Randomized pilot study of an individualized multimodal exercise, nutrition, and behavior intervention in breast cancer patients treated with ovarian function suppression: protocol proposal for The OvS Breast ENBI Project

Introduction: Breast cancer (BC) is the most common malignancy among women in Spain and worldwide. Ovarian function suppression (OFS) is recommended as an adjuvant strategy for high-risk hormone receptor (HR)-positive premenopausal BC patients. However, OFS is associated with unfavorable changes in body composition, weight gain, and adverse cardiorespiratory and emotional effects. Multimodal, individualized interventions integrating nutrition, exercise, and psycho-oncological support have demonstrated safety and efficacy in promoting healthy body composition, weight control, and cardiorespiratory fitness (CRF). This study aims to evaluate the impact of a personalized multicomponent intervention in premenopausal BC patients receiving adjuvant OFS.

Methods and analysis: We present the ENBI project study protocol proposal as a single-center, open-label, 2:1 randomized pilot study designed to assess the effects of a 12-week individualized program (nutrition, exercise, and psycho-oncological support) versus the World Health Organization (WHO) healthy lifestyle recommendations. Participants are premenopausal HR-positive BC patients undergoing adjuvant OFS. The study duration is estimated at 15 months. The primary endpoint is weight and body composition change, measured via scale and bioelectrical impedance analysis at baseline, post-intervention, and at 6- and 12-month follow-up. Secondary outcomes include CRF, cardiac variability, muscle strength, physical function, laboratory parameters, patient-reported outcomes (quality of life, fatigue, physical activity), systemic therapy-associated adverse events, and nutritional and psychological status. Exploratory outcomes include inflammatory markers (C-reactive protein, tumor necrosis factor alpha, adiponectin) and oncostatin-M. Due to the lack of prior data, the sample size was pragmatically set based on the Hospital General Universitario Gregorio Marañón (HGUGM) Tumor Board registry, with an estimated recruitment of 30 patients.

Ethics and dissemination: The HGUGM Drug Research Ethics Committee (CEIm) has approved the study protocol. Results will be presented at national and international conferences and published in a peer-reviewed journal.

Trial registration number: NCT06727487

Introduction

Breast cancer (BC) is the most common and incident cancer among Spanish women. Hormone receptor (HR) - positive BC is the most prevalent subtype, accounting for approximately 75% of all BC cases (1).

Ovarian function suppression (OFS) combined with endocrine therapy (gonadotropin-releasing hormone agonists (GnRHa) administered along with tamoxifen (TAM) or aromatase inhibitors (AI)) have demonstrated a benefit in terms of relapse-free survival (RFS) and overall survival (OS) in premenopausal women diagnosed with HR-positive BC, particularly among younger patients with high-risk pathological features (2–4). Accordingly, international clinical guidelines recommend OFS in such clinical scenarios (5, 6).

However, relevant cardiorespiratory, metabolic, sexual, as well as emotional adverse events have been associated with OFS (2, 7): Early body composition changes such as fat mass and weight increases (8, 9) have been directly associated to higher BC relapse risk (10, 11) along with a reduced adherence to endocrine treatment (12).

Body fat gain, along with muscle mass loss, results in a proinflammatory (13) and a dysfunctional immune system, which has been linked to cardiovascular disease development and poor outcomes in cancer patients (14–16). In addition, chronic inflammation has been linked to cancer development (17). Within this framework, it should be noted that skeletal muscle acts as an endocrine organ whose contraction releases myokines (cytokines or peptides) that can exert an anti-inflammatory action (18).

Current evidence suggests that multimodal, individualized interventions combining nutrition, exercise, and psycho-oncological support tailored to physiological needs, baseline physical condition and potential adverse events are safe (19). This integrative approach has been shown to be effective in achieving a healthy weight and body composition in BC patients (20, 21), may contribute to improve immune function (22, 23) and enhance cardiorespiratory fitness (CRF) leading to a positive impact on quality of life (QoL) (20, 23).

