Cardiotoxicity of breast cancer drug treatments

Highlights

• •Some breast cancer therapies increase cardiotoxicity/cardiovascular complication risk.
• •Mechanisms include blockage of HER2 which has underlying cardioprotective properties.
• •This clinical trial systematic review summarises treatment cardiovascular effects.

Abstract

Breast cancer (BC) is a leading cause of cancer-related mortality among women worldwide. BC is regarded as a systemic disease. Consequently, the majority of BC patients undergo systemic therapy to reduce the risk of distant metastasis (DM) and associated mortality. Although systemic therapies improve patients’ outcome, they are associated with significant side effects, particularly cardiotoxicity and cardiovascular complications. Such side effects vary significantly in severity and duration. Cardiotoxicity may remain undetected for years post-treatment until the symptoms of heart failure (HF) present in the patient, which can reduce life expectancy, quality of life, and even lead to death. Therefore, it is vital to investigate the cardiotoxic and cardiovascular risks of BC treatment regimens to identify patients who would benefit most from cardiac monitoring. As it stands, cardiotoxicity is reported from individual studies or for selected drug therapies only. This review fulfils a gap in the literature by combining clinical studies of cardiotoxicity together from clinical trial data published on clinicaltrials.gov.uk.

Graphical abstract

Introduction

Breast cancer (BC), the most common cancer in women and second leading cause of cancer associated mortality, is considered a systemic disease. Although standard staging techniques do not detect metastatic disease in the majority of cases at initial diagnosis, the epidemiology and pattern of metastatic disease and the detection of circulating tumour cells in early-stage disease suggest that some tumour cells escape the primary tumour prior to surgical resection [1]. As current clinical stratification of BC cannot accurately identify patients at high risk of distant metastasis (DM), the majority of BC patients receive systemic therapies. Pharmacological treatment of BC (Fig. 1) is determined by the patient's risk-benefit ratio and depends on multiple factors including tumour burden, patient's health, age, menopausal status and personal preferences [2].

Fig. 1.

An overview of breast cancer treatment by subtype. HR+ (ER+/PR+) = hormone positive breast cancers; HER2+ (human epidermal growth factor receptor 2 positive breast cancer); TNBC = triple negative breast cancer; ET= endocrine therapy; ChT = chemotherapy; RT = radiotherapy; OFS = ovarian function suppression. Treatment shown for early and metastatic breast cancer with fundamental differences explained in terms of goals of treatment and use of the different therapies involved. T1 (T1a, T1b, and T1c): tumour is 2 cm or less. T2: tumour is more than 2cm but less than 5cm. N0: cancer not spread to nearby lymph nodes. N+: cancer spread to the nearby lymph nodes. Image created in CorelDRAW.

The most concerning side effects of cancer therapy include cardiotoxicity, cardiac dysfunction and heart failure (HF) - a slowly progressing condition which can reduce quality of life and increase mortality [3,4]. Although BC patient outcomes have improved, and patients are living longer, they have increased risks of developing cardiovascular co-morbidities due to chemotherapy adverse effects [5]. Cardiovascular disease (CVD) is a leading cause of death in developed nations with an estimated 19 million deaths in 2020 [5]. Therefore, early detection of cardiotoxicity caused by BC treatments is essential to support implementation of early interventions to prevent further cardiovascular damage. In addition, the pharmacogenetic risks of CVD chemotoxicity have distinct frequencies in women of African descent, alongside altered tumour biology [6,7]. Further impacts of race and ethnicity are emerging [8], including limitations in biospecimens and clinicopathological and genetic data, from diverse populations [9], and this likely extends into BC cardiotoxicity trials.

Cardiotoxicity describes functional and/or structural damage to the heart by external stimuli which can result in cardiac dysfunction and myocardial damage [10]. Clinical manifestations of cardiotoxicity can include, but are not limited to, arrythmias, cardiomyopathy, decreased left ventricular ejection fraction (LVEF), acute coronary syndromes (ACS) and HF [11]. There are several definitions of therapy associated cardiotoxicity. The “American Society of Echocardiology and European Association of Cardiovascular Imaging” published an expert consensus defining cancer therapeutics related cardiac dysfunction (CTRCD) as LVEF decreasing >10 percentage points, with a final value of <53 % [12]. The ‘Cardiac Review and Evaluation Committee of Trastuzumab-associated Cardiotoxicity’ defined the phenomenon as a LVEF reduction of ≥5 %-<55 % with symptoms of HF or asymptomatic reduction of LVEF of ≥10 % to a final value of <55 % [13]. Whilst LVEF is diagnosed using cardiac imaging such as 2D echocardiography, the cut off value for LVEF is still under debate and values differ between studies.

Two overall types of cardiotoxicities have been proposed. Type 1 is dose dependent, causing irreversible cardiac damage, often associated with a class of drugs called anthracyclines. Type 1 cardiotoxicity is caused by cardiomyocyte injury leading to cell death. It can be categorised as acute (occurring <1 week of therapy) where abnormalities can be detected via electrocardiography (ECG), or chronic (within a year or after) [14]. Type 2 is non-dose dependent and reversible, with no structural changes to the myocytes. Trastuzumab, for example, causes asymptomatic type 2 cardiotoxicity, changes in LVEF are the only detection method currently [14]. Due to its reversibility, cardiotoxicity can be halted by pausing treatment until the patient's cardiac profile improves [15,16]. These two classifications do have limitations and exceptions. For example, anthracycline cardiotoxicity can be reversible if detected within 3–6 months of a decline in ejection fraction [17], and would not therefore always be classified as type 1. Trastuzumab is most frequently type 2 but can cause irreversible damage in patients with pre-existing cardiac diseases [15]. Therefore, having a better understanding of how cancer therapies can affect the heart will help clinicians make informed choices to reduce or prevent cardiotoxicity. This systematic review summarises the cardiovascular effects of current BC drug treatments based on clinical trial data.

Methods

This systematic clinical trial data review extrapolated cardiotoxic effects of current BC treatments. Appendix 1 and the PRISMA flowchart (Fig. 2) provide the full details of the study review process. All published studies were included in this systematic review as per the criteria in Fig. 2. Table 1 provides clinical trial details.

Fig. 2.

PRISMA flowchart showing the study selection process to identify relevant clinical trials reporting on the cardiac safety of breast cancer treatments. Image created in CorelDRAW.

Table 1.

A summary of the clinical trials investigating the cardiac safety of treatments in breast cancer. Source information: ClinicalTrials.govID. The number of participants stated is the number of participants included in the study, not the number of participants analysed.

