An Interdisciplinary Ecosystem for the Prevention of Cardiotoxicity in Older Patients With Breast Cancer: Protocol for a Prospective and Multicentric Study

JMIR Preprints Sacco et al An interdisciplinary ecosystem for the psychosocial and behavioural management of Cardiotoxicity in elderly breast cancer patient: a prospective clinical study Gaia Giulia Angela Sacco, Ketti Mazzocco, Anastasia Constantinidou, Andri Papakonstantinou, Davide Mauri, Grigorios Kalliatakis, Manolis Tsiknakis, Domen Ribnikar, Dorothea Tsekoura, Valantis Aidarinis, Keramida Kalliopi, Oikonomopoulou Panagiota, Athos Antoniades, Federica Rizzi, Georgia Karanasiou, Anca Bucur, Elsa Pacella, Daniela Cardinale, Carlo Cipolla, Elisabetta Munzone, Dimitris Fotiadis, Giuseppe Curigliano, Gabriella Pravettoni Submitted to: JMIR Research Protocols on: June 20, 2024 Disclaimer: © The authors. All rights reserved. This is a privileged document currently under peer-review/community review. Authors have provided JMIR Publications with an exclusive license to publish this preprint on it's website for review purposes only. While the final peer-reviewed paper may be licensed under a CC BY license on publication, at this stage authors and publisher expressively prohibit redistribution of this draft paper other than for review purposes. https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al Table of Contents Original Manuscript ....................................................................................................................................................................... 5 https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al An interdisciplinary ecosystem for the psychosocial and behavioural management of Cardiotoxicity in elderly breast cancer patient: a prospective clinical study Gaia Giulia Angela Sacco1*; Ketti Mazzocco1, 2*; Anastasia Constantinidou3; Andri Papakonstantinou4; Davide Mauri5; Grigorios Kalliatakis6; Manolis Tsiknakis7; Domen Ribnikar8; Dorothea Tsekoura9; Valantis Aidarinis9; Keramida Kalliopi10; Oikonomopoulou Panagiota10; Athos Antoniades11; Federica Rizzi12; Georgia Karanasiou13; Anca Bucur14; Elsa Pacella15; Daniela Cardinale1; Carlo Cipolla1; Elisabetta Munzone1; Dimitris Fotiadis13; Giuseppe Curigliano1, 2; Gabriella Pravettoni1, 2 1Istituto Europeo di Oncologia IRCCS Milano IT 2Department of Oncology and Hemato-oncology, University of Milan Milan IT 3Medical Oncology Department, Bank of Cyprus Oncology Centre Nicosia CY 4Oncology-Pathology Dept., Karolinska Institutet - Cancer Center Karolinska (CCK) Solna SE 5Medical oncology department, General Hospital of Lamia Lamia GR 6Computation, Computational BioMedicine Laboratory (CBML), Foundation for Research and Technology-Hellas (FORTH) Heraklion GR 7Department of Electrical & Computer Engineering, Hellenic Mediterranean University (HMU) Chania GR 8Medical Oncology Department, Institute of Oncology Ljubljana Ljubljana SI 92nd Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens Athens GR 102nd Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens Athens GR 11Stremble, Stremble Ventures LTD Germasogeia CY 12IMS - Istituto di Management Sanitario Bresso IT 13Department of Materials Science and Engineering, UOI - University of Ioannina Ioannina GR 14Philips Research Europe Eindhoven NL 15ESC, European Society of Cardiology Sophia Antipolis FR *these authors contributed equally Abstract Background: Over 50% of newly diagnosed breast cancer patients are 65+ years old. Due to age-related factors and the presence of comorbidities, these patients are particularly vulnerable to developing cardiac toxicity associated with cancer treatments, which may lead to suboptimal interventions and undertreatment, resulting in poorer health outcomes, Quality of Life (QoL) deterioration and increased healthcare costs. Given the underrepresentation of elderly breast cancer patients in clinical trials and the increasing recognition of psycho-social and behavioural factors’ impact on cardiovascular (CV) disease onset, broader and interdisciplinary studies are required to develop new and innovative best practices for this clinical population. Objective: Using an innovative eHealth approach combining the CARDIOCARE (CARDIOCARE – “An Interdisciplinary Approach for the Management of the Elderly Multimorbid Patient with Breast Cancer Therapy Induced Cardiac Toxicity” – Grant Agreement 945175) Mobile App and technologically advanced wearable devices (i.e., the Garmin Venu SQ watch and the Polar h10), the CARDIOCARE prospective study pursues a twofold aim: 1) testing the effectiveness of the CARDIOCARE mobile App to monitor and assess elderly breast cancer patients’ intrinsic capacity and QoL and evaluating CARDIOCARE eHealth interventions effectiveness on these parameters 2) developing a holistic, patient-centred risk prediction model, specific for the detection of cardiotoxicity before it clinically emerges. Methods: The study is prospective and multicentric and involves six clinical and five technical partners across Europe. Seven hundred fifty elderly breast cancer patients (? 