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untitled h2

4 5 **ClinicalTrials.gov ID: [Not yet assigned]**
6 Last review date: October **13th, 2023.**
7 8 **Study Identification Unique Protocol ID: 023-005-OMI(CEI-05022)**
9 10 11 **Brief Title:** Improving Lifestyle Behavior by "Joven, Fuerte y Saludable" 12 Multidisciplinary Program. Official Title: Efecto de Una intervención Multidisciplinaria 13 de Estilo de Vida Sobre el Exposoma de Pacientes premenopáusicas Con cáncer 14 de Mama Estadios I-III.  
15
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20 abstract

48 What this study adds 16 **Title:** Improving Lifestyle Behavior by "Joven, Fuerte y Saludable" Multidisciplinary 17 Program. Official Title: Efecto de Una intervención Multidisciplinaria de Estilo de Vida 18 Sobre el Exposoma de Pacientes premenopáusicas Con cáncer de Mama Estadios 19 I-III.  
21 **Background.** Breast cancer (BC) is the leading cause of cancer-related death and 22 disability in young women. Patients with BC experience physical symptoms and 23 psychosocial distress that adversely affect their quality of life (QoL), physical 24 functioning, and psychological well-being. "Joven & Fuerte'' is a navigation program 25 for young women with BC at the National Cancer Institute in Mexico City. The 26 program proposes an hybrid model (face-to-face and virtual) to support patients on 27 aspects such as oncology, nutrition literacy, and psychology with mindfulness.  
28 **Methods.** The study was initially planned as a randomized controlled trial to ensure 29 accurate results. However, during the pilot study, it was adapted to meet the specific 30 needs of patients such as oncology consultations and in consideration of living 31 arrangements. Two groups will be compared: one receives hybrid education and the 32 other, a hybrid education and personalized intervention. Patients who agreed for the 33 face-to-face sessions were assigned to the personalized interventions group, and 34 others, to the hybrid education group. The intervention group receives an in-person 35 consultation to evaluate their physical measurements and an interdisciplinary 36 assessment by experts. Patients can ask for virtual assistance through Zoom and 37 WhatsApp in case of any issues during the intervention. In addition, educational 38 materials such as healthy lifestyle guides and videos can be accessed through 39 Facebook and YouTube groups upon request. To ensure the comprehension of the 40 material, follow-up sessions are conducted through phone calls, video calls, or on-41 site visits. Validated questionnaires will assess lifestyle habits, QoL status, and 42 levels of distress, anxiety, and depression.  
43 What is already known on this topic 44 - Breast cancer and its treatment impacts the lifestyle and quality of life of 45 patients.  
46 - Improvement in nutrition, lifestyle, and psychological wellbeing positively 47 impacts the prognosis of breast cancer and quality of life or survivors.  
49 - Provides interventions for patients living far from a hospital.  
50 - Evaluates the health advantages of educational and personalized 51 interventions.  
52 - Examines how lifestyle changes affect the quality of life, mental health, and 53 physical functioning of patients with breast cancer receiving cancer treatment.  
54 How this study might affect research, practice, or policy 55 - This hybrid approach is both viable and economical for public institutions.  
56 - The findings of this study will reveal the effects of these interventions and their 57 potential benefits to patients.
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58 introduction

59 Breast cancer (BC) is a leading cause of death in women worldwide, especially in 60 Latin America, where patients often present with advanced stages of aggressive 61 subtypes of BC at a younger age (1). The risk of BC depends on various factors, 62 including hormone replacement therapy history, reproductive history, alcohol or 63 tobacco consumption, physical activity, and dietary habits, that are collectively called 64 exposome (2). Exposome refers to the exposure to environmental influences and 65 biological responses throughout a person's life from the prenatal stage. It can be 66 influenced by the environment, diet, behavior, and endogenous processes (3).  
67 External exposome refers to environmental factors such as mental stress, climate, 68 and lifestyle. In contrast, internal exposome are changes within an organism such 69 as increased stress hormones, inflammatory cytokines, and oxidative stress (4).  
70 Constant exposure to environmental factors, such as an unhealthy lifestyle, can 71 cause cellular damage and contribute to the growth and evolution of tumors. Once 72 cellular damage occurs, internal exposome promotes changes that create a harmful 73 environment, favoring cancer cells to acquire mechanisms to cope with stress and 74 drugs, leading to a resistance to oncological treatments (5).  
75 Obesity is part of the personal exposome and can impact the internal exposome, 76 potentially affecting BC patients. A significant percentage of patients diagnosed with 77 BC (70.9%) are overweight or obese at the time of diagnosis (6). This weight gain 78 usually occurs during systemic treatment, with 25% of patients gaining weight within 79 six months, 32% between 6-12 months, and 20% between 12-18 months after 80 diagnosis (7). Young women with breast cancer (YWBC) also experience and 81 increase in weight since the initiation of oncological treatment and up to the second 82 year of diagnosis (from 39% at baseline to 46% in two years), highlighting the 83 importance of evaluating the implications of weight gain and whether early 84 intervention would help control the risk factors mentioned earlier (8). Obesity may 85 also be associated with worse disease-free and overall survival (9).
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113 methods

