Cancer Therapy-Related Cardiac Dysfunction in Breast Cancer Patients Receiving Combination Therapy of Candesartan and Carvedilol for Primary Prevention: A Prospective Longitudinal Study.

INTRODUCTION
Cardiovascular disease (CVD) is one of the most prevalent and serious complications related to cancer therapy among patients with breast cancer who are undergoing cardiotoxic chemotherapy.1 In a prospective cohort, compared with cancer-free women, breast cancer survivors were at a greater risk of all-cause mortality for many years, and the CVD mortality risk even began to increase after 8 years of diagnosis.2
Anthracyclines (ACs) and trastuzumab (TZ), which are the most widely used agents for treating breast cancer, have been associated with left ventricular (LV) dysfunction, particularly in patients with prior radiotherapy to the left chest or mediastinum or with preexisting CVD or cardiovascular (CV) risk factors.3 ACs have shown dose-dependent early and late irreversible cardiotoxic effects that cause myofibrillar degradation, cardiomyocyte apoptosis and necrosis, leading to cardiomyopathy or end-stage heart failure (HF).4 TZ, either alone or in combination with an AC-based regimen, has also contributed to a high incidence of cancer therapy-related cardiac dysfunction (CTRCD),5 which is thought to be due to the inhibition of cardioprotective human epidermal growth factor receptor 2 (HER2) signaling or increased oxidative stress.67 Neurohormonal activation is one of the most important mechanisms underlying the development or progression of HF, and neurohormonal antagonists such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and beta-blockers (BBs) have significantly reduced morbidity and mortality in patients with HF.8 It can be inferred from these observations that ACEIs/ARBs and BBs may be useful for the primary prevention of CTRCD, and several randomized clinical trials (RCTs) have demonstrated the cardioprotective effects of these drugs.91011121314 However, Boekhout et al.15 reported that the use of candesartan during adjuvant TZ therapy following ACs did not prevent a reduction in left ventricular ejection fraction (LVEF), and some RCTs that previously reported the beneficial effects of concomitant treatment with ACEIs/ARBs or BBs on myocardial injury reported conflicting results in the extended follow-up of participants.1617
The aim of this study was to evaluate the incidence, severity and predictors of CTRCD under cardioprotective therapy with a combination of candesartan and carvedilol among breast cancer patients. Additionally, for subjects scheduled to receive AC and/or TZ, we explored whether the factors associated with the risk of developing CTRCD differ depending on the baseline CV toxicity risk.

METHODS

Study design and participants
This was a prospective cohort study to examine the incidence, severity, and predictors of CTRCD in a primary prevention strategy with combined candesartan and carvedilol therapy among breast cancer patients receiving chemotherapy and/or TZ.
We included 851 consecutive female patients > 18 years of age with a normal LVEF (> 55%) treated with chemotherapy and/or TZ for breast cancer from September 2012 to November 2021 at our institution. The exclusion criteria were preexisting HF or current or prior symptoms of HF; prior history of cardiomyopathy, coronary artery disease, or peripheral artery disease; valvular heart disease (≥ moderate); congenital heart disease; prior cardiac surgery; significant arrhythmias or conduction delay; presence of intracardiac devices; prior chemotherapy or radiation therapy; cancer stage IV; contraindications or prior intolerance to the use of ACEI/ARB or BB; baseline systolic blood pressure (BP) < 90 mmHg; baseline heart rate < 60 bpm; inadequate baseline echocardiographic images or missing data; oncologic life expectancy of < 12 months; and inability or refusal to provide written informed consent or withdrawal of consent. The remaining 586 patients were enrolled (Fig. 1). We further performed baseline CV toxicity risk assessment in patients scheduled to receive cardiotoxic cancer therapy (e.g., AC and/or TZ), and individuals were classified into low, intermediate, and high or very high CV toxicity risk groups on the basis of the new HF Association-International Cardio-Oncology Society risk stratification.3