Clinical trial ID	No of participants (n=)	Drug and dose	Cardiac symptoms investigated	Result
1. NCT00542451	406 with node negative HER2+ BC	80 mg of Paclitaxel per m2 BSA weekly for 12 weeks and a loading dose of 4 mg of IV Trastuzumab per kg of bodyweight on day 1, followed by 2 mg/kg weekly, total of 12 doses. After 12 weeks of Trastuzumab, the dose could be continued weekly, or the regimen could be changed to 6 mg/kg every 3 weeks to complete a full year of IV treatment with Trastuzumab.	Grade III/IV cardiac LVD related AEs.	2/406 (0.5 %) of participants experienced LVD associated adverse effects.
2. NCT00374322	3166 early BC	Lapatinib Arm: 1500 mg of Lapatinib orally once a day for 12 months. Placebo: matching placebo orally once daily for 12 months	Primary cardiac event: cardiac death (due to HF, myocardial infarction, or arrhythmia; or probable cardiac death defined as sudden, unexpected death within 24 h of a definite or probable cardiac event); severe symptomatic CHF (as per New York Heart Association [NYHA] Class III or IV and an absolute decrease in LVEF of more than 10 percentage points from Baseline and to a LVEF value below 50 %). Secondary cardiac event: asymptomatic or mildly symptomatic cardiac events (NYHA Class I or II) and a significant decrease in LVEF, defined as an absolute decrease in LVEF of more than 10 percentage points from Baseline and to an LVEF value below 50 %	Lapatinib Arm (n = 1573): No patients experienced cardiac death, 2 patients had severe symptomatic CHF and 6 patients had a secondary cardiac event. Placebo Arm (n = 1574): 1 patient experienced cardiac death, 3 patients experienced severe symptomatic CHF and 6 patients had a secondary cardiac event
3. NCT02445586	52 HER+ advanced BC	Docetaxel: dose in line with local prescribing guidelines Pertuzumab: 840 mg IV loading dose on day 1 of the first treatment cycle (1 cycle=21 days) followed by 420 mg IV every 3 weeks. Trastuzumab: IV loading dose of 8 mg/kg on day 1 of cycle 1 (1 cycle=21 days) then IV 6 mg/kg every 3 weeks	CHF	0/52 patients exhibited CHF (from baseline until end of study, approximately up to 3 years
4. NCT00045032 (HERA)	5099 with HER2+ primary BC	Trastuzumab loading dose of 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and continued every 3 weeks for 1 year (or 2 years in Arm 2) or until disease recurrence, whichever occurred first	Primary endpoint: symptomatic New York Heart Association (NYHA) Class III or IV CHF confirmed by a cardiologist with a drop in LVEF at least 10 percentage points from Baseline and to a value less than (<) 50 %, and documentation of definite or probable cardiac death. Definite cardiac death included CHF, myocardial infarction, or primary arrhythmia. Probable cardiac death included unexpected sudden death within 24 h of a cardiac event (syncope, cardiac arrest, chest pain, infarction, arrhythmia) without documented aetiology. Secondary: NYHA Class I or II CHF with a drop in LVEF measured by MUGA scans/ECG, unless the subsequent assessment of LVEF indicated a return to levels that did not meet the definition of a significant LVEF drop. A significant LVEF drop was defined as an absolute reduction of at least 10 percentage points from baseline and to a value <50 %	Observation group (n = 1744): 0.11 % experienced primary cardiac event, 0.86 % experienced secondary cardiac event. Arm 1 (1-year Trastuzumab therapy) (n = 1682): 1.07 % experienced primary cardiac event and 4.4 % experienced secondary cardiac event. Arm 2 (2-year Trastuzumab therapy) (n = 1673): 1.02 % experienced primary cardiac event and 7.29 % experienced secondary cardiac event
5. NCT00553358 (NeoALLTO)	455 HER2+ with primary BC	Arm 1: Oral Lapatinib 1000 mg daily plus Trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly maintenance dose for 6 weeks. This was followed by Lapatinib 750 mg daily plus Trastuzumab (2 mg/kg IV weekly) plus weekly Paclitaxel (80 mg/m2 IV) for a further 12 weeks. Arm 2: Oral Lapatinib 1500 mg daily for 6 weeks, followed by Lapatinib plus weekly Paclitaxel (80 mg/m2 IV) for a further 12 weeks. Arm 3: Trastuzumab 4 mg/kg IV loading dose followed by weekly 2 mg/kg IV for 6 weeks, followed by Trastuzumab plus weekly Paclitaxel (80 mg/m2 IV) for a further 12 weeks	Primary cardiac endpoint. AEs were collected from the first dose of the study treatment until 30 days post treatment up to 31 weeks	Arm 1: 2/149 (1.3 %) experienced the primary cardiac endpoint Arm 2: 0/151 experienced the primary cardiac endpoint Arm 3: 1/148 (0.7 %) experienced the primary cardiac endpoint
6. NCT02896855 (PUFFIN)	243 HER2+ metastatic BC	Arm A: Placebo + Trastuzumab + Docetaxel Placebo was matched to Pertuzumab. Trastuzumab (8 mg/kg loading dose in cycle 1 followed by 6 mg/kg for the remaining cycles). Docetaxel 75 mg/m2 every 3 weeks until disease progression or unacceptable toxicity. Arm B: Pertuzumab + Trastuzumab + Docetaxel Pertuzumab 840 mg loading dose for the first cycle followed by 420 mg for the remaining cycles. Docetaxel and Trastuzumab as dosed in Arm A. Arm A crossover: participants who were on study treatment were unblinded and were given the option to replace the placebo with Pertuzumab	Symptomatic LVSD Asymptomatic LVEF	0 patients in all Arms experienced symptomatic LVSD (Arm A n = 120, Arm B n = 122, Arm A crossover n = 12). 0 patients experienced asymptomatic LVEF in Arm A and Arm A crossover, but 2 participants (1.6 %) experienced asymptomatic LVEF decline in Arm B
7. NCT00567190 (CLEOPATRA)	808 HER2+ metastatic BC	Arm 1: Placebo + Docetaxel and Trastuzumab. Placebo IV (matching Pertuzumab) every 3 weeks and Trastuzumab loading dose of 8 mg/kg in cycle 1 then 6 mg/kg once every 3 weeks plus Docetaxel 75 mg/m2 (up to 100 mg) every 3 weeks for at least 6 cycles (1 cycle = 21 days). Arm 2: Pertuzumab + Docetaxel and Trastuzumab. Pertuzumab loading dose of 840 mg on cycle 1 then 420 mg once every 3 weeks. Docetaxel and Trastuzumab as dosed in Arm 1. Arm 3: crossover from placebo to Pertuzumab + Trastuzumab and Docetaxel. Drugs as dosed in Arm 1 and 2	Any LVD or a serious AE suggestive of CHF. All cardiac-related AEs were graded for severity according to NCI-CTCAE v3.0. Asymptomatic (Grades 1–2) and symptomatic (Grades 3–5) LVSD both coded to the MedDRA preferred term LVD. Investigator-assessed events of symptomatic LVD were also graded for severity of symptoms according to Classes I (least severe) to IV (most severe) of the NYHA Classification	LVD assessed by the investigator (all classes) Arm 1: 7/396 (1.8 %) Arm 2: 6/408 (1.5 %) Arm 3: 1/50 (2 %) Any LVD (all grades) Arm 1:34/396 (8.6 %) Arm 2: 32/408 (7.8 %) Arm 3: 3/50 (6 %) SAE suggestive of CHF (all grades) Arm 1:8/396 (2 %) Arm 2: 8/408 (2 %) Arm 3: 1/50 (2 %)
8. NCT00365365	214	Arm 1 (n = 78): Doxorubicin and Cyclophosphamide followed by Docetaxel and Bevacizumab in HER2- patients. -4 cycles of Doxorubicin 60 mg/m2 and Cyclophosphamide 600 mg/m2 (AC) + Bevacizumab 15 mg/kg -4 cycles of Docetaxel 100 mg/m2 (T) + Bevacizumab -Bevacizumab maintenance therapy for total of 52 weeks from date of first dose Arm 2 (n = 75): Docetaxel, Doxorubicin and Cyclophosphamide (TAC) with Bevacizumab in HER2- patients. -6 cycles of Docetaxel 75 mg/m2, Doxorubicin 50 mg//m2 and Cyclophosphamide 500 mg/m2 (TAC) with Bevacizumab 15 mg/kg -Bevacizumab maintenance therapy as above Arm 3 (n = 59): Docetaxel, Carboplatin and Trastuzumab (TCH) with Bevacizumab in HER2+ patients. -6 cycles of Docetaxel 75 mg/m2, Carboplatin AUC 6 mg/mL/min IV and Trastuzumab maintenance dose of 6 mg/kg (loading dose of 8 mg/kg for first cycle only) (TCH) with Bevacizumab 15 mg/kg -Bevacizumab and Trastuzumab as maintenance therapy for 52 weeks as described above	Grade 3–4 CHF	Arm 1: 1/78 (1.28 %) participant in the first Arm experienced Grade 3/4 CHF when followed up to 3 years. Arm 2: 3/75 (4 %) participants in the second Arm experienced Grade 3/4 CHF when followed up to 3 years. Arm 3: 1/59 (1.69 %) participant in the third Arm experienced Grade 3/4 CHF when followed up to 3 years
9. NCT02586025 (PEONY)	329 early stage or locally advanced HER2+ BC	Arm 1: Pertuzumab, Trastuzumab and chemotherapy Trastuzumab, 8 mg/kg loading dose in cycle 1, followed by 6 mg/kg in cycles 2–4. Pertuzumab, 840 mg loading dose in cycle 1, followed by 420 mg from cycles 2–4 Docetaxel, 75 mg/m2 from cycles 1–4. After surgery, participants received Fluorouracil 500–600 mg/m2, Epirubicin 90–120 mg/m2, and Cyclophosphamide 500–600 mg/m2 every 3 weeks from cycles 5–7. A loading dose of Trastuzumab 8 mg/kg was then given in cycle 8, followed by a maintenance dose of 6 mg/kg in cycles 9–20. A loading dose of Pertuzumab 840 mg was given in cycle 8, followed by 420 mg from cycles 9–20. Arm 2: Trastuzumab, 8 mg/kg loading dose in cycle 1, followed by 6 mg/kg in cycles 2–4 with Docetaxel 75 mg/m2 and placebo in cycles 1–4. After surgery, participants received chemotherapy as above in Arm 1 (Fluorouracil, Epirubicin and Cyclophosphamide), followed by Trastuzumab 8 mg/kg loading dose in cycle 8, followed by 6 mg/kg from cycles 9–20 and placebo from cycles 8–20	Primary cardiac event: HF (NYHA Class III or NYHA Class IV and a drop in LVEF of at least 10 % points from baseline and to below 50 %. Secondary cardiac event: asymptomatic or mildly symptomatic (NYHA Class II) drop in LVEF confirmed by MUGA or ECG	Arm 1: 0/218 experienced a primary or secondary cardiac event from baseline to end of study (6 years). Arm 2: 0/110 experienced a primary or secondary cardiac event from baseline to end of study (6 years)
10. NCT00943670	51 HER2+ with locally advanced or metastatic BC	Arm 1: Trastuzumab emtansine (T-DM1). IV administration on day 1 every 3 weeks (1 cycle = 3 weeks) at a dose of 3.6 mg/kg. Arm 2: T-DM1 and Pertuzumab given after TDM-1 at a loading dose of 840 mg on day 1, with a maintenance dose of 420 mg every 3 weeks	Decreased ejection fraction (a decrease from baseline that is more than or equal to 15 %) Grade 3 LVEF (EF between 20 and 40 %)	Arm 1 (n = 51): 1 patient had Grade 3 LVEF when followed up to a year. Arm 2 (n = 20): 1 patient had decreased ejection fraction of more than or equal to 15 % from baseline but none had Grade 3 LVEF when followed up to a year
11. NCT02658734	70 with HER2+ unresectable locally advanced or metastatic BC	All patients received 3.6 mg/kg of Trastuzumab Emtansine IV on day 1 of a 21-day cycle which was repeated every 3 weeks	CHF	0/70 had CHF
12. NCT00446030	127 with node positive or high-risk node negative BC	Arm 1: HER2- participants were given the following: Docetaxel 75 mg/m2 on day 1 for cycles 1–6, Doxorubicin 50 mg/m2 on day 1 for cycles1–6 and Cyclophosphamide 500 mg/m2 on day 1 for cycles 1–6 plus Bevacizumab 15 mg/kg on day 1 for cycles 1–6 (1 cycle = 3 weeks) and then every 3 weeks for 52 weeks as maintenance. Arm 2: HER2+ participants were given Docetaxel (as in Arm 1), Carboplatin 6 mg/ml/min and Trastuzumab 8 mg/kg loading dose on day 3 for cycle 1, then maintenance 6 mg/kg on day 1 for cycles 2–6 plus Bevacizumab (as in Arm 1). 1 cycle = 3 weeks, continued for 6 cycles and then Bevacizumab and Trastuzumab every 3 weeks for 52 weeks as maintenance	Grade 3/4 clinical CHF symptoms include LVEF, CHF and cardiomyopathy	Arm 1: 4.3 % of 92 participants had Grade 3/4 clinical CHF when followed up to 2 years. Arm 2: 0 % of 34 participants had Grade 3/4 clinical CHF when followed up to 2 years
13. NCT00083174 (ExCel)	4560 menopausal patients	Arm 1: Exemestane 25 mg daily in the morning. Arm 2: placebo tablet daily in the morning	Cardiac events including MI and angina requiring surgical intervention, fatal and non-fatal strokes and all vascular deaths	Arm 1 (n = 2240): 4.7 % (106/2240) had a cardiac event when followed up to 5 years. Arm 2 (n = 2248): 4.9 % (111/2248) had a cardiac event when followed up to 5 years
