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

doi:10.1200/PO.16.00011

Window-of-Opportunity Study of Valproic Acid in Breast Cancer Testing a Gene Expression Biomarker

JCO Precis Oncol. 2017 Apr 7:1:PO.16.00011. doi: 10.1200/PO.16.00011. eCollection 2017.

Affiliation

¹ , , , , , , , , and , University of Utah; , , , , and , Huntsman Cancer Institute, Salt Lake City; , Brigham Young University, Provo, UT; , University of Arizona, Tucson, AZ; and , Advanced Imaging Research Center, Portland, OR.

Abstract

Purpose: The anticancer activity of valproic acid (VPA) is attributed to the inhibition of histone deacetylase. We previously published the genomically derived sensitivity signature for VPA (GDSS-VPA), a gene expression biomarker that predicts breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study that examined the tolerability of VPA and 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 than 1.5 cm. After a biopsy, women were given VPA for 7 to 12 days, increasing from 30 mg/kg/d orally divided into two doses per day to a maximum of 50 mg/kg/d. After VPA treatment, serum VPA level was measured and then breast surgery or biopsy was performed. Tumor proliferation was assessed by using Ki-67 immunohistochemistry. Histone acetylation of peripheral blood mononuclear 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). Fifty-two 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 serum VPA level correlated with a change in histone acetylation of peripheral blood mononuclear cells (ρ = 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 levels and histone acetylation. VPA treatment 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.