TY - JOUR
T1 - Genome-wide DNA methylation signatures to predict pathologic complete response from combined neoadjuvant chemotherapy with bevacizumab in breast cancer
AU - Hsu, Ping Ching
AU - Kadlubar, Susan A.
AU - Siegel, Eric R.
AU - Rogers, Lora J.
AU - Todorova, Valentina K.
AU - Su, L. Joseph
AU - Makhoul, Issam
N1 - Publisher Copyright:
© 2020 Hsu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/4
Y1 - 2020/4
N2 - 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 intravenously during multiple cycles of systemic treatments. However, the effect of the treatment is only evaluated upon the completion of therapy. Here, data from a clinical trial of 40 breast cancer patients with very aggressive disease and poor prognosis were studied aiming to identify epigenetic signatures in blood-derived DNA at baseline as potential non-invasive markers to predict pCR and to determine if treatment-related changes inepigenetic 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 (DM) CpGs were located in promoter CpG-island regions for responders and in the open-sea region for non-responders. In 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 possible development of BRD9 as a biomarker for treatment selection before neoadjuvant therapy with chemotherapy and bevacizumab, and indicate DNMT3B as a potential target to improve clinical response. Further prospective validation of these findings is warranted.
AB - 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 intravenously during multiple cycles of systemic treatments. However, the effect of the treatment is only evaluated upon the completion of therapy. Here, data from a clinical trial of 40 breast cancer patients with very aggressive disease and poor prognosis were studied aiming to identify epigenetic signatures in blood-derived DNA at baseline as potential non-invasive markers to predict pCR and to determine if treatment-related changes inepigenetic 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 (DM) CpGs were located in promoter CpG-island regions for responders and in the open-sea region for non-responders. In 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 possible development of BRD9 as a biomarker for treatment selection before neoadjuvant therapy with chemotherapy and bevacizumab, and indicate DNMT3B as a potential target to improve clinical response. Further prospective validation of these findings is warranted.
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U2 - 10.1371/journal.pone.0230248
DO - 10.1371/journal.pone.0230248
M3 - Article
C2 - 32298288
AN - SCOPUS:85083489071
SN - 1932-6203
VL - 15
JO - PloS one
JF - PloS one
IS - 4
M1 - e0230248
ER -