14. NCT00248170 (FACE)	4172	Arm 1: Letrozole 2.5 mg oral once daily. Arm 2: Anastrozole 1 mg oral once daily	Cardiovascular events include ischaemic heart disease, cardiac failures, cerebrovascular accidents and thromboembolic events	Ischaemic heart disease: 2.4 % in Letrozole group (n = 2049) and 1.5 % in Anastrozole group (n = 2062). Cardiac failures: 1.5 % in Letrozole group (n = 2049) and 0.7 % in Anastrozole group (n = 2062). Cerebrovascular accidents: 1.6 % in Letrozole group (n = 2049) and 1.5 % in Anastrozole group (n = 2062). Thromboembolic events: 1.2 % in Letrozole group (n = 2049) and 1.2 % in Anastrozole group (n = 2062)
15. NCT00849472	101 with locally advanced BC	All patients received Doxorubicin and Cyclophosphamide (AC) followed by weekly Paclitaxel and concurrent Pazopanib. Doxorubicin at a dose of 60 mg/m2 and Cyclophosphamide 600 mg/m2 every 21 days for 4 cycles. Followed by weekly Paclitaxel at 80 mg/m2 on days 1, 8 and 15 every 28 days for 4 cycles. This is given with concurrent Pazopanib 800 mg once daily to be continued until a week before surgery. Post surgery, Pazopanib was restarted at the same dose 4–6 weeks post-surgery and continued for 6 months	Grade 3 LVD (symptomatic CHF) and 4 LVD (poorly controlled refractory CHF, ventricular assist or heart transplant)	0/101 experienced cardiotoxicity after AC completion. 0/101 experienced cardiotoxicity after AC, Paclitaxel and preoperative Pazopanib. 0/42 experienced cardiotoxicity during postoperative treatment with Pazopanib
16. NCT00464646	105	Cohort A (women with unresected advanced BC). Neoadjuvant Epirubicin 90 mg/m2 and Cyclophosphamide 600 mg/m2 (EC) every 21 days for 4 cycles. Docetaxel 100 mg mg/m2 on day 1 every 21 days for 4 cycles. Trastuzumab pre surgery 4 mg/kg for first dose then weekly 2 mg/kg until 1–7 days before surgery. Post surgery 8 mg/kg for first dose then 6 mg/kg every 3 weeks for 13 doses. Bevacizumab: on cycles 1–4, 15 mg/kg on day 1 of cycle 4 only, for cycles 5–7, 15 mg/kg on day 1 every 21 days for 3 cycles. Post surgery dose is 15 mg/kg every 3 weeks for 13 doses. Cohort B: women with resected pN2 or pN3 BC. Adjuvant therapy with EC (dosed as in cohort A) every 21 days for 4 cycles followed by Docetaxel (dosed as in cohort A) every 21 days for 4 cycles. Trastuzumab dose will be 4 mg/kg for first dose then 2 mg/kg weekly on days 1, 8, and 15. Three weeks after last Docetaxel dose, the 6 mg/kg of Trastuzumab will continue every 3 weeks for 13 doses. For cycles 5–8, 15 mg/kg of Bevacizumab will be given on day 1 every 21 days for 4 cycles starting 3 weeks after last dose of Docetaxel, every 3 weeks for 13 doses	NYHA Class III/IV CHF and cardiac death	Cohort A: 4/70 (5.7 %) experienced a cardiac event. Cohort B: 0/29 experienced a cardiac event
17. NCT01196052	153	Trastuzumab Emtansine 3.6 mg/kg IV on day 1 of each 3-week cycle up to 17 cycles.	Cardiac death or severe CHF (NYHA Class III or IV) with a decrease in LVEF of 10 % or more from baseline to under 50 %	0/143 experienced a cardiac event when followed up to 12 weeks after treatment. 2.7 % of 148 patients also had an asymptomatic decline in LVEF (under 50 % to a max decline of 10 % or more from baseline) when followed to end of TDM-1 treatment (up to 51 weeks)
18. NCT00550771 (STUDY P05048)	181	Arm 1: Pegylated Liposomal Doxorubicin (PLD) Based Regimen. PLD 35 mg/m2 IV + Cyclophosphamide 600 mg/m2 IV given every 21 days + Trastuzumab 2 mg/kg IV (first dose 4 mg/kg IV) given once weekly for 4 courses (12 weeks) followed by Paclitaxel 80 mg/m2 IV with Trastuzumab 2 mg/kg IV given weekly for 12 weeks (4 courses). Arm 2: Doxorubicin Based Regimen. Doxorubicin 60 mg/m2 IV + Cyclophosphamide 600 mg/m2 IV given every 21 days for 4 courses (12 weeks) followed by Paclitaxel 80 mg/m2 IV with Trastuzumab 2 mg/kg IV (first dose 4 mg/kg) given weekly for 12 weeks (4 courses)	Level 1: Cardiac death due to HF, myocardial infarction or arrhythmia, or probable cardiac death defined as sudden, unexpected death within 24 h of a definite or probable cardiac event, or severe symptomatic HF, concomitant with a LVEF drop of >10 percentage points from baseline and to ≤50 % LVEF. Level 2: Asymptomatic systolic dysfunction or mildly symptomatic HF concomitant with an LVEF drop of >10 percentage points from baseline and to <50 % LVEF; the LVEF drop was to have been confirmed within 3–4 weeks	During 8 cycles of chemotherapy: Arm 1: 1/120 experienced level 1 cardiotoxicity and 1/120 experienced level 2 cardiotoxicity. Arm 2: 0/59 experienced level 1 cardiotoxicity and 3/59 experienced level 2 cardiotoxicity. During 1 year of Trastuzumab: In Arm 1: 1/116 (0.86 %) experienced level 1 cardiotoxicity and 4/116 (3.44 %) experienced level 2 cardiotoxicity during 1 year of Trastuzumab In Arm 2: 0/52 experienced level 1 cardiotoxicity and 10/52 (19.2 %) experienced level 2 cardiotoxicity during 1 year of Trastuzumab
19. NCT00006110	82	Doxorubicin + Cyclophosphamide in combination with Paclitaxel and Trastuzumab (AC-TP). Trastuzumab: 4 mg/kg loading dose in week 1 then 2 mg/kg weekly thereafter for 12 weeks. Cyclophosphamide: 600 mg/m2, every 3 weeks for four cycles. Doxorubicin hydrochloride: 60 mg/m2, every 3 weeks, up to 12 weeks. Paclitaxel: 90 mg/m2 weekly, 1 hour after Trastuzumab, given weekly up to 12 weeks or 175 mg/m2, every 3 weeks, up to 12 weeks if not receiving Trastuzumab	Asymptomatic LVEF <50 % CHF	Arm 1: Trastuzumab after AC-TP (Doxorubicin and Cyclophosphamide) 1/52 (1.9 %) had asymptomatic LVEF <50 %. 0/52 had CHF. Arm 2: Trastuzumab after TP (patients in the treatment group after having taxol and Trastuzumab. 8/50 (16 %) had asymptomatic LVEF<50 %. 1/50 (2 %) had CHF. Arm 3: Trastuzumab regimen at 1.5 years. 3/43 (7 %) had asymptomatic LVEF<50 %. 1/43 (2.3 %) had CHF
20. NCT00004888	84	Arm 1: Pegylated Liposomal Doxorubicin (PLD) 30 mg/m2 IV followed by Docetaxel 60 mg/m2 IV one hour after PLD completion, every 3 weeks for a total of 8 cycles. Dexamethasone 8 mg orally twice a day was administered the day before, the day of, and the day following Docetaxel. The maximum allowed cumulative dose of PLD was 240 mg/m2. Pyridoxine 200 mg orally daily was started on day 1 of cycle 1 and continued daily while the patient was on PLD. Arm 2: Trastuzumab was administered at a dose of 4 mg/kg on day 1, then 2 mg/kg IV weekly plus chemotherapy with PLD and Docetaxel every 3 weeks for 8 cycles as in Arm 1.	Grade 1: Decline of LVEF ≥10 % but <20 % of baseline value. Grade 2: LVEF below lower limit of normal (50 %) or decline of LVEF ≥20 % of baseline value. Grade 3: CHF responsive to treatment	Arm 1: 16 treated patients reported a cardiotoxic event (Grade 1: n = 7, Grade 2: n = 8, Grade 3: n = 1). Arm 2: 37 treated patients reported a cardiotoxic event (Grade 1: n = 30, Grade 2: n = 7, Grade 3: n = 0). Results include after cycle 4, after cycle 8 and 30 or more days after last cycle)
21. NCT00119262	226	Arm A: Dose dense Bevacizumab, Cyclophosphamide and Doxorubicin, followed by Paclitaxel and Bevacizumab, followed by Bevacizumab*. Arm B: Dose dense Doxorubicin and Cyclophosphamide, followed by Paclitaxel and Bevacizumab, followed by Bevacizumab*. *doses not stated	CHF including those with symptomatic decline in LVEF to or below the lower limit of normal. Decrease from baseline in LVEF>15 % Or >10 % decline from baseline to below the lower limit of normal after AC	Arm A: 2.9 % of 103 patients analysed had CHF. 7.4 % of 94 patients analysed had LVEF decline post Doxorubicin and Cyclophosphamide.15.3 % of 72 patients analysed had LVEF decline post Bevacizumab. Arm B: 2.5 % of 120 patients analysed had CHF. 3.5 % of 113 patients analysed had LVEF decline post Doxorubicin and Cyclophosphamide. 11.6 % of 86 patients analysed had LVEF decline post Bevacizumab
22. NCT01572038	1436	Pertuzumab and Trastuzumab plus a Taxane (subject to investigators choice) once every 3 weeks until study end, toxicity, disease progression, death or consent withdrawal. Pertuzumab is recommended to commence on day 1 of the cycle and Trastuzumab and Taxane on Day 2 Pertuzumab: loading dose of 840 mg on day 1 or day 2 followed by 420 mg on day 1 or day 2 on subsequent cycles. Trastuzumab: loading dose of 8 mg/kg on day 1 or day 2 of treatment followed by a maintenance dose of 6 mg/kg on subsequent cycles. Taxane (Docetaxel, Paclitaxel or Nab-Paclitaxel) given in line with clinical guidelines as decided by the investigator	CHF LVEF – decrease from baseline more than or equal to 10 %	478/1436 (33.3 %) of participants experienced CHF when followed from baseline until 28 days after last dose of study treatment. Of the 546 participants analysed, 115 participants (21.1 %) experienced a decline of 10 % or more in LVEF from baseline at the end of the study
23. NCT02019277 (SAPPHIRE)	50	Pertuzumab administered at a loading dose of 840 mg on day 1 of first treatment cycle (1 cycle = 21 days) followed by 420 mg on day 1 of each subsequent cycle. Trastuzumab administered at a SC dose of 600 mg on day 2 of first treatment cycle, and on day 1 of each subsequent cycle if both Pertuzumab and Trastuzumab were well tolerated in the first cycle. Taxane treatment (Docetaxel, Paclitaxel, or Nabpaclitaxel) was administered according to clinical and local prescribing guidelines. Treatment continued until progression of disease, toxicity, or withdrawal of consent. Participants with unacceptable toxicity or disease progression were switched to standard treatment of the investigator's choice	NYHA functional classification includes: Class I (no limitation in physical activity; ordinary physical activity does not cause fatigue, breathlessness or palpitation), Class II (slight limitation of physical activity; ordinary physical activity results in fatigue, palpitation, breathlessness or angina pectoris), Class III (marked limitation of physical activity; less than ordinary activity will lead to symptomatically 'moderate' HF) and Class IV (inability to carry out any physical activity without discomfort; symptoms of CHF are present even at rest) LVEF <50 %	Timeline: baseline up to 28 days after last study drug given (up to 36 months). 6 % of participants had a Class I AE suspected of cardiac origin. 4 % of participants had a Class II AE suspected of cardiac origin. 2 % of participants had a Class III AE suspected of cardiac origin. No participants had a Class IVAE suspected of cardiac origin. 8 % reported to have a LVEF of under 50 % at any time during the study
24. NCT00796978	56	Trastuzumab IV on day 1 (over 30–90 min). Treatment repeats every 3 weeks for up to 52 weeks in the absence of disease progression or unacceptable toxicity	Cardiac death due to CHF, MI or undocumented arrhythmia, death without definitive cause or symptoms of CHF as defined by NYHA Class III or IV symptoms. LVD	3.6 % of 55 patients experienced a cardiac event and 9.1 % of 55 patients experienced asymptomatic LVD at 1 year of treatment
