Breast Cancer and Therapy-Related Cardiovascular Toxicity

Abstract

The global incidence of breast cancer is on the rise, a trend also observed in South Korea. However, thanks to the rapid advancements in anticancer therapies, survival rates are improving. Consequently, post-treatment health and quality of life for breast cancer survivors are emerging as significant concerns, particularly regarding treatment-related cardiotoxicity. In this review, we delve into the cardiovascular complications associated with breast cancer treatment, explore surveillance protocols for early detection and diagnosis of late complications, and discuss protective strategies against cardiotoxicity in breast cancer patients undergoing anticancer therapy, drawing from multiple guidelines.

INTRODUCTION

Globally, breast cancer ranks as the most commonly diagnosed cancer among females, with approximately 2.3 million new cases reported in 2020, and its prevalence is on the rise [1]. Fortunately, findings from a global cancer surveillance report by the CONCORD Working Group covering the years 2000 to 2014 indicate an age-standardized 5-year net survival rate of approximately 85%–90% for breast cancer in developed countries, including South Korea, reflecting an overall improvement in survival rates over time [2]. However, the risk of treatment-related cardiovascular (CV) toxicity, including heart failure (HF), among cancer survivors is becoming increasingly concerning over the long term [3,4,5]. Moreover, newer anticancer agents, such as immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs), are being rapidly developed and used concomitantly or sequentially with traditional anticancer drugs known to have cardiotoxic effects; however, their combined CV toxicity has not been fully clarified. This review considers recent issues in breast cancer treatment, focusing on treatment-related CV complications, surveillance protocols for early detection and diagnosis of late complications, and protective strategies against cardiotoxicity, drawing from recent guidelines such as those from the European Society of Cardiology (ESC-2022) [6], American Society of Clinical Oncology (ASCO-2017) [7], and European Society for Medical Oncology (ESMO-2020) [8].

CV DISEASES IN PATIENTS WITH BREAST CANCER

A nationwide population-based cohort study conducted in Korea from 2002 to 2013 [9] revealed that 4% of breast cancer patients had preexisting CV diseases at the time of their cancer diagnosis, while 8% were newly diagnosed with CV diseases, primarily within 5 years following their cancer diagnosis. Additionally, both preexisting and newly diagnosed CV diseases were associated with higher mortality rates. Notably, cancer and CV diseases share genetic and molecular mechanisms in their pathophysiology, including gene mutations such as those in the TET2 gene, systemic inflammation, oxidative stress conditions, and common risk factors such as advanced age, obesity, hypertension, diabetes, hyperlipidemia, vascular diseases, and smoking [9,10,11,12]. Moreover, several anticancer therapies are known to be cardiotoxic [6]. Pediatric, adolescent, and young adult survivors of cancer are at a heightened risk of incident CV diseases compared to the general population, a risk that persists for over 30 years, particularly among those who have undergone high-dose cardiac radiation [3,5] and anthracycline (AC) therapies [3,4].

Competing mortality rates from CV causes and due to primary cancer in adult survivors of cancer may vary according to age group and cancer type. Strongman et al. [13] demonstrated that mortality due to primary cancer was higher than that from CV causes in cancer survivors aged under 60 years; however, CV mortality in elderly patients has surpassed cancer mortality over time. In their study, among breast cancer survivors, the crossover points at which CV disease mortality rates equal cancer mortality rates were 12.7 years (95% confidence interval [CI], 11.6–21.6) for those aged 65–79 years and 7.1 years (95% CI, 6.3–12.6) for those aged 80 years and above. Therefore, more careful CV monitoring is required in older survivors of cancer.

COLLABORATIVE APPROACH: MULTIDISCIPLINARY TEAM-BASED DECISION MAKING

Interrupting the use of a specific anticancer drug in patients with cancer, even if cardiotoxicity occurs, is complicated. This is especially true in scenarios where chemotherapy regimens are limited or if the chemotherapeutic agent offers a significant survival benefit compared with other agents. Consequently, it is crucial to assess the CV risks of patients prior to the initiation of anticancer treatment. Moreover, for high-risk patients, cardiac monitoring protocols should be planned for the entire duration of anticancer therapy, using a collaborative approach (Figure 1) [6,14].

Figure 1. Collaborative approach strategy for cardiotoxicity monitoring.

