Abstract PD03-06: Simvastatin radiosensitizes differentiated and stem-like breast cancer cell lines and is associated with improved local control in inflammatory breast cancer patients treated with post-mastectomy radiation
Authors: Lacerda L , Reddy J , Liu D , Larson R , Masuda H , Brewer T , Debeb B , Xu W , Hortobagyi GN , Buchholz TA , Ueno NT , Woodward WA 
Published: August 2014

Among women with non-inflammatory triple-negative and triple-negative inflammatory breast cancer (IBC), the 5-yr actuarial rates of local failure after radiation are 11%–35% and 45%, respectively, in part influenced by the contribution of radioresistant cancer stem cells to these cancers. Herein we explored the radiosensitization of breast cancer stem-like cells in vitro and examined the influence on local control after post-mastectomy radiation (PMRT) among IBC patients taking statins.

SUM149, SUM159 and MCF-7 cells were cultured in standard monolayer cultures and stem cell enriching anchorage independent clonogenic cultures with simvastatin and treated with increasing concentrations of radiation. Survival curves were generated and t-test was used to compare surviving fraction (SF) of groups. p &lt; 0.05 was considered significant. Clinical information was extracted from the charts of 534 Stage III IBC patients treated with neoadjuvant systemic therapy, mastectomy and PMRT from 1970–2011. Clinical characteristics between statin and no statin cohorts were compared using the chi-square statistic. Local regional recurrence-free survival (LRFS) was determined using the Kaplan Meier method and compared with log rank.

Simvastatin radiosensitized all cell lines in both types of clonogenic culture assays. The triple-negative IBC cell line SUM149 had the greatest response to combined treatment regardless of the radiation dose used in monolayer cultures (SF2: 0.417 vs 0.319, SF4: 0.136 vs 0.075, SF6: 0.026 vs 0.018, in control vs treated respectively, all p &lt; 0.0001) and in anchorage independent cultures (SF2: 0.880 vs 0.762, SF4: 0.863 vs 0.492, SF6: 0.920 vs 0.492, in control vs treated respectively, all p &lt; 0.0001). The triple-negative non-IBC cell line SUM159 was more sensitive to combined treatment in monolayer cultures (p &lt; 0.001) than in stem cell enriching cultures. In a retrospective clinical study of 534 IBC patients, 84 patients used a statin. Median follow-up time for the entire cohort was 2.6 yrs. As expected, statin users were older (80% vs 44% over 50, p &lt; 0.001) and were more often obese than non-statin users (59% vs 42%, p &lt; 0.001). Receptor status was balanced between these groups. Statin users were more often pathologically node-negative (p &lt; 0.01) and had fewer grade III tumors (p &lt; 0.04). On univariate analysis actuarial 3-yr LRFS was higher among statin users, 89% vs 75%, p = 0.009. On multivariate analyisis TNBC (HR = 0.369, p &lt; 0.0001), lymphatic invasion (HR = 0.430, p = 0.0007), neoadjuvant pathological response (HR = 0.242, p = 0.006) and statin use (HR = 0.422, p = 0.03) were independently associated with higher LRFS.

Patients with IBC and triple negative non-IBC breast cancer have the highest rates of local failure and no available known radiosensitizers. Here we report significant improvement in local control after PMRT among statin users with IBC and significant radiosensitization across triple-negative and IBC cell lines of multiple subtypes using simvastatin. Clinical value in patients without hypercholesterolemia remains to be established. These encouraging data suggest simvastatin may be an appropriate radiosensitizing agent for clinical trials.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-06.