On the other hand, securing high patient adherence to these programs is critical, and, in this context, psycho-oncological support and behavioral interventions would be able to stimulate lifestyle changes in BC patients and improve adherence rates (24, 25).

To date, there is no consensus on optimal exercise prescription or nutritional strategies in premenopausal BC patients undergoing OFS. Therefore, we consider that tailored interventions to patients´ specific characteristics and factors influencing adherence remain essential. This pilot study evaluates the feasibility and preliminary effects of a personalized multimodal program (nutrition, exercise, and psycho-oncology) for premenopausal BC patients receiving adjuvant OFS.

Methods and analysis

Main outcomes

The primary outcome of the study is to evaluate the impact of the combined intervention on weight and body composition. Secondary outcomes aim to evaluate the impact of the combined intervention program on exercise capacity, nutritional status, psychological outcomes, and treatment-related side effects.

Study design

This is a proposed study protocol of a single-center, open-label, 2:1 randomized pilot trial (ClinicalTrials.gov: NCT06727487). Premenopausal HR-positive BC patients undergoing adjuvant OFS treatment will be randomized to receive either a 12-week individualized exercise, nutritional and psycho-oncological intervention (intervention group) or WHO healthy lifestyle recommendations (control group). Cross-over is allowed for patients in the control group after the final follow-up (Figure 1). See Standard Protocol Items Recommendations for Interventional Trials (SPIRIT) checklist at Supplementary Appendix 1.

Figure 1

Figure 1. ENBI study design scheme. Patients are randomly assigned to a 12 week-intervention arm (2-day per week exercise training session, 3 one-to-one nutritional intervention sessions and 3 group psycho-oncological support sessions) or control arm.

Randomization and masking

An independent researcher will generate the allocation sequence using a computer-based randomization program and a concealed allocation list. No stratification factors are applied due to the pilot nature of the study. Study oncologists at HGUGM will enroll participants and ensure that all inclusion criteria are fulfilled and no exclusion criteria are present. The group assignment will not be revealed to participants until enrollment is confirmed.

This is an open-label trial; no blinding is applied to participants, providers, or outcome assessors.

Study setting and participants

The trial is conducted at Hospital General Universitario Gregorio Marañón (HGUGM), in collaboration with Ejercicio y Cáncer Center and Universidad Pontificia Comillas.

Eligible patients should meet the following inclusion and exclusion criteria:

Inclusion criteria

● At least 18 and up to 45 years of age at the time of consent.

● Histologically confirmed HR-positive stage I to III invasive BC.

● Premenopausal status is clinically defined as a patient who maintains menstruation prior to chemotherapy initiation if he has taken place and/or regular menstruation at the time of consent.

● Completed locoregional treatment (surgery and radiotherapy).

● Ongoing adjuvant treatment, including OFS drugs, is expected to be maintained for at least 4 months at the time of consent.

● Functional status by the Eastern Cooperative Oncology Group (ECOG) scale 0-1.

● Ability to understand and give informed consent (IC).

● Exclusion criteria

● Any medical contraindication to exercise practice.

● Any American Thoracic Society (ATS) contraindications for cardiopulmonary exercise testing (26).

● Active metastatic BC or other concurrent cancer diagnosis at the time of consent.

● Pregnant or breastfeeding women.

● Alcohol or other drug abuse (excluding smoking) is defined as a pattern of usual consumption that results in physical, mental, or social functioning impairment.

● Any condition that makes the patient ineligible is based on the investigator’s criteria.

Intervention

This study is expected to run for 1 year and 3 months: Study intervention has a duration of 12 weeks, and the follow-up period will last 12 months from the end of the intervention period.

