Abstract S5-05: Impact of pre-operative exercise on breast cancer gene expression
Authors: Ligibel JA , Irwin M , Dillon D , Barry W , Giobbie-Hurder A , Frank E , Winer EP , McTiernan A , Cornwell M , Pun M , Brown M , Jeselsohn R 
Published: March 2017

Background: Exercise is linked to a lower risk of developing and dying from breast cancer, but the biological mechanisms through which exercise could impact breast cancer are unclear. In animal models, exercise impacts tumor formation and progression, but there are few data regarding direct effects of exercise on tumor tissue in humans. The Pre-Operative Health and Body (PreHAB) Study was a randomized window of opportunity trial designed to explore the impact of exercise on molecular pathways in women with breast cancer.

Methods: Inactive women with Stage I-III breast cancer were enrolled through Dana-Farber Cancer Institute and Yale University prior to surgery. Participants were randomized 1:1 to an aerobic and strength training exercise intervention or mind body control intervention and participated in the interventions between enrollment and the time of surgery. Tumor tissue was collected at enrollment and surgery; samples were reviewed by a breast pathologist and were macrodissected to include sections of tumor with at least 10% cellularity. Capture RNA-sequencing of the transcriptome coding regions was performed using the Illumina Truseq RNA access platform.

Results: 49 women were randomized (27 exercise and 22 control). At baseline, mean age was 52.6, BMI was 30.2kg/m2 and exercise was 49 min/wk. Mean time between enrollment and surgery was 4.2 weeks. Participants in the exercise arm significantly increased exercise vs. controls (increase of 203 vs. 23 min/wk, p&lt;0.0001). Transcriptomic analysis was performed on the tumors from the pre and post intervention biopsies from 32 patients (16 exercise and 16 control). Quality Control analysis of the RNA-sequencing data showed an average read depth of 25 million reads per sample, mapping ∼79% to exonic regions. Principal Component Analysis revealed no read bias or batch effects and unsupervised clustering showed that pre- and post-operative samples clustered together by patient. Differential gene expression analysis by DEseq2 revealed a limited number of individual genes with significant changes after the intervention. KEGG pathway analysis, however, of 214 KEGG pathways using the bioconductor package GAGE (Generally Applicable Gene-Set Enrichment for Pathway Analysis) demonstrated upregulation of 13 unique pathways between the baseline biopsy and surgical excision in exercise participants and none in mind body participants (q&lt;0.1). The top ranked upregulated pathway was cytokine-cytokine receptor interactions (q=6.93E-05, set size=238 genes). Il6, CCL3 and other cytokines are among the genes upregulated in this pathway. Analysis also demonstrated downregulation of 13 unique pathways (q&lt;0.1) including cell cycle, RNA transport and DNA replication pathways, in exercise participants over the intervention period.

Conclusions: A pre-operative exercise intervention led to alterations in gene expression in tumor tissue in women with breast cancer. Validation in additional data sets and an analysis of which cellular compartments within the tumor are responsible for the changes is needed. These findings demonstrate that exercise may have a direct effect on breast tumor tissue in humans, providing new insights into the biologic mechanisms through which exercise could lower the risk of developing and dying from breast cancer.

Citation Format: Ligibel JA, Irwin M, Dillon D, Barry W, Giobbie-Hurder A, Frank E, Winer EP, McTiernan A, Cornwell M, Pun M, Brown M, Jeselsohn R. Impact of pre-operative exercise on breast cancer gene expression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S5-05.