CV = cardiovascular; DM = diabetes mellitus; HT = hypertension; CVD = cardiovascular disease; HF = heart failure; VHD = valvular heart disease; CAD = coronary artery disease; LVEF = left ventricular ejection fraction; AC = anthracycline; RT = radiotherapy; DOX = doxorubicin; ECG = electrocardiography; TTE = transthoracic echocardiography; cTn = cardiac troponin; NP = natriuretic peptide.

^*In anthracycline and anti-human epidermal growth factor 2 therapies; ^†If CV toxicity develops.

The hemodynamic conditions and severity of comorbid diseases in patients undergoing anticancer therapies can fluctuate due to factors, such as sympathetic stimulation from emotional or physical stress and changes in volume status, including fluid loading during chemotherapy infusion and dehydration from chemotherapy-related gastrointestinal problems. In addition, vascular endothelial growth factor-targeting drugs can cause uncontrolled or severe hypertension owing to their underlying mechanisms. Therefore, personalized patient surveillance should be maintained throughout the entire period of anticancer therapy.

MONITORING FOR ANTICANCER THERAPY-RELATED CARDIOTOXICITY

CV toxicity is typically monitored using transthoracic echocardiography (TTE), serologic cardiac biomarkers, and electrocardiography (ECG) [6,15]. If echocardiographic images are of poor quality or nondiagnostic, cardiac magnetic resonance imaging (MRI) may serve as an alternative [16]. TTE is recommended to assess the global longitudinal strain (GLS) and 3-dimensional left ventricular ejection fraction (LVEF) if feasible, in addition to estimating the 2-dimensional LVEF using the biplane Simpson method. LVEF, assessed using 2- and 3-dimensional methods, indirectly measures myocardial function by tracking volumetric changes in the left ventricle across end-diastole and end-systole (Figure 2). Conversely, GLS directly evaluates myocardial function by quantifying myocardial deformation between end-diastole and end-systole. GLS measurement is particularly useful for screening patients with subclinical cardiac dysfunction who exhibit mildly reduced or low-normal LVEF [17]. Therefore, the GLS value can serve as an early marker for cancer therapy-related cardiac dysfunction (CTRCD). Figure 3 illustrates the decrease in GLS values and the shift to an abnormal cardiac troponin (cTn) level prior to a significant decline in LVEF in a patient undergoing AC-containing chemotherapy over a period of 3 months.

Figure 2. Assessment of cardiac function on echocardiography: left ventricular ejection fraction and global longitudinal strain.

LVEF = left ventricular ejection fraction; GLS = global longitudinal strain; Ai, Bi = cylinder volumes, L = left ventricular longitudinal diameter; Ld = length at diastolic period; Ls = length at systolic period; V = volume; n = number of cylinders; EDV = end-diastolic volume; ESV = end-systolic volume.

Figure 3. Serial transthoracic echocardiography of a 60-year-old female with breast cancer undergoing doxorubicin-docetaxel chemotherapy. (A) Baseline TTE, (B) TTE 3 months later.

TTE = transthoracic echocardiography; ANT_SEPT = anteroseptal; SEPT = septal; ANT = anterior; INF = inferior; POST = posterior; LAT = lateral; GLS = global longitudinal strain; LVEF = left ventricular ejection fraction; cTn = cardiac troponin; Δ = change.

CTRCD: Definition and screening methods

CTRCD is generally defined as a decrease in GLS of ≥ 15% from baseline or a decline in LVEF of ≥ 10% to an absolute LVEF of < 50%–53%, although the cut-off values vary according to guidelines [18,19]. If CTRCD is suspected, a follow-up TTE for confirmation is recommended within 2 to 3 weeks because the measurements are load-dependent [20,21]. Additionally, GLS values are vendor-dependent; thus, follow-up TTE should be performed with the same equipment.

Serologic cardiac biomarkers, including cTn and natriuretic peptides (NPs) such as brain natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), are easier to measure than TTE; thus, they are useful for screening CTRCD in patients with low- and moderate-CV risk or for monitoring CTRCD between follow-up TTE measurements. However, NP and cTn levels may be influenced by clinical characteristics, including age, sex, and comorbid conditions, such as chronic kidney disease, lung disease, atrial fibrillation (AF), and obesity [22,23,24]. Therefore, serial changes in the levels of cardiac biomarkers should be considered during anticancer therapies, in addition to their absolute levels [15].