25. NCT00976989	225	Arm 1: 5-Fluorouracil, Epirubicin with Cyclophosphamide (FEC), Trastuzumab and Pertuzumab every three weeks for three cycles, followed by Docetaxel, Trastuzumab and Pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery. Arm 2: FEC every three weeks for three cycles, followed by Docetaxel, Trastuzumab and Pertuzumab every three weeks, for three cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 21 as adjuvant therapy post-surgery. Arm 3: Trastuzumab, Carboplatin, Docetaxel (TCH) and Pertuzumab every three weeks, for six cycles as neoadjuvant therapy. Trastuzumab every three weeks from Cycle 7 up to Cycle 17 as adjuvant therapy post-surgery	Symptomatic cardiac events LVEF decline Cardiac symptoms associated with symptomatic LVSD Asymptomatic LVEF	(% of patients with measured outcome) Arm 1: n = 72; Arm 2: n = 75; Arm 3: n = 76. Arm 1: 0 % had symptomatic cardiac events. Arm 2: 2.7 % had symptomatic cardiac events. Arm 3: 1.3 % had symptomatic cardiac events. Arm 1: 5.6 % had LVEF decline in neoadjuvant period. Arm 2: 5.3 % had LVEF decline in neoadjuvant period. Arm 3: 3.9 % had LVEF decline in neoadjuvant period. (neoadjuvant/adjuvant/follow up) Arm 1: 1.4 %, 0 %, 0 % had cardiac symptoms associated with symptomatic LVSD. Arm 2: 2.7 %, 0 %, 1.3 % had cardiac symptoms associated with symptomatic LVSD. Arm 3: 0 %, 1.5 %, 0 % had cardiac symptoms associated with symptomatic LVSD. (neoadjuvant/adjuvant/follow up) Arm 1: 5.6 %, 3 %, 0 % of participants had an asymptomatic LVEF event Arm 2: 4 %, 0 %, 11.1 % of participants had an asymptomatic LVEF event. Arm 3: 2.6 %, 4.8 %, 4.3 % of participants had an asymptomatic LVEF event
26. NCT01855828	50	During weeks 1–12, patients received Pertuzumab, Trastuzumab, and Paclitaxel concomitantly; during weeks 13–24 patients will receive Pertuzumab and Trastuzumab with chemotherapy agents 5-fluorouracil, Epirubicin, and Cyclophosphamide (FEC). Pertuzumab administered once every 3 weeks for 24 weeks (8 doses total): First dose is 840 mg, maintenance dose is 420 mg. Trastuzumab: For weeks 1–12, the loading dose was 4 mg/kg, maintenance dose was 2 mg/kg weekly for 12 doses and then weeks 13–24, the dose was 6 mg/kg administered every 3 weeks (4 doses total). Paclitaxel: 80 mg/m2 every week from week 1 to 12 for 12 doses in total. 5-fluorouracil: 500 mg/m2 every 3 weeks during weeks 13–24 (4 doses total). Epirubicin: 75 mg/m2 every 3 weeks during weeks 13–24 (4 doses total). Cyclophosphamide: 500 mg/m2 for every 3 weeks during weeks 13–24 (4 doses total). Doses the same in all Arms	Clinically symptomatic CHF. Asymptomatic decrease in LVEF>10 %. Decrease of LVEF below normal level	0/50 participants had symptomatic CHF. 14/50 (28 %) of participants had an asymptomatic decrease in LVEF. 1/50 (2 %) of participants had LVEF below the normal level All measured events were up to 1 year after surgery
27. NCT03493854 (FeDeriCa)	500	Arm A: IV Pertuzumab and IV Trastuzumab and 8 cycles of ChemotherapyChoice of chemotherapy was decided by the investigator -4 cycles of dose dense Doxorubicin and Cyclophosphamide once every 2 weeks with granulocyte colony-stimulating factor (G-CSF) followed by weekly Paclitaxel for 12 weeks OR -4 cycles of Doxorubicin and Cyclophosphamide once every 3 weeks followed by Docetaxel every 3 weeks for the remaining 4 cycles. IV Pertuzumab and IV Trastuzumab every 3 weeks for 4 cycles with a taxane. Another 14 cycles of Pertuzumab and Trastuzumab were given post-surgery Arm B: SC fixed dose Pertuzumab and Trastuzumab with 8 cycles of chemotherapy decided by the investigator -4 cycles of dose dense Doxorubicin and Cyclophosphamide every 2 weeks with G-CSF followed by weekly Paclitaxel for 12 weeks OR -4 cycles of Doxorubicin and Cyclophosphamide every 3 weeks for 4 cycles followed by Docetaxel every 3 weeks for the remaining 4 cycles. A fixed dose SC administration of Pertuzumab and Trastuzumab was given every 3 weeks for 4 cycles with the taxane part of the chemotherapy. Another 14 cycles of Pertuzumab and Trastuzumab were given post-surgery	Primary cardiac event i.e. symptomatic ejection fraction decrease (HF) of NYHA Class III or IV and a drop in LVEF of at least 10 % from baseline and to below 50 % or cardiac/probable cardiac death. Secondary cardiac event i.e. asymptomatic LVSD of NYHA Class II which is a decrease in LVEF of at least 10 % below 50 %.	Arm A: 0/252 had a primary cardiac event and 4/252 (1.6 %) had a secondary cardiac event in the neoadjuvant phase. 1/252 had a primary cardiac event and 15/252 (6 %) had a secondary cardiac event in the adjuvant phase. Arm B: 2/248 had a primary cardiac event (0.8 %) and 1/248 (0.4 %) also had a secondary cardiac event in the neoadjuvant phase. 2/248 had a primary cardiac event and 8/248 (3.2 %) had a secondary cardiac event in the adjuvant phase
28. NCT01570036	275	Arm 1: Trastuzumab + NeuVax Vaccine Trastuzumab monotherapy every 3 weeks for 1 year at a loading dose of 8 mg/kg and at a maintenance dose of 6 mg/kg every 3 weeks. The first loading dose given no sooner than 3 weeks and no later than 12 weeks after standard care with chemotherapy/radiotherapy. The NeuVax vaccine administered after completion of the third Trastuzumab infusion scheduled every 3 weeks for 6 total vaccinations, 30–120 min post administration of Trastuzumab. Once the full course of vaccinations administered, patients received the NeuVax booster vaccine every 6 months for a duration of 30 months. Arm 2: Trastuzumab as above in Arm 1. Patients received 250 mcg of GM-CSF only every 3 weeks for 6 total inoculations, 30–120 min post administration of Trastuzumab. The GM-CSF only inoculation series begins after completion of the third Trastuzumab administration. After completion of the six GM-CSF inoculations, patients received a total of four booster inoculations to be administered at 12, 18, 24, and 30 months from the date of the first Trastuzumab dose	Percentage of ejection fraction reduction of 10 % or more from baseline	0/136 in Arm 1 and 0/137 In Arm 2 experienced a reduction of 10 % or more in ejection fraction from baseline when followed up to 24 months
29. NCT00712881	126 HER2+ BC	Arm 1: Doxorubicin (MYOCET) and Cyclophosphamide and Trastuzumab (MCH) plus Docetaxel and Trastuzumab (TH) MCH: Liposomal Doxorubicin Hydrochloride 60 mg/m2, Cyclophosphamide 600 mg/m2, Trastuzumab 8 or 6 mg/kg on day 1 for 4 cycles. (1 cycle = 21 days). Trastuzumab 8 mg/kg as loading dose for first cycle and then 6 mg/kg for the subsequent cycles. After 4 cycles, participants received 4 cycles of TH; Docetaxel 100 mg/m2 and Trastuzumab 6 mg/kg. Arm 2: Doxorubicin (anthracycline) and Cyclophosphamide (AC) and then Docetaxel and Trastuzumab (TH) AC: free Doxorubicin Hydrochloride 60 mg/m2 and Cyclophosphamide 600 mg/m2 on day 1 for 4 cycles (1 cycle = 21 days). After 4 cycles of AC, patients received TH (dose is the same as in Arm 1)	Class III or IV NYHA CHF. Class III – cardiac disease which causes a limitation in physical activity. Class IV – cardiac disease which causes the inability to engage in physical activity without discomfort. Symptoms of HF and angina can be present at rest. Change in LVEF from baseline	Class III or IV NHYA CHF 0/63 participants in Arm 1 and 0/63 participants in Arm 2 experienced this cardiac outcome from baseline up to the end of cycle 8. Change in LVEF 0/62 participants in Arm 1 and 0/63 participants in Arm 2 had more than a 10 % average change in LVEF from baseline when followed up to 5 years
30. NCT03674112 (PHranceSCa)	160 with HER+ early BC	Arm A: Pertuzumab and Trastuzumab IV (IV P + H) for 3 cycles followed by fixed dose combination subcutaneous (FDC SC) of the same drugs for 3 cycles (1 cycle = 21 days). Participants could then choose one of the two study treatments to continue for the remaining anti-HER2 treatment cycles, of which there were 18 in total. Arm B: Pertuzumab and Trastuzumab FDC SC for 3 cycles followed by Pertuzumab and Trastuzumab IV for 3 cycles (1 cycle = 21 days). Participants could then choose one of the two study treatments to continue for the remaining anti-HER treatment cycles, of which there were 18 in total. Loading dose of 1200 mg of Pertuzumab and 600 mg Trastuzumab followed by maintenance dose of 600 mg of Pertuzumab and 600 mg Trastuzumab once every 3 weeks Pertuzumab IV 840 mg loading dose then 420 mg IV once every 3 weeks. Trastuzumab IV 8 mg/kg loading dose then 6 mg/kg every 3 weeks. Doses are the same for both Arms. Arm A: Those in Arm A and B who received IV P + H during the treatment cross over period of the study. Arm B: Those in Arm A and B who received FDC SC P + H during the treatment cross over period of the study. Arm C: Those in Arm A and B who received IV P + H during the treatment cross over period of the study and decided to continue with this regime for the treatment continuation period. Arm D: Those in Arm A and B who received FDC SC P + H during the treatment cross over period of the study and decided to continue with this regime for the treatment continuation period	HF At least one event of LVEF decrease	HF Arm A: 0/160 experienced HF. Arm B: 0/160 experienced HF. Arm C: 0/21 experienced HF. Arm D: 0/138 experienced HF. LVEF decrease Arm A: 3/160 (1.9 %) experienced at least one event of LVEF decrease. Arm B: 4/160 (2.5 %) experienced at least one event of LVEF decrease. Arm C: 1/21 (4.8 %) experienced at least one event of LVEF decrease. Arm D: 0/138 experienced at least one event of LVEF decrease
31. NCT00436566	122 with early stage HER2+ BC	Standard doses of Doxorubicin and Cyclophosphamide (AC) followed by 80 mg/m2 of Paclitaxel for 12 weeks with standard dose of Trastuzumab weekly for 12 weeks then every 3 weeks for 9 months. This is given with a daily dose of 750 mg of Lapatinib when given with Paclitaxel and Trastuzumab and 1000 mg of Lapatinib when given alone with Trastuzumab for 12 months in total	CHF Drop in 10 % or more in LVEF from baseline to any point post baseline (up to 5 years)	0/109 participants experienced CHF in 6 months during active treatment 63/104 participants (60.6 %) experienced a drop in 10 % or more in LVEF from baseline between any 2 points in 5 years
32. NCT02132949 (BERENICE)	401 with HER2+ locally advanced, inflammatory or early-stage BC	Cohort A (dose dense Doxorubicin with Cyclophosphamide, Paclitaxel, Pertuzumab and Trastuzumab). Neoadjuvant Doxorubicin IV 60 mg/m2 once every 2 weeks and IV Cyclophosphamide 600 mg/m2 once every 2 weeks for 4 cycles. This is followed by IV Paclitaxel 80 mg/m2 once weekly for 12 weeks. Pertuzumab was given as an 840 mg loading dose and then 420 mg once every 3 weeks and Trastuzumab 8 mg/kg loading dose then 4 mg/kg once every 3 weeks with Paclitaxel for 4 cycles. 8 cycles of chemotherapy were given before surgery. Adjuvant treatment with Trastuzumab and Pertuzumab once every 3 weeks up to 13 cycles (17 cycles of Trastuzumab and Pertuzumab given altogether). Patients also received radiotherapy and adjuvant hormonal treatment. Cohort B: 5-fluorouracil, Epirubicin, and Cyclophosphamide with Docetaxel, Pertuzumab, and Trastuzumab Neoadjuvant treatment of IV 5-fluorouracil at a dose of 500 mg/m2 once every 3 weeks followed by IV Epirubicin 100 mg/m2 once every 3 weeks and Cyclophosphamide 600 mg/m2 once every 3 weeks for 4 cycles. This was followed by Docetaxel with an initial dose of 75 mg/m2 in cycle 5 and increased to 100 mg/m2 for cycles 6–8. Pertuzumab and Trastuzumab as in neoadjuvant treatment in Cohort A but with Docetaxel for 4 cycles. 8 cycles of chemotherapy were given before surgery. Adjuvant treatment as above in Cohort A	At least one event of NYHA Class III or IV HF. At least one event with LVEF decline of at least 10 % points from baseline and to below 50 %.	Cohort A NYHA Class III or IV HF: Neoadjuvant (n = 199) - 1.5 %. Adjuvant (n = 181) – 0. Follow up (n = 199) – 0. LVEF decline: Neoadjuvant (n = 199) - 6.5 %. Adjuvant (n = 181) – 7.7 %. Follow up (n = 199) – 6 %. Cohort B NYHA Class III or IV HF. Neoadjuvant (n = 198) - 0 %. Adjuvant (n = 190) – 0.5 %. Follow up (n = 198) - 0.5 %. LVEF decline: Neoadjuvant (n = 198) - 2 %. Adjuvant (n = 190) – 10.5 %. Follow up (n = 198) – 3.5 %.

