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Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer

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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.

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Acknowledgments

We are grateful to the Breast Cancer Research Foundation for funding the clinical trial, and to Larry Norton for his support of this project, the Doris Duke Charitable Foundation for funding the research fellowship for Liz Garwood, the Association of Women Surgeons for funding the fellowship for Anjali Kumar, and to Novartis for providing fluvastatin for the trial. We thank Pamela Derish for her assistance editing this manuscript and Loretta Chan, Jessica Gibbs, Hannah Green, Margaret Hill, Bernadette Libao, Carleen Gentry, John Parr, Juan Lessing and Rajiv Sharma for their work and contributions that made the completion of this manuscript possible. Support for this study was generously provided by the Breast Cancer Research Foundation and in part, by the Doris Duke Charitable Foundation and the Association of Women Surgeons.

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Authors and Affiliations

  1. Department of Surgery, University of California, San Francisco, CA, USA

    Elisabeth R. Garwood, E. Shelley Hwang, Michael Campbell & Laura J. Esserman

  2. Pennsylvania State University College of Medicine, Hershey, PA, USA

    Elisabeth R. Garwood

  3. Department of Surgery, University of California, East bay, Oakland, CA, USA

    Anjali S. Kumar

  4. Department of Pathology, University of California, San Francisco, CA, USA

    Frederick L. Baehner & Alfred Au

  5. Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA

    Dan H. Moore

  6. Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, USA

    Nola Hylton & Chris I. Flowers

  7. Department of Surgery, Beth Israel Deaconness Medical Center, Boston, MA, USA

    Beth-Ann Lesnikoski

  8. Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA

    Judy Garber

  9. Department of Medicine, University of Chicago, Chicago, IL, USA

    Olofunmilao Olopade

  10. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Elisa Rush Port

  11. Carol F. Buck Breast Care Center, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA

    Laura J. Esserman

Authors
  1. Elisabeth R. Garwood
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  2. Anjali S. Kumar
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  3. Frederick L. Baehner
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  11. Olofunmilao Olopade
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  12. Elisa Rush Port
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  13. Michael Campbell
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  14. Laura J. Esserman
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Correspondence to Laura J. Esserman.

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Garwood, E.R., Kumar, A.S., Baehner, F.L. et al. Fluvastatin reduces proliferation and increases apoptosis in women with high grade breast cancer. Breast Cancer Res Treat 119, 137–144 (2010). https://doi.org/10.1007/s10549-009-0507-x

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  • DOI: https://doi.org/10.1007/s10549-009-0507-x

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