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Performing Data Mining And Integrative Analysis Of Biomarker in Breast Cancer Using Multiple Publicly Accessible Databases
Published on: May 17, 2019
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Window-of-Opportunity Study of Valproic Acid in Breast Cancer Testing a Gene Expression Biomarker.
Adam L Cohen1, Leigh Neumayer1, Ken Boucher1
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.
JCO Precision Oncology
|September 11, 2020
Summary
Valproic acid (VPA) is a well-tolerated breast cancer treatment that reduces tumor proliferation. A genomic biomarker, GDSS-VPA, predicts this response, supporting its use in triple-negative breast cancer drug development.
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Valproic acid (VPA) exhibits anticancer activity through histone deacetylase inhibition.
- The genomically derived sensitivity signature for VPA (GDSS-VPA) is a gene expression biomarker predicting VPA sensitivity in breast cancer.
- Previous research established GDSS-VPA's predictive capability in vitro and in vivo.
Purpose of the Study:
- To assess the tolerability of VPA in women with breast cancer.
- To evaluate the ability of the GDSS-VPA biomarker to predict biologic changes in breast tumors following VPA treatment.
- To investigate VPA's effect on tumor proliferation and histone acetylation.
Main Methods:
- A window-of-opportunity study involving women with untreated breast cancer (tumor size >1.5 cm).
- VPA administration for 7–12 days, with dose escalation from 30 to 50 mg/kg/d.
- Assessment of serum VPA levels, tumor proliferation (Ki-67), histone acetylation, and dynamic contrast-enhanced MRI.
Main Results:
- VPA was generally well-tolerated, with 52% of patients tolerating the maximum dose.
- Serum VPA levels correlated with histone acetylation changes in peripheral blood mononuclear cells (ρ = 0.451; P = .024).
- Tumor proliferation decreased post-VPA treatment, particularly in triple-negative breast cancer (TNBC) cases. Higher GDSS-VPA scores predicted greater Ki-67 reduction (AUC, 0.66).
Conclusions:
- VPA is a tolerable treatment option for breast cancer, demonstrating a correlation between serum levels and pharmacodynamic effects.
- VPA treatment effectively reduces breast tumor proliferation, with the GDSS-VPA biomarker predicting this response.
- Histone deacetylase inhibition via VPA represents a viable strategy for TNBC drug development, utilizing gene expression biomarkers.