Abbreviations: AE: adverse event. BC: breast cancer. CHF: congestive heart failure. HF: heart failure. LVEF: left ventricular ejection fraction. LVD: left ventricular dysfunction. LVSD: left ventricular systolic dysfunction.

Results

Overview of endocrine therapy cardiotoxicity

Endocrine therapy, mainly Tamoxifen and aromatase inhibitors (AIs) are used as adjuvant therapies in the treatment of ER+/PR+ BC (Fig. 1). The former is the first line of treatment for most patients with ER+ BC, whereas AIs are preferred for post-menopausal women [18]. Tamoxifen, the first line of therapy for most pre-menopausal women with ER+ and PR+ BC, is given for 5–10 years as standard [2]. It inhibits ERα dependent oestrogen signalling [19] but exhibits cardioprotective characteristics such as reducing atherosclerosis progression [20]. RCTs (randomized controlled trials) have shown it reduces the risk of CVD by 33 % in comparison to a placebo/no treatment [21].

AIs are either non-steroidal, such as Anastrozole and Letrozole, or steroidal, such as Exemestane. They can be used as adjuvant therapy for ER+ early BC in postmenopausal women (Fig. 1) after 2–3 years of treatment with Tamoxifen [18] or for patients who become menopausal during their initial 5 years of Tamoxifen treatment [2]. AIs inhibit androgen to oestrogen conversion, reducing endogenous oestrogen levels (Fig. 3), but oestrogen depletion has been associated with increased CVD risk. A population matched cohort study found that treatment with AIs in a sequential setting after Tamoxifen, doubled the risk of myocardial infarction compared to continuing Tamoxifen [22].

