Multimodal lifestyle intervention during neoadjuvant chemotherapy in patients with early breast cancer as a strategy to improve treatment response: Protocol of the DIANA randomized clinical trial

Breast cancer (BC) represents a major global health concern. Lifestyle factors influence both prevention and prognosis, but evidence on their impact on oncological response to BC treatment remains limited. We present the protocol of a randomized clinical trial designed to assess whether a multimodal intervention-combining physical exercise, psychological support, and nutritional counseling during neoadjuvant chemotherapy (NAC)-could improve pathological response, measured by the Residual Cancer Burden (RCB) index, in women with early BC. A total of 216 women will be randomized (1:1) to control (standard of care, n = 108) or intervention (n = 108). The intervention consists of a supervised, individualized multimodal prehabilitation program that combines physical exercise, psychotherapy, and nutritional support delivered throughout NAC (4-6 months). Tumor pathology, including microenvironment analysis, will be assessed before NAC and after surgery. Data will be collected at baseline, preoperatively, and at 1 and 12 months postoperatively. Long-term oncological outcomes will be reported annually for a minimum of 5 years, with the intention to extend to 10 years. We hypothesize that the intervention group will show higher pathological response rates than controls, with a targeted 20-percentage point improvement in the rate of favorable RCB response (fRCB, defined as RCB class 0 or I), from approximately 40% in the control group to 60% in the intervention group. Additional expected benefits include improved tolerance to NAC, better quality of life, enhanced postoperative recovery, and optimized physical, psychological, and nutritional status. Differences in tumor microenvironment profiles are also anticipated. Ethics approval was granted by the Ethics Committee of the Hospital Clínic de Barcelona (HCB/2023/1036, 26 March 2024). Written informed consent will be obtained from all participants. The DIANA trial will provide evidence on multimodal prehabilitation as a non-invasive, cost-efficient strategy to improve both health and oncological outcomes in BC. Findings will be disseminated via peer-reviewed publications, conference presentations, and patient groups. Trial Registration Number: NCT07107594.