60years old) are randomised into either the intervention group or the control arm, with only patients in the former receiving access to eHealth psychological, behavioural, and functional interventions implemented on the CARDIOCARE eHealtHeart App. Patients will be recruited in the six clinical centres and will undergo clinical procedures to collect multi-modal data including clinical data, cardiac imaging, biochemical and psychological biomarkers and omics, intrinsic capacity, and QoL indicators, measured at baseline (T0) and every three months, up to 12 months (T5). https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al Results: CARDIOCARE is a project funded by Horizon 2020 and enrollment (WP4) started in May 2023. Recruitment and first data analysis are currently underway. Conclusions: The CARDIOCARE prospective study will contribute to developing new best practice guidelines for managing elderly multimorbid breast cancer patients while preserving their intrinsic capacity and improving their QoL. Furthermore, the CARDIOCARE Mobile App and the wearable devices will allow clinicians to identify trajectories across the cardiotoxicity disease continuum and thus intervene in a preventative way on higher-risk patients. Such a healthcare approach will also benefit the healthcare system, which currently spends almost 40% of its resources on patients over 60, with long-term care and hospital admissions being the primary cost drivers. Clinical Trial: NCT06334445 (JMIR Preprints 20/06/2024:63455) DOI: https://doi.org/10.2196/preprints.63455 Preprint Settings 1) Would you like to publish your submitted manuscript as preprint? Please make my preprint PDF available to anyone at any time (recommended). 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I understand that if I later pay to participate in <a href="https://jmir.zendesk.com/hc/en-us/articles/360008899632-What-is-the-PubMed-Now-ahead-of-print-option-when-I-pay-the-APF-" target="_blank">JMIR’s PubMed Now! service</a> service, my accepted manuscript PDF will automatically be made openly available. https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al Original Manuscript https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al An interdisciplinary ecosystem for the psychosocial and behavioural management of Cardiotoxicity in elderly breast cancer patient: a prospective clinical study Authors: Gaia Giulia Angela Sacco1, Ketti Mazzocco1,2, Anastasia Constantinidou3, Andri Papakonstantinou4, Davide Mauri5, Grigorios Kalliatakis6, Manolis Tsiknakis7, Domen Ribnikar8, Dorothea Tsekoura9, Valantis Aidarinis9, Keramida Kalliopi10, Oikonomopoulou Panagiota10, Athos Antoniades11, Federica Rizzi12, Anca Bucur14, Elsa Pacella15, Georgia Karanasiou13, Daniela Cardinale1, Carlo Cipolla1, Elisabetta Munzone1, Dimitris Fotiadis13, Giuseppe Curigliano1,2, Gabriella Pravettoni1,2 Affiliations: 1 European Institute of Oncology, IRCCS, Milano, Italy 2 Department of Oncology and Hemato-oncology, University of Milan, Italy 3 Medical Oncology Department, Bank of Cyprus Oncology Centre, Nicosia, Cyprus 4 Oncology-Pathology Dept., Karolinska Institutet - Cancer Center Karolinska (CCK), Solna, Sweden 5 Medical oncology department, General Hospital of Lamia, Lamia, Greece 6 Computation, Computational BioMedicine Laboratory (CBML), Foundation for Research and Technology-Hellas (FORTH), Heraklion, Greece 7 Department of Electrical & Computer Engineering, Hellenic Mediterranean University (HMU), Greece 8 Medical Oncology Department, Institute of Oncology Ljubljana, Ljubljana, Slovenia 9 2nd Department of Surgery, Aretaieio University Hospital, National and Kapodistrian University of Athens, Athens, Greece 10 2nd Department of Cardiology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece 11Stremble, Stremble Ventures LTD, Germasogeia, Cyprus 12 IMS - Istituto di Management Sanitario, Bresso, Italy 13 Department of Materials Science and Engineering, UOI - University of Ioannina, Ioannina, Greece 14 Philips=Research Europe, Eindhoven, The Netherlands 15ESC, European Society of Cardiology, Sophia Antipolis, France Corresponding author: Gaia Giulia Angela Sacco European Institute of Oncology, IRCCS, Milano, Italy Mobile: +393392057169 e-mail: [email protected] https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al