Fig. 3.

An overview of the mechanisms underlying treatment-related cardiotoxicity. Anthracyclines can induce cardiotoxicity by upregulation of death receptors in cardiomyocytes. Alkylating agents directly bind to DNA and cause DNA strand breaks. Taxanes can stimulate histamine receptors in cardiac cells causing damage. HER2 targeted therapy e.g. Trastuzumab can cause cardiac cell disruption by interfering with the ErbB/NRG-1 signalling pathway and affect myocyte development. Endocrine therapy such as Aromatase Inhibitors can cause cardiotoxicity by reducing the amount of endogenous oestrogen which increases the risk of CVD (cardiovascular disease). Image created using Inkscape.

A meta-analysis of 19 RCTs stated that AIs were associated with an increased risk of cardiovascular events compared to Tamoxifen, possibly due to the cardioprotective effects of the latter. This is reflected in clinical guidelines which list ischaemic heart disease as a major adverse event (AE) associated with AIs [21]. Another meta-analysis containing 17 RCTs indicated that AIs did not increase cardiovascular event risks compared to control groups [23]. This contradicts a cohort study with 17,922 patients showing AI use increased HF and cardiovascular mortality risks compared to Tamoxifen users [24].

Ovarian suppression, achieved by administration of gonadotropin releasing hormone (GnRH) [25], is often considered in addition to endocrine therapy for premenopausal women diagnosed with ER+ invasive BC [18]. This can benefit women who are more likely to experience cancer recurrence and have been offered chemotherapy [18]. No clinical trials studying the cardiovascular implications of GnRH have been conducted however a cohort study (n = 172,850) found the use of GnRH agonists in female BC patients reduced the risk of developing ischaemic heart disease, which could indirectly reduce the risk of cardiotoxicity [26].

Cardiotoxicity of BC chemotherapy agents

Chemotherapy regimens are based on the biological characteristics of the tumour, patient co-morbidities and menopausal status [25]. Standard regimens usually include an anthracycline, alkylating agent and a taxane [25]. Chemotherapy can be given with or without anti-HER2 therapy as adjuvant/neoadjuvant therapy. A subsequential regime of an anthracycline and a taxane based therapy is the standard treatment for most patients [2].

Anthracyclines are a class of antibacterial drugs derived from Streptomyces bacteria, used in a variety of cancers. Doxorubicin, Epirubicin, Daunorubicin and Idarubicin are the most common anthracyclines used clinically [5]. These agents work by interfering with DNA replication and metabolism, causing DNA damage and apoptosis, especially in rapidly proliferating cells such as tumour cells and cardiomyocytes [27]. The proposed mechanism of anthracycline cardiotoxicity is thought to be via oxidative stress damage resulting in cardiomyocyte death. Anthracyclines could also induce cardiotoxicity by upregulation of death receptors such as TNFR1, Fas, DR4 and DR5 in cardiomyocytes (Fig. 3) [28], as this cascade induced apoptosis in human stem cell derived cardiomyocytes [29]. Patients treated with anthracyclines (equivalent dose to Doxorubicin of 385 mg/m²,19 trials; n = 660) had a LVEF decline of 5.4 % compared to the placebo group [30] suggesting they are not as toxic as previously thought. However, previous use of anthracyclines was found to be a risk factor in Trastuzumab induced cardiotoxicity [31].

Cyclophosphamide, an alkylating agent, works by directly binding to DNA and causing DNA strand breaks (Fig. 3) [32]. It is used as part of a combination regime with surgery, radiotherapy or other cytotoxic drugs for BC. The incidence of cardiotoxicity with Cyclophosphamide is 7–28 % and the onset of cardiotoxicity is acute as it occurs 1–10 days after first administration [32]. Myocarditis and thrombosis are its two major cardiovascular side effects [3,32], as well as endothelial dysfunction [32]. Cardiotoxicity risk is associated with higher doses [33], which are rarely administered in BC protocols [34].

Taxanes such as Paclitaxel and Docetaxel interrupt cell division and metabolism [35]. They used in combination regimes for BC and induce cardiotoxicity by causing histamine release, stimulating histamine receptors in cardiac cells (Fig. 3). This can result in cardiac damage including myocardial ischaemia, arrythmias and electrical signalling problems [34]. The interference of taxanes with anthracycline excretion could increase the risk of ventricular dysfunction, however HF risk is low compared to combination regimes with anthracyclines [35].

Cardiotoxicity of targeted therapies Anti-HER2 therapies have significantly improved outcomes for BC patients who have HER2 over-expression. The first HER2 targeted therapy developed was Trastuzumab (brand name Herceptin) [36], a humanised monoclonal antibody against HER2 [37]. It can cause cardiotoxicity by targeting HER2 receptors in cardiomyocytes, interfering with their survival and proliferation [38], hindering myocyte repair processes following anthracycline induced cardiotoxicity [37], and by affecting myocyte development by interfering with the ErbB/Neuregulin-1 signalling pathway [39]. It has also been suggested that Trastuzumab prevents differentiation of human cardiosphere-derived cells (hCDCs) (Fig. 3), including cardiac stem cells and cells with regenerative properties [40].

HER2 signalling blockage reportedly increases risks for asymptomatic decreased LVEF which could lead to HF. The cardiotoxic effects of Trastuzumab show early onset of occurrence and are non-dosage dependent. HER2 inhibition also prevents cell repair and limits cell proliferation [41]. In comparison to anthracyclines, Trastuzumab cardiotoxicity usually displays type 2 cardiotoxicity characteristics, it is reversible with no structural changes, and cardiac function recovers a few months after Trastuzumab therapy cessation [15]. Mice with cardiac specific HER2 deletion demonstrated cardiac dysfunction in the form of dilated cardiomyopathy and systolic dysfunction, indicating HER2 signalling is important in maintaining myocardial function [42]. HER2 downstream signalling is important for foetal development and stress management in cardiomyocytes. Anti-HER2 therapies could contribute to cardiotoxicity by inhibiting these protective mechanisms, especially when other risk factors/stressors of cardiomyocytes are present such as treatment with anthracyclines or cardiovascular co-morbidities [43].

There are many studies looking at the cardiac safety of Trastuzumab alone and with chemotherapy agents. A meta-analysis of 10 RCTs (n = 11,882 patients) found that BC patients treated with Trastuzumab or Trastuzumab plus anthracyclines had a higher risk of experiencing congestive heart failure (CHF) and decreased LVEF [44]. A contradicting 13 study meta-analysis (n = 1391, HER2+ BC) found no significant differences in LVEF or cardiac failure with concurrent use of Trastuzumab and anthracyclines compared to without [45].

Pertuzumab, a HER2 targeted therapy, is as effective as Trastuzumab in early and metastatic BC [46]. One study found it to be well tolerated in terms of cardiac dysfunction with no increases in cardiac dysfunction when given with Trastuzumab or anthracyclines [47]. A meta-analysis (8 RCTs, n = 8420) found that although low, patients receiving Pertuzumab had an increased risk of HF when compared to a placebo. Concomitantly, the drug had no effect on left ventricular systolic dysfunction (LVSD) leading to the authors concluding that clinical use should not be discouraged in low cardiac risk patients [46].

Lapatinib is a dual protein kinase inhibitor, selective for HER2 and epidermal growth factor receptors. It is approved for use in metastatic HER2+ BC with Capecitabine in patients who have previously had anthracyclines, Trastuzumab or taxane therapy [48]. It has a similar cardiotoxicity profile to Trastuzumab [34], however cardiotoxicity incidence is thought to be low and any cardiac effects seen were after anthracycline/Trastuzumab therapy which are known to be cardiotoxic. The mechanism behind Lapatinib has not been widely investigated, due to its low cardiotoxicity incidence rate, but is thought to be due to blockage of HER2 signalling, similar to Trastuzumab [49].

Trastuzumab Deruxtecan (T-DXd; Fig. 4), sold under the brand name ENHERTU is an antibody drug conjugate consisting of the HER2 targeting antibody Trastuzumab and Deruxtecan, a cytotoxic topoisomerase I inhibitor derived from exatecan) [50]. It can be used for HER2 expressing tumours including BC [51]. T-DXd drug delivers the cytotoxic compound, which is linked to the targeting antibody, to the cell. There are currently six clinical trials investigating T-DXd in metastatic BC (DESTINY-Breast05, 06, 07, 08, 09, 12) however results have not yet been published and DESTINY-Breast02, 03 and 04 did not investigate cardiotoxicity as a measured outcome.

Fig. 4.

Mechanism of action of Trastuzumab Deruxtecan on breast cancer cells. Trastuzumab (a monoclonal antibody) is covalently linked to Deruxtecan. Trastuzumab attaches to the HER2 protein and delivers the cytotoxic drug directly to the cancerous cell. The cell internalises the cytotoxic compound, killing the cell and releases it to neighbouring cells in a phenomenon called the bystander effect. Image created using Inkscape.

Several clinical trials have reported that cardiotoxicity was not prevalent in chemotherapy and targeted therapy regimens. In 406 HER2+ patients receiving adjuvant Paclitaxel and Trastuzumab only 0.5 % experienced Grade III/IV cardiac left ventricular dysfunction (LVD) related AEs (ClinicalTrials.govID:NCT00542451). In patients taking Lapatinib (n = 1573), two patients had severe symptomatic CHF compared to three placebo control patients (n = 1574). Six patients in each group had a secondary cardiac event and there was one cardiac death in the control group (ClinicalTrials.govID:NCT00374322), indicating Lapatinib is relatively safe from a cardiovascular perspective. Investigations into Pertuzumab with Trastuzumab and Docetaxel (n = 52) found no CHF suggesting the combination regime was safe in BC (ClinicalTrials.govID:NCT02445586).

