Neoadjuvant chemotherapy (NACT) is increasingly used in breast cancer. The best proof of NACT efficacy is pathological complete response (pCR), i.e. the absence of invasive tumour on post-NACT surgical histopathology. While it is known that physical exercise can help patients to better tolerate and complete often harsh cancer treatments, it is an emerging area of research to understand if and how exercise exerts anti-tumour effects and improves oncological outcomes.

The main aim of the Neo-ACT trial is to examine if a physical exercise intervention during NACT can increase pCR rates in breast cancer. Secondary aims are residual cancer burden, radiological tumour response, patient-related outcomes (health-related quality of life, physical activity), physiological outcomes (muscle strength, cardiorespiratory fitness), cancer treatment-related toxicities (cognitive dysfunction, chemotherapy completion rates) and long-term sick leave. Furthermore, the trial will explore how physical exercise affects anti-tumoral mechanisms inherent to therapy or host by hypothesis-generating translational analyses.

712 patients with primary invasive breast cancer will be randomized to either a supervised intervention of high-intensity interval and resistance training during NACT, supported by an exercise app, or to usual care, and followed for two years. Physical activity is meticulously tracked. By offering patients active involvement, the trial contributes strongly to the concept of personalized medicine.

The Neo-ACT assesses the primary endpoint pathological complete response (pCR) and the secondary endpoints Residual Cancer Burden (RCB), objective tumour response (RECIST), all-cause, breast cancer-specific, and recurrence-free survival at 2, 5 and 10 years, health-related quality of life assessed by the EORTC QLQ-C30 and BR23 questionnaires, self-reported physical activity (Modified Godin Leisure Time Physical activity questionnaire), toxicity-related outcomes (chemotherapy completion rates, number of unplanned hospital admissions during NACT, objective cognitive dysfunction (Amsterdam Cognition Scan), cardiac toxicity and sick leave), device-measured physical activity level (Fitbit activity tracker), muscle strength (handgrip strength test and hypothetical 1-RM maximal leg muscle strength tests), and cardiorespiratory fitness (Ekblom-Bak submaximal cycle test).

Participants randomized to the exercise group will complete 120 min exercise sessions per week from initiation of NACT to surgery (approx. five months):

• Progressive home exercise program by an individualised mobile phone application, supported by local physiotherapists
• Initial exercise intensity individually tailored to each patient's fitness at baseline and rate of perceived exertion during the program and adapted if required
• Sessions will begin with a 3-minute moderate intensity (12-13 on Borg's Rate of Perceived Exertion (RPE) scale) warm-up.

Inclusion Criteria:

• Patients with primary invasive breast cancer cT1-T3 cN0-2
• Full tumour biology available before initiation of NACT
• Oral and written consent
• Age ≥ 18 years

Exclusion Criteria:

• Pregnancy or breast-feeding
• Bilateral invasive breast cancer
• The presence of musculoskeletal, neurological, respiratory, metabolic or cardiovascular conditions that may prevent safe completion of the exercise demands of the study
• Currently performing equal to or more than 150 mins of moderate to high intensity aerobic exercise and 2 sessions per week of moderate intensity resistance exercise

IPD will be available after study completion upon reasonable request submitted to the PI and with all legal and ethical requirements being fulfilled.

Study protocol, SAP and ICF available on trial homepage presently. Open access. CSR and analytic code available on request, see above.