• Change in health-related quality of life assessed by the Functional Assessment of Cancer Therapy - Breast plus Arm Morbidity (FACT-B+4) questionnaire [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Score achieved in the Functional Assessment of Cancer Therapy - Breast plus Arm Morbidity (FACT-B+4) questionnaire, a specific validated scale to assess quality of life of women with breast cancer. It comprises 27 items within 5 areas of assessment: physical well-being (7 items), social and family environment (7 items), emotional well-being (7 items), functional well-being (6 items) and worries related to the diagnosis and treatment of the disease (9 items). Each item is scored by means of a Likert scale from 0 to 5, with higher scores representing better results. The total score is obtained by adding the scores for each item, and ranges from a minimum of 0 (worst posible result) to a maximum of 146 (best possible result).
• Change in tolerance to chemotherapy: number of participants with significant cardiovascular and non-cardiovascular adverse effects throughout the study [ Time Frame: Every 3 months during study completion and at the end of the study at an average of 18 months ]
  Significant cardiovascular and non-cardiovascular adverse effects during treatment, threatening life, requiring admission, prolonging hospitalization, being clinically relevant or causing chemotherapy interruptions
• Change in global functional capacity assessed by conventional ergometry, cardiopulmonary exercise testing (CPET) or the 6-minute walking test (6MWT). [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Change in functional capacity assessed by conventional ergometry, cardiopulmonary exercise test or the 6-minute walking test (6MWT) (metabolic equivalents: METs or peak oxygen consumption: VO2) * . *Due to COVID-19 pandemic, participants' assessment with CPET had to be stopped for safety concerns. In such cases, functional capacity was estimated from the maximum work rate in the 6-minute walking test (6MWT). This test measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes, which is well correlated with VO2. The 6MWT has been proved to be valid and reliable for functional capacity assessment in the study population.
• Change in localized lower limb functional capacity assessed by number of repetitions performed within 30 seconds in the sit-to-stand test [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Number of repetitions in the sit-to-stand test within 30 seconds
• Change in shoulder functional capacity assessed by range of degrees in shoulder movement by goniometry [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Range of degrees in shoulder movement measured by goniometry
• Change in upper limb strength measured by dynamometry (kg) [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Kilograms by dynamometry of right and left upper limbs
• Change in shoulder pain and disability assessed by the SPADI (shoulder pain and disability index (SPADI) questionnaire [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Score achieved in the SPADI (shoulder pain and disability index) questionnaire. The pain dimension consists of five questions regarding the severity of an individual's pain, functional activities are assessed with eight questions. Each question may be scored from 0 to 10. Verbal anchors for the pain dimension are 'no pain at all' (0) and 'worst pain imaginable' (10) ,and those for the functional activities are 'no difficulty' (0) and 'so difficult it required help' (10). The scores from both dimensions are averaged to produce a total score ranging from 0 (best) to 100 (worst).
• Change in cardiovascular risk profile as assessed by the presence or absence of classic cardiovascular risk factors [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Dyslipidemia, Diabetes mellitus, Arterial Hypertension, Smoking status
• Change in anthropometric parameters: height in cm [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Height measured in cm
• Change in anthropometric parameters: weight in kg [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Weight measured in kg
• Change in anthropometric parameters: body mass index (BMI) in kg/m^2 [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Weight and height will be combined to report BMI in kg/m^2
• Change in anthropometric parameters: abdominal circumference in cm [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Abdominal perimeter measured with a tape measure in cm
• Change in resting heart rate measured by pulse oximetry (beats per min) [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Resting heart rate by pulse oximetry (beats per min)
• Change in resting blood pressure (mmHg) measured by sphygmomanometer [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Resting blood pressure by sphyngomanometer in mmHg
• Change in biomarkers NT-ProBNP [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Value of NT-ProBNP(pg/mL) in blood tests
• Change in biomarkers: troponin [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Value of troponin I (ng/mL) in blood tests
• Change in biomarkers: haemoglobin [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Value of haemoglobin (g/dL) in blood tests
• Change in dietary pattern as assessed by the PREDIMED (PREvención con DIeta MEDiterránea) questionnaire [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Validated questionnaire to assess adherence to Mediterranean diet, including 14 questions regarding dietary habits, rated with 0 or +1 points. Global score is calculated by summing points and ranges from 0 to 14, with higher score representing higher adherence.
• Change in the score for depression assessed by Zigmond and Snaith questionnaire to rate anxiety and depression [ Time Frame: Baseline and at study completion at an average of 18 months, plus at the end of training (at an average of 12 to 15 months) in the intervention group ]
  Score achieved in the depression subscale of the Zigmond and Snaith test for anxiety or depression, a self-applied questionnaire. Depression scale includes 7 items each, scored on Likert scale from 0 to 3. Global score ranges from 0 to 21, with higher scores representing greater depression. The authors suggest that scores higher than eleven would indicate "case" and more than eight would be considered "probable case" (Zigmond and Snaith, 1983).
• Change in the score for anxiety assessed by the Zigmond and Snaith questionnaire to rate depression and anxiety [ Time Frame: Baseline and at study completion, plus at the end of training (at an average of 12 to 15 months) in the intervention group ]
  Score achieved in the anxiety subscale of the Zigmond and Snaith test for anxiety or depression, a self-applied questionnaire. Anxiety scale includes 7 items each, scored on Likert scale from 0 to 3. Global score ranges from 0 to 21, with higher scores representing greater anxiety. The authors suggest that scores higher than eleven would indicate "case" and more than eight would be considered "probable case" (Zigmond and Snaith, 1983).
• Change in physical activity (minutes of dedicated physical activity) [ Time Frame: Baseline and at study completion at an average of 18 months ]
  Minutes of In- and out-of-hospital dedicated physical activity
• Change in physical activity assessed by the score in the Godin Leisure Test Exercise Questionnaire (GLTEQ) [ Time Frame: Baseline and at study completion at an average of 18 months ]
  Score achieved in the Godin Leisure Test Exercise Questionnaire (GLTEQ) for quantification of physical activity. Activities are classified into three subgroups: "strenuous," "moderate," and "light." The scores corresponding to the energy expenditure (metabolic equivalent (MET)) are obtained by multiplying activities performed for more than 15 min in a week with their coefficients. The numbers represent the MET intensity values (strenuous/ exhausting exercises: 9 METs, moderate exercises: 5 METs, and light exercises: 3 METs).The increasing scores are associated with the increasing number of exercise behaviors, providing references about the contribution of physical activity to health: the activity score of 24 units and more as active (substantial benefits); the activity score of 14-23 units as moderately active (some benefits); and the activity score of 13 units and less as inactive (less substantial or low benefits).
• Change in lymphedema assessed by perimeter of the upper limb by cirtometry (cm), stage and grade [ Time Frame: Baseline after surgery and 2-4 weeks after the end of chemotherapy (at an average of 12 to 15 months) ]
  Perimeter of the upper limb by cirtometry (cm), stage and grade as defined by the Spanish Society of Rehabilitation and Physical Medicine

