An integrated omics approach highlights how epigenetic events can explain and predict response to neoadjuvant chemotherapy and bevacizumab in breast cancer
Fleischer, Thomas ; Haugen, Mads Haugland ; Ankill, Jørgen ; Silwal-Pandit, Laxmi ; Børresen-Dale, Anne Lise ; Hedenfalk, Ingrid LU
; Hatschek, Thomas
; Tost, Jörg
; Engebraaten, Olav
and Kristensen, Vessela N.
(2024)
In Molecular Oncology
- Abstract
Treatment with the anti-angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic data in breast cancer patients to predict response to therapy and pinpoint response-related epigenetic events. Fresh-frozen tumor biopsies taken before, during, and after treatment from human epidermal growth factor receptor 2 negative non-metastatic patients receiving neoadjuvant chemotherapy with or without bevacizumab were subjected to molecular profiling. Here, we report that DNA methylation... (More)
Treatment with the anti-angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic data in breast cancer patients to predict response to therapy and pinpoint response-related epigenetic events. Fresh-frozen tumor biopsies taken before, during, and after treatment from human epidermal growth factor receptor 2 negative non-metastatic patients receiving neoadjuvant chemotherapy with or without bevacizumab were subjected to molecular profiling. Here, we report that DNA methylation at enhancer CpGs related to cell cycle regulation can predict response to chemotherapy and bevacizumab for the estrogen receptor positive subset of patients (AUC = 0.874), and we validated this observation in an independent patient cohort with a similar treatment regimen (AUC = 0.762). Combining the DNA methylation scores with the scores from a previously published protein signature resulted in a slight increase in the prediction performance (AUC = 0.784). We also show that tumors receiving the combination treatment underwent more extensive epigenetic alterations. Finally, we performed an integrative expression–methylation quantitative trait loci analysis on alterations in DNA methylation and gene expression levels, showing that the epigenetic alterations that occur during treatment are different between responders and non-responders and that these differences may be explained by the proliferation–epithelial-to-mesenchymal transition axis through the activity of grainyhead like transcription factor 2. Using tumor purity computed from copy number data, we developed a method for estimating cancer cell-specific methylation to confirm that the association to response reflects DNA methylation in cancer cells. Taken together, these results support the potential for clinical benefit of the addition of bevacizumab to chemotherapy when administered to the correct patients.
(Less)
- author
- Fleischer, Thomas
; Haugen, Mads Haugland
; Ankill, Jørgen
; Silwal-Pandit, Laxmi
; Børresen-Dale, Anne Lise
; Hedenfalk, Ingrid
LU
; Hatschek, Thomas
; Tost, Jörg
; Engebraaten, Olav
and Kristensen, Vessela N.
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- epub
- subject
- keywords
- bevacizumab, breast cancer, chemotherapy, DNA methylation, epigenetics, multiomics
- in
- Molecular Oncology
- publisher
- Elsevier
- external identifiers
-
- scopus:85191683981
- pmid:38671580
- ISSN
- 1574-7891
- DOI
- 10.1002/1878-0261.13656
- language
- English
- LU publication?
- yes
- id
- 45e6c800-f0c8-4993-bd92-14339be9a9da
- date added to LUP
- 2024-05-15 11:57:21
- date last changed
- 2024-05-29 13:46:49
@article{45e6c800-f0c8-4993-bd92-14339be9a9da,
abstract = {{<p>Treatment with the anti-angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic data in breast cancer patients to predict response to therapy and pinpoint response-related epigenetic events. Fresh-frozen tumor biopsies taken before, during, and after treatment from human epidermal growth factor receptor 2 negative non-metastatic patients receiving neoadjuvant chemotherapy with or without bevacizumab were subjected to molecular profiling. Here, we report that DNA methylation at enhancer CpGs related to cell cycle regulation can predict response to chemotherapy and bevacizumab for the estrogen receptor positive subset of patients (AUC = 0.874), and we validated this observation in an independent patient cohort with a similar treatment regimen (AUC = 0.762). Combining the DNA methylation scores with the scores from a previously published protein signature resulted in a slight increase in the prediction performance (AUC = 0.784). We also show that tumors receiving the combination treatment underwent more extensive epigenetic alterations. Finally, we performed an integrative expression–methylation quantitative trait loci analysis on alterations in DNA methylation and gene expression levels, showing that the epigenetic alterations that occur during treatment are different between responders and non-responders and that these differences may be explained by the proliferation–epithelial-to-mesenchymal transition axis through the activity of grainyhead like transcription factor 2. Using tumor purity computed from copy number data, we developed a method for estimating cancer cell-specific methylation to confirm that the association to response reflects DNA methylation in cancer cells. Taken together, these results support the potential for clinical benefit of the addition of bevacizumab to chemotherapy when administered to the correct patients.</p>}},
author = {{Fleischer, Thomas and Haugen, Mads Haugland and Ankill, Jørgen and Silwal-Pandit, Laxmi and Børresen-Dale, Anne Lise and Hedenfalk, Ingrid and Hatschek, Thomas and Tost, Jörg and Engebraaten, Olav and Kristensen, Vessela N.}},
issn = {{1574-7891}},
keywords = {{bevacizumab; breast cancer; chemotherapy; DNA methylation; epigenetics; multiomics}},
language = {{eng}},
publisher = {{Elsevier}},
series = {{Molecular Oncology}},
title = {{An integrated omics approach highlights how epigenetic events can explain and predict response to neoadjuvant chemotherapy and bevacizumab in breast cancer}},
url = {{http://dx.doi.org/10.1002/1878-0261.13656}},
doi = {{10.1002/1878-0261.13656}},
year = {{2024}},
}