The effect of exercise alone and in combination with systemic therapy on breast cancer

Abstract

Exercise following a breast cancer diagnosis is known to improve outcomes. In multiple pre-clinical cancer models, exercise alone has shown to inhibit tumour growth. Some of the suggested mechanisms for this benefit include exercise-induced recruitment and activation of anti-cancer immune cells, release of myokines and alterations in intrinsic metabolic cellular pathways. Exercise has also shown to improve tumour blood flow, which may translate to improved chemotherapy delivery to otherwise hypo-perfused tumour regions. Whether exercise acts an adjunct to our current systemic therapies in improving breast cancer outcomes is a question that remains unanswered. The overall hypothesis of this thesis is that exercise suppresses breast cancer tumour growth. We confirmed this in two different in vivo models of breast cancer. Given our positive results, we proceeded to test a series of questions necessary to move our findings into clinical practice; 1. Does exercise act as an adjunct to systemic breast cancer therapy, 2. Does exercise shift the tumour immune microenvironment (TIME) to an immunosuppressive phenotype, 3. Is it feasible to exercise immediately after and during neoadjuvant chemotherapy for early stage breast cancer. We tested the combination of exercise and doxorubicin chemotherapy in two different in vivo models of breast cancer, and found no additional benefit on tumour growth with the combination treatment compared to doxorubicin alone. We did find an exercise-induced shift in the TIME to include immune cells with cytotoxic properties, associated with tumour growth suppression in one in vivo model of breast cancer. Concordantly, where exercise showed to be ineffective in suppressing breast cancer growth in vivo, no clear shift in the TIME was observed. Our clinical study confirmed that exercising immediately after, and during neoadjuvant chemotherapy using a partially supervised exercise program was feasible, safe and well received by patients. We showed that our exercise intervention maintained quality of life, improved muscle strength and reduced sedentary behaviour. Exploratory findings from our study also suggest that exercise acutely may abrogate immunosuppressive effects of chemotherapy on circulating immune cells. Due to the methodological challenges and complexities involved with conducting exercise-studies in in vivo models, we propose that future studies interrogating the effects of exercise on breast cancer focus on clinical studies in the neoadjuvant setting in order to better understand the underlying mechanisms for the benefits already observed with exercise after a breast cancer diagnosis.