AN INTERDISCIPLINARY ECOSYSTEM FOR THE PSYCHOSOCIAL AND BEHAVIOURAL MANAGEMENT OF CARDIOTOXICITY IN ELDERLY BREAST CANCER PATIENT: A PROSPECTIVE CLINICAL STUDY ABSTRACT Background: Over 50% of newly diagnosed breast cancer patients are 65+ years old. Due to age-related factors and the presence of comorbidities, these patients are particularly vulnerable to developing cardiac toxicity associated with cancer treatments, which may lead to suboptimal interventions and undertreatment, resulting in poorer health outcomes, Quality of Life (QoL) deterioration and increased healthcare costs. Given the underrepresentation of elderly breast cancer patients in clinical trials and the increasing recognition of psycho-social and behavioural factors’ impact on cardiovascular (CV) disease onset, broader and interdisciplinary studies are required to develop new and innovative best practices for this clinical population. Objectives: Using an innovative eHealth approach combining the CARDIOCARE (CARDIOCARE – “An Interdisciplinary Approach for the Management of the Elderly Multimorbid Patient with Breast Cancer Therapy Induced Cardiac Toxicity” – Grant Agreement 945175) Mobile App and technologically advanced wearable devices (i.e., the Garmin Venu SQ watch and the Polar h10), the CARDIOCARE prospective study pursues a twofold aim: 1) testing the effectiveness of the CARDIOCARE mobile App to monitor and assess elderly breast cancer patients’ intrinsic capacity and QoL and evaluating CARDIOCARE eHealth interventions effectiveness on these parameters 2) developing a holistic, patient-centred risk prediction model, specific for the detection of cardiotoxicity before it clinically emerges. Methods: The study is prospective and multicentric and involves six clinical and five technical partners across Europe. Seven hundred fifty elderly breast cancer patients (≥ 60years old) are randomised into either the intervention group or the control arm, with only patients in the former receiving access to eHealth psychological, behavioural, and functional interventions implemented on the CARDIOCARE eHealtHeart App. Patients will be recruited in the six clinical centres and will undergo clinical procedures to collect multi-modal data including clinical data, cardiac imaging, biochemical and psychological biomarkers and omics, intrinsic capacity, and QoL indicators, measured at baseline (T0) and every three months, up to 12 months (T5). Results: CARDIOCARE is a project funded by Horizon 2020 and enrollment (WP4) started in May 2023. Recruitment and first data analysis are currently underway. Conclusions: The CARDIOCARE prospective study will contribute to developing new best practice guidelines for managing elderly multimorbid breast cancer patients while preserving their intrinsic capacity and improving their QoL. Furthermore, the CARDIOCARE Mobile App and the wearable devices will allow clinicians to identify trajectories across the cardiotoxicity disease continuum and thus intervene in a preventative way on higher-risk patients. Such a healthcare approach will also benefit the healthcare system, which currently spends almost 40% of its resources on patients over 60, with long-term care and hospital admissions being the primary cost drivers. Trial Registration: NCT06334445 https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al KEYWORDS: breast cancer; elderly; cardiotoxicity; prospective study; eHealth; mobile application; risk prediction model INTRODUCTION Over 50% of newly diagnosed breast cancer patients are older than 65 and are particularly vulnerable to the cardiotoxic effects of cancer treatment and the onset of multiple comorbidities due to age-related risk factors (Reddy et al., 2017; Singh et al., 2018). The cumulative effect of risk factors in the elderly breast cancer patient resembles a “snowball effect”, where baseline age-related risk factors and cancer-related changes are further exacerbated by direct therapy-induced cardiotoxicity (Carioli et al., 2020; Montazeri et al., 2014), resulting in severe multimorbid conditions and mortality. Underestimating the cardiotoxicity risk in this vulnerable population may lead to inappropriate interventions and undertreatment, resulting in poorer health outcomes, Quality of Life (QoL) deterioration, and increased healthcare costs. Considering that elderly cancer patients are systematically underrepresented in clinical trials (Reddy et al., 2017), there are currently limited means to effectively address the complex needs of these patients and their caregivers, often resulting in undertreatment and suboptimal health outcomes, with negative consequences on patients’ QoL (Reddy et al., 2017). Therefore, in line with