The HERA study found 0.11 % of 1744 patients had a primary cardiac event and 0.86 % had a secondary event. In the Herceptin 1 year Arm, 1.07 % of 1682 participants had a primary cardiac event and 4.4 % had a secondary event. In the Herceptin 2-year Arm, 1.02 % of 1673 participants had a primary event however 7.29 % had a secondary cardiac event. (ClinicalTrals.govID:NCT00045032).

The NeoALTTO study investigated primary cardiac endpoints from the first dose to 30 days post treatment, up to 31 weeks, with weekly Paclitaxel (Arm 1: Lapatinib+Trastuzumab; n = 149; Arm 2: Lapatinib: n = 151; Arm 3: Trastuzumab; n = 148). Two people (1.3 %) experienced the cardiac endpoint in the first Arm, none in the second Arm and one person (0.7 %) in the third Arm (ClinicalTrials.govID:NCT00553358). No major cardiac dysfunction was observed [52].

The PUFFIN trial investigated symptomatic LVD from the first dose until 42 days after the last dose, up to 52 months. Arm A (n = 120) had placebo+Trastuzumab+Docetaxel, and Arm B (n = 122) had Pertuzumab+Trastuzumab+Docetaxel. Arm A crossover (n = 12) consisted of Arm A participants who chose to replace the placebo with Pertuzumab after the study was unblinded. No patients experienced symptomatic LVSD following assessment using MUGA and ECHO scans. No Arm A or crossover Arm A patients experienced LVEF asymptomatic decline, but two Arm B patients (1.6 %) experienced this cardiac outcome (ClinicalTrials.govID:NCT02896855).

The randomised, double-blind study CLEOPATRA study evaluated Pertuzumab with Trastuzumab and Docetaxel in HER2+ metastatic BC. Seven of 396 participants in Arm 1 (placebo+Trastuzumab+Docetaxel) experienced symptomatic LVD compared to six participants in Arm 2 (n = 408;Pertuzumab+Trastuzumab+Docetaxel). The third Arm (n = 50 crossover from the placebo to Pertuzumab) had only one participant who experienced symptomatic LVD. Furthermore, any LVD of all grades was observed in 34 participants in Arm 1, 32 participants in Arm 2, and three participants in Arm 3. Serious AEs, suggestive of CHF (all grades), were observed in eight participants in Arms 1 and 2, and one participant in Arm 3 (ClinicalTrials.govID:NCT00567190).

The safety and efficacy, including cardiac safety, of Bevacizumab and Docetaxel based chemotherapy regimens with or without Trastuzumab was investigated in 214 participants. Less than 5 % of patients experienced cardiac symptoms such as Grade 3–4 CHF when chemotherapy agents were given with Bevacizumab, Docetaxel and Trastuzumab (ClinicalTrials.govID:NCT00365365). The PEONY trial investigated cardiac events in 329 HER2+ BC patients treated with Trastuzumab, Pertuzumab and chemotherapy vs those treated with Trastuzumab and chemotherapy plus a placebo. No participants experienced a primary or secondary cardiac event in either Arm (ClinicalTrials.govID:NCT02586025).

A phase II study investigated the decrease in ejection fraction of more than or equal to 15 % from baseline. One participant in Arm 1 (n = 51) receiving T-DM1 experienced a Grade 3 LVEF (ejection fraction between 20 and 40 %). One participant experienced a decrease of 15 % or more in Arm 2 (T-DM1 and Pertuzumab; n = 20) but no patients in Arm 2 had Grade 3 LVEF (ClinicalTrials.govID:NCT00943670). Similarly, a clinical trial investigating the cardiac safety of T-DM1 in 70 patients with HER2+ BC (who previously had Trastuzumab and a taxane) found that no patients had CHF (ClinicalTrials.govID:NCT02658734).

A pilot study on the safety and efficacy of two Docetaxel based regimens with Bevacizumab investigated the incidence of Grade III/IV clinical CHF. In Arm 1 4.3 % of 92 participants (chemotherapy with Bevacizumab) had Grade III/IV clinical CHF compared to none of the 34 Arm 2 participants (chemotherapy with Bevacizumab+Trastuzumab) (ClinicalTrials.govID:NCT00446030). The study concluded that cardiotoxicity was not increased when Bevacizumab was added to a Docetaxel based regime given with Trastuzumab [53]. The ExCel trial showed that of the 2240 patients taking Exemestane, 4.7 % had a cardiac event compared to 4.9 % on placebos (n = 2248) (ClinicalTrials.govID:NCT00083174) suggesting Exemestane does not increase cardiotoxicity risk.

The FACE trial investigated cardiovascular events whilst taking AIs. For patients on Letrozole (n = 2049), 2.4 % had ischaemic heart disease compared to 1.5 % taking Anastrozole (n = 2062). 1.5 % of Letrozole users had cardiac failures compared to 0.7 % on Anastrozole. 1.6 % of Letrozole users had cerebrovascular accidents compared to 1.5 % on Anastrozole. In both groups, 1.2 % had thrombotic events (ClinicalTrials.govID:NCT00248170).

Another study investigated cardiac outcomes for treatment with Pazopanib and neoadjuvant chemotherapy. None of the 101 patients exhibited cardiotoxicity after completion of Doxorubicin+Cyclophosphamide (AC) and none had cardiotoxicity after completion of AC+Paclitaxel and concurrent Pazopanib. None of the 42 participants exhibited cardiotoxicity during the postoperative period where they received Pazopanib (ClinicalTrials.govID:NCT00849472).

A phase II study investigated whether adding Bevacizumab to standard chemotherapy and Trastuzumab would affect heart function. In Cohort 1 (women with unresected advanced BC), four (5.7 %) had Class III/IV CHF/cardiac death. In Cohort 2 (women with resected pN2 or pN3 BC), none of the 29 participants had these cardiac events (ClinicalTrials.govID:NCT00464646).

Another trial investigating the safety of TDM-1 after anthracycline-based chemotherapy found that none of the 143 participants had a cardiac event (cardiac death or severe CHF as defined by NYHA Class III or IV with a decrease in LVEF of 10 % or more from baseline to under 50 %). Only 2.7 % out of the whole population study (n = 148) had an asymptomatic LVEF decline (ClinicalTrials.govID:NCT01196052).

In contrast to the studies above, there are several studies which have shown that cardiotoxicity is prevalent in those receiving systemic drug treatment. Study P05048 compared the safety of two adjuvant chemotherapy regimens in HER2+ BC. During the 8 cycles of chemotherapy, one participant in Arm 1 (Pegylated Liposomal Doxorubicin n = 120) had level 1 cardiotoxicity and one participant had level 2 cardiotoxicity (defined in Table 1). In Arm 2 (Doxorubicin; n = 59), no participants had level 1 cardiotoxicity, but three participants had level 2. During the 1 year of Trastuzumab treatment (n = 116), one participant in Arm 1 had level 1 cardiotoxicity and four had level 2. In Arm 2 (n = 52), no participants had level 1 cardiotoxicity but ten had level 2 (ClinicalTrials.govID:NCT00550771). The combination of different chemotherapy agents with targeted therapy can also contribute towards cardiotoxicity. For example cardiotoxicity was more prevalent when Trastuzumab was given after Paclitaxel and Trastuzumab, compared to after Doxorubicin+Cyclophosphamide (Table 1; ClincialTrials.govID:NCT00006110). Adding Trastuzumab to some chemotherapy regimens increased patient numbers experiencing a cardiotoxic event (ClinicalTrials.govID:NCT00004888).

Another clinical trial looked at the cardiotoxic outcomes of Doxorubicin, Cyclophosphamide and Bevacizumab. In Arm A (dose dense Bevacizumab, Cyclophosphamide and Doxorubicin followed by Paclitaxel+Bevacizumab followed by Bevacizumab) 2.9 % of 103 participants had CHF and 7.4 % of 94 evaluable participants had a decrease in baseline LVEF of more than 15 % or 10 % decline from baseline to below the lower limit of normal after Doxorubicin and Cyclophosphamide. Additionally, 15.3 % of 72 participants also exhibited the same decline in LVEF after Bevacizumab. In Arm B (dose dense Doxorubicin+Cyclophosphamide followed by Paclitaxel+Bevacizumab followed by Bevacizumab), 2.5 % of 120 participants had CHF and 3.5 % of 113 participants analysed exhibited LVEF decline after Doxorubicin and Cyclophosphamide. LVEF decline was also observed after Bevacizumab in 11.6 % of the 86 participants analysed in Arm B (ClinicalTrials.govID:NCT00119262).

The PERUSE study investigated CHF in HER2+ BC patients receiving Pertuzumab with Trastuzumab and a Taxane. Out of 1436 participants, 33.3 % (478) experienced CHF and 21.1 % (115 out of 546) had more than or equal to a 10 % decrease in LVEF from baseline at the end of the study (ClinicalTrials.govID:NCT01572038). The SAPPHIRE study investigated safety, efficacy and tolerability of subcutaneous Pertuzumab and Trastuzumab with taxane therapy (Docetaxel, Paclitaxel and Nab-paclitaxel) in HER2+ metastatic BC. Of the 50 participants with adverse effects of suspected cardiac origin (NYHA classified), 6 % had a Class I event, 4 % Class II, 2 % Class III, with no Class IV events. In addition, 8 % of the patients had a LVEF under 50 % at any point of time during the study (ClinicalTrials.govID:NCT02019277).

One trial found that 3.6 % of 55 patients experienced a cardiac event (cardiac death due to CHF, MI or undocumented arrhythmia, death without definitive cause or symptoms of CHF as defined by NYHA Class III/IV symptoms) with one year of Trastuzumab and 9.1 % experienced LVD at 1 year of treatment (ClinicalTrials.govID:NCT00796978).

