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Breast Cancer Research
Published in: Breast Cancer Research 1/2022

Open Access 01-12-2022 | Breast Cancer | Research

DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival

Authors: Christine Aaserød Pedersen, Maria Dung Cao, Thomas Fleischer, Morten B. Rye, Stian Knappskog, Hans Petter Eikesdal, Per Eystein Lønning, Jörg Tost, Vessela N. Kristensen, May-Britt Tessem, Guro F. Giskeødegård, Tone F. Bathen

Published in: Breast Cancer Research | Issue 1/2022

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Abstract

Background

Locally advanced breast cancer is a heterogeneous disease with respect to response to neoadjuvant chemotherapy (NACT) and survival. It is currently not possible to accurately predict who will benefit from the specific types of NACT. DNA methylation is an epigenetic mechanism known to play an important role in regulating gene expression and may serve as a biomarker for treatment response and survival. We investigated the potential role of DNA methylation as a prognostic marker for long-term survival (> 5 years) after NACT in breast cancer.

Methods

DNA methylation profiles of pre-treatment (n = 55) and post-treatment (n = 75) biopsies from 83 women with locally advanced breast cancer were investigated using the Illumina HumanMethylation450 BeadChip. The patients received neoadjuvant treatment with epirubicin and/or paclitaxel. Linear mixed models were used to associate DNA methylation to treatment response and survival based on clinical response to NACT (partial response or stable disease) and 5-year survival, respectively. LASSO regression was performed to identify a risk score based on the statistically significant methylation sites and Kaplan–Meier curve analysis was used to estimate survival probabilities using ten years of survival follow-up data. The risk score developed in our discovery cohort was validated in an independent validation cohort consisting of paired pre-treatment and post-treatment biopsies from 85 women with locally advanced breast cancer. Patients included in the validation cohort were treated with either doxorubicin or 5-FU and mitomycin NACT.

Results

DNA methylation patterns changed from before to after NACT in 5-year survivors, while no significant changes were observed in non-survivors or related to treatment response. DNA methylation changes included an overall loss of methylation at CpG islands and gain of methylation in non-CpG islands, and these changes affected genes linked to transcription factor activity, cell adhesion and immune functions. A risk score was developed based on four methylation sites which successfully predicted long-term survival in our cohort (p = 0.0034) and in an independent validation cohort (p = 0.049).

Conclusion

Our results demonstrate that DNA methylation patterns in breast tumors change in response to NACT. These changes in DNA methylation show potential as prognostic biomarkers for breast cancer survival.
Appendix
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Metadata
Title
DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival
Authors
Christine Aaserød Pedersen
Maria Dung Cao
Thomas Fleischer
Morten B. Rye
Stian Knappskog
Hans Petter Eikesdal
Per Eystein Lønning
Jörg Tost
Vessela N. Kristensen
May-Britt Tessem
Guro F. Giskeødegård
Tone F. Bathen
Publication date
01-12-2022
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2022
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-022-01537-9

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