the World Health Organisation’s view that health is a state of complete physical, mental, and social well-being (World Health Organization, 2006), broader, interdisciplinary, and patient-oriented clinical trials able to provide new evidencebased best practices for managing elderly breast cancer patients are urgently needed. To date, the most effective approach to minimize cardiotoxicity is early detection and early onset of prophylactic treatment. However, although advances have been made in the detection and management of cardiac toxicity based on imaging techniques (i.e., 2D and 3D Echocardiography and cardiac MRI - Magnetic Resonance Imaging), such instruments lack the sensitivity to detect subclinical changes, and indeed detect cardiac toxicity only once a functional impairment emerges, precluding any chance of effective prevention. Moreover, psychological conditions such as depression, distress, and anxiety - often observed in cancer patients after diagnosis (Mohamed et al., 2017) - can increase the risk of cardiovascular complications (Bussotti and Sommalunga, 2018). Furthermore, people presenting negative affectivity and social inhibition are exposed to a higher risk of cardiovascular disease than those not presenting such personality assets and that this kind of negative affectivity is significantly associated with higher systolic and diastolic blood pressure (Denollet et al. 2003; Lin et al. 2020). Similarly, prolonged exposure to stressful life circumstances may predict subsequent hypertension and cardiovascular disease (Rosengren et al., 2004). Therefore, the Integrated Care for Older People (ICOPE) guidelines recommend that ECGs and biomarkers (e.g., troponin I, BNP) assessments, as well as a detailed evaluation of patients’ intrinsic capacity - defined as their overall physical and psycho-social characteristics - are included in a gold-standard follow-up protocol to establish new, holistic, and patient-oriented best practices for the management of elderly cancer patients at risk of cardiotoxic effects associated with https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al oncological treatments (Chianca et al., 2022). NOVELTY AND STUDY AIM So far, no extensive studies have allowed the collection of all necessary data to create a meaningful assessment of elderly breast cancer patients’ intrinsic capacity and QoL. Thus, the CARDIOCARE prospective study will adopt technologically advanced tools to collect a large amount of data on elderly breast cancer patients’ physical, psycho-social, and behavioural parameters to better identify patients at risk of developing cardiotoxicity due to oncological treatments and improve their psychological and physical well-being during and after their oncological care pathway. Since August 2021, a CARDIOCARE retrospective study has been running with breast cancer patients aged ≥ 65 with and without cardiovascular diseases at baseline (T0) and patients ≥ 55 with a breast cancer diagnosis and cardiac damage and toxicity before starting any active treatment for breast cancer. Multimodal retrospective data have been retrieved from existing databases in five of the six clinical centres belonging to the CARDIOCARE consortium (BOCOC, IEO, KSBC, NKUA, and UOI), to develop a risk prediction model for cardiotoxicity in the elderly breast cancer population to be refined and validated through the CARDIOCARE prospective study. In the prospective study, the cardiotoxicity risk prediction model will be enriched with novel biochemical, -omics (metagenomics, microRNA (miRNAs), Single Nucleotide Polymorphisms (SNPs)), and psychological markers to better assess how patients’ intrinsic capacity (physical and mental) and QoL are affected by cancer and anticancer treatments and how they influence the risk of developing cardiac toxicity. Furthermore, the CARDIOCARE prospective study will be the first one to observe, in a clinical study setting, how the gut microbiome of elderly breast cancer patients is affected by different oncological treatments, and if any association exists between the gut microbiome, cardiac toxicity etiopathogenesis and intrinsic capacity, paving the way for future potential biotic treatments. OBJECTIVE(S) AND RATIONALE - Stratify patients aged ≥ 60 with breast cancer based on their risk of developing cardiotoxicity. Rationale: So far, multiple studies have explored the effects of specific risk factors; however, these have yet to deal comprehensively with the impact of clinical, biological, psychological, and behavioural risk factors and their interactions. - Evaluate the effects of eHealth psychological and behavioural interventions on elderly breast cancer patients’ intrinsic capacity and QoL and on their risk of developing cardiac toxicity. Rationale: Although recent studies associate psychosocial and behavioural characteristics with the risk of developing cardiovascular diseases, these studies on elderly patients with breast cancer are still limited (Pedersen et al. 2017). However, gaining such knowledge is necessary to generate hypotheses on using eHealth interventions to support this clinical population. https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al Procedure May be one single or two visits Day 0 Mont h 3 Mont h 6 Mont h 9 Mont h 12 14-25 days after the end of treatment* ** Day -15 T0 (screenin g) T1 (baselin e) Treatme nt start T2 T3 T4 T5 Tn hematology and biochemistry) * ECHO assessment** X X X X§ X ECG assessment X X X X§ X Plasma troponin I level assessment X& X& X X X X Mammography (if patient did not undergo mastectomy) X X Plasma BNP assessment X X X X X Plasma myeloperoxidase and highsensitivity CRP (if available) X X X X X I/E checklist X Collect blood sample for genetic analysis X Collect plasma sample for miRNA analysis X X Collect stool sample X X Oncological treatment (plan/changes), cycle X X X X X X Information on treatment status (ongoing/complete d) X X X X Concomitant medications X X X X X X§ X X Gastrointestinal X X https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al Procedure May be one single or two visits Day 0 Mont h 3 Mont h 6 Mont h 9 Mont h 12 14-25 days after the end of treatment* ** Day -15 T0 (screenin g) T1 (baselin e) Treatme nt start T2 T3 T4 T5 Tn Symptom Rating Score (GSRS) Patient Lifestyle questionnaire X X Verify completion of selfadministered scales/questionnai res (ePsycHeart App) # X X X X X X Cognitive effect assessment (if the center has specialized personnel) X X X Verify collection of data from wearable devices X X Collect information on patient’s out-ofpocket expenses X X Hand Grip Test X X X AE assessment X X X X X X X Legend: ICF: Informed Consent Form BP: Blood Pressure HR: Heart Rate ECHO assessment: Echocardiographic assessment ECG: Electrocardiogram I/E checklist: Inclusion/Exclusion criteria checklist AE: Adverse Events § Only if possible. ¥ These visits can be conducted in presence or remotely, if the center can involve the required experts. The psychological visit consists of meeting the patient in person (if already in the clinical https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al centre) or remotely to touch base about the study: how they feel about it and whether they would like something to be different / modified. Within the visit, a motivational intervention will also be carried out to minimise drop-outs as much as possible. * Including cholesterols, glucose levels and renal and liver function tests, if available: IL-6, TNF- , HRV, CRP, Fibrinogen, and Ferritin.α **Including right and left ventricles dimensions and functions and diastolic function. ***at the first visit after the end of each treatment which should be within 14-25 days. The time of these sample collections will vary in relation to the therapeutic schedule of the patient. # Please refer to Table 2 for the precise list of the questionnaires and scales requested at each time point. & Troponin can be analyzed either at Screening OR at Baseline RECRUITMENT AND FOLLOW-UP Patient recruitment started in May 2023. In October 2023 a new amended version of the protocol (version 1.2) had been approved. The decision to amend the old protocol and create a new version of the Prospective Clinical Study Protocol in the face of emerging new evidence (Booth et al., 2022; Lyon et al. 2022), an amendment was proposed on the definition of cardiotoxicity and on inclusion criteria related to age and treatment. More specifically: - the identification of cardiotoxicity includes also the so-called MACEs - Major Cardiovascular Adverse Effects, and more specifically the intra-patient assessment of MACEs, taxanes and endocrine therapies +/- CDK 4/6 inhibitors were included among the inclusion criteria, - the inclusion criteria of age decrease from =>65 to =>60 years of age. STATISTICAL PROCEDURE STATISTICAL CONSIDERATIONS ON THE DESIGN The primary statistical analysis will use an intention-to-treat (ITT) approach. Therefore, all patients involved in the study will be included in the final analysis. However, based on the literature, patients who do not achieve at least three months of follow-up from the start of treatment will not be included in the analysis (Keramida et al., 2019; Sawaya et al., 2011). Results will be presented using descriptive statistics (mean, standard deviation, median and range for continuous variables, and proportions for nominal variables). Patient baseline characteristics will be compared using a two-sample t-test or a nonparametric test for continuous variables, and Pearson’s Chi-square test will be used for qualitative variables. All statistical analyses will be performed using two-tailed tests and adopting a 5% significance level. The effect of the interventions on the primary endpoint will be analysed using the Cox proportional hazards model. Point estimates and 95% confidence intervals will be calculated for the hazard ratio of the control group versus the experimental group. Any statistically significant difference between the two groups at baseline will be balanced by the multivariable adjustment. A logistic regression or Cox proportional hazards model will also be used to https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al evaluate the effect of the interventions on the secondary endpoints in the two groups. Continuous variables, such as those obtained from imaging and biochemical and molecular biomarkers, will be summarised descriptively at baseline and follow-up visits. The differences between the two groups during the different follow-up visits will be evaluated by the analysis of covariance, considering the respective baseline measurement as a covariant. Finally, for the cost-effectiveness analysis, the health and QoL outcomes that will emerge during the study will be used to calculate the Quality-Adjusted Life-Years (QALYs). The costs will be combined with the QALYs for the cost-utility analysis to estimate the cost-per-QALYs associated with implementing the CARDIOCARE model and the interventions foreseen by it. The Incremental Cost-Effectiveness Ratio (ICER) will also be calculated to evaluate the CARDIOCARE model’s effectiveness compared to current care practices. The ICER, which will be calculated using a threshold approach, will therefore allow us to better understand how to distribute and allocate the different healthcare resources. SAMPLE SIZE CONSIDERATIONS To identify the adequate sample size for the CARDIOCARE prospective study, a power analysis was performed with 2-tailed alpha = 0.05 and 1 - beta = 0.80. Based on that, and considering the 21% incidence of cardiotoxicity in our target population and the expected 10% drop-out rate, it was estimated that a total of 736 patients (that is, 368 patients in the intervention arm and 368 patients in the control arm) would be large enough to detect a 40% relative risk reduction in the incidence of increased levels of troponin I (taken as a cardiotoxicity proxy) in this population. Such a sample size would also allow the evaluation of the effectiveness of the behavioural and psychological interventions integrated into the study in mitigating, preventing, or delaying the onset of cardiotoxicity associated with oncological therapies for elderly breast cancer patients. The sample size calculation was followed by Fisher's exact test, performed using G*Power software version 3.1.9.4. Considering our power analysis results and the number of patients affected by breast cancer each year, all clinical centres in the CARDIOCARE consortium agreed on the final recruitment goal of 750 patients (375 for the intervention arm and 375 for the control one). DATA COLLECTION STORAGE AND SECURITY A well-defined Data Management Plan has been submitted, providing detailed information on the procedures that will be implemented for data collection, storage, protection, retention, reuse and/or destruction, complying with the General Data Protection Regulation (GDPR). By design, a robust data protection and security strategy will be implemented in all data collection and storage procedures in the CARDIOCARE platform. As part of the CARDIOCARE Data Management and High-Performance Computing (HPC), an electronic Case Report Form (eCRF) - accessible by all clinical partners - has been developed to serve as the data entry tool for all patient data. eCRF data will be uploaded and stored encrypted to the platform and systematically backed up in external RAID drives. An audit Log operation will be implemented to view the users’ access history to the system, enabling the detection of any potential data https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al security breaches. After final quality checks at the end of the prospective study, the eCRF will be frozen and exported to the technical partners for statistical analysis performance. All members of the CARDIOCARE consortium will take appropriate organisational and technical measures to prevent any event of abuse, accidental loss, destruction, or damage of collected data, enabling reinstate the system promptly if necessary. Data quality, completeness and integrity will be ensured with visits by the Independent Data Monitoring Committee (IDMC) members, who will certify, in each clinical centre, the files’ consistency, adherence to the study protocol and Good Clinical Practice guidelines, the accuracy of the eCRF forms, and the compliance with safety reporting. Investigators of each clinical centre will facilitate the IDMC members’ jobs by cooperating and enabling direct access to all data sources to be verified. Strict confidentiality of all personal and study-related data is ensured. All recruiting centres will sign an agreement document detailing their commitment towards complying with the relevant laws, regulations, codes of practice and obligations to publication. ETHICS COMPLIANCE All involved clinical centres submitted the new version (1.2) of the CARDIOCARE prospective study protocol to their Ethics Committees and got official approval. This multicentric prospective study has been designed to comply with national (i.e., Good Clinical Practices) and international declarations (i.e., the Declaration of Helsinki) regulating proper ethical research involving human subjects, with Written Informed Consent which will be obtained from all participating patients. In particular, the study conduct is in line with the following regulations and norms: - The Declaration of Helsinki, ethical principles for medical research involving human subjects, revised October 2013. - The Convention for the Protection of Human Rights and Dignity of the Human Being concerning the Application of Biology and Medicine: Convention on Human Rights and Biomedicine, Oviedo 1997. - The Council for International Organizations of Medical Sciences, in collaboration with the World Health Organization, International Ethical Guidelines for Biomedical Research Involving Human Subjects, revised in 2016. - The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Biomedical and Behavioral Research. Department of Health, Education, and Welfare (DHEW) publication (DHEW-05-78-0012), Washington, DC, 1978. RESULTS The active phase of the recruitment process began in May 2023 and preliminary results will be published in a scientific journal and made available for consultation on the CARDIOCARE project website. Data analysis and dissemination of the study results will be performed in 2024 and 2025. https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al DISCUSSION The CARDIOCARE risk prediction model for cardiac toxicity will allow healthcare providers to identify and monitor trajectories across the field of cardiotoxicity and thus advise and intervene promptly on high-risk patients while saving resources on those presenting a low risk of developing cardiotoxicity. The model will be particularly tailored to detect the risk for cardiotoxicity in elderly breast cancer patients, that are at almost the same risk of cardiovascular disease as breast cancer relapse (Bardia et al. 2012; Park et al. 2017). Furthermore, even when not fatal, elderly breast cancer women are especially prone to develop cardiac morbidity as a collateral effect of oncological treatments (Zagar et al., 2016). Indeed, in this clinical population, cancer treatment cardiotoxic effects are often added to baseline agerelated factors and pre-existing morbidity, leading to drug interaction complications resulting from polypharmacy (Chang et al., 2019; Mandelblatt et al., 2018), poorer health outcomes, and intrinsic capacity and QoL deterioration (Depboylu, 2020). Considering the above, the CARDIOCARE mobile App, with its contents and health monitoring system, will provide elderly breast cancer women with the opportunity to learn how to best manage their multimorbidity while preserving and enhancing their physical and psychological intrinsic capacity as well as their overall QoL, including their relationship with others. They will also benefit from the continuous and home-based care that the mobile App allows by notifying them promptly when one or more health parameters are sub-optimal, clinician-developed suggestions on how to intervene to improve such parameters will follow right after. In addition, the present study gives an opportunity to test the feasibility of digital tools (devices and mobile application) among this specific population of elderly patients (>=60) and identify the possible areas that need improvement so that, in the future, these types of digital tools and interventions can be successfully applied to the specific segment of patients considered here. Healthcare providers will also vastly benefit from the health monitoring and technologically advanced tools employed for the current prospective study. Such devices, including the Mobile App, will provide clinicians with information on their