Echocardiography
All eligible patients underwent baseline echocardiography within 1 month before the initiation of chemotherapy or TZ. Serial echocardiograms were performed every 3 months during cancer therapy, 6 months after the completion of cancer therapy and annually thereafter, regardless of the treatment regimens. Conventional two-dimensional (2D) echocardiography and real-time three-dimensional echocardiography (RT-3DE) were performed by experienced sonographers blinded to the patients’ details according to the American Society of Echocardiography guidelines.1819
Images were recorded and stored digitally on a secure fileserver in the original Digital Imaging and Communications in Medicine format for offline analysis. All the scans were reviewed and interpreted by two experienced sonographers who were blinded to the patients’ clinical information. Offline analysis of three-dimensional (3D) data was performed via commercially available vendor-independent software (4D LV-analysis Version 3.1; Tom Tec Imaging System GmbH, Unterschleissheim, Germany). The software automatically measured the LV volume, LVEF and myocardial strain values, and the global longitudinal strain (GLS) was calculated by averaging the regional values of 17 myocardial segments in the three apical views (4-, 3-, and 2-chamber views) at end-systole.20

Cardioprotective therapy
Candesartan and carvedilol were initiated concurrently on the first day of chemotherapy or TZ and continued during and after cancer therapy. Patients without preexisting hypertension were started and maintained on minimal doses of candesartan (4 mg q.d.) and carvedilol (3.125 mg q.d.). Patients receiving candesartan and/or carvedilol for hypertension maintained their previous doses. Other hypertensive medications were changed to candesartan and/or carvedilol, and the starting dose was determined by the individual physician’s decision. The doses were titrated every 3 months to a maximum dose or until intolerable side effects developed. When patients discontinued either of the two drugs, the last available echocardiogram performed during the administration of both medications was used for analysis.

CTRCD definition
CTRCD was defined according to the 2022 European Society of Cardiology Cardio-Oncology guidelines: a reduction in LVEF and/or a relative decline in GLS among asymptomatic patients or the development of new HF symptoms.3 Asymptomatic CTRCD was further classified as follows: mild CTRCD, LVEF ≥ 50% and new relative decline in GLS by > 15% from baseline; moderate CTRCD, new LVEF reduction by ≥ 10% indicating an LVEF of 40–49% or new LVEF reduction by < 10% indicating an LVEF of 40–49% and new relative decline in GLS by 15% from baseline; severe CTRCD, new LVEF reduction to < 40%.

Statistical analysis
The data are expressed as the mean ± standard deviation or median [interquartile range (IQR)] for continuous variables and as the number (%) for categorical variables. Comparisons of the variables between two groups were performed using an unpaired Student’s t-test or Mann–Whitney U test for continuous variables and a χ2 test or Fisher’s exact test for categorical variables. Multiple comparisons were assessed by one-way analysis of variance combined with a Bonferroni post hoc analysis or the Kruskal–Wallis H test and the χ2 test or Fisher’s exact test, as appropriate. The Kaplan-Meier curves with log-rank test was used to estimate the event free survival rate for CTRCD occurrence among the four cancer treatment subgroups. Hazard ratios (HRs) along with corresponding 95% confidence intervals (CIs) were calculated to assess the predictors of CTRCD using Cox proportional hazards models. Multivariate Cox regression analyses with the forward selection method were performed to identify the independent predictors of CTRCD after adjusting the covariates found to be significant in the univariate analysis or known to affect LV function.
All the statistical analyses were conducted using SPSS version 22.0 software (IBM Corp., Armonk, NY, USA), and a two-sided P value less than 0.05 was considered to indicate statistical significance.

Ethics statement
The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and the study protocol was reviewed and approved by the Institutional Review Board of The Catholic University of Korea (HC17OIMI0001). All the participants were informed about the research objectives, research protocol, alternative treatment options, and possible side effects, and all the participants provided written informed consent prior to enrollment.

RESULTS
Among the 586 eligible patients, 9 (1.5%) dropped out before the first follow-up echocardiogram (Supplementary Table 1). Finally, 577 patients (median age, 57.0 years; IQR, 51.0–63.0 years) were included. Among these patients, 543 (94.1%) had completed the planned cancer therapy while maintaining cardioprotective therapy at the time of analysis. Eight (1.3%) patients discontinued cardioprotective medications due to non-serious side effects (e.g., dizziness, lightheadedness, or orthostatic hypotension). The subjects were categorized into four regimen groups on the basis of the presence or absence of AC or TZ as follows: AC/non-TZ (n = 257, 44.5%), AC/TZ (n = 111, 19.2%), non-AC/TZ (n = 47, 8.1%), and non-AC/non-TZ (n = 162, 28.1%).

