Phase I biomarker modulation study of atorvastatin in women at increased risk for breast cancer
- 455 Downloads
Selective estrogen receptor modulators (SERMs), tamoxifen, and raloxifene that reduce the risk of breast cancer are limited to only estrogen receptor-positive (ER+) breast cancer. In addition, patient acceptance of SERMs is low due to toxicity and intolerability. New agents with improved toxicity profile that reduce risk of ER-negative breast cancer are urgently needed. Observational studies show that statins can reduce breast cancer incidence and recurrence. The objective of this prospective short-term prevention study was to evaluate the effect of a lipophilic statin, atorvastatin, on biomarkers in breast tissue and serum of women at increased risk. Eligible participants included women with previous history of carcinoma in situ, or atypical hyperplasia, or 5 year breast cancer projected Gail risk >1.67 %, or lifetime breast cancer risk >20 % calculated by models including Claus, Tyrer-Cuzick, Boadicea, or BRCAPRO. Patients underwent baseline fine needle aspiration (FNA) of the breast, blood collection for biomarker analysis, and were randomized to either no treatment or atorvastatin at 10, 20, or 40 mg/day dose for 3 months. At 3 months, blood collection and breast FNA were repeated. Biomarkers included C-reactive protein (CRP), lipid profile, atorvastatin, and its metabolites, Ki-67, bcl-2, EGFR, and pEGFR. Baseline genotype for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) was also measured. Among 60 patients evaluated, a significant reduction in serum CRP, cholesterol and low-density lipoprotein (LDL), and increase in atorvastatin metabolites in serum and breast FNAs was demonstrated. No changes were observed in other tissue biomarkers. This study shows that atorvastatin and its metabolites are detectable in breast samples and may lower serum CRP among women without hyperlipidemia.
KeywordsBreast cancer risk Statins Atorvastatin Breast cancer biomarkers
The study was funded by NCI-DCP# MDA05-6-01 contract grant. We thank Dr. Madhumita Ghosh for the critical reading and editing of the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest.
- 1.Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371–1388CrossRefPubMedGoogle Scholar
- 2.Goss PE, Ingle JN, Ales-Martinez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, McTiernan A, Robbins J, Johnson KC, Martin LW, Winquist E, Sarto GE, Garber JE, Fabian CJ, Pujol P, Maunsell E, Farmer P, Gelmon KA, Tu D, Richardson H, Investigators NCMS (2011) Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364:2381–2391CrossRefPubMedGoogle Scholar
- 8.Higgins MJ, Prowell TM, Blackford AL, Byrne C, Khouri NF, Slater SA, Jeter SC, Armstrong DK, Davidson NE, Emens LA, Fetting JH, Powers PP, Wolff AC, Green H, Thibert JN, Rae JM, Folkerd E, Dowsett M, Blumenthal RS, Garber JE, Stearns V (2012) A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer. Breast Cancer Res Treat 131:915–924CrossRefPubMedGoogle Scholar
- 9.Vinayak S, Schwartz EJ, Jensen K, Lipson J, Alli E, McPherson L, Fernandez AM, Sharma VB, Staton A, Mills MA, Schackmann EA, Telli ML, Kardashian A, Ford JM, Kurian AW (2013) A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk. Breast Cancer Res Treat 142:389–398CrossRefPubMedGoogle Scholar
- 11.Arun B, Valero V, Logan C, Broglio K, Rivera E, Brewster A, Yin G, Green M, Kuerer H, Gong Y, Browne D, Hortobagyi GN, Sneige N (2007) Comparison of ductal lavage and random periareolar fine needle aspiration as tissue acquisition methods in early breast cancer prevention trials. Clin Cancer Res 13:4943–4948CrossRefPubMedGoogle Scholar
- 13.Harper-Wynne C, Ross G, Sacks N, Salter J, Nasiri N, Iqbal J, A’Hern R, Dowsett M (2002) Effects of the Aromatase Inhibitor Letrozole on Normal Breast Epithelial Cell Proliferation and Metabolic Indices in Postmenopausal Women: a Pilot Study for Breast Cancer Prevention. Cancer Epidemiol Biomark Prev 11:614–621Google Scholar
- 15.Fabian C, Kimler B, Donnelly J, Sullivan D, Klemp J, Petroff B, Phillips T, Metheny T, Aversman S, Yeh H-W, Zalles C, Mills G, Hursting S (2013) Favorable modulation of benign breast tissue and serum risk biomarkers is associated with >10 % weight loss in postmenopausal women. Breast Cancer Res Treat 142:119–132CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Fabian CJ, Kimler BF, Zalles CM, Klemp JR, Petroff BK, Khan QJ, Sharma P, Setchell KDR, Zhao X, Phillips TA, Metheny T, Hughes JR, Yeh H-W, Johnson KA (2010) Reduction in Ki-67 in Benign Breast Tissue of High-Risk Women with the Lignan Secoisolariciresinol Diglycoside. Cancer Prev Res 3:1342–1350CrossRefGoogle Scholar
- 17.Fabian CJ, Kimler BF, Anderson J, Tawfik OW, Mayo MS, Burak WE Jr, O’Shaughnessy JA, Albain KS, Hyams DM, Budd GT, Ganz PA, Sauter ER, Beenken SW, Grizzle WE, Fruehauf JP, Arneson DW, Bacus JW, Lagios MD, Johnson KA, Browne D (2004) Breast cancer chemoprevention phase I evaluation of biomarker modulation by Arzoxifene, a third generation selective estrogen receptor modulator. Clin Cancer Res 10:5403–5417. doi: 10.1158/1078-0432.CCR-04-0171.CrossRefPubMedGoogle Scholar
- 18.Ollberding NJ, Kim Y, Shvetsov YB, Wilkens LR, Franke AA, Cooney RV, Maskarinec G, Hernandez BY, Henderson BE, Le Marchand L, Kolonel LN, Goodman MT (2013) Prediagnostic leptin, adiponectin, C-reactive protein, and the risk of postmenopausal breast cancer. Cancer Prev Res (Phila). 6:188–195CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Lippman ME, Krueger KA, Eckert S, Sashegyi A, Walls EL, Jamal S, Cauley JA, Cummings SR (2001) Indicators of lifetime estrogen exposure: effect on breast cancer incidence and interaction with raloxifene therapy in the multiple outcomes of raloxifene evaluation study participants. J Clin Oncol 19:3111–3116PubMedGoogle Scholar