Monitoring of arrhythmia in patients receiving cancer therapy

Cancer can cause arrhythmias due to chronic inflammation and metabolic changes, and both cancer and arrhythmia have common risk factors such as obesity, alcohol abuse, and smoking [25]. Moreover, various anticancer chemotherapies can trigger ECG changes and arrhythmias, either directly or secondarily through cardiomyopathies caused by ischemic origins or CTRCD [25,26].

QT prolongation occurs frequently during chemotherapy and is linked to torsade de pointes, ventricular fibrillation, and sudden cardiac death [27]. A study reported that significant corrected QT prolongation (> 450 ms) occurred in 15% of patients after the first cycle of AC chemotherapy and increased with subsequent cycles [28]. Additionally, electrolyte imbalances, including hypokalemia, and various drugs, such as antibiotics, antidepressants, and antiemetics, can contribute to QT prolongation. AF is one of the significant complications of chemotherapy [29,30]. Therefore, ECG monitoring is essential both at the start of chemotherapy and throughout its course, with Holter monitoring being considered if necessary.

AC- AND ANTI-HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 THERAPY-RELATED CARDIOTOXICITY

Case: ACs followed by trastuzumab

A 59-year-old woman with no prior medical history was diagnosed with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (T3N1M0, stage 3A) and underwent neoadjuvant chemotherapy with doxorubicin (DOX) (cumulative dose = 300 mg/m²) and docetaxel, followed by right modified radical mastectomy. Subsequently, the patient was scheduled for a year of trastuzumab treatment. Before commencing trastuzumab, TTE revealed an LVEF of 61% with no evidence of structural heart disease. However, four months into trastuzumab treatment, the patient complained of dyspnea, and her LVEF plummeted to 29%. Following consultation with a cardiologist and discussion with her oncologist, trastuzumab treatment was halted until her LVEF improved. The patient received guideline-directed medical therapy for HF, including angiotensin-converting enzyme inhibitors, beta blockers (BBs), and spironolactone. During serial TTE follow-ups over 7 years, her LVEF fluctuated between 30%–50%, ultimately leading to the cessation of further chemotherapy.

Risk factors for AC- and HER2-targeted therapy-related cardiotoxicity

Traditional CV risk factors, including advanced age (generally ≥ 65 years, with a particularly high risk in those aged ≥ 75 to 80 years), hypertension, diabetes mellitus (DM), chronic kidney disease, current or significant past smoking history, and obesity (body mass index > 30 kg/m²), are known concurrent risk factors for AC- and trastuzumab-related cardiotoxicity [6,7,31]. Additionally, preexisting CV comorbidities, such as HF or LVEF < 50%, significant valvular heart disease, coronary artery disease or angina, and arrhythmias like AF, contribute to increased cardiotoxicity risk [6,7,31]. Prior exposure to other cardiotoxic anticancer therapies, including ACs, trastuzumab, and mediastinal or left chest radiotherapy, further increases the risk. A previous randomized controlled trial (RCT) showed that CTRCD occurred in 8% of patients with HER2-positive breast cancer receiving the AC regimen alone and in 27% of those receiving the AC regimen with trastuzumab treatment [32]. Furthermore, if the total planned cumulative dose of AC is ≥ 250 mg/m² of DOX or its equivalent, the risk of cardiotoxicity is high, even when used alone [6]. In the present case, the patient received a cumulative dose of DOX of 300 mg/m², followed by trastuzumab treatment. This might have been the etiology of irreversible HF despite the absence of any CV risk factors.

Genetic susceptibility to AC-related cardiotoxicity may also play a role in the development of cardiotoxicity. Recent genetic studies utilizing genomes from pediatric and adult cancer survivors have identified specific genetic variants that are susceptible to AC-related cardiotoxicity, which may explain the high inter-individual variability for CTRCD [33,34]. These variants are involved in the pathogenesis of topoisomerase 2β-mediated DNA damage, AC transport and metabolic pathways, oxidative stress generation, altered iron homeostasis, and sarcomere dysfunction [33,34,35,36,37,38,39,40,41,42,43]. In the near future, genetic testing could be explored to identify high-risk patients, in addition to evaluating clinical risk factors.

