title: Fluvastatin reduces proliferation and increases apoptosis  in women with high grade breast cancer.
abstract: The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3-6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P < 0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.
authors.affiliation: Department of Surgery, University of California, San Francisco, CA, USA.
authors.forename: Elisabeth R
authors.initials: ER
authors.lastname: Garwood
authors.forename: Anjali S
authors.initials: AS
authors.lastname: Kumar
authors.forename: Frederick L
authors.initials: FL
authors.lastname: Baehner
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Alfred
authors.initials: A
authors.lastname: Au
authors.forename: Nola
authors.initials: N
authors.lastname: Hylton
authors.forename: Chris I
authors.initials: CI
authors.lastname: Flowers
authors.forename: Judy
authors.initials: J
authors.lastname: Garber
authors.forename: Beth-Ann
authors.initials: BA
authors.lastname: Lesnikoski
authors.forename: E Shelley
authors.initials: ES
authors.lastname: Hwang
authors.forename: Olofunmilao
authors.initials: O
authors.lastname: Olopade
authors.forename: Elisa Rush
authors.initials: ER
authors.lastname: Port
authors.forename: Michael
authors.initials: M
authors.lastname: Campbell
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Esserman
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D002097:C-Reactive Protein / Q000096:biosynthesis; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000188:drug therapy*; D053148:Caspase 3 / Q000096:biosynthesis; D049109:Cell Proliferation / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000627:therapeutic use*; D005260:Female; D000077340:Fluvastatin; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007211:Indoles / Q000627:therapeutic use*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D008875:Middle Aged
chemical_list: D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D019394:Ki-67 Antigen; D000077340:Fluvastatin; D002097:C-Reactive Protein; D053148:Caspase 3