86 Weight gain in patients with BC is often associated with several factors, including 87 systemic treatment, diagnosis at a young age, and lifestyle changes resulting from 88 the disease or treatment. However, the primary mechanism underlying weight gain 89 is reduced physical activity (10). The combination of chemotherapy and endocrine 90 therapy is linked to higher weight gain, especially in patients who are premenopausal 91 (a gain of up to 24 kg). In contrast, those who are postmenopausal tend to lose 92 weight (11).  
93 BC patients have reported experiencing physical symptoms and psychological 94 distress, which can negatively impact their quality of life (QoL). These symptoms can 95 affect their physical functioning, psychological well-being, and social support levels 96 (12). Particularly, YWBC is a vulnerable population with specific concerns such as 97 fertility, self-image, QoL, sexuality, and personal goals (13) and experience high 98 anxiety and depression (14). Maintaining a healthy lifestyle can improve QoL and 99 lead to better prognoses and lower mortality rates (15). For example, exercise can 100 reduce breast cancer-related death risk by 30% and all-cause death risk by 41%
101 (16). Patients undergoing oncology treatment face various nutritional challenges that 102 differ based on the type and stage of cancer, and the treatments may worsen these 103 challenges. Early nutritional screening and interventions are crucial in the cancer 104 population, as emphasized in the clinical guidelines (ASPEN/ESPEN) (17).  
105 The Instituto Nacional de Cancerología (INCAN) in Mexico City offers a program 106 called "Joven & Fuerte" for young women diagnosed with BC. However, the attention 107 was not systematic and it was difficult to measure the benefits of the intervention. So 108 the present study proposes a psychological intervention, side effect management, 109 physical activity, sleep hygiene, and psychological strategies, with onsite and remote 110 interventions to improve patient adherence and ensure timely attention. The study 111 aims to evaluate the impact of early intervention on metabolic control in newly 112 diagnosed BC patients, their QoL, and clinical outcomes. 114 A controlled trial design was adopted in which patients were assigned to two 115 intervention groups according to the nutritional, psychological, or rehabilitation risk 116 at baseline or according to their geographical localization. The first group will receive 117 a hybrid multidisciplinary lifestyle education intervention, whereas the second group 118 will receive an individualized hybrid multidisciplinary lifestyle intervention.  
119 For sample size estimation, we used internal statistics from the Mammary Tumor 120 Department at the INCAN, which has an annual average of 109 women diagnosed 121 and treated based on the selection criteria. Considering the effect on metabolic and 122 inflammatory parameters, a study by Dieli-Conwright et al. (18) was followed to 4 123 identify the difference in the decrease in insulin parameters by 14%. A confidence 124 level of 95% and power of 80% were considered with a control: intervention ratio of 125 1:1. Thus, a sample size of 132 patients was obtained. Considering a probable loss 126 of 10%, 146 patients were invited to participate in the study, with 73 patients per 127 group.
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128 inclusion criteria

129 - Women aged ≥18 and <40 years who were diagnosed with stage I-III BC,
130 confirmed by pathology and image at the INCAN
131 - Candidates for multidisciplinary treatment, including surgery, 132 chemotherapy, and/or hormonal treatments.  
133 - Signed the informed consent form 134 - Have access to a mobile phone or any electronic device with an active 135 internet connection to receive the program information.
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151 selection and group assignment

