Window-of-opportunity study of valproic acid in breast cancer testing a gene expression biomarker

Adam L. Cohen, Leigh Neumayer, Ken Boucher, Rachel E. Factor, Gajendra Shrestha, Mark Wade, John G. Lamb, Kylee Arbogast, Stephen R. Piccolo, Joanna Riegert, Matthias Schabel, Andrea H. Bild, Theresa L. Werner

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Purpose The anticancer activity of valproic acid (VPA) is attributed to the inhibition of histone deacetylase.Wepreviouslypublished thegenomically derived sensitivity signature forVPA(GDSSVPA), agene expression biomarker thatpredictsbreast cancer sensitivity toVPAinvitro andinvivo. Weconducted a window-of-opportunity study that examined the tolerability ofVPAand the ability of the GDSS-VPA to predict biologic changes in breast tumors after treatment with VPA. Patients and Methods Eligible women had untreated breast cancer with breast tumors larger than1.5cm.Afterabiopsy,womenweregivenVPAfor7to12days, increasingfrom30mg/kg/dorally dividedintotwodosesperday toamaximumof50mg/kg/d.AfterVPAtreatment, serumVPAlevel wasmeasured and then breast surgery or biopsywas performed.Tumor proliferationwas assessed byusingKi-67immunohistochemistry.Histone acetylationofperipheralbloodmononuclear cells was assessed by Western blot. Dynamic contrast-enhanced magnetic resonance imaging scans were performed before and after VPA treatment. Results Thirty women were evaluable. The median age was 54 years (range, 31-73 years). Fiftytwo percent of women tolerated VPA at 50 mg/kg/d, but 10% missed more than two doses as a result of adverse events. Grade 3 adverse events included vomiting and diarrhea (one patient) and fatigue (one patient). The end serumVPAlevel correlated with a change in histone acetylation of peripheral blood mononuclear cells (r = 0.451; P = .024). Fifty percent of women (three of six) with triple-negative breast cancer had a Ki-67 reduction of at least 10% compared with 17% of other women. Women whose tumors had higher GDSS-VPA were more likely to have a Ki-67 decrease of at least 10% (area under the curve, 0.66). Conclusion VPA was well tolerated and there was a significant correlation between serum VPA levelsand histone acetylation.VPAtreatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. Inhibition of histone deacetylase is a valid strategy for drug development in triple-negative breast cancer using gene expression biomarkers.

Original languageEnglish (US)
Pages (from-to)1-11
Number of pages11
JournalJCO Precision Oncology
Volume2017
Issue number1
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Cohen, A. L., Neumayer, L., Boucher, K., Factor, R. E., Shrestha, G., Wade, M., Lamb, J. G., Arbogast, K., Piccolo, S. R., Riegert, J., Schabel, M., Bild, A. H., & Werner, T. L. (2017). Window-of-opportunity study of valproic acid in breast cancer testing a gene expression biomarker. JCO Precision Oncology, 2017(1), 1-11. https://doi.org/10.1200/PO.16.00011