title: A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk.
abstract: Pre-clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention. We conducted a single-arm, biomarker modulation trial of lovastatin among women with increased risk of breast cancer. Eligibility criteria included a deleterious germline mutation in BRCA1, BRCA2, CDH1, or TP53; lifetime breast cancer risk of ≥20 % as estimated by the Claus model; or personal history of estrogen receptor and progesterone receptor-negative breast cancer. Participants received 40 mg of lovastatin orally twice daily for 6 months. We evaluated the following biomarkers before and after lovastatin use: breast duct cytology (primary endpoint), serum lipids, C-reactive protein, insulin-like growth factor-1, IGF binding protein-3, lipid peroxidation, oxidative DNA damage, 3-hydroxy-3-methylglutaryl CoA reductase genotype, and mammographic density. Thirty women were enrolled, and 26 (86.7 %) completed the study. For the primary endpoint of changes in breast duct cytology sampled by random periareolar fine needle aspiration, most participants [57.7 %, 95 % confidence interval (CI) 38.9-74.5 %] showed no change after lovastatin; 19.2 % (CI 8.1-38.3 %) had a favorable change in cytology, 7.7 % (95 % CI 1.0-25.3 %) had an unfavorable change, and 15.4 % (95 % CI 5.5-34.2 %) had equivocal results due to acellular specimens, usually after lovastatin. No significant changes were observed in secondary biomarker endpoints. The study was generally well-tolerated: 4 (13.3 %) participants did not complete the study, and one (3.8 %) required a dose reduction. This trial was technically feasible, but demonstrated no significant biomarker modulation; contributing factors may include insufficient sample size, drug dose and/or duration. The results are inconclusive and do not exclude a favorable effect on breast cancer risk.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Shaveta
authors.initials: S
authors.lastname: Vinayak
authors.forename: Erich J
authors.initials: EJ
authors.lastname: Schwartz
authors.forename: Kristin
authors.initials: K
authors.lastname: Jensen
authors.forename: Jafi
authors.initials: J
authors.lastname: Lipson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Alli
authors.forename: Lisa
authors.initials: L
authors.lastname: McPherson
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Fernandez
authors.forename: Vandana B
authors.initials: VB
authors.lastname: Sharma
authors.forename: Ashley
authors.initials: A
authors.lastname: Staton
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Mills
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Schackmann
authors.forename: Melinda L
authors.initials: ML
authors.lastname: Telli
authors.forename: Ani
authors.initials: A
authors.lastname: Kardashian
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.forename: Allison W
authors.initials: AW
authors.lastname: Kurian
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000328:Adult; D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism*; D044963:Biopsy, Fine-Needle; D000071060:Breast Density; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002097:C-Reactive Protein / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008148:Lovastatin / Q000009:adverse effects / Q000627:therapeutic use*; D042361:Mammary Glands, Human / Q000002:abnormalities* / Q000166:cytology* / Q000187:drug effects; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects; D010349:Patient Compliance
chemical_list: D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D008055:Lipids; D000080242:8-Hydroxy-2'-Deoxyguanosine; D002097:C-Reactive Protein; D008148:Lovastatin; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D003849:Deoxyguanosine