152 Patients will be recruited through an active program at the INCAN, where potential 153 candidates will be identified and invited by the navigator at the program "Joven &
154 Fuerte." After they sign the informed consent form (ICF), patients will be assigned 155 into one of the two groups:
156 Group 1: Hybrid multidisciplinary lifestyle education intervention.  
138 - Those with cardiomyopathy or ventricular dysfunction (NYHA >II),
139 arrhythmia secondary to left ventricular ejection alterations that require 140 medication, previous myocardial infarction, or angina pectoris in the last 141 six months 142 - Receiving treatment for cardiovascular or cerebrovascular disease, 143 inflammatory bowel disease, malabsorption syndrome, rheumatoid 144 arthritis, lupus, thyroid diseases, or Cushing syndrome 145 - Unable to walk for at least 1 km 146 - Have cardiovascular, respiratory, or musculoskeletal diseases that 147 impede physical activity 148 - Pregnant or breastfeeding 149 - Have psychiatric conditions impeding active participation in this protocol 150 - Do not understand Spanish
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157 group 2 individualized hybrid

158 The initial proposal was randomized assignment to each group; however, the pilot 159 study revealed challenges for patients who lived far from the hospital, in other states, 160 or had personal obligations such as family or work. Therefore, the randomization 161 process was adapted to meet the patients' needs. The intervention aims to facilitate 162 patients' adherence and follow-up with healthcare providers. Additionally, patient 163 preferences were considered when assigning them to a group.
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164 intervention

165 The individualized hybrid multidisciplinary lifestyle intervention consists of four phases. During the **initial phase**, (1 166 st month), patients undergo psychological, 167 nutritional, and physical evaluations using validated questionnaires. Weekly follow-168 ups are scheduled to answer any questions and provide educational materials.  
169 Psychological intervention for the management of stress, anxiety, or other sleep 170 disorders begins during this phase. Changes in diet and physical activity levels are 171 prepared based on baseline questionnaires and adjusted to their needs and 172 preferences to facilitate adherence to the intervention. Basic nutritional orientation is 173 provided covering topics such as identification of food groups using guides such as 174 "My Plate" (19) from the American Association of Diabetes, how to read nutrition 175 facts labels, and explanation on following a healthy diet, with available food groups 176 in the country.  
177 In the **consolidation phase**, from second to sixth month, patients undergo follow-178 ups every two weeks on-site or remotely, depending on the patient's preference.  
179 Follow-up was to monitor patients' symptoms and adjust their diet and exercise 180 routines accordingly. Psychological intervention will be tailored to individual needs if 181 a patient experiences symptoms such as nausea, vomiting, diarrhea, or fatigue. This 182 phase aims to help patients become independent and manage their activities without 183 professional help. A personalized diet and exercise plan will be created for each 184 patient, considering their socioeconomic status. The local food groups available to 185 each patient are prescribed. The Avena Health application will monitor water 186 consumption, physical activity, and nutritional adherence if the patient has access.  
The **maintenance phase**, from seventh to 12th 187 month, the patients will be followed 188 up every two months. Anthropometric measures, blood tests, and questionnaires will 189 be used to assess their progress. The objective of this phase is to reinforce the 190 recommendations of previous phases.  
191 The patients undergo check-ins every three months during the follow-up phase, 192 which begins after 12 months. In the medium term, anthropometric measures and 193 questionnaires will be used to evaluate patient adherence to multidisciplinary 194 interventions. Any questions or concerns will be addressed during the checks. See 195 **Figure 1.**
196  
  
7
197 Figure 1. Joven, Fuerte y Saludable, Protocol Design.  
  
