Preventing Breast Cancer Therapy-related Cardiovascular Toxicity With a Daily-adapted Program With Mhealth Support (ATOPE-PRO)

ATOPE-PRO: Effects on the Prevention of Breast Cancer Therapy-related Cardiovascular Toxicity of a Daily-adapted and Individualized Program With Support From a Mobile Application

ATOPE-PRO, was developed with the intention of consolidating the integration of an innovative system for the prevention of cancer therapy-related cardiovascular toxicity (CTR-CVT) in the continuum care of women with breast cancer in health services. It is a step further towards personalized medicine by optimizing the already available tools and integrating artificial intelligence. Breast cancer survival increases every year, a situation that poses new challenges for health professionals. The European Society for Medical Oncology, a reference in Europe, has just highlighted the need to anticipate to and prevent sequelae derived from the disease and its treatments. This, in addition to having a positive impact on improving the quality of life of people suffering from this disease, would mean a reduction in the risk of recurrence, the appearance of other tumors and other diseases, and death from cancer or other causes, which have a personal impact and represent an overload of the healthcare system. To this end, ATOPE- PRO aims to optimize and refine tools already developed in the previous project (ATOPE, Pl18/01840), integrating artificial intelligence to help identify CTR-CVT, risk profiles, and effective and safe doses (at a clinical level) early on, implementing the program in a longer term, and transferring the results to the social sector (social level). The project has 4 stages: Phase 0 or start-up (to make improvements and analyse usability); Phase 1 for piloting and optimization; Phase 2, to verify efficacy (randomized controlled clinical trial) and Phase 3, in which a deep analysis will be performed and future projects will be conceived.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer Female
• Intervention / Treatment: Behavioral: Individualised health recommentations; Behavioral: Individualised physical exercise program; Behavioral: General health recommendations

Detailed Description

More and more women are experiencing breast cancer at younger ages, yet survival rates have become very promising. However, years after cancer treatment, related sequelae (physical, psychological, or emotional) may emerge, responsible for post-disease fatalities in many women. The occurrence of these sequelae largely depends on treatment-induced toxicity and individual health status, which is related to lifestyle habits. Among these sequelae, cancer-related cardiovascular toxicity (CTR-CVT) is noteworthy, with an incidence close to 40% in breast cancer, closely linked to treatments such as chemotherapy (especially anthracyclines), targeted therapy (trastuzumab), and radiotherapy (left side or mediastinum), causing DNA and mitochondrial damage. Traditionally defined as a reduction in left ventricular ejection fraction (LVEF) ≥50% in its mildest form, and a decrease in global longitudinal strain (GLS) of >15% from baseline and/or an increase in cardiac markers (cardiac troponin I or T cTnI/cTnT >99th percentile, brain natriuretic peptide BNP ≥35 pg/mL, or NT-proBNP ≥125 pg/mL) to severe (requiring inotropic support, mechanical circulatory support, or consideration for transplantation), adding the need for monitoring through various tests, not just LVEF, as it would be too late to detect it. The risk detection of TCVRC is based on medical treatments, which sometimes are insufficient since many patients theoretically considered low-risk develop TCVRC. This has led to the need to study and include other patient-related factors at the time of diagnosis, such as previous presence of cardiovascular diseases, age, lifestyle habits, and comorbidities, to be considered for overall cardiovascular and oncological prognosis and individualized surveillance of TCVRC, along with additional factors that add to the complexity of risk assessment such as cancer type, duration, and doses of oncological treatment. However, the scientific evidence supporting the inclusion of some of these parameters is of questionable quality (level C) and, moreover, they are not usually included in routine assessments, making them less applicable.

To improve the situation and achieve proper prevention of TCVRC, it is necessary to identify parameters with good sensitivity for early detection that can preferably be performed routinely by different healthcare professionals involved in the continuum of care, as well as related risk factors. With this information, the implementation of interventions that could limit treatment interruptions and improve survival after breast cancer would be facilitated. In this context, the European Society of Cardiology Guidelines highlight, in addition to the improvement of detection tools, the inclusion of new parameters, the creation of large data registries, the use of artificial intelligence, or the determination of new risk stratification algorithms, among others.