• Change in health-related quality of life assessed by the Functional Assessment of Cancer Therapy - Breast plus Arm Morbidity (FACT-B+4) questionnaire [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Score achieved in the Functional Assessment of Cancer Therapy - Breast plus Arm Morbidity (FACT-B+4) questionnaire, a specific validated scale to assess quality of life of women with breast cancer. It comprises 27 items within 5 areas of assessment: physical well-being (7 items), social and family environment (7 items), emotional well-being (7 items), functional well-being (6 items) and worries related to the diagnosis and treatment of the disease (9 items). Each item is scored by means of a Likert scale from 0 to 5, with higher scores representing better results. The total score is obtained by adding the scores for each item, and ranges from a minimum of 0 (worst posible result) to a maximum of 146 (best possible result).
• Change in tolerance to chemotherapy: number of participants with significant cardiovascular and non-cardiovascular adverse effects throughout the study [ Time Frame: Every 3 months during study completion and at the end of the study at an average of 18 months ]
  Significant cardiovascular and non-cardiovascular adverse effects during treatment, threatening life, requiring admission, prolonging hospitalization, being clinically relevant or causing chemotherapy interruptions
• Change in global functional capacity assessed by conventional ergometry or cardiopulmonary exercise testing (CPET) [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Change in functional capacity assessed by conventional ergometry or cardiopulmonary exercise test (metabolic equivalents: METs or peak oxygen consumption: VO2)
• Change in localized lower limb functional capacity assessed by number of repetitions performed within 30 seconds in the sit-to-stand test [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Number of repetitions in the sit-to-stand test within 30 seconds
• Change in shoulder functional capacity assessed by range of degrees in shoulder movement by goniometry [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Range of degrees in shoulder movement measured by goniometry
• Change in upper limb strength measured by dynamometry (kg) [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Kilograms by dynamometry of right and left upper limbs
• Change in shoulder pain and disability assessed by the SPADI (shoulder pain and disability index (SPADI) questionnaire [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Score achieved in the SPADI (shoulder pain and disability index) questionnaire. The pain dimension consists of five questions regarding the severity of an individual's pain, functional activities are assessed with eight questions. Each question may be scored from 0 to 10. Verbal anchors for the pain dimension are 'no pain at all' (0) and 'worst pain imaginable' (10) ,and those for the functional activities are 'no difficulty' (0) and 'so difficult it required help' (10). The scores from both dimensions are averaged to produce a total score ranging from 0 (best) to 100 (worst).
• Change in cardiovascular risk profile as assessed by the presence or absence of classic cardiovascular risk factors [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Dyslipidemia, Diabetes mellitus, Arterial Hypertension, Smoking status
• Change in anthropometric parameters: height in cm [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Height measured in cm
• Change in anthropometric parameters: weight in kg [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Weight measured in kg
• Change in anthropometric parameters: body mass index (BMI) in kg/m^2 [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Weight and height will be combined to report BMI in kg/m^2
• Change in anthropometric parameters: abdominal circumference in cm [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Abdominal perimeter measured with a tape measure in cm
• Change in resting heart rate measured by pulse oximetry (beats per min) [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Resting heart rate by pulse oximetry (beats per min)
• Change in resting blood pressure (mmHg) measured by sphygmomanometer [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Resting blood pressure by sphyngomanometer in mmHg
• Change in biomarkers NT-ProBNP [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Value of NT-ProBNP(pg/mL) in blood tests
• Change in biomarkers: troponin [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Value of troponin I (ng/mL) in blood tests
• Change in biomarkers: haemoglobin [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Value of haemoglobin (g/dL) in blood tests
• Change in dietary pattern as assessed by the PREDIMED (PREvención con DIeta MEDiterránea) questionnaire [ Time Frame: Baseline and at the end of the study at an average of 18 months ]
  Validated questionnaire to assess adherence to Mediterranean diet, including 14 questions regarding dietary habits, rated with 0 or +1 points. Global score is calculated by summing points and ranges from 0 to 14, with higher score representing higher adherence.
• Change in the score for depression assessed by Zigmond and Snaith questionnaire to rate anxiety and depression [ Time Frame: Baseline and at study completion at an average of 18 months, plus at the end of training (at an average of 12 to 15 months) in the intervention group ]
  Score achieved in the depression subscale of the Zigmond and Snaith test for anxiety or depression, a self-applied questionnaire. Depression scale includes 7 items each, scored on Likert scale from 0 to 3. Global score ranges from 0 to 21, with higher scores representing greater depression. The authors suggest that scores higher than eleven would indicate "case" and more than eight would be considered "probable case" (Zigmond and Snaith, 1983).
• Change in the score for anxiety assessed by the Zigmond and Snaith questionnaire to rate depression and anxiety [ Time Frame: Baseline and at study completion, plus at the end of training (at an average of 12 to 15 months) in the intervention group ]
  Score achieved in the anxiety subscale of the Zigmond and Snaith test for anxiety or depression, a self-applied questionnaire. Anxiety scale includes 7 items each, scored on Likert scale from 0 to 3. Global score ranges from 0 to 21, with higher scores representing greater anxiety. The authors suggest that scores higher than eleven would indicate "case" and more than eight would be considered "probable case" (Zigmond and Snaith, 1983).
• Change in physical activity (minutes of dedicated physical activity) [ Time Frame: Baseline and at study completion at an average of 18 months ]
  Minutes of In- and out-of-hospital dedicated physical activity
• Change in physical activity assessed by the score in the Godin Leisure Test Exercise Questionnaire (GLTEQ) [ Time Frame: Baseline and at study completion at an average of 18 months ]
  Score achieved in the Godin Leisure Test Exercise Questionnaire (GLTEQ) for quantification of physical activity. Activities are classified into three subgroups: "strenuous," "moderate," and "light." The scores corresponding to the energy expenditure (metabolic equivalent (MET)) are obtained by multiplying activities performed for more than 15 min in a week with their coefficients. The numbers represent the MET intensity values (strenuous/ exhausting exercises: 9 METs, moderate exercises: 5 METs, and light exercises: 3 METs).The increasing scores are associated with the increasing number of exercise behaviors, providing references about the contribution of physical activity to health: the activity score of 24 units and more as active (substantial benefits); the activity score of 14-23 units as moderately active (some benefits); and the activity score of 13 units and less as inactive (less substantial or low benefits).
• Change in lymphedema assessed by perimeter of the upper limb by cirtometry (cm), stage and grade [ Time Frame: Baseline after surgery and 2-4 weeks after the end of chemotherapy (at an average of 12 to 15 months) ]
  Perimeter of the upper limb by cirtometry (cm), stage and grade as defined by the Spanish Society of Rehabilitation and Physical Medicine

• Adherence and compliance to cardiac rehabilitation program (intervention group) assessed by number of training sessions attended/ number of sessions planned [ Time Frame: At the end of the cardiac rehabilitation program at an average of 12 to 15 months ]
  Number of training sessions attended / number of sessions planned
• Security of the cardiac rehabilitation program assessed by number of adverse events during training (intervention group) [ Time Frame: At the end of the cardiac rehabilitation program at an average of 12 to 15 months ]
  Adverse events during training
• Changes in expectations regarding the cardiac rehabilitation program assessed by a questionnaire (intervention group) [ Time Frame: Baseline and at the end of the cardiac rehabilitation program at an average of 12 to 15 months ]
  Program-related expectations at baseline and at the end of the program' are collected through an open question "What do you expect to achieve by participating in the program?" Responses regarding expectations will be categorized by the evaluator within the following areas: psychological sphere and/or social sphere and/or physical sphere. Global expectations of benefit are scored from 0 (no benefit) to 10 (highest benefit).
• Satisfaction with the cardiac rehabilitation program assessed by a questionnaire (intervention group) [ Time Frame: At the end of the cardiac rehabilitation program at an average of 12 to 15 months ]
  Satisfaction at the end of the program is assessed by a questionnaire including 9 questions concerning comfort with training sessions, training spaces and development of the program, which are scored from 0 (worse posible result) to 10 (best posible result). Total score is calculated by adding for each question, and ranges from 0 to 90. * Due to the introduction of telematic exercise training during COVID-19 pandemic, questions were slightly modified to include assessment of satisfaction with this training modality.

• Adherence and compliance to cardiac rehabilitation program (intervention group) assessed by number of training sessions attended/ number of sessions planned [ Time Frame: At the end of the cardiac rehabilitation program at an average of 12 to 15 months ]
  Number of training sessions attended / number of sessions planned
• Security of the cardiac rehabilitation program assessed by number of adverse events during training (intervention group) [ Time Frame: At the end of the cardiac rehabilitation program at an average of 12 to 15 months ]
  Adverse events during training
• Changes in expectations regarding the cardiac rehabilitation program assessed by a questionnaire (intervention group) [ Time Frame: Baseline and at the end of the cardiac rehabilitation program at an average of 12 to 15 months ]
  Program-related expectations at baseline and at the end of the program' are collected through an open question "What do you expect to achieve by participating in the program?" Responses regarding expectations will be categorized by the evaluator within the following areas: psychological sphere and/or social sphere and/or physical sphere. Global expectations of benefit are scored from 0 (no benefit) to 10 (highest benefit).
• Satisfaction with the cardiac rehabilitation program assessed by a questionnaire (intervention group) [ Time Frame: At the end of the cardiac rehabilitation program at an average of 12 to 15 months ]
  Satisfaction at the end of the program is assessed by a questionnaire including 9 questions concerning comfort with training sessions, training spaces and development of the program, which are scored from 0 (worse posible result) to 10 (best posible result). Total score is calculated by adding for each question, and ranges from 0 to 90.

Cardiovascular toxicity caused by chemotherapy is the leading cause of death in patients who survive cancer. Physical exercise during chemotherapy has shown to improve quality of life and decrease the risk of death. The objective of this project is to determine whether an intervention through a comprehensive cardiac rehabilitation program including supervised physical exercise is able to prevent anthracyclines and / or anti-HER-2 antibodies-induced cardiotoxicity in women with breast cancer.

For this purpose, the investigators intend to conduct a randomized controlled study including female patients managed under the same cardiotoxicity prevention protocol (clinical, laboratory and echocardiographic follow-up assessment). Patients will be randomized to a non-pharmacological intervention (participation in a multidisciplinary cardiac rehabilitation program with supervised exercise training) or control (conventional management and physical activity recommendation)*.

The investigators hypothesize that a cardiac rehabilitation program may limit chemotherapy-induced cardiotoxicity in women with breast cancer, improve cardiac remodeling assessed by echocardiography and enhance their global cardiovascular risk profile to a greater extent, compared to control group.

* OF NOTE: Due to the COVID-19 pandemics, several modifications to the original protocol were introduced for safety reasons or motivated by the health situation, namely:

1. Intervention: Change from centre-based to telematic supervised exercise training sessions provided within the cardiac rehabilitation program (intervention group)
2. Secondary outcome 4: Change in functional capacity assessed by conventional ergometry or cardiopulmonary exercise test OR the 6-minute walking test (metabolic equivalents: METs or peak oxygen consumption: VO2)
3. Recruiting centres: One centre (Hospital Universitari Vall d'Hebron) withdrew from the study due to the impossibility of assuming its execution.

• Cardiotoxicity
• Cardiac Rehabilitation

• Experimental: Cardiac Rehabilitation
  Patients enrolled in the integrated exercise-based cardiac rehabilitation program (centre-based or telematic)
  Intervention: Other: Cardiac rehabilitation
• No Intervention: Conventional management
  Patients with conventional management and physical activity recommendation

Inclusion Criteria:

• First diagnosis of breast cancer at early stages (I, II, III)
• Treatment with anthracyclines and / or anti-HER-2 antibodies (trastuzumab and / or pertuzumab)
• Possibility of completing a cardiac rehabilitation program (centre-based or telematic) and programmed visits.
• Providing written informed consent.

Exclusion Criteria:

• Patients with previous history of heart disease or heart failure.
• Left ventricular dysfunction (left ventricular ejection fraction <53%) at baseline.
• Metastatic disease.
• Patients carrying an implantable cardioverter defibrillator.
• Patients with physical or mental limitation to carry out an exercise program.