198 **Components of the Multidisciplinary Individualized Intervention**
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199 nutritional intervention

200 Patients will undergo a comprehensive nutritional assessment and receive guidance 201 on maintaining a healthy diet balanced with macronutrients. Assessment of 202 symptoms that affect nutritional or metabolic status; anthropometric indicators such 203 as weight, height, waist circumference, arm circumference, waist-to-hip ratio, and 204 body composition determined by bioelectrical impedance analysis (BIA) will be 205 collected at baseline and follow-up; and biochemical parameters such as blood 206 glucose, insulin, HbA1c, total, low-density lipoprotein-cholesterol, high-density 207 lipoprotein-cholesterol, triglycerides, and c-reactive protein (CRP) will be assessed.  
208 Recommendations will be tailored to the individual's needs and budget and any 209 adverse effects related to their cancer treatment, focusing on a healthy, moderately 210 hypocaloric diet (for those who are overweight, obese, or at metabolic risk) or an 211 isocaloric diet for those who are underweight, considering the individualized 212 requirements of energy, protein, carbohydrate, lipids, vitamins, and minerals.  
213 Dietetic assessment measures adherence to the diet prescription through a typical  
214 feeding model or 24-hour recall. Participants will meet the program nutritionist 215 according to the visit frequency described for each phase.
216 A webpage will be available with weekly modules on nutrition, and patients will be 217 invited to workshops to resolve any obstacles they encounter while implementing 218 recommendations. A virtual class would be offered if someone could not attend the 219 workshop. A workbook with educational information and a diary section will also be 220 provided, allowing patients to share their thoughts on the intervention, challenges 221 they face, and questions.
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222 physical activity intervention 235

223 Patients will be prescribed a customized regimen of dynamic aerobic exercise to 224 improve their physical capacity. A stress test determines maximum effort capacity 225 and identifies contraindications. The rehabilitation team will evaluate the 226 performance status of patients using the Karnofsky Index (a functional scale) and 227 Eastern Cooperative Oncology Group (ECOG). Patients receive personalized 228 treatment based on their diagnoses. In addition, they will receive a digital or physical 229 guide of exercises appropriate for their disease stage. They should perform these 230 exercises 3-5 times weekly for at least 150 minutes, including resistance training and 231 moderate-intensity aerobics. Patients with special needs, such as those with 232 lymphedema, post-surgery, or active treatment, can also undergo various exercises.  
233 A healthcare professional trained in oncological rehabilitation will supervise all the 234 exercise sessions.  
236 During the diagnosis and treatment of BC, workshops will be held in collaboration 237 with a psychology team to assess the emotional symptoms. Patients will receive 238 videos of relaxation techniques and their anxiety levels will be monitored using a 239 thermometer anxiety tool. _Patients who score more than four will complete 240 depressive and anxiety symptom questionnaires (the Patient Health Questionnaire, 241 PHQ-9 and Generalized Anxiety Disorder, GAD-7, respectively) and will be referred 242 for group or individual therapy. The number of therapy sessions will be limited to 243 eight for individual interventions and two for each multidisciplinary intervention 244 phase. The questionnaires will be administered at the beginning and at three, six, 245 nine, and 12 months.  
246 Psychological interventions will involve cognitive-behavioral therapy, which will focus 247 on changing cognition and behaviors to reduce symptoms of stress, anxiety, and 248 depression. Treatment will also address the emotional discomfort caused by the 249 diagnosis and treatment and its impact on family and couple dynamics, social and 250 work life, body image, sexuality, and fertility etc. During the sessions, a clinical 251 history will be taken, with which a Clinical Map of Pathogenesis and Goal Scope Map 252 will be generated according to the Nezú and Nezú model (4). This assessment 253 allows the development of a therapy focused on the patient's needs and, to identify 254 intervention strategies for achieving specific goals, such as psychoeducation, 255 relaxation training, cognitive restructuring, problem-solving therapy, behavioral 256 activation, and assertive communication training. Patients can choose between 257 hybrid formats such as Zoom and WhatsApp and onsite sessions with specialists.  
258 *Mindfulness + oncologic rehabilitation intervention* 259 The oncological rehabilitation and mindfulness program consists of four modalities:
260 - Group face-to-face, 261 - Individuals face-to-face 262 - Group online, and 263 - Individual online 264 The program can be applied at different time points during patient treatment: before, 265 after, and after surgery with chemotherapy and/or radiotherapy.  
266 Physical exercises include different activity levels for patients to improve their 267 flexibility, range of motion, strength, and recovery capacity; exercises included in the 268 program are aimed at working different parts of the body, combined into different 269 techniques divided into static, moving, breathing, and meditation techniques, and 270 Thai-Chi and Qi Gong, as part of the mindfulness program. The contents of the 271 program are presented in **Table 1.**  
| PROGRAM                   | ONCOLOGIC                    | EXERCISES                           | MOVEMENT                           | STATIC        | BREATHING   | MEDITATION   |
|---------------------------|------------------------------|-------------------------------------|------------------------------------|---------------|-------------|--------------|
| ADMISSION                 | REHABILITATION               | TECHNIQUES                          | TECHNIQUES                         | TECHNIQUES    | TECHNIQUES  |              |
| Interview (E)             | Flexibility (RFi)            | Neck (C)                            | Expansion  and  contraction  (ECS) | Body scan (on | Conscious   |              |
| the floor) (EA)           | breathing  (RCS)             | Static  meditation  (ME)            |                                    |               |             |              |
| Initial  evaluation  (EI) | Range of movement            | Upper limbs                         | Expansion                          |               |             |              |
| (RRM.ii)                  | (MS)                         | and  contraction on  the wall (ECP) | Body scan                          | Conscious     |             |              |
| (seated) (ES)             | breathing (5  words)  (RCS5) | Static  meditation  (seated)  (MES) |                                    |               |             |              |  
| EDUCATIONAL  MATERIAL Welcome to the  program! (BVP) Benefits of  oncologic  rehabilitation  (BFRO)   |
|-------------------------------------------------------------------------------------------------------|  
| Questionnaire  application  (AC)   | Strength (Rfza. III)   | Lower limbs                     | 21 movements                                              | Internal                   |                                  |
|------------------------------------|------------------------|---------------------------------|-----------------------------------------------------------|----------------------------|----------------------------------|
| (MI)                               | (21M)                  | circulation  channel (CIC)      | Breathing  awareness  (chest, costal,  abdominal)  (RAWS) | Lay down  meditation  (MA) | Benefits of  mindfulness  (BFAP) |
| Postural                           | Recovery (RR.IV)       | Legs (P)                        | Tai Chi's 13                                              |                            |                                  |
| hygiene (HP)                       | movements (13M)        | Abdominal                       | Walking                                                   |                            |                                  |
| breathing (RA)                     | meditation  (MC)       | Stress  consequences  (CSCE)    |                                                           |                            |                                  |
| Integration of  the program  (IP)  | Thorax (T)             | 5 animals (Qi                   | Breath count                                              | Moving                     |                                  |
| Gong) (5A)                         | (CR)                   | meditation  (MCM)               | Cortisol (CZ)                                             |                            |                                  |
| Psychological  intervention  (IPS) | Hip (H)                | Sixth sense (SS) Nutrition (NT) |                                                           |                            |                                  |  
273 *Codes used in this intervention are marked in bold and in parentheses.
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274

