on the placebo and tamoxifen arms separately.&#x2028; Results:&#x2028; Mammographic density at entry, BMI, breast cancer risk (from the Cuzick-Tyrer model) and change in density during the first 12-18 months of treatment were all significant in the multivariate model. In the tamoxifen arm (N=504, 48 cases and 456 controls), only change in mammographic density was significant (P = 0.05). For the 46% of women in the tamoxifen arm whose density reduced by 10% or more, the risk of breast cancer was reduced by 52% relative to the control group (P = 0.01) while for the 54% of women whose density was not reduced by 10 % there was only a non-significant 8% reduction in breast cancer risk.&#x2028; Discussion:&#x2028; Our findings suggest that the impact of tamoxifen on risk reduction is predictable by the changes it induces on breast density after 12-18 months of treatment. Changes in breast density may therefore constitute an early indicator of treatment efficacy, which would be useful for the evaluation of new chemoprevention therapies. Furthermore, by measuring density changes between baseline and initial follow up mammograms in high risk women receiving tamoxifen, it may be possible to determine which women are actually benefiting from the intervention (and should therefore continue treatment), and those who might benefit more from alternative risk reducing strategies. These findings need confirmation in an independent study.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 61.