patients’ health, more integrated than the information they can obtain through standard Electronic Health Records (EHR) tools. The CARDIOCARE Mobile App and the wearable devices used for the study will, indeed, inform healthcare providers about several characteristics of their patients (psychological, behavioural, cognitive, and functional) which, based on the most updated scientific literature, are particularly relevant to determine the risk of elderly breast cancer patients of developing cardiac toxicity when exposed to oncological therapy (Bussotti and Sommalunga, 2018; Wang et al., 2023; Chan et al., 2023; Hill et al., 2023). Furthermore, by being informed on their patients’ intrinsic capacity (physical and psychological) and other QoL-related aspects, healthcare providers can more easily and quickly identify each patient’s care gaps and specific needs, and develop new and more integrated best practices, facilitating the implementation of personalised, patient-centred care. The innovative CARDIOCARE model of care and its risk prediction model for cardiac toxicity hold promise from a socio-economic perspective as well. It is to be underlined that almost 40% of public spending in the healthcare sector concerns people over 60, with long-term care and hospital admissions being the primary cost drivers (Joling et al., 2018). Since healthcare https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al systems that successfully provide effective community-based care and services are likely to significantly optimise their public spending (Joling et al., 2018), healthcare institutions and insurance companies are seeking new ways to decrease treatment costs for chronic diseases such as cancer. Moreover, previous research has highlighted considerably higher mortality rates among breast cancer patients with low socio-economic status (i.e., education, employment, income) compared to those whose socio-economic status is higher (Yu, 2009; Lundqvist et al., 2016). This is a critical datum, since socio-economic disadvantage may result in later-stage diagnosis and poorer access to and quality of care received. Using technologically advanced tools - provided to patients by the clinical centres - able to consistently monitor several health parameters beyond the time the patient stays at the clinical centre, the CARDIOCARE healthcare model attempts, on the one hand, to address the economic and societal challenges that afflict both our healthcare system finances and the patients in the lower socio-economic groups. Additionally, once the prospective study is concluded and the data analysed, a costeffectiveness analysis will be performed, comparing the CARDIOCARE healthcare model to current practices. ACKNOWLEDGEMENTS This work has been funded the European Union’s Horizon 2020 Research and Innovation Program under Grant Agreement No 945175. CONFLICTS OF INTEREST The authors have no conflicts of interest to declare. All co-authors have seen and agree with the contents of the manuscript and there is no financial interest to report. REFERENCES 1. Bardia, A., Arieas, E. 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Breast cancer therapy-associated cardiovascular disease.XNature reviews Clinical oncology,X13(3), 172-184. https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint] JMIR Preprints Sacco et al ABBREVIATIONS CV: Cardiovascular ICF: Informed Consent Form BP: Blood Pressure HR: Heart Rate ECHO assessment: Echocardiographic assessment ECG: Electrocardiogram I/E checklist: Inclusion/Exclusion criteria checklist AE: Adverse Event BPN: Brain Natriuretic Peptide CRP: C-Reactive Protein CRS: Cardio Recording Session HGS: Hand Grip Session QoL: Quality of Life Cardiac MRI: Cardiac Magnetic Resonance Imaging miRNA: microRNA SNP: Single Nucleotide Polymorphism eCRF: electronic Case Report Form HER2: Human Epidermal Growth Factor Receptor 2 EW = Expressive Writing BPS = Best Possible Self ABCDE: A = Activating event or situation; B = Beliefs; C = Consequences; D = Disputation of beliefs; E = Effective new approach GSRS: Gastrointestinal Symptom Rating Score ITT approach: Intention-to-treat approach QALYs: Quality-Adjusted Life-Years ICER: Incremental Cost-Effectiveness Ratio GDPR: General Data Protection Regulation HPC Platform: High-Performance Computing platform IDMC: Independent Data Monitoring Committee EHR: Electronic Health Records APPENDIX Table 2. Self-administered scales for each study time points Psychological and behavioral assessment May be one single or two visits Day 0 Mont h 3 Mont h 6 Mont h 9 Mont h 12 Day -15 T0 T1 (baseline ) Treatmen t start T2 T3 T4 T5 https://preprints.jmir.org/preprint/63455 [unpublished, non-peer-reviewed preprint]