275 Finally, sessions will be completed by ensuring that the patients are aware of the 276 importance of how stress impacts health, reminding them that specific at-home 277 exercise techniques could improve their physical condition.
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278 educative intervention 279 psychologic

280 Virtual educational intervention was adjusted to STREAM intervention for BC after 281 adapting it for our population (20). Based on our experience with the Joven & Fuerte 282 program this intervention with continue for 10 weeks, from the beginning of the 283 diagnosis, which, is when the patient requires understanding and assimilating their 284 diagnosis and the life changes that cancer treatments will represent, as well as adapt 285 to the institution. This intervention intends to manage the emotional stress of this 286 phase in collaboration with the psychology and mindfulness team.  
287 Questionnaires will be administered to evaluate QoL (QLQ-C30 and QLQ-BR23) at 288 the baseline and at three, six, 12, and 18 months, and healthy lifestyle (WCFR/AICR)
289 at the beginning and end of the intervention in both groups.  
290 While these activities are performed, patients will participate in a mindfulness 291 workshop for 10 weeks, which includes breathing counting techniques (Zazen), 292 guided meditations (five words of self-composure), meditation exercises with static 293 movement (BaDuanJin), conscious walking (Kinjun), body scan, energy 294 concentration work and physical movement (five healing animals), moving 295 meditation (TaiChi), and yoga. All of these techniques are intended to be tools for 296 the patient to deal with the stress she faces during her BC diagnosis.
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297 healthy lifestyle educative intervention