Demarcation between reversible and irreversible CTRCD

In four major trials evaluating the efficacy and safety of trastuzumab treatment, including the HERceptin Adjuvant (HERA) [44], National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 [45], North Central Cancer Treatment Group (NCCTG) N9831 [46,47], and Breast Cancer International Research Group (BCIRG) 006 [48], significant HF, classified as New York Heart Association (NYHA) grades III–IV with a decline in LVEF of ≥ 10% from baseline to a final LVEF < 50%, occurred in 0.4%–4% of patients undergoing trastuzumab treatment. Asymptomatic declines in LVEF, classified as NYHA grades I–II with the same LVEF decline criteria, occurred in 3–18% of patients undergoing trastuzumab treatment. Discontinuation of trastuzumab due to CTRCD occurred in 4.3% of patients in the HERA trial and 19% in the NCCTG N9831 trial. However, most patients experiencing CTRCD recovered within 6 months after trastuzumab discontinuation, and the long-term CV outcomes were favorable, with most CV events occurring during the treatment phase [45,49]. Conversely, a retrospective study by Yoon et al. [50] showed that persistent cardiotoxicity of ≥ 6 months was observed in 20% of patients with breast cancer undergoing trastuzumab treatment. In their study, 70% of those with persistent cardiotoxicity underwent prior AC administration (a cumulative dose of DOX = 356 ± 55 mg/m²), and TTE follow-up between the end of AC treatment and the start of trastuzumab was not mandatory. Therefore, it remains uncertain whether the cardiotoxicity is due to ACs, trastuzumab, or a combination of both.

Generally, AC-related cardiotoxicity is recognized as dose-dependent and irreversible, in contrast to the dose-independent and reversible nature of cardiotoxicity associated with HER2-targeted therapy [31,51]. Furthermore, AC-related cardiotoxicity is primarily observed within approximately 30 days following its administration but can manifest up to 6–10 years later [52,53]. Many patients with HER2-positive breast cancer undergo AC chemotherapy before trastuzumab treatment, as observed in the present case. Consequently, LV dysfunction observed during trastuzumab treatment often does not improve despite the interruption of trastuzumab and optimized management for HF. Careful CV monitoring is required when cardiotoxic chemotherapy is administered concomitantly or sequentially.

Surveillance protocols for cardiotoxicity

Surveillance protocols for cardiotoxicity based on recent guidelines are outlined in Table 1 [6,7,8]. During AC chemotherapy, TTE measurements are usually recommended at the initiation period, upon reaching a cumulative dose of ≥ 250 mg/m² of DOX or its equivalent, and within 12 months after completing chemotherapy. TTE can be performed more frequently, every two cycles of chemotherapy, and additionally within 3 months after completing chemotherapy for high-risk patients. Serologic cardiac biomarker measurements are recommended every two cycles of chemotherapy or every cycle for high-risk patients. An ECG should be performed initially. If arrhythmia-associated symptoms occur during anticancer therapy, follow-up ECG and/or Holter monitoring should be considered. For patients undergoing HER2-targeted therapy, monitoring for CTRCD is recommended by performing TTE with cardiac biomarkers at the initiation of treatment, every 3 months during chemotherapy, and within 12 months after completing chemotherapy. Additionally, for high-risk patients, it is advised to conduct further monitoring within 3 months post-chemotherapy. The frequency of cardiac monitoring for HER2-targeted therapy has not been established based on risk stratification, as suggested by a broad consensus on expert opinions. Therefore, TTE may be performed more frequently in high-risk patients [6], whereas in low- or moderate-risk patients, it can be performed less frequently and complemented by cardiac biomarkers [14].

Table 1. Breast cancer therapy-related cardiotoxicity, monitoring protocols for early detection, and treatment strategies.