Patients allocated to the control group will receive standard WHO lifestyle guidance and virtual materials for BC survivors. Patients assigned to the multidisciplinary intervention program will also be provided with the same virtual material and will follow a 12-week combined intervention program (see TIDieR guide recommendations for each intervention at Supplementary Appendix 2):

● A combined 2-day per week exercise training session guided by an exercise physiologist specialized in oncology: It will include cardiovascular exercise planned at 55-100% of Heart Rate Reserve (HRR) which will be controlled by pulsometer and physical condition-adapted strength exercise planned at 40-70% of One-repetition maximum (1 RM) estimated from the 5-RM test using the Reynolds equation.). Exercise intensity will also be assessed through the Borg perception of effort scale (27). Each session incorporated neuromotors, strength, and cardiovascular exercises, beginning with low-intensity activities and progressively increasing in intensity and difficulty every three weeks (by increments of 5%). Intensity was increased only if participants were capable of achieving the prescribed level; otherwise, the workload was maintained and adapted in the following session. All variables related to adherence and safety—including attendance, adaptations in intensity or activities, and dropouts—were systematically recorded.

● Three one-to-one nutritional intervention sessions guided by a cancer expert nutritionist: Nutritional behavior will be evaluated to stablish effective methods to achieve healthier diet habits.

● Three group psycho-oncological support sessions: Emotional status and motivation will be assessed; the main objective of this intervention consists of stimulating motivation to change lifestyle habits toward healthier ones and increasing adherence to them (28).

To promote participants’ retention, regular contact and reminders will be used. If a participant discontinues the intervention, efforts will be made to collect primary outcome data at scheduled timepoints.

Efficacy assessment

The primary endpoint is to evaluate the impact of the combined intervention on weight and body composition. This endpoint will be assessed by the following variables: weight, height, body mass index (IMC), waist and hip circumferences, waist-to-hip ratio (WHR), fat mass, lean mass, and extracellular water, which will be obtained with Tanita BC-601 Gold weight scale and bioelectrical impedance analysis, as well as a measuring tape.

The secondary endpoints include evaluating the impact of combined intervention on 1) CRF estimated by Bruce test and maximum oxygen uptake (VO2max), 2) cardiac variability assessed by resting and maximal heart rate (HR) (29), 3) endurance performance measured by capillary lactate levels at rest, maximum effort and two minutes after maximum effort (29), 4) muscle strength evaluated by upper body dynamometry and five-maximal repetition text in shoulder press and squat, 5) physical function assessed by 30-second sit-to-stand test and 6-minute walking test, and 6) potentially modifiable laboratory parameters such as complete blood count, glucose levels, complete liver and renal function panels, electrolyte concentrations, protein and albumin levels, complete lipid profile and thyroid function.

Patient reported outcomes (PROs) are also considered secondary endpoints. They will be assessed and collected using validated questionnaires: 1) EuroQoL-5D (30) (QoL), 2) FACIT-Fatigue (31) (fatigue), 3) International Physical Activity Questionnaire (32) (IPAQ) (physical activity level), 4) Rosenberg self-esteem scale (33) (self-esteem), 5) Hospital Anxiety and Depression Scale (34) (HADS) (anxiety and depression levels).

Concerning systemic therapy-associated adverse events, investigators will evaluate and grade them according to CTCAE version 5 as secondary endpoints (lymphedema, peripheral neuropathy, arthralgias, irritability, insomnia, vaginal dryness, decreased libido, hot flashes).

Finally, nutritional and psychological status are also included as secondary endpoints. Nutritional status will be assessed by a 3-day nutritional record (27, 35), PREDIMED Mediterranean Diet Adherence Score (36) and compliance with WCRF/AICR cancer prevention recommendations (37, 38). Positive and negative affect scale (PANAS) (39), transtheoretical model of physical activity change questionnaire (40, 41) and MOS social support survey (42, 43) will serve to evaluate psychological status.

Primary and secondary endpoints will be assessed immediately before the 12-week intervention period and at the end of it. They will be also evaluated at 6- and 12-months follow up timepoints (see Figure 2 study schedule).

