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.
ASJC Scopus subject areas
- Cancer Research