Therapy	Drugs	Cardiotoxicity	Monitoring		Diagnosis/Treatment
ACs	Doxorubicin, epirubicin	LV dysfunction, HF	TTE:		LVEF < 50%†:
				- Baseline, DOX ≥ 250 mg/m2*, 12 M post-Tx		- HF therapy: RAS-Is, BBs
				- Additionally, every 2 cycles and 3 M post-Tx in high-risk patients		- The withdrawal of the AC use‡
				- HF symptoms (occurrence)	Consider dexrazoxane for DOX* ≥ 300 mg/m2 or liposomal ACs in high-risk patients
			Cardiac biomarkers (cTn, NPs):
				- Baseline, every 2 cycles (every cycle in high- risk patients), DOX ≥ 250 mg/m2*, 3 M post-Tx
				- Additionally, 12 M post-Tx in high-risk patients
		Arrhythmia, QT prolongation	ECG, Holter monitoring (if symptomatic)
HER2-targeted drugs	Trastuzumab, pertuzumab	LV dysfunction, HF	TTE and cardiac biomarkers (cTn, NPs):		LVEF < 40%†:
				- Baseline, every 3 M, 12 M post-Tx		- HF therapy: RAS-Is, BBs
				- Additionally, 3 M post-Tx in high-risk patients		- The withdrawal of the culprit drug use until LVEF is recovered to ≥ 40%§ and symptoms are absent
					LVEF = 40%–49%:
						- HF therapy: RAS-Is, BBs
						- Continue chemotherapy under frequent CV monitoring if asymptomatic
					TTE every 3–6 weeks until stable
Antimetabolites	5-FU, capecitabine	Coronary vasospasm, ventricular arrythmia	Chest pain, ECG, cardiac biomarkers, TTE, Holter, coronary angiography		Nitrates, CCBs for coronary vasospasm
					Consider interrupting the culprit drug use or changing the infusion regimen

AC = anthracycline; LV = left ventricular; HF = heart failure; TTE = transthoracic echocardiography; DOX = doxorubicin; M = month; Tx = treatment; cTn = cardiac troponin; NP = natriuretic peptide; ECG = electrocardiography; LVEF = left ventricular ejection fraction; RAS-Is = renin-angiotensin system inhibitors (including renin-angiotensin-converting enzyme inhibitors and angiotensin receptor blockers); BB = beta blocker; HER2 = human epidermal growth factor 2; CV = cardiovascular; FU = fluorouracil; CCB = calcium channel blocker; ESC = European Society of Cardiology; ESMO = European Society for Medical Oncology.

^*A cumulative dose of DOX or its equivalent AC, and then every 2 cycles (additionally administration of DOX of 100 mg/m² or epirubicin of 200 mg/m²) thereafter; ^†If signs and symptoms of HF do not resolve and/or the LVEF remains < 40% after interrupting the culprit drug, and there are no alternative therapeutic options, reconsideration of the culprit drug’s use may be warranted; ^‡If the LVEF recovers to ≥ 50% and symptoms are absent or mild, AC chemotherapy may be resumed with guideline-based HF management and close CV monitoring after a risk-benefit ratio assessment. ^§If the LVEF recovers to ≥ 40% (as per ESC-2022 guidelines) or ≥ 50% (as per ESMO-2020 guidelines) and symptoms are absent, HER2-targeted therapy should be considered with HF management.

If significant CTRCD with LVEF < 50% occurs during AC-containing or HER-2 targeted chemotherapy, HF management should be initiated, and it is recommended to make decisions regarding the continuation or interruption of chemotherapy through a multidisciplinary team (MDT) approach. Considering the restart of chemotherapy after the improvement of LVEF and symptoms should be done with frequent CV monitoring, following a discussion with the MDT. For asymptomatic patients experiencing mild CTRCD with LVEF ≥ 50% accompanied by a significant drop in GLS or increased cardiac biomarkers, it is recommended to continue the chemotherapy with HF management and frequent CV monitoring.

ANTIMETABOLITE-RELATED CARDIOTOXICITY

If atypical chest pain occurs during treatment with 5-fluorouracil (5-FU) or its oral prodrug capecitabine, coronary vasospasm should be initially suspected (Table 1). It should also be differentially diagnosed from ischemic heart disease, arrhythmia, or other cardiomyopathies. 5-FU-associated coronary vasospasm mainly occurs during the first administration of 5-FU but can also occur after several cycles of infusion [54]. Its incidence has been reported in the range of 1%–5% in prospective studies [55]; however, it might be underreported, as it can be overlooked due to atypical chest pain presentation. Currently, there is no evidence that prophylactic use of anti-anginal medications effectively prevents coronary vasospasm [56].