311 On **Table 2**, educational subjects reviewed on every intervention phase are 312 described.  
313
298 The healthy lifestyle education intervention was adapted from the Diabetes 299 Prevention Program (DPP)(21) funded by the National Institute of Diabetes and 300 Digestive and Kidney Diseases (NIDDK) and has been used in BC studies, such as 301 SUCCESS (22), MEDEA (23), and PASAPAS (24). This educational material is 302 planned to be given to all intervention groups. Every week, in a hybrid format, 303 patients will receive a WhatsApp or, through the Facebook group, the written 304 information, video, and/or audio of the subjects included in the program. Additionally, 305 patients will receive a manual with a weekly description of the topic to be discussed 306 and the activities they must carry out that week in a way that the patient will have 307 the whole week to carry out her activities; on Friday, a session will be opened both 308 on Zoom or WhatsApp, or in the case of patients who can physically go to the 309 institute in person. The expert will also be available so that the patient can share her 310 doubts and difficulties faced during the week.  
| Intervention phase      | Follow-up   | Week                | Title                  | Content             |
|-------------------------|-------------|---------------------|------------------------|---------------------|
| Intensive phase: weekly | 1           | 1                   | Welcome to the program | Introduction        |
| follow-up               | 2           | 2                   | Caloric balance        | Caloric restriction |
| 3                       | 3           | Type of fatty acids | Caloric restriction    |                     |
| 4                       | 4           | Reducing calories,  | Caloric restriction    |                     |
| controlling portions    |             |                     |                        |                     |  
| 5                    | 5                  | Muscular movement              | Physical activity           |                    |
|----------------------|--------------------|--------------------------------|-----------------------------|--------------------|
| 6                    | 6                  | Working with your              | Behavioral support          |                    |
| surroundings         |                    |                                |                             |                    |
| 7                    | 7                  | Problem-solving                | Behavioral support          |                    |
| 8                    | 8                  | Being active: a way of living  | Physical activity           |                    |
| 9                    | 9                  | Healthy eating                 | Caloric restriction         |                    |
| 10                   | 10                 | Healthy eating and breast      | Breast cancer and           |                    |
| cancer               | nutrition          |                                |                             |                    |
| 11                   | 11                 | Preparing a better breakfast,  | Caloric restriction and     |                    |
| lunch, and dinner    | behavioral support |                                |                             |                    |
| 12                   | 12                 | Progress review                | Recap and evaluation        |                    |
| Consolidation phase: | 13                 | 14                             | Answering negative thoughts | Behavioral support |
| two-week follow-up   | 14                 | 16                             | The slope in changing to a  | Behavioral support |
| healthy lifestyle    |                    |                                |                             |                    |
| 15                   | 18                 | Intensifying physical activity | Physical activity           |                    |
| 16                   | 20                 | 10 ways to control hunger      | Behavioral support          |                    |
| 17                   | 22                 | What to eat on holidays        | Behavioral support          |                    |
| 18                   | 24                 | Making balance and             | Recap and evaluation        |                    |
| celebrating success  |                    |                                |                             |                    |
| 19                   | 28                 | How to stay motivated          | Behavioral support          |                    |  
12  
| Maintenance phase:    | 20     | 32                           | Recovering from excess   | Behavioral support   |
|-----------------------|--------|------------------------------|--------------------------|----------------------|
| monthly follow-up     | eating |                              |                          |                      |
| 21                    | 36     | Weight loss review           | Caloric restriction      |                      |
| 22                    | 40     | How to adapt to long-lasting | Behavioral support       |                      |
| success               |        |                              |                          |                      |
| 23                    | 44     | Preparing for what's yet to  | Recap and evaluation     |                      |
| come                  |        |                              |                          |                      |
| 24                    | 48     | Congratulations! You         | Recap and evaluation     |                      |
| finished the program! |        |                              |                          |                      |  
315 *Barriers and facilitators for the multidisciplinary program implementation* 316 As this program is being implemented for the first time and with the aim of enhancing 317 patient care, the assessment of barriers will be carried out through questionnaires 318 administered to both program staff and enrolled patients. The purpose is to identify 319 the barriers faced by each party, thereby enabling the provision of solutions 320 alongside the interventions. The questionnaire design was based on the CFIR/RE-321 AIM framework, a tool used to assess the success of program implementation (25, 322 26).
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323 data analysis

324 Descriptive statistics will be performed for the clinical and demographic data.  
325 Inferential comparisons will be made by calculating the relative risk with 95%
326 confidence intervals. To compare the effect between groups, a statistical comparison 327 with the Kolmogorov-Smirnov test will be performed, and depending on the 328 distribution of data, parametric (normal distribution) or non-parametric (non-normal 329 distribution) tests will be applied. To evaluate the differences between groups, 330 Student's T test for related groups or the Mann-Whitney test will be used, while for 331 the analysis of repeated samples, analysis of variance (ANOVA) will be used for 332 three or more variables, depending on the nature of the data. 333 Chi-square and Fisher's tests will be used to compare categorical variables, and the 334 alpha value will be set to 0.05. Bivariate analysis will be performed to identify 335 differences between groups and associations with survival concerning the measured 336 clinical variables and biomarkers. To analyze the existing correlation with the clinical 337 variables, Pearson or Spearman regression with a 95% confidence interval will be 338 used, depending on the nature of the data distribution. To determine the associations 339 between independent variables, multivariate logistic regression models were used, 340 adjusting for the remaining clinical variables.
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341 discussion

342 Although various interventions provide nutritional and physical activity counseling, 343 most of them are focused on patients who have survived cancer and do not include 344 those who have been diagnosed recently. Emotional support is also not taken into 345 account. A recent meta-analysis published by Cochrane reviewed 20 studies and 346 involved 2028 patients with breast cancer who received interventions for weight loss.  
347 The results showed that these interventions for survivors of breast cancer with 348 obesity resulted in moderate weight reduction, improved body mass index and waist 349 circumference, and enhanced quality of life through diet and exercise interventions 350 (7). It appears that a multidisciplinary approach could lead to even better results, and 351 probably it has to be since the diagnosis to start a mentality switch since the 352 beginning of the disease.  
353 Nutritional interventions in patients with cancer ensure adequate intake of energy 354 and nutrients during oncological treatment, which results in an improved response 355 and reduced toxicity of pharmacological anti-cancer therapies. These health 356 changes reduce the long-term side effects of treatment and promote long-term 357 overall health (27). The Women's Intervention Nutrition Study (WINS) demonstrated 358 the impact of nutritional intervention on the prognosis and survival of BC, with a low-359 fat diet promoting modest weight loss, improving metabolic biomarkers, and 360 positively affecting disease-free survival (28). According to lifestyle guidelines 361 recommended by the World Cancer Research Fund (WCRF)/American Institute for 362 Cancer Research (AICR), a fiber- and soy-rich diet and limited consumption of fatty 363 acids (especially saturated fatty acids) can improve survival after BC diagnosis (27).  
364 According to research by Demark-Wahnefried et al., women undergoing 365 chemotherapy may experience a decrease in energy expenditure due to reduced 366 activity despite same calorie intake (29). The Health, Eating, Activity, and Lifestyle 367 (HEAL) study also found that patients who engaged in less exercise and physical 368 activity had a higher risk of weight gain. Patients who underwent chemotherapy 369 experienced a more significant decrease in exercise time (3.6 hours per week) than 370 those who underwent surgery (1.6 hours per week). Furthermore, a study showed 371 that all patients who underwent chemotherapy experienced amenorrhea; therefore, 372 changes in hormones and menopause could impact metabolism, affecting body  
373 composition and the waist-to-hip ratio. This can result in increased estrogen and 374 insulin levels (30).
375 Oncological rehabilitation (OR) and mindfulness stimulate specific neurovascular 376 terminals that activate ATP, improve bloodstream flow, and stimulate the 377 parasympathetic nervous system (PNS), thereby generating serotonin and 378 endorphins, relaxing muscles, improving digestion, and reducing insomnia. It also 379 prevents sarcopenia and stimulates immunoglobulins and the osteomioarticular 380 system (OMAS). Mindfulness provides a profound knowledge of the mind and its 381 discriminative processes, allowing free radicals to be dosed. Through extensive 382 practice, the patient learns how to regulate their attention and manages to focus on 383 the present, which enhances the experience itself and the exercises at hand (31).  
384 Psychological treatments for patients with BC indicated that cognitive behavioral and 385 psycho-educational therapies have a significant positive impact. These therapies 386 improved QoL, reduced anxiety and depression, and improved mood. The study 387 found that treatment lasting between six and twelve weeks achieved better 388 psychological results than shorter or longer interventions (32). Relaxation 389 techniques are commonly used in mindfulness programs and psychological 390 interventions to alleviate symptoms of depression, anxiety, stress, and fear of 391 recurrence. Survivors of BC have reported improved sleep quality after practicing 392 these techniques. (33). Cognitive-behavioral approaches have successfully 393 overcome fatigue and improved sleep quality. (34). A randomized trial conducted by 394 Rogers et al. revealed that physical activity positively impacted overall sleep quality 395 compared to usual care in BC patients. (35).
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406 conclusion

407 Although there have been several studies on interventions for breast cancer patients, 408 such as those related to nutrition, physical activity, mindfulness, or psychological 409 support, these interventions have typically been conducted separately and focused 396 Patients with BC have benefitted from virtual psychological interventions. One study 397 called the Web-Based Stress Management for Newly Diagnosed Patients with 398 Cancer (STREAM) developed an online stress management program that 399 significantly improved the QoL for patients in the intervention group (73.2%)
400 compared to the control group (59%). The Hospital Anxiety and Depression scale 401 (HADS) score decreased, mainly due to reduced levels of distress (20). Another 402 study used a web-based psychological intervention called Web-Based Self-403 Management for Psychological Adjustment After Primary Breast Cancer (BREATH),
404 which resulted in lower levels of distress (84%) and clinical deterioration (16%) for 405 the intervention group (36).  
410 primarily on survivors. This highlights the necessity for multidisciplinary 411 interventions, as proposed in this study.
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412 acknowledgments

413 The authors thank the CAAI (Centro de Apoyo para la Atención Integral) of the 414 Instituto Nacional de Cancerología for the facilities and spaces for the 415 implementation of workshops for the described intervention.
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416 contributors

417 Cruz-Ramos: protocol design, principal researcher, and draft preparation. Fajardo-418 Espinoza: Protocol design, draft preparation, nutritional intervention design, and 419 implementation. Martinez-Palacios: Draft preparation and hybrid educational 420 intervention design. Pérez-Camargo: Nutritonal intervention design and 421 implementation. Cedillo-Compeán: Oncological rehabilitation intervention design 422 and implementation. Rodríguez-Fonseca: Mindfulness specialist, hybrid educational 423 intervention design and implementation. Blandón-Hernández and Labra-Alvarado:
424 Psychological and Mindfulness Intervention Implementation. Gálvez-Hernández and 425 Bejarano-Colina: Psychological intervention design and implementation. Villarreal-426 Garza: Reviewer and protocol design. Cabrera-Nieto, Barranco-Cortés, González-427 Pérez, Madariaga-Cobos: Nutritional intervention implementation. Bargalló-Rocha, 428 Matus-Santos, Espinosa-Fernández and Cabrera-Galeana oncological follow-up 429 protocol and patient reference to the program. Mohar-Betancourt: Reviewer and 430 protocol design.
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433 patient consent for publication.

435 The authors declare that this study was conducted according to the Declaration of 436 Helsinki, and all procedures were performed with adequate understanding and 437 written consent from the individuals. The study protocol was approved by the Ethics 438 Committee of Instituto Nacional de Cancerología (023-005-OMI, CEI-025022).
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439 funding

440 None. At the time of publication, the project had not received any specific grant from 441 public, commercial, or not-for-profit funding agencies or laboratories.
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442 data availability statement.

443 Study results are not available yet.  
444 445 1. Amadou A, Torres-Mejía G, Hainaut P, Romieu I. Breast cancer in 446 Latin America: global burden, patterns, and risk factors.  
447 2. Bessonneau V, Rudel RA. Mapping the human exposome to uncover 448 the causes of breast cancer. Int J Environ Res Public Health. 2020 Jan 1;17(1).  
449 3. Fang M, Hu L, Chen D, Guo Y, Liu J, Lan C, et al. Exposome in human 450 health: Utopia or wonderland? Vol. 2, The Innovation. Cell Press; 2021.  
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