The order of the drugs given in the regimens could also cause an increase in the risk of cardiotoxicity. A 3-Arm study administered a combination of Pertuzumab+Trastuzumab either concomitantly with anthracycline based chemotherapy (Arm 1 n = 72), consecutively with anthracycline based chemotherapy (Arm 2 n = 75), or concomitantly with chemotherapy which excludes anthracyclines (Arm 3 n = 76). No Arm 1 patients had a symptomatic cardiac event, 2.7 % had an event in Arm 2, and 1.3 % had an event in Arm 3. Furthermore, 5.6 %, 5.3 % and 3.9 % had a LVEF decline (during the neoadjuvant period) in Arms 1, 2 and 3 respectively (ClinicalTrials.govID:NCT00976989). Another study investigated the cardiac safety of Pertuzumab+Trastuzumab with concomitant chemotherapy (Paclitaxel, 5-FU, Epirubicin and Cyclophosphamide (T-PEC)) in 50 participants up to a year post surgery. No patients experienced symptomatic CHF, 14 patients (28 %) experienced an asymptomatic decrease in LVEF >10 % and one patient (2 %) had a decrease in LVEF below the normal level (ClinicalTrials.govID:NCT01855828).

Drug formulation could also influence the cardiotoxicity risk. The FeDeriCa study evaluated subcutaneous administration of a fixed dose combination of Trastuzumab+Pertuzumab with chemotherapy in HER2+ early BC. No patients in Arm A (n = 252 IV Pertuzumab+IV Trastuzumab+chemotherapy) experienced a primary cardiac event in the neoadjuvant phase, however four experienced a secondary cardiac event. Arm B (SC fixed dose of Pertuzumab and Trastuzumab+chemotherapy) had 248 patients, two patients had a primary cardiac event in the neoadjuvant phase, one with HF and significant LVEF decline, whilst the other died from a probable cardiac death. One patient in Arm B also experienced a secondary cardiac event (ClinicalTrials.govID:NCT03493854). A phase 2 study investigated Trastuzumab with the NeuVAx vaccine (HER2 protein E75 peptide administered with the immunoadjuvant GM-CSF) versus the HER2 vaccine with GM-CSF alone. No patients in either Arm experienced cardiotoxicity measured via mean reduction in ejection fraction (%) (ClinicalTrials.govID:NCT01570036). Another study (MYOCET) had no patients in Arm 1 (n = 63; liposomal Doxorubicin Hydrochloride with Cyclophosphamide+Trastuzumab followed by Docetaxel+Trastuzumab) or Arm 2 (n = 63; free Doxorubicin Hydrochloride and Cyclophosphamide followed by Docetaxel+Trastuzumab) with Class III or IV CHF. Furthermore, no participants in either Arm experienced more than a 10 % reduction in LVEF from baseline in the 5-year follow up period (ClinicalTrials.govID:NCT00712881). This suggested there was no increase/decrease in cardiotoxicity risk between free Doxorubicin Hydrochloride and liposomal Doxorubicin Hydrochloride with Docetaxel+Trastuzumab.

The PHranceSCa study evaluated 160 HER2+ BC patients who were randomised to receive IV Pertuzumab and Trastuzumab or the fixed dose combined subcutaneous (FDC SC) versions of the same drugs. Then they chose which treatments to continue with (IV or FDC SC). The study found that 0/160 participants in Arm A (three cycles of IV Pertuzumab and Trastuzumab in the treatment crossover) had a HF event, the same was observed in n = 160 Arm B participants (three cycles of fixed dose subcutaneous Pertuzumab and Trastuzumab (PH FDC SC) during treatment crossover). In Arm C (n = 0/21;continued to receive IV Pertuzumab and Trastuzumab after the treatment crossover), and Arm D (n = 0/138; PH FDC SC continued treatment after the crossover) no participants had HF. 1.9 % of participants (3/160) in Arm A, 2.5 % of participants (4/160) in Arm B, 4.8 % of Arm C (1/21) and 0/138 in Arm D had decreased LVEF (ClinicalTrials.govID:NCT03674112).

Cardiotoxicity is not always apparent during treatment, as symptoms can manifest years after therapy. One study had no participants (n = 0/109) experience CHF over 6 months on treatment with Doxorubicin+Cyclophosphamide followed by weekly Paclitaxel and Trastuzumab plus Lapatinib, Paclitaxel and Trastuzumab. However, 63/104 participants (60.6 %) experienced a drop in 10 % or more in LVEF from baseline between any two points in 5 years (ClinicalTrials.govID:NCT00436566).

The BERENICE study investigated cardiotoxicity (at least one NYHA Class III event or IV HF/LVEF decline of at least 10 % from baseline and to below 50 %) during the treatment of Pertuzumab and Trastuzumab with chemotherapy. In Cohort A (dose dense Doxorubicin, Paclitaxel with Pertuzumab and Trastuzumab), 1.5 % had a cardiac event in the neoadjuvant period (n = 199), 0 % in the adjuvant period (n = 181) and 0 % in the treatment follow up period (n = 199). Furthermore 6.5 % of participants had at least one confirmed event of LVEF decline in the neoadjuvant period but 7.7 % of participants had LVEF decline in the adjuvant period and 6 % in the follow up period. In Cohort B (5-Fluorouracil, Epirubicin and Cyclophosphamide with Docetaxel, Pertuzumab and Trastuzumab), no participants had a cardiac event in the neoadjuvant period (n = 198), 0.5 % had a cardiac event in the adjuvant period (n = 190) and 0.5 % in the treatment follow up period (n = 198). Furthermore, 2 % had a LVEF decline in the neoadjuvant period, 10.5 % in the adjuvant period and 3.5 % in the follow up period (ClinicalTrials.govID:NCT02132949).

Conclusion

The cardiotoxic effects of cancer therapy are apparent, however the extent to which it causes harm, especially in differing populations, is unclear as the nature of the cancer can also exert negative cardiovascular system effects. The most common drug therapies in BC, anthracyclines and Trastuzumab, are cardiotoxic in nature and similar effects are seen following treatment in other cancers. BC patients can be particularly affected is due to the blockage of HER2 which has underlying cardioprotective properties, therefore targeting this receptor leaves individuals at a higher risk of developing cardiotoxic complications.

Suitable downstaging of cancer prognoses and de-escalation of treatment may reduce treatment-related CVD morbidity [54]. Advancement in human pluripotent stem cell technology may pinpoint adverse effects of therapies, identify cardioprotective agents, and support anticancer drug-induced cardiotoxicity research. Careful monitoring of real-time tumour responses and pre-treatment assessment of genetic predispositions for cardiotoxicity, such as higher frequencies of cardiotoxicity risk alleles, could be transformative. For example, previously identified cardiotoxicity risk alleles are most prevalent in populations of African descent, which could potentially explain their higher CVD rates. Additionally, integrating routine cardiac imaging and biomarker monitoring into treatment protocols for patients with these alleles can facilitate timely management of cardiotoxicity. Educating healthcare providers and patients about the importance of cardiovascular risk mitigation, during cancer therapy especially for these high-risk patients, is crucial to improving outcomes. These measures can reduce disparities in cardiotoxicity outcomes and enhance long-term quality of life for breast cancer survivors who are at most risk of mortality. Furthermore, precision medicine, pre-screening all patients prior to treatment for adverse events, may be a straightforward approach to overcoming mortality burdens, prevent CVD and improve treatment adherence and efficacy.

This review has the potential to serve as a valuable resource for clinicians as it offers insights into BC treatment cardiotoxicity which can aid better decision making, and improve patient outcomes whilst reducing treatment adverse effects. This review will act as a useful reference point for clinicians and other healthcare professionals to compare known studies in one resource.

Funding sources

This work was supported by the NCI-CRUK Cancer Grand Challenge [SAMBAI: CRUK Cancer Grand Challenge: CGCATF-2023/100029 and NCI Cancer Grand Challenge: 1OT2CA297505-01], philanthropic donation [36,565,532], the BBSRC Doctoral Training Program [BB/T008369/1; BB/I024291/1], PhD scholarship funded by the Egyptian Ministry of Higher Education and Scientific Research, The Grundy Educational Trust, and the School of Veterinary Medicine and Science, University of Nottingham.

CRediT authorship contribution statement

Maria Haque: Writing – review & editing, Writing – original draft, Visualization, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Nehal Atallah: Writing – review & editing, Writing – original draft, Validation, Investigation, Conceptualization. Rodhan Patke: Writing – review & editing, Writing – original draft, Visualization, Software, Investigation. Anna E Harris: Writing – review & editing, Writing – original draft, Validation, Investigation. Corinne L Woodcock: Writing – review & editing, Writing – original draft, Validation, Investigation. Dhruvika Varun: Writing – review & editing, Writing – original draft, Validation, Investigation. Rachel L Thompson: Writing – review & editing, Writing – original draft, Validation, Investigation. Jorja Jackson-Oxley: Writing – review & editing, Writing – original draft, Validation, Investigation. Cyntholia H Okui: Writing – review & editing, Investigation. Alexander Dean: Writing – review & editing, Investigation. Mansour Alsaleem: Writing – review & editing, Investigation. Emad Rakha: Writing – review & editing, Supervision, Investigation, Funding acquisition, Conceptualization. Sheeba Irshad: Writing – review & editing, Investigation. Melissa B Davis: Writing – review & editing, Supervision, Investigation, Funding acquisition. Jennie N Jeyapalan: Writing – review & editing, Supervision, Project administration, Investigation, Funding acquisition. Nigel P Mongan: Writing – review & editing, Writing – original draft, Visualization, Supervision, Software, Resources, Project administration, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization. Catrin S Rutland: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.