Effect of regular high-intensity interval training on response to doxorubicin/cyclophosphamide-based neoadjuvant chemotherapy

Several intervention studies have demonstrated that regular physical exercise during neoadjuvant chemotherapy (NAC) is feasible and safe, helps to maintain physical capacity, cardiopulmonary function and quality of life and may lead to improved survival. We reasoned that enrolling breast cancer (BC) patients receiving NAC into a regular exercise program provides a unique opportunity to gain deeper insight into the molecular mechanisms underlying the effects of exercise on tumour biology and response to therapy. We conducted a randomised pilot trial to assess the effect of regular high-intensity interval training (HIIT) on response to doxorubicin/cyclophosphamide-based NAC and to identify exercise-induced alterations in the tumours' gene expression profile and composition of immune tumour microenvironment in patients with locally advanced BC. 10 patients with locally advanced non-metastatic BC who were scheduled to receive NAC were enrolled in the study as HIIT/CB group. Identification of eligible patients took place at the Latvian Oncology Center, Riga East University Hospital. Inclusion criteria: previously untreated primary BC; stage IIA-B, IIIA-C (TNM: T1-4, N0-3, M0) at diagnosis; diagnosis established by core needle biopsy; age 30-65 years, prescribed doxorubicin/cyclophosphamide-based NAC. Exclusion criteria: cardiac pathologies (assessed by electrocardiogram); blood transfusion in the last six months; another oncological disease; previous chemotherapy, hormonal or X-ray treatment; participation in another clinical trial. In addition, clinical samples of 10 patients from a matched retrospective control group (Ctrl/BCP) were retrieved from the Latvian Genome Database. The study protocol was approved by the Latvian Central Medical Ethics Committee (approvals No. 4066 and 01-29.1/487). All HIIT/CB group participants underwent physical capacity tests at the Health Care and the Sports Science Research Laboratory, Latvian Academy of Sport Education before the onset of NAC and after the last course of NAC (before the BC surgery). The UNCCRI Treadmill protocol consisting of twenty-one 1-minute stages, with increments in speed and/or grade at each stage was used to obtain VO2peak data. The HIIT intervention consisted of 2 to 3 exercise sessions per week for 6 months. The HIIT session started with a 6-minute warm-up period at about 65-70% HRmax followed by 4*4-min high-intensity intervals (85%-95% of HRmax) combined with 3 min period of active recovery (55-70% of HRmax). At the beginning of the intervention, each participant underwent one supervised training session to get familiar with the HIIT protocol and received HR sensor (Polar H10) and uploaded Polar Flow application. Subsequently, HIIT participants individually completed home-based training sessions and shared the sessions' data with the investigators. Once the NAC was completed, patients underwent BC surgery and tumour and adjacent normal tissue specimens were collected from the surgical material. Tissue specimens were macroscopically dissected by a histopathologist during surgery and stored in RNALater (Applied Biosystems, USA) at -20°C until processing. The “tumour bed” was marked before the NAC with 3-millimetre titanium metal clips to allow precise identification of the tumour site after the NAC.