Figure 2

Figure 2. Schedule for patient enrolment, combined intervention, and assessment of the ENBI study.

Biomarker study

The biomarker test proposed for this study aims to evaluate the potential impact of the combined intervention on pro-inflammatory markers (C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α)), anti-inflammatory markers (adiponectin (13)) and oncostatin-M (multifunctional myokine that has been related to apoptosis stimulation in BC cell lines (44)).

Study schedule

Assessments and enrollment schedule are summarized in Figure 2. We define week 1 to 3 as the moment in which patients are enrolled and demographic information is collected. Initial and final assessments take place the week before and after the 12-week intervention period (week 4 and 17), respectively. Blood for secondary endpoints and biomarker analysis is collected on week 4 and 17. On week 40 and 64, 6 and 12 months after the 12-week intervention respectively, a new general assessment (physical, nutritional and psycho-oncological evaluation) along with blood collection for secondary endpoints take place.

Statistical analysis

Given the pilot nature of this randomized study, a formal sample size calculation was not performed. The absence of prior empirical data precludes the estimation of an adequate sample size based on a predefined primary endpoint or an anticipated effect size between study arms. Instead, the sample size was determined pragmatically, with the primary aim of assessing feasibility and generating preliminary data to inform future adequately powered trials. Therefore, the sample size has been considered based on HGUGM Tumor Board patient registry with a total recruitment estimation of 30 HR-positive BC patients under 45 years old undergoing adjuvant treatment including OFS drugs expected to be maintained for at least 4 months at the time of study inclusion.

Data will be analyzed using Stata version 15 (StataCorp. 2017. Stata Statistical Software: Release 15. College Station, TX: StataCorp LLC) and SPSS Version 18 (IBM Corp. Released 2021. IBM SPSS Statistics for Windows, Version 29.0. Armonk, NY: IBM Corp).

Descriptive statistics will be generated for all clinical characteristics and outcome measures as appropriate.

The Kruskal-Wallis test for primary endpoints will assess between-groups range difference adjusted to initial values. The primary analysis will follow the intention-to-treat principle. If feasible, missing data will be addressed using appropriate imputation methods, such as multiple imputations. A multiple regression model will be performed to analyze the intervention program’s impact on body composition changes and weight. A nonparametric Kruskal-Wallis test for secondary endpoints and biomarker analysis will also evaluate between-arms range differences adjusted to initial values.

Data management

Patient information will be handled in accordance with the Organic Law 3/2018, of December 5, on Personal Data Protection and guarantee of digital rights and the Regulation (EU) 2016/679 of the European Parliament and Council of 27^th April 2016 on Data Protection. Patient data will be handled pseudonymized, where included patients receive an alphanumeric code; only study investigators have access to patient identification and the final dataset.

HGUGM and Ejercicio y Cáncer center will conduct patient registration and codification, randomization, data collection, cleaning and monitoring electronically. No Data Monitoring Committee has been established due to the pilot nature of the study, but internal monitoring will ensure data quality. All data collected during the study will be securely stored and anonymized to prevent identification by third parties. PROs data will be collected directly from patients through electronic devices (smart-phones, tablets or personal computers). Individual records (informed consent, medical history records, laboratory data, etc.) will be securely maintained at HGUGM.

Strengths and limitations of this study

This is a study with a comprehensive approach which integrates nutrition, exercise, and psycho-oncological support and provides a holistic intervention that addresses multiple aspects of patients’ health. The study’s individual care for each participant’s specific needs, would potentially enhance effectiveness and adherence to the intervention. The trial includes a wide range of primary, secondary, and exploratory outcomes and incorporates detailed measures, allowing for a thorough assessment of the intervention’s impact on various health parameters.

