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A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

ABSTRACT: Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had completed all planned treatment of a prior stage 0-III breast cancer received simvastatin 40 mg orally daily for 24-28 weeks. At baseline and end-of-study, we measured circulating concentrations of high-sensitivity C-reactive protein (hsCRP), estrogens, and fasting lipids; breast density on contralateral breast mammogram; and quality of life by Rand Short Form 36-Item health survey. Fifty women were enrolled with a median age of 53 years. Total cholesterol, LDL cholesterol, triglyceride, and hsCRP fell significantly during the study (P values < 0.001, <0.001, 0.003, and 0.05, respectively). Estrone sulfate concentrations decreased with simvastatin treatment (P = 0.01 overall), particularly among post-menopausal participants (P = 0.006). We did not observe a significant change in circulating estradiol or estrone concentrations, contralateral mammographic breast density, or reported physical functioning or pain scores. This study demonstrates the feasibility of short-term biomarker modulation studies using the contralateral breast of high-risk women. Simvastatin appears to modulate estrone sulfate concentrations and its potential chemopreventive activity in breast cancer warrants further investigation.

SUBMITTER: Higgins MJ

PROVIDER: S-EPMC3536477 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

Higgins Michaela J MJ Prowell Tatiana M TM Blackford Amanda L AL Byrne Celia C Khouri Nagi F NF Slater Shannon A SA Jeter Stacie C SC Armstrong Deborah K DK Davidson Nancy E NE Emens Leisha A LA Fetting John H JH Powers Pendleton P PP Wolff Antonio C AC Green Hannah H Thibert Jacklyn N JN Rae James M JM Folkerd Elizabeth E Dowsett Mitchell M Blumenthal Roger S RS Garber Judy E JE Stearns Vered V

Breast cancer research and treatment 20111111 3

Observational studies have demonstrated a decreased incidence of cancers among users of HMG CoA reductase inhibitors (statins) and a reduced risk of recurrence among statin users diagnosed with early stage breast cancer. We initiated a prospective study to identify potential biomarkers of simvastatin chemopreventive activity that can be validated in future trials. The contralateral breast of women with a previous history of breast cancer was used as a high-risk model. Eligible women who had comp ...[more]

PMID: 22076478

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Project description:Lymphocyte and breast tissue samples from overweight woman at increased risk of breast cancer before and after 1 month of intermittant energy restriction Introduction Observational studies indicate that weight loss and energy restriction reduce breast cancer risk. Intermittent energy restriction (IER) reduces weight as well as, or more than continuous energy restriction (CER), but its effect on the breast and systemic metabolism as indicators of breast cancer risk are not known. Methods We assessed the effect of IER ( 2 days of 65% energy restriction) for one menstrual cycle on the breast (breast gene expression and fat cell size) and systemic metabolism (insulin resistance, lipids, serum and urine metabolites) in 23 overweight premenopausal women at high risk of breast cancer. Unsupervised hierarchical analysis selected 100 genes with the highest variance between pre and post IER biopsies in 20 subjects, whilst mass spectrometry was used to assess corresponding changes in serum (LCMS) and urine metabolites (GCMS) in 23 subjects in the restricted and unrestricted days of the IER. Results Women lost on average 4.8% (± 2.0) of body weight and 8.0% (± 5.0) of body fat. Insulin resistance (HOMA) was reduced by 29.8% (±17.8) on the restricted days and by 11%(±34) on the unrestricted days of the IER. Over 250 serum and urine metabolites significantly increased or decreased during the two restricted days and most returned to normal after the subsequent five day period . In the breast tissue, approximately half (In 11) of the subjects displayed down regulation of several metabolic pathways including lipid synthesis, growth factors and hormones, whilst epithelial genes including milk proteins, secretoglobulins and mucins were up-regulated and several metabolic pathways down-regulated including lipid synthesis, growth factors and hormones. In the other nine subjects there was no appreciable effect of IER on the breast. CorrespondingThe gene changes were not seen in peripheral blood lymphocytes, and there was no reduction in breast fat cell size. The two groups defined by change in gene expression or lack of it did not differ in the degree of weight or fat loss, other systemic metabolic markers, or histological assessment of the biopsies. Conclusion We conclude that breasts vary in response to short-term IER, the mechanism of which requires further investigation. Trial registration ISRCTN77916487

Project description:Despite positive results from large phase III clinical trials proved that it is possible to prevent estrogen-responsive breast cancers with selective estrogen receptor modulators and aromatase inhibitors, no significant results have been reached so far to prevent hormone non-responsive tumors. The Ductal Lavage (DL) procedure offers a minimally invasive method to obtain breast epithelial cells from the ductal system for cytopathologic analysis. Several studies with long-term follow-up have shown that women with atypical hyperplasia have an elevated risk of developing breast cancer. The objective of the proposed trial is to assess the efficacy and safety of a daily administration of nimesulide or simvastatin in women at higher risk for breast cancer, focused particularly on hormone non-responsive tumor risk. The primary endpoint is the change in prevalence of atypical cells and cell proliferation (measured by Ki67) in DL or fine needle aspirate samples, after 12 months of treatment and 12 months after treatment cessation. METHODS-DESIGN: From 2005 to 2011, 150 women with a history of estrogen receptor negative ductal intraepithelial neoplasia or lobular intraepithelial neoplasia or atypical hyperplasia, or unaffected subjects carrying a mutation of BRCA1 or with a probability of mutation >10% (according to BRCAPRO) were randomized to receive nimesulide 100mg/day versus simvastatin 20mg/day versus placebo for one year followed by a second year of follow-up.This is the first randomized placebo controlled trial to evaluate the role of DL to study surrogate endpoints biomarkers and the effects of these drugs on breast carcinogenesis. In 2007 the European Medicines Agency limited the use of systemic formulations of nimesulide to 15 days. According to the European Institute of Oncology Ethics Committee communication, we are now performing an even more careful monitoring of the study participants. Preliminary results showed that DL is a feasible procedure, the treatment is well tolerated and the safety blood tests do not show any significant liver toxicity. There is an urgent need to confirm in the clinical setting the potential efficacy of other compounds in contrasting hormone non-responsive breast cancer. This paper is focused on the methodology and operational aspects of the clinical trial.(ClinicalTrials.gov Identifier: NCT01500577).

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A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

Publications

A short-term biomarker modulation study of simvastatin in women at increased risk of a new breast cancer.

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