Upon the occurrence of coronary vasospasm, withdrawal or continuation of 5-FU treatment should be considered based on the risk-to-benefit ratio estimation. Some case reports have described successful rechallenge with 5-FU infusion after administering strong anti-anginal medications, including calcium channel blockers (CCBs) and nitrates, accompanied by close monitoring and/or a transition from continuous infusion to a bolus infusion or dose reduction regimen [57]. However, re-initiation of 5-FU can induce serious complications such as myocardial infarction, fatal arrhythmia, and sudden cardiac death [58,59,60].

PRIMARY AND SECONDARY PREVENTION FOR CTRCD

Renin-angiotensin system inhibitors (RAS-Is), including renin-angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and BBs

When CTRCD occurs, optimized management of HF, including RAS-Is and BBs, is recommended regardless of the presence or absence of symptoms and the severity of CTRCD [6,7,8]. However, RCT data supporting HF management in asymptomatic patients with mild CTRCD are limited [61].

Several RCTs and meta-analyses have shown that the prophylactic use of RAS-Is or BBs tends to decrease the decline in LVEF associated with CTRCD, although the statistical significance of these findings is not consistent across studies [62,63,64,65]. However, there is no conclusive evidence that its prophylactic use significantly reduces the incidence of HF. Additionally, concerns regarding increased hypotension have been raised [66,67]. Therefore, the prophylactic use of RAS-Is or BBs to prevent CTRCD can be considered for high-risk patients after careful evaluation of the risk-benefit ratio.

Separately, using RAS-Is as antihypertensive drugs can benefit patients with hypertension undergoing cardiotoxic chemotherapy, a benefit not observed with BBs. In a previous study [68], we demonstrated that RAS-Is improved clinical outcomes against DOX-related toxicity in patients with breast cancer and hypertension, compared to normotensive patients receiving DOX-containing chemotherapy. Moreover, RAS-Is and CCBs have shown more favorable CV outcomes compared to BBs and thiazide/thiazide-like diuretics in patients with hypertension and breast cancer undergoing DOX therapy [69]. Additionally, CCBs have demonstrated comparable CV outcomes to RAS-Is in patients with hypertension receiving DOX therapy. CCBs are superior to RAS-Is in lowering both central and peripheral blood pressures, reducing blood pressure variability, and decreasing arterial stiffness [70,71]. Therefore, the selection of antihypertensive medications should be tailored to patients’ clinical conditions. When dual antihypertensive therapy is necessary, the combination of CCBs and RAS-Is is recommended [6].

Statins

Several experimental studies have demonstrated that statins reduce oxidative stress and cardiac inflammation, potentially preventing AC-related cardiotoxicity [72]. Clinical studies have also shown protective effects of statins against CTRCD [73] and HF [74,75]. However, two recent major RCTs evaluating the efficacy of statins in preventing CTRCD, including the Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT) [76] and Statins TO Prevent the Cardiotoxicity from Anthracyclines (STOP-CA) [77], showed conflicting results (Table 2). Both studies matched participants in a 1:1 ratio between the statin (atorvastatin 40 mg/day) and control groups during AC chemotherapy. The STOP-CA trial included patients with lymphoma who received a higher cumulative dose of AC in their chemotherapy regimens, whereas the PREVENT trial included patients with breast cancer and lymphoma at rates of 85% and 15%, respectively. Consequently, the median cumulative dose of ACs was 300 mg/m² in the STOP-CA trial and 240 mg/m² in the PREVENT trial. The outcomes, estimated by changes in LVEF following AC chemotherapy, showed a positive protective effect in the STOP-CA trial but not in the PREVENT trial. Based on these results, the prophylactic use of statins remains controversial but may be considered for high-risk patients scheduled to receive high cumulative doses of ACs [78].

Table 2. Two randomized controlled trials evaluating the efficacy of prophylactic use of statins during anthracycline-containing chemotherapy.

