Response to Preoperative Radiation Therapy in Relation to Gene Expression Patterns in Breast Cancer Patients

• Published in: International journal of radiation oncology, biology, physics Vol. 106; no. 1; pp. 174 - 181
• Main Authors: Bosma, Sophie C.J., Hoogstraat, Marlous, van der Leij, Femke, de Maaker, Michiel, Wesseling, Jelle, Lips, Esther, Loo, Claudette E., Rutgers, Emiel J., Elkhuizen, Paula H.M., Bartelink, Harry, van de Vijver, Marc J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2020
• Subjects: Biopsy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Breast Neoplasms - radiotherapy; Breast Neoplasms - surgery; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - pathology; Carcinoma, Ductal, Breast - radiotherapy; Carcinoma, Ductal, Breast - surgery; Clinical Trials, Phase II as Topic - statistics & numerical data; Female; Frozen Sections; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic - radiation effects; Humans; Mastectomy; Multicenter Studies as Topic - statistics & numerical data; Neoadjuvant Therapy; Precision Medicine; Radiation Tolerance - genetics; RNA, Messenger - analysis; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Neoplasm - analysis; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Sequence Analysis, RNA; Transcriptome; Treatment Outcome
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/j.ijrobp.2019.09.002

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.
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.
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.
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.