Pre-operative Exercise During Neoadjuvant Chemotherapy in Patients With Breast Cancer (Neo-Train)

Neo-Train: Pre-operative Exercise During Neoadjuvant Chemotherapy in Patients With Breast Cancer - a Randomized Controlled Trial

Danish Cancer Society, University Hospital Southampton NHS Foundation Trust, Region Zealand, Naestved, Slagelse and Ringsted Hospitals

The Neo-Train study is a randomized controlled trial investigating the effects of supervised pre-operative aerobic and resistance exercise in patients with breast cancer during neoadjuvant chemotherapy.

The long neoadjuvant chemotherapy period in patients with breast cancer brings a time window of opportunity to investigate the potential of pre-operative exercise to increase treatment efficacy with improved tumour regression. A possible improvement in chemotherapy completion, lift in physical function, alleviated toxicities as well as changes in biological markers can also be investigated. 120 patients with newly diagnosed breast cancer who start neoadjuvant chemotherapy will be randomized to the intervention arm (n=60) and control arm (n=60). Participants in the intervention arm will be prescribed a prehabilitation program consisting of thrice weekly combined supervised aerobic and resistance exercise during the neoadjuvant chemotherapy period. Participants will be screened for psychological distress four times and in case of moderate-severe distress be advised to visit the local Cancer Society Support Center where participants will be assessed and offered free services based on their psychosocial needs and available offers. Participants in the control arm will receive usual care. Outcomes will be measured at baseline (diagnosis), during neoadjuvant chemotherapy, during the week before breast surgery, at breast surgery and at 3 months follow up. The participants will receive the recommended neoadjuvant chemotherapy regimens in Denmark - currently up to 24 weeks. With expected chemotherapy dose delays, the time of breast surgery is expected to be within 30 weeks from baseline. The treatment plans will be individually modified based on tumour response and expected side effects to treatment. A subgroup of participants may change neoadjuvant chemotherapy regimen and be referred to breast surgery early. In these participants, the last measurement during chemotherapy will be used, and the 3 months follow up measurement will still be scheduled at 3 months after breast surgery. The study procedures will be pre-tested in a pilot study with 6 patients who will all receive the prehabilitation program.

Due to the nature of the intervention, it is not possible to blind the participants, care providers or investigators. However, the outcome assessors of the primary endpoint (MRI assessment) will not be informed of the patients' allocation. Further, the statistician and data manager are blinded as the group allocation will be coded.

The prehabilitation program includes combined high-intensity interval training on a cycle ergometer and machine-based resistance exercise of large muscle groups supervised by a physiotherapist. Exercise sessions will take place in physiotherapy departments at local hospitals or in municipality rehabilitation centres 3 times a week during the neoadjuvant chemotherapy period and ending in the week before breast surgery (maximum estimated 29 weeks depending on number of chemotherapy cycles, dose delays and time of breast surgery). Participants will be screened for psychological distress four times and in case of moderate-severe distress be advised to visit the local Cancer Society Support Center where participants will be assessed and offered free services based on their psychosocial needs and available offers. Participation will be monitored.

Sequential MRI scans follow the individual treatment plan in a period of up to 30 weeks from baseline (diagnostic MRI before start of neoadjuvant chemotherapy) to MRI performed by the end of the course of neoadjuvant chemotherapy before breast surgery.

Relative dose intensity in percentage defined as the ratio of received mg/m2 per week compared to planned mg/m2 per week according to standard guidelines.

Changes in VO2 max estimated from maximum power output from baseline measured by a progressive cycle ergometer test (watt max test).

Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery

Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery

Changes in hand grip strength from baseline measured by hand-held dynamometer in kilograms. Maximum kilograms obtained of 3 measurements on each hand.

Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery

Changes in self-reported health-related quality of life from baseline assessed on the Functional Assessment of Cancer Therapy - Breast Cancer (FACT-B).

Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery

Changes in self-reported general anxiety from baseline assessed on the Generalised Anxiety Disorder 7-item (GAD-7).

Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery

Changes in self-reported depression from baseline assessed on the Patient Health Questionnaire-9 (PHQ-9).

Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery

Changes in self-reported psychological distress from baseline assessed on the Distress Thermometer (DT).

Baseline, week 13 during neoadjuvant chemotherapy, during the week before breast surgery, 3 months after breast surgery

Frequency of participants referred to municipal rehabilitation, participation and types of activities attended identified from a self-reported questionnaire.

Sequential clinical examinations of the breast following the individual treatment plan in a period of up to 30 weeks from baseline to time of breast surgery

Description of tumour infiltrating lymphocyte population (percentage of cells) evaluated by a pathologist from the tumour surgical specimen at breast surgery.

Description of tumour vascularity density and structure evaluated by a pathologist from the tumour surgical specimen at breast surgery.

Changes in cell free DNA from blood samples. Furthermore, circulating tumour DNA will be investigated if possible.

Changes in glucose, hba1c, zinc, magnesium, phosphate and C reactive protein (CRP) levels from blood samples.

In vitro cell proliferation response with sera collected from blood samples before and after exercise.

Approximately between week 1-4 during neoadjuvant chemotherapy and within 6 weeks before breast surgery

Inclusion Criteria: Patients newly diagnosed with histologically verified breast cancer and scheduled for neoadjuvant chemotherapy Female gender Aged ≥ 18 years old Signed informed consent Exclusion Criteria: Patients ineligible for or who have declined to receive neoadjuvant chemotherapy Contraindications to magnetic resonance imaging (MRI) Physical or cognitive disabilities preventing exercise or physical testing Inability to read and understand Danish Based on clinical judgement, the physician assesses that the patient is not suitable for inclusion