TY - JOUR
T1 - Response to Preoperative Radiation Therapy in Relation to Gene Expression Patterns in Breast Cancer Patients
AU - Bosma, Sophie C J
AU - Hoogstraat, Marlous
AU - van der Leij, Femke
AU - de Maaker, Michiel
AU - Wesseling, Jelle
AU - Lips, Esther
AU - Loo, Claudette E
AU - Rutgers, Emiel J
AU - Elkhuizen, Paula H M
AU - Bartelink, Harry
AU - van de Vijver, Marc J
N1 - Funding Information:
This study was financially supported by the Dutch Cancer Society-KWF grant NKI 2009-4389 and the Cancer Society in Stockholm.
Publisher Copyright:
© 2019 Elsevier Inc.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - PURPOSE: We aimed to study radiation-induced gene expression changes and to identify differences in gene expression between patients with and without response to radiation therapy (RT) for invasive breast cancer with the purpose of exploring whether a predictive signature could be developed. Such a signature could assist in optimizing individualized locoregional treatment.METHODS AND MATERIALS: RNA-seq using next-generation sequencing was performed on fresh frozen samples from pretreatment biopsies and post-RT surgery specimens from patients with low-risk breast cancer treated within the multicenter preoperative accelerated partial breast irradiation trial. Patients were treated with preoperative RT (10 × 4 Gy in 10 days or 5 × 6 Gy in 5 days) and a lumpectomy 6 weeks thereafter. The response of the tumor to RT was evaluated by pathologic assessment. To analyze the gene expression data, unsupervised and supervised clustering was performed. Gene expression profiles were compared between biopsies of responders and nonresponders and between samples before and after RT.RESULTS: Ninety-four samples from 77 patients were analyzed: 68 pretreatment biopsies and 26 post-RT surgery specimens. Six patients had a (near) complete pathologic response, 3 patients had a good response, 32 patients had a partial response, and 22 patients had no or very limited response. Comparing patients with and without response to RT, 25 genes were significantly differentially expressed and were not linked to a pathway. Comparison of samples before and after RT identified significant changes in gene expression. Genes involved in p53 signaling, TNFA1 signaling, apoptosis, epithelial mesenchymal transition, and inflammatory response were upregulated. Genes involved in mitotic spindle, G2M checkpoint, and E2F targets were downregulated.CONCLUSIONS: Radiation-induced gene expression changes mainly involved p53 signaling, cell cycle regulation, DNA repair, and inflammatory response. No clinically significant differences could be identified in gene expression between patients with and without response to RT.
AB - PURPOSE: We aimed to study radiation-induced gene expression changes and to identify differences in gene expression between patients with and without response to radiation therapy (RT) for invasive breast cancer with the purpose of exploring whether a predictive signature could be developed. Such a signature could assist in optimizing individualized locoregional treatment.METHODS AND MATERIALS: RNA-seq using next-generation sequencing was performed on fresh frozen samples from pretreatment biopsies and post-RT surgery specimens from patients with low-risk breast cancer treated within the multicenter preoperative accelerated partial breast irradiation trial. Patients were treated with preoperative RT (10 × 4 Gy in 10 days or 5 × 6 Gy in 5 days) and a lumpectomy 6 weeks thereafter. The response of the tumor to RT was evaluated by pathologic assessment. To analyze the gene expression data, unsupervised and supervised clustering was performed. Gene expression profiles were compared between biopsies of responders and nonresponders and between samples before and after RT.RESULTS: Ninety-four samples from 77 patients were analyzed: 68 pretreatment biopsies and 26 post-RT surgery specimens. Six patients had a (near) complete pathologic response, 3 patients had a good response, 32 patients had a partial response, and 22 patients had no or very limited response. Comparing patients with and without response to RT, 25 genes were significantly differentially expressed and were not linked to a pathway. Comparison of samples before and after RT identified significant changes in gene expression. Genes involved in p53 signaling, TNFA1 signaling, apoptosis, epithelial mesenchymal transition, and inflammatory response were upregulated. Genes involved in mitotic spindle, G2M checkpoint, and E2F targets were downregulated.CONCLUSIONS: Radiation-induced gene expression changes mainly involved p53 signaling, cell cycle regulation, DNA repair, and inflammatory response. No clinically significant differences could be identified in gene expression between patients with and without response to RT.
KW - Biopsy
KW - Breast Neoplasms/genetics
KW - Carcinoma, Ductal, Breast/genetics
KW - Clinical Trials, Phase II as Topic/statistics & numerical data
KW - Female
KW - Frozen Sections
KW - Gene Expression Profiling/methods
KW - Gene Expression Regulation, Neoplastic/radiation effects
KW - Humans
KW - Mastectomy
KW - Multicenter Studies as Topic/statistics & numerical data
KW - Neoadjuvant Therapy
KW - Precision Medicine
KW - RNA, Messenger/analysis
KW - RNA, Neoplasm/analysis
KW - Radiation Tolerance/genetics
KW - Sequence Analysis, RNA
KW - Transcriptome
KW - Treatment Outcome
UR - http://www.scopus.com/inward/record.url?scp=85073014506&partnerID=8YFLogxK
U2 - 10.1016/j.ijrobp.2019.09.002
DO - 10.1016/j.ijrobp.2019.09.002
M3 - Article
C2 - 31525407
SN - 0360-3016
VL - 106
SP - 174
EP - 181
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 1
ER -