CTRCD incidence and severity
During a median follow-up of 17.9 months (IQR, 10.2–27.7 months), 142 (24.6%) patients experienced CTRCD, and all of them were asymptomatic. Patients treated with non-AC/non-TZ showed a significantly higher event free survival rate for the CTRCD occurrence than those treated with AC and/or TZ (log-rank P < 0.001, Fig. 2A). The annualized event rate for CTRCD was the highest in the AC/TZ group, followed by the AC/non-TZ and the non-AC/TZ groups, and it was the lowest in the non-AC/non-TZ group (8.9% vs. 7.1% vs. 2.8% vs. 2.4%, respectively; P < 0.001) (Fig. 2B). Most CTRCD cases had mild severity (96.5%), of which the proportion of patients receiving the AC/non-TZ regimen was the highest (52.6%), followed by those receiving the AC/TZ (32.8%) regimen, and the lowest percentage of patients treated with non-AC-based regimens. Moderate CTRCD was observed in 4 patients (3 patients receiving the AC/TZ regimen and 1 patient receiving the AC/non-TZ regimen), and severe CTRCD occurred in only 1 patient receiving the AC/non-TZ regimen (Fig. 3). Time trajectories of LVEF and LVGLS over the follow-up period in each of the four cancer treatment groups are also presented (Supplementary Fig. 1).

Patient characteristics
The baseline characteristics of patients who developed CTRCD are summarized in Table 1. Compared with the non-CTRCD group, the CTRCD group was older (median age, 59.0 vs. 56.0 years; P = 0.001) and had a higher body mass index (BMI) and a higher systolic BP. Patients with CTRCD were more likely to have a previous history of hypertension (32.4% vs. 15.9%; P < 0.001) than were those without CTRCD, and previous use of ACEIs/ARBs (18.3% vs. 9.0%; P = 0.002), BBs (4.2% vs. 0.5%; P = 0.004), and diuretics (7.7% vs. 1.1%; P < 0.001) was more common in the CTRCD group than in the non-CTRCD group. The prevalence of diabetes mellitus and dyslipidemia and initial laboratory findings were not significantly different between the two groups. The median 3D LVEF was 64.0% (IQR, 63.0–66.0), with no significant difference between the two groups (P = 0.740). Patients with CTRCD had lower E and septal e’ velocities than those without CTRCD did, but the Avg E/e’ ratio and LA volume index did not differ and the septal s’ velocity was similar between them. The median 3D GLS was 24.1% (IQR, 23.0–25.3), and the CTRCD group had a higher 3D GLS than the non-CTRCD group did (median, 24.9% vs. 23.9%; P < 0.001).
We found no significant difference in the laterality of breast cancer between the two groups; however, the CTRCD group had a greater proportion of patients with stage II disease or higher than the non-CTRCD group did, and AC-based regimens were more frequently used in the CTRCD group than in the non-CTRCD group. Among the study population, 368 (63.8%) patients received doxorubicin, and the mean cumulative dose of doxorubicin was 140.9 mg/m2. Doxorubicin was administered more often to the CTRCD group than to the non-CTRCD group (85.9% vs. 56.6%; P < 0.001), and its cumulative dose was significantly greater in the CTRCD group (mean, 189.2 vs. 125.1 mg/m2; P < 0.001), but the proportion of patients administered high-dose doxorubicin (> 250 mg/m2) was not significantly different between the two groups (12.6% vs. 7.9%; P = 0.150). TZ (40.8% vs. 23.0%; P < 0.001) and taxane were administered more often to the CTRCD group than to the non-CTRCD group, but the use of cyclophosphamide was more common in the non-CTRCD group than in the CTRCD group. Radiation therapy was implemented more frequently in the CTRCD group than in the non-CTRCD group, and the CTRCD group received a higher radiation dose than the non-CTRCD group did. The proportion of patients who received hormone therapy was similar between the two groups. Baseline characteristics according to the four regimens are shown in Supplementary Table 2.
A total of 415 patients who received AC and/or TZ were classified into low-risk (n = 224, 54.0%), intermediate-risk (n = 177, 42.7%) and high-risk (n = 14, 3.4%) or very high-risk (n = 0, 0.0%) groups. Overall, the incidence of CTRCD was the highest in the high-risk group, followed by the intermediate-risk group, and the lowest in the low-risk group (64.3% vs. 37.9% vs. 25.0%; P < 0.001). Similar results were observed in subjects treated with AC-based regimens; however, in those receiving TZ without AC, CTRCD most commonly occurred in low-risk patients with no statistical significance (24.2% vs. 14.3% vs. 0.0%; P = 0.700) (Supplementary Table 3).

