Abstract PD1-03: Cholesterol, cholesterol lowering medication use, and breast cancer outcomes in the BIG 1-98 study

Abstract

Abstract Background: Cholesterol lowering medications (CLM)—statins in particular—may exert anti-cancer effects. A proposed mechanism involves attenuated signaling through the estrogen receptor by the cholesterol metabolite, 27-hydroxycholesterol, which correlates with systemic total cholesterol. Assessment of cholesterol levels and use of cholesterol-lowering medications among breast cancer patients receiving endocrine treatment may enrich our understanding of factors affecting endocrine therapy effectiveness and the role of statins and cholesterol in cancer survival. Aim: To investigate the prognostic effect of baseline cholesterol level and baseline CLM use, and to study the effect on outcome of concurrent use of CLM and endocrine therapy in the BIG 1-98 study. Design and Methods: The BIG 1-98 study enrolled 8,010 postmenopausal women with early-stage, estrogen receptor-positive invasive breast cancer from 1998-2003. Participants were randomized to five years of tamoxifen, letrozole, or their sequence. Cholesterol levels and use of CLM were assessed at baseline and every six months up to 5.5 years. Multivariable prognostic models of baseline cholesterol or baseline CLM use were adjusted for patient- and tumor characteristics and treatment regimen. Prognostic analyses of baseline cholesterol were restricted to women not taking CLM at baseline. Marginal structural modeling was used to investigate the relationship between initiation of CLM during endocrine therapy and outcome. Median follow-up was approximately 8 years. Endpoints were: disease-free survival (DFS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Results: Among 7,963 women who received at least one dose of endocrine therapy, 637 reported use of CLM at baseline, including statins (n=490) and non-statins (n=147). Compared with non-users, women on CLM at baseline were older, more often had a history of diabetes, were more likely to use hormone replacement therapy, and were more often diagnosed with smaller tumors or node-negative disease. During follow-up, 2,005 DFS-events, 1,303 BCFI-events and 1,004 DRFI-events were reported. Among non-users of CLM at baseline, baseline cholesterol levels showed a significant U-shaped association with BCFI and DRFI when grouped according to the quartiles of the distribution; however, these results were not maintained using cardiovascular risk-based cholesterol cut points. Prognostic models also suggested that use of any CLM at baseline was associated with better DFS compared with non-use (HRadj=0.82, 95% CI: 0.68, 0.99); similar, but non-significant associations were seen for BCFI (HRadj=0.83, 95% CI: 0.65, 1.06) and DRFI (HRadj=0.81, 95% CI: 0.61, 1.09). Results from the marginal structural modeling showed no differences in outcomes for women who initiated CLM during endocrine therapy compared with those who did not. Conclusions: In the BIG 1-98 study investigating the use of tamoxifen, letrozole or their sequence as endocrine therapy in the adjuvant setting, use of cholesterol-lowering therapy at baseline was associated with beneficial tumor characteristics. The effects on clinical outcome need further investigation. Citation Format: Borgquist S, Giobbie-Hurder A, Ahern T, Garber JE, Colleoni M, Láng I, Debled M, Ejlertsen B, Coates AS, Goldhirsch A, Price KN, Gelber RD, Regan MM, Thürlimann B. Cholesterol, cholesterol lowering medication use, and breast cancer outcomes in the BIG 1-98 study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD1-03.