Abstract B17: Phase I prevention study of atorvastatin in women at increased risk for breast cancer
Authors: Arun Banu , Gong Yun , Liu Diane , Litton Jennifer , Gutierrez-Barrera Angelica , Sajan Blessy , Lee Jack j. , Vornik Lana A. , Cornelison Terri , Hortobagyi Gabriel N. , Lippman Scott , Brown Powel H. , Sneige nour 
Published: January 2014

Abstract
Background: Currently FDA approved chemopreventive agents for breast cancer risk reduction include the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifen. However, acceptance amongst high risk women is low due to side effects that include thromboembolic events, uterine cancer and menopausal symptoms. Furthermore, SERMs only reduce the incidence of estrogen receptor (ER) negative breast cancer. Therefore, agents with a favorable toxicity profile that reduce incidence of ER negative and ER positive breast cancer are urgently needed. Atorvastatin is a statin that inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMGcoA) reductase. Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. In animal models, statins have been shown to be also effective against ER negative breast cancer. The aim of this study was to evaluate atorvastatin's potential chemopreventive effect by first demonstrating changes in breast cancer risk biomarkers in women at increased risk for breast cancer.
Methods: High risk patients were randomized 1:1:1:1 to daily 10mg, 20mg, or 40mg Atorvastatin for 3 months, or to no treatment. High risk was defined as having a previous history of ductal carcinoma insitu (DCIS), lobular carcinoma insitu (LCIS), or atypical hyperplasia, or life time breast cancer risk greater than 20% by models including Gail, Claus, Tyrer-Cuzick, Boadicea, or BRCAPRO. All patients underwent baseline and 3 months blood collection and fine needle aspiration (FNA) of the breast for analysis of modulation in biomarkers. Biomarkers to be examined included in the blood: CRP, lipid profile, levels of atorvastatin, HMGcoA genotype and in breast FNA samples: Cytology, Ki 67, EGFR, bcl-2, CC3, and LXR evaluated by immunohistochemistry.
Results: Between 2008 and 2012, 66 high risk women were randomized and 60 completed the study. Mean age was 51.8 years (range 27-69). One patient in the 20 mg arm experienced grade 3 toxicity (myalgia) that was not study drug related; 5 patients in the control arm, 6 in the 10mg, 9 in the 20mg and 4 in the 40 mg arm experienced grade 2 toxicity; only minority of them related to the study drug (arthraligia, myalgia, skin rash); 2 patients in the control arm, 3 in the 10 mg, 4 in the 20mg and 12 in the 40mg arm experienced grade 1 toxicity; only 10% of them possibly related to the study drug (arthralgia, myalgia, diarrhea, skin rash).
Conclusion: Compliance during our atorvastatin phase I biomarker modulation study was very good. Atorvastatin was well tolerated with minority of the patients experiencing side effects, most of which were not related to the study drug. Biomarker analysis is ongoing and will be presented. This study was supported by the NCI N01CN35159 award.
Citation Format: Banu Arun, Yun Gong, Diane Liu, Jennifer Litton, Angelica Gutierrez-Barrera, Blessy Sajan, Jack j. Lee, Lana A. Vornik, Terri Cornelison, Gabriel N. Hortobagyi, Scott Lippman, Powel H. Brown, nour Sneige. Phase I prevention study of atorvastatin in women at increased risk for breast cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B17.