Factors associated with the risk of developing CTRCD
The univariate and multivariate Cox regression analyses for the factors associated with the risk of developing CTRCD are presented in Table 2. In the univariate analysis, the use of AC and/or TZ regimens (vs. non-AC/non-TZ); older age; higher BMI; diabetes mellitus; hypertension; dyslipidemia; previous use of ACEIs/ARBs or BBs; higher fasting glucose level; better baseline 3D GLS; cancer stage II or higher (vs. stage I); and radiation therapy were related to CTRCD risk. After adjustment for the confounding variables, older age, hypertension (adjusted HR, 2.230; 95% CI, 1.464–3.395; P < 0.001), lower 3D LVEF and better 3D GLS at baseline, and stage II or higher were significantly associated with the development of CTRCD under cardioprotective medical therapy for primary prevention.
We performed subgroup analyses to assess whether the factors associated with the risk of developing CTRCD differed by the degree of baseline CV toxicity risk. In patients with low CV risk, higher BMI, diabetes mellitus, hypertension (adjusted HR, 5.471; 95% CI, 2.440–12.269; P < 0.001), and better baseline 3D GLS were independent predictors of CTRCD (Table 3). On the other hand, in patients with intermediate-to-high CV toxicity risk, high-dose doxorubicin (adjusted HR, 2.763; 95% CI, 1.348–5.664; P = 0.006), hypertension (adjusted HR, 2.147; 95% CI, 1.329–3.469; P = 0.002), and lower baseline LVEF were significantly associated with the risk of developing CTRCD (Table 4).

DISCUSSION
In this prospective longitudinal cohort study of breast cancer patients who received chemotherapy and/or TZ, and we found that even under primary prevention with combined candesartan and carvedilol, the development of CTRCD was still not uncommon. Previous hypertension was associated with CTRCD in both the low- and intermediate-to-high baseline CV toxicity risk groups among patients treated with AC and/or TZ regimen.
Two recently published meta-analyses of RCTs revealed the preventive effects of ACEIs or ARBs and BBs on the reduction in LVEF after AC or TZ-containing chemotherapy. However, the studies in the meta-analyses were highly heterogeneous and lacked adjustments for patient-level variables possibly affecting LV function, including comorbidities, previous medications, or additional treatments. Furthermore, most of the included studies were conducted on a small number of patients in which cardioprotective medications were maintained only during chemotherapy.2122 The prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA) was a 2 × 2 factorial RCT of 130 patients with early breast cancer that examined the cardioprotective effect of concomitant use of candesartan or metoprolol during AC-containing adjuvant therapy.9 At the completion of adjuvant therapy, the reduction in LVEF was significantly attenuated in the candesartan group; however, the extended follow-up data demonstrated a progressive decline in LVEF after randomization and revealed that candesartan did not prevent a reduction in LVEF at 2 years.916 To our knowledge, there is limited evidence regarding the optimal duration of cardioprotective therapy in breast cancer survivors who have received cardiotoxic cancer therapy. This is the largest prospective longitudinal cohort study on the basis of detailed demographic and clinical data of breast cancer patients treated with neurohormonal antagonists for the primary prevention of CTRCD. We investigated for the first time the long-term risk of developing CTRCD under maintenance of combined cardioprotective therapy with candesartan and carvedilol.
Unfortunately, no studies have shown statistically significant benefits of neurohormonal therapies during cardiotoxic cancer therapy in reducing the risk of HF or other clinical adverse outcomes, possibly because most studies enrolled patients with a low baseline CV toxicity risk.3 In this prospective cohort of female patients with breast cancer, more than 70% of the study population received AC and/or TZ, and substantial proportion of them had intermediate or high baseline CV toxicity risk (n = 191, 46.0%). In line with the results of previous reports investigating the effects of pharmacological prevention on CTRCD risk,91011121314151617 the development of HF was not observed throughout the study period, and almost all patients completed cancer therapy. However, asymptomatic CTRCD was prevalent and 21.8% of CTRCD patients had GLS below normal value (< 18.0%). Although most cases were mild, one patient who received AC discontinued anticancer therapy due to the development of severe LV dysfunction. