Abstract 815: Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer

Abstract

Abstract Neoadjuvant chemotherapy is given before surgery to patients with primarily unresectable, advanced-stage cancers to render the tumor resectable, and to facilitate breast conservation. Previously, we have reported a prospective phase II trial for women with stage IIA-B/IIIA-B-C breast cancer with improved pathologic complete response (pCR) when using bevacizumab in the neoadjuvant setting. Chemotherapy agents are given orally or intravenously during multiple cycles of systemic treatments. However, the effect of the treatment can only be evaluated upon the completion of therapy. Here, we aim to identify epigenetic signatures in blood for patients at baseline as non-invasive markers to predict their pCR from the treatment, and to determine if treatment-related changes in epigenetic profiles reflect responsiveness to therapy. We performed genome-wide DNA methylation profiling using blood-derived DNA, and found that pre-treatment methylation status of BRD9 was predictive of responsiveness to therapy. Post-treatment global methylation differences were also observed between responders and non-responders. Most differentially methylated CpGs were located in promoter CpG island regions for responders, but in the open sea region for non-responders. DNMT3B was hypomethylated while most of the other genes were hypermethylated after 4 cycles of treatment. Hypomethylation of DNMT3B could potentially lead to the increased methylation of oncogenes and genes responsible for cell growth and proliferation, facilitating responsiveness to the therapy. These results support the development of BRD9 as a biomarker for treatment selection before neoadjuvant therapy with bevacizumab, and indicate DNMT3B as a potential target to improve clinical response. Citation Format: Ping-Ching Hsu, Susan Kadlubar, Eric Siegel, Lora J. Rogers, Valentina K. Todorova, Joseph Su, Issam Makhoul. Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 815.