There is a lack of access to structured physical exercise programs for cancer patients, even though adaptation of exercise to their health status is crucial, as excessive doses could be harmful. Ondulatory exercise prescription may be more suitable for cancer patients, as it allows better adaptation to their health status. So far, one of the systems to achieve this has been prescription based on heart rate variability (HRV) previously used in the sports world and in some cardiovascular pathologies but promising and little studied in the cancer world. However, given the complexity of this disease, its treatments, and the impact it has on different spheres of these patients' health, the inclusion of additional markers is suggested to further optimize personalized exercise programs based on individual needs. With the support of current technologies, monitoring and control of physiological parameters are facilitated, potentially reducing the costs of in-person supervision by healthcare professionals but also the potential health risks in these patients when engaging in physical exercise.

Regarding these interventions, both physical activity and exercise have been recognized as potent multi-effect non-pharmacological therapies in the treatment of TCVRC, although to achieve optimal physiological adaptations and individualization, physical exercise programs must be correctly prescribed. In recent years, interest has shifted towards supervised high-intensity interval exercise, which has been shown to be safe, well-tolerated, effective for TCVRC treatment, and cost-effective. However, most physical exercise programs implemented are general programs with linear prescriptions and questionable adherence. To address adherence issues, physical exercise programs have been combined with behavioral change programs, showing promising short-term results but with loss in the medium/long term. In this regard, the use of technology and patient monitoring, which provide continuous feedback and have proven to be an effective and useful tool for establishing a healthy lifestyle, could offer a solution for both patients and professionals in improving adherence.

ATOPE-PRO aims to integrate into the usual care continuum of women with breast cancer a personalized and individualized mhealth model (ATOPE+ 2.0) for TCVRC prevention, which will allow us to advance towards precision clinical care, to complete its implementation and transfer of results, resulting in an improvement in quality of life, recurrence, and death, meeting the standards requested, through refining and automating the process, ensuring adherence, and offering safe and effective doses of physical exercise.

• Study Type: Interventional
• Enrollment (Estimated): 102
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Irene Cantarero Villanueva, PhD; Phone Number: +34 637007250; Email: irenecantarero@ugr.es
• Study Contact Backup: Name: Isabel Blancas López-Barajas, PhD; Phone Number: +34 958257235; Email: iblancas@ugr.es

Study Locations

• Spain
  • Granada, Spain, 18016
    • University of Granada

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Recently diagnosed with stage I-III breast cancer
• Treatments predisposing to cardiotoxicity (anthracyclines, targeted therapies, radiotherapy)
• Signed informed consent form
• Medical authorisation to participate
• Smartphone user level

Exclusion Criteria:

• Patient underwent previous cancer treatments.
• Patients were previously diagnosed with cancer
• Pregnant patients. Patients performing other type of therapeutic exercise at diagnosis time with an intake >or = to 150 moderate-intensity or 75 min of vigorous-intensity a day
• Therapeutic exercise practice not recommended because psychiatric or cognitive disorders or cute or chronic condition that prevents exercise (advanced lung disease, oxygen requirement, stenosis >70%, metastasis etc.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Group; Health recommendations (educational videos) + Individualised exercise intervention	Behavioral: Individualised health recommentations; Individualised recommendations for physical activity and exercise, lifestyle, stress management and symptom management with solid scientific evidence established by health organisations and scientific reference committeess through the ATOPE-PRO mobile application based on patients reported status.; Behavioral: Individualised physical exercise program; Follow-up of an individualised exercise program adjusted by daily monitoring of the level of physical, physiological and psychological condition.
Other: Control Group; Health recommendations (educational videos)	Behavioral: General health recommendations; Recommendations for physical activity and exercise, lifestyle, stress management and symptom management with solid scientific evidence established by health organisations and scientific reference committeess through the ATOPE-PRO mobile application.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiotoxicity	Echocardiography: left ventricular ejection fraction expressed as percentage.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Systolic function	Echocardiography: Strain longitudinal global expressed as percentage.	At diagnosis before treatments, after 6 months, and one year after diagnosis.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of cardiovascular events	Clinical records registration expressed as number (N) of cardiovascular events.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Comorbidities	Any chronic pathological condition different from the oncologic one will be registed by a clinical interview, an expressed in results as number (N) and type.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Heart rate variability	Assessment of cardiac autonomic system balance by a Holter registration, registering the log-transformed root mean square of successive R-R intervals (lnRMSSD) and expressed as milliseconds (ms).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Heart rate	Resting heart rate registration by a Holter, expressed as beats per minute (bpm).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Blood pressure	Systolic and diastolic blood pressure levels registration after evaluation by a digital sphygmomanometer, expressed as mmHg (mercury millimetres).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Cardiac damage	Collection of capillary samples for Cardiac troponin T measurement, with results expressed as ng/L, indicating higher values thatn 40ng/L cardiotoxicity or other cardiac injuries.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Cardiac Damage	Blood test for high-sensitivity cardiac troponin I evaluation, considering normal values below 14ng/L.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Endothelial status	By registering ascorbic acid levels provided by blood test, being the reference range of 0.6-2 mg/dL	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Cardiorespiratory Fitness	A Treadmill Ergometric Test will be performed in order to evaluate VO2 peak values, calcultated as the highest VO2 value in liters per minute during the test. Cut-off points will be set at low(<13 mL·kg-1·min-1), moderate (13.916.9 mL·kg-1·min-1), and high (≥17 mL·kg-1·min-1), considering a minimal clinically important difference a 6% of Vo2 peak change.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Quadriceps muscle thickness	Quadriceps muscular ecography will be used, expressing results as centimeters (cm).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Body Fat Mass	Bioelectrical impedance analysis (BIA) will be perfomerd by using an Inbody 720 for measuring body fat mass, expressed in kilograms (kg).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Height	Bioelectrical impedance analysis (BIA) will be perfomerd by using an Inbody 720 for measuring body fat mass, expressed in kilograms (kg). A tallimeter will be used to register height, expressed in meters (m).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Weight	Bioelectrical impedance analysis (BIA) will be perfomerd by using an Inbody 720 for measuring body weight, expressed in kilograms (kg).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Body Mass Index	By registering height and weight, Body mass index (BMI) will be calculated as weight (kg)/ height (m^2), expressed as kg/m^2.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Body Fat Percentage	Bioelectrical impedance analysis (BIA) will be perfomerd by using an Inbody 720 for measuring body fat percentage, expressed as a percentage (%).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Physical Activity level	International physical activity questionnaire (IPAQ) will be used to report physical activity levels of participants, expressed as Metabolic Equivalent of Task per week (METs/week).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Sleep duration	Sleep duration time, expressed as hours (h), will be recorded by activity bracelets.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Fatigue	A Likert 0-10 scale will be applied, indicating 0 the absence of the symptom, and a 10 'the most' of the symptom.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Total Cholesterol	Total cholesterol (TC) will be obtained through blood test and expressed as mg/dl.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Triglycerides level	Obtained through blood test and expressed as mmol/L.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
LDL-C level	Low-density lipoprotein cholesterol will be obtained through blood test and expressed as mg/dl.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
HDL-C level	High-density lipoprotein cholesterol will be obtained through blood test and expressed as mg/dl.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Total antioxidant capacity	Oxidative Stress TAC biomarker will be assessed by blood test, expressing its results as mM-TE units.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Oxidative status	Thiobarbituric Acid Reactive Substances concentration Oxidative Stress TBARS biomarker will be assessed by blood test, being results expressed as the number of milligrammes of malonaldehyde per kilogramme of sample	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Epigenetic profile	miRNA expression profile quantification: analysis of miRNA expression profile by massive sequencing with specific equipment, reporting changes in expression pre and post intervention as Log2 fold change (Log2FC).	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Inflammatory status	C-reactive protein levels obtained by blood samples, expressed as mg/dl.	At diagnosis before treatments, after 6 months, and one year after diagnosis.
Immune status	Interleuquin-6 (IL-6) levels obtained by blood samples, expressed as pg/ml.	At diagnosis before treatments, after 6 months, and one year after diagnosis.

Collaborators and Investigators

• Sponsor: Universidad de Granada
• Collaborators: Instituto de Salud Carlos III; Hospital Clinico Universitario San Cecilio
• Investigators: Principal Investigator: Irene Cantarero Villanueva, PhD, Universidad de Granada

Publications and helpful links

General Publications

• Postigo-Martin P, Penafiel-Burkhardt R, Gallart-Aragon T, Alcaide-Lucena M, Artacho-Cordon F, Galiano-Castillo N, Fernandez-Lao C, Martin-Martin L, Lozano-Lozano M, Ruiz-Vozmediano J, Moreno-Gutierrez S, Illescas-Montes R, Arroyo-Morales M, Cantarero-Villanueva I. Attenuating Treatment-Related Cardiotoxicity in Women Recently Diagnosed With Breast Cancer via a Tailored Therapeutic Exercise Program: Protocol of the ATOPE Trial. Phys Ther. 2021 Mar 3;101(3):pzab014. doi: 10.1093/ptj/pzab014.
• Gonzalez-Santos A, Postigo-Martin P, Gallart-Aragon T, Esteban-Cornejo I, Lopez-Garzon M, Galiano-Castillo N, Arroyo-Morales M, Illescas-Montes R, Artacho-Cordon F, Martin-Martin L, Forneiro-Perez R, Lozano-Lozano M, Fernandez-Lao C, Ruiz-Vozmediano J, Sanchez-Salgado C, Cantarero-Villanueva I. Neurotoxicity prevention with a multimodal program (ATENTO) prior to cancer treatment versus throughout cancer treatment in women newly diagnosed for breast cancer: Protocol for a randomized clinical trial. Res Nurs Health. 2021 Aug;44(4):598-607. doi: 10.1002/nur.22136. Epub 2021 May 7.
• Postigo-Martin P, Gil-Gutierrez R, Moreno-Gutierrez S, Lopez-Garzon M, Gonzalez-Santos A, Arroyo-Morales M, Cantarero-Villanueva I. mHealth system (ATOPE+) to support exercise prescription in breast cancer survivors: a reliability and validity, cross-sectional observational study (ATOPE study). Sci Rep. 2022 Sep 8;12(1):15217. doi: 10.1038/s41598-022-18706-7.
• Gonzalez-Santos A, Lopez-Garzon M, Gil-Gutierrez R, Salinas-Asensio MDM, Postigo-Martin P, Cantarero-Villanueva I. Nonlinear, Multicomponent Physical Exercise With Heart Rate Variability-Guided Prescription in Women With Breast Cancer During Treatment: Feasibility and Preliminary Results (ATOPE Study). Phys Ther. 2023 Sep 1;103(9):pzad070. doi: 10.1093/ptj/pzad070.

Helpful Links

• S. Moreno-Gutierrez et al., "ATOPE+: An mHealth System to Support Personalized Therapeutic Exercise Interventions in Patients With Cancer," in IEEE Access, vol. 9, pp. 16878-16898, 2021, doi: 10.1109/ACCESS.2021.3049398.

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: July 11, 2024
• First Submitted That Met QC Criteria: July 18, 2024
• First Posted (Actual): July 24, 2024

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Rehabilitation; Telemedicine; Quality of life; Prevention; Breast Neoplasms; Physical Exercise; Cancer therapy-related cardiovascular toxicity; Health related lifestyle
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Behavior; Skin and Connective Tissue Diseases; Breast Neoplasms; Motor Activity
• Other Study ID Numbers: PI23/01646

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No