This study offers an opportunity to investigate cardiorespiratory and metabolic health in a BC patient population of increasing importance with long-term survival expectations, while also examining the influence of physiological characteristics and overall health status on responses to multimodal strategies incorporating exercise, nutrition, and psycho-oncological intervention.

To the best of our knowledge, this is the first study to investigate the feasibility and preliminary effects of an integrative approach combining individualized physical exercise, nutrition, and psycho-oncological support interventions in a highly specific subgroup of young breast cancer patients undergoing ovarian function suppression.

There are some limitations, such as a single-center design, which may limit the generalizability of the findings to other settings or populations. Moreover, the pragmatic pilot sample size may restrict the statistical power and robustness of the conclusions drawn from the study.

Identification of potential sources of bias

Exercise programs trials for cancer patients can have biases that may affect their effectiveness and accessibility. Some potential biases that we identify are described below:

Exercise programs studies often target specific age and gender groups, potentially excluding younger or older patients who might benefit from tailored interventions and even leading to gender-specific findings that may not be universally applicable; furthermore, research frequently focuses on certain frequent cancer types, such as breast or prostate cancer, which may not address the needs of patients with less common cancers. Unfortunately, considering the nature of this study, designed to assess the potential benefits of a multimodal approach in a specific subgroup of BC patients, we acknowledge that sex, age, and gender biases are intrinsic to this research and, as such, are not subject to control.

Due to the limited ethnic and racial diversity in our country and community, this type of study may not adequately capture the heterogeneity of wider populations, which could restrict the external validity of the findings.

Addressing these biases will require more inclusive research approaches to ensure the generalizability and equitable benefit of exercise programs for all cancer patients.

Author contributions

BH: Methodology, Conceptualization, Supervision, Investigation, Software, Funding acquisition, Writing – review & editing, Project administration, Visualization, Writing – original draft, Formal analysis, Validation, Resources, Data curation. MC: Conceptualization, Writing – review & editing, Data curation, Investigation, Writing – original draft, Project administration, Validation. CS: Writing – original draft, Validation, Conceptualization, Writing – review & editing, Investigation. BA: Project administration, Writing – original draft, Methodology, Investigation, Conceptualization, Writing – review & editing. MG-OC: Supervision, Writing – review & editing, Conceptualization, Investigation, Writing – original draft. MM: Writing – original draft, Funding acquisition, Resources, Visualization, Project administration, Supervision, Writing – review & editing, Methodology, Conceptualization. LV: Methodology, Conceptualization, Investigation, Writing – original draft, Writing – review & editing. SL-T: Writing – review & editing, Writing – original draft, Validation, Conceptualization, Methodology, Investigation. YJ: Writing – review & editing, Methodology, Investigation, Writing – original draft, Conceptualization, Validation. IED-G: Investigation, Writing – review & editing, Writing – original draft, Validation, Methodology. PJ: Validation, Methodology, Conceptualization, Investigation, Writing – review & editing, Writing – original draft. MMJ: Methodology, Validation, Visualization, Supervision, Conceptualization, Writing – original draft, Writing – review & editing. TM: Conceptualization, Investigation, Validation, Writing – review & editing, Writing – original draft, Methodology. MMB: Resources, Visualization, Writing – original draft, Data curation, Formal analysis, Validation, Writing – review & editing, Conceptualization, Software, Methodology. JT: Funding acquisition, Resources, Conceptualization, Validation, Project administration, Writing – review & editing, Visualization, Supervision, Writing – original draft, Methodology, Formal analysis. SC: Investigation, Resources, Formal analysis, Visualization, Software, Writing – review & editing, Funding acquisition, Data curation, Validation, Methodology, Project administration, Conceptualization, Writing – original draft, Supervision.

Funding

The author(s) declare financial support was received for the research, and/or publication of this article. This study has received external funding by Daiichi Sankyo España, S.A.U. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

Acknowledgments

We thank study participants, their families, investigators and institutions collaborating in this study.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2025.1622622/full#supplementary-material

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