Characteristics		PREVENT	STOP-CA
Age (yr), mean ± SD		49 ± 12	50 ± 17
No. of subjects (case:control)		139:140	150:150
Cancer type
	Breast	85%	0%
	Lymphoma	15%	100%
Intervention		Atorvastatin 40 mg/day	Atorvastatin 40 mg/day
Median cumulative AC dose		240 mg/m2	300 mg/m2
Follow-up duration		24 months	12 months
Primary end point		ΔLVEF/initial LVEF	ΔLVEF ≥ 10% decline to < 55%
	Case vs. Control	3.2% ± 0.7% vs. 3.3% ± 0.6%	13 vs. 33 events
	p-value	0.93	0.002

PREVENT = the Preventing Anthracycline Cardiovascular Toxicity with Statins; STOP-CA = the Statins TO Prevent the Cardiotoxicity from Anthracycline; SD = standard deviation; AC = anthracycline; Δ = change; LVEF = left ventricular ejection fraction

Sodium-glucose cotransporter 2 (SGLT2) inhibitors

Experimental and clinical studies have shown that SGLT2 inhibitors inhibit intracellular glucose metabolism [79], reduce inflammatory cytokines [79,80], and improve endothelial function [81]. Furthermore, several RCTs have demonstrated that SGLT2 inhibitors improve CV outcomes in patients with HF, regardless of type 2 DM [82,83,84,85]. Recent retrospective studies have shown that SGLT2 inhibitors improve CV outcomes in patients with DM and cancer receiving AC chemotherapy [86,87,88]. In addition, the use of SGLT2 inhibitors was associated with reduced mortality compared with patients without DM and those with DM not using SGLT2 inhibitors [87]. Experimental studies involving cancer cell lines and animal models have demonstrated that SGLT2 inhibitor treatment reduces glucose uptake and mitochondrial function in cancer cells, thereby decreasing cell proliferation and clonogenic survival [89,90]. This contributes to inhibiting the development and growth of cancer cells [89,91,92]. However, whether the effects of SGLT2 inhibitors on clinical outcomes are consistent in cancer patients without DM has not been clarified. Fortunately, prospective studies, such as EMPAgliflozin in prevention of chemotherapy-related CardioToxicity (EMPACT; NCT05271162), are ongoing to evaluate the cardioprotective effects of SGLT2 inhibitors in high-risk patients undergoing AC chemotherapy.

Dexrazoxane

Meta-analyses have demonstrated that dexrazoxane significantly reduces the relative risk of HF by up to 71%–76% in patients receiving AC therapy, without significant differences in response rate, progression-free survival, and overall survival [93,94,95]. However, the use of dexrazoxane is limited to the prevention of cardiotoxicity in women with metastatic breast cancer who have received a cumulative dose of DOX of 300 mg/m² or its equivalent and are continuing DOX therapy [94].

PRESENT AND FUTURE ANTICANCER DRUGS AND EXPECTED CARDIOTOXICITY: ICIs AND ADCs

The anticancer efficacies of recently developed ICIs and ADCs are outstanding; however, their cardiotoxic risks have not yet been fully clarified. Adverse effects of ICIs, such as pembrolizumab and atezolizumab, are associated with immune-related toxicity [96]. Cardiotoxicity from ICIs, including myocarditis, pericarditis, arrhythmia, and HF, occurs rarely, affecting approximately 0.1%–1% of cases [97,98,99]. However, the risk may increase with combination therapy and can be fulminant or fatal [97,100]. Baseline and serial ECGs and cardiac biomarker assessments are not predictive of ICI-mediated cardiotoxicity. However, changes in cardiac biomarkers, particularly cTn, are considered sensitive for early detection of cardiotoxicity. A cohort study showed that the incidence of ICI-related HF was higher in patients with previous HF or valvular heart disease [101]. Echocardiography should be considered first when cardiotoxicity is suspected. If not diagnostic, cardiac MRI and biopsy should be considered. Currently, when ICI-mediated cardiotoxicity of grade 2 (characterized by cTn elevation with mild symptoms) or higher, as defined by the Common Terminology Criteria for Adverse Events, occurs, it is recommended to discontinue ICIs and administer early high-dose corticosteroids (1–2 mg/kg/day of prednisolone) [97,98].

ADCs, including trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1), have lower cardiotoxicity than trastuzumab. A meta-analysis on T-DXd-related cardiotoxicity reported an incidence of LVEF decline of 1.95% (95% CI, 0.65%–3.73%) and an incidence of HF of 0.26% among patients with breast cancer [102]. A retrospective pharmacovigilance study using VigiBase, the World Health Organization database for adverse drug reaction reports, indicated that trastuzumab had a higher rate of HF reports (12%) compared with ADCs (1.9% for pertuzumab, 1.7% for T-DM1, and 1.2% for T-DXd) [103]. Additionally, combination therapy involving trastuzumab with pertuzumab or other HER2 tyrosine kinase inhibitors was associated with higher odds of HF reports than the combination of trastuzumab with platinum-based chemotherapy [103]. The study also found that pertuzumab (reporting odd ratio [ROR], 0.13; 99% CI, 0.07–0.23), T-DXd (ROR, 0.06; 99% CI, 0.03–0.15), and T-DM1 (ROR, 0.10; 99% CI, 0.07–0.14) had lower odds of HF compared to trastuzumab in patients with breast cancer. However, the combination therapy of pertuzumab and T-DM1 presented higher odds of HF reporting than T-DM1 monotherapy in patients with metastatic breast cancer (ROR, 3.35; 99% CI, 2.04–5.52). Therefore, combination therapies involving trastuzumab with pertuzumab or pertuzumab with T-DM1 may require close monitoring.

LONG-TERM SURVEILLANCE FOR BREAST CANCER SURVIVORS

In a study investigating patients who underwent radiotherapy for breast cancer between the 1970s and the early 1980s, long-term CV mortality increased persistently over 15 years [104]. A population-based cohort in England demonstrated that the incidence of each CV disease increased with a cumulative DOX dose of 150 mg/m² or with calculated heart doses of radiotherapy in patients with Hodgkin lymphoma, compared with an age- and sex-matched population, as follows: HF at an average heart dose of 3.3 Gy (range, 0.3–20.5), ischemic heart disease at an average of 7.8 Gy (range, 0.8–24.0), and valvular heart disease at an average of 12.6 Gy (range, 0.8–33.1) [105]. Therefore, long-term CV monitoring is required even after the completion of cancer therapy, particularly in patients who have undergone AC therapy or mediastinal or left chest radiotherapy.

Generally, after the completion of cancer therapy, reassessing CV risk is recommended [6]. High risk includes high-dose AC (cumulative DOX dose ≥ 250 mg/m² or epirubicin dose ≥ 600 mg/m²), high-dose radiotherapy (mean heart dose of ≥ 15–25 Gy as per ESC-2022 or ≥ 30 Gy in ASCO-17), and the combination of lower-dose AC (DOX dose of 100–249 mg/m²) and lower-dose radiotherapy (5–15 Gy in ESC-2022 or < 30 Gy in ASCO-17), and the presence of CTRCD of more than moderate grade (LVEF < 50%) during treatment [6,7]. Among patients receiving low-dose AC or trastuzumab alone, those aged ≥ 60 years or with multiple CV risk factors (≥ 2), including smoking, hypertension, diabetes, dyslipidemia, and obesity, are also considered high risk [7]. High-risk patients are advised to undergo ECG and TTE with GLS assessment at 6–12 months and 2 years post-treatment [7,8], or at 1, 3, and 5 years post-treatment [6]. Given that CV toxicity due to mediastinal or left chest radiotherapy can manifest with a delay, it is recommended to commence CV surveillance at 5 years post-treatment, and then continue every 5 years thereafter [6,8].

CONCLUSION

As breast cancer therapies continue to evolve and the number of cancer survivors increases, treatment-related CV toxicity has emerged as a significant concern. In particular, AC-based and/or HER2-targeted therapies may lead to CTRCD during treatment and within 5 years after completion [6]. Additionally, heart radiation due to radiotherapy can increase the risk of delayed CV disease for more than 30 years. Therefore, comprehensive CV risk assessment, vigilant monitoring for early detection, and appropriate management of CV diseases are essential before, during, and after cancer treatment. This necessitates a collaborative MDT approach that includes oncologists, cardiologists, and radiologists.

Emerging evidence regarding the cardioprotective potential of statins and SGLT2 inhibitors, as well as traditional HF management, offers promising avenues for both research and clinical practice. Moreover, newly developed regimens, including ICIs, ADCs, and HER2 tyrosine kinase inhibitors, appear to be safer than earlier chemotherapeutic agents in terms of cardiotoxicity, although their effects are not fully understood. Ultimately, our hope is for cancer survivors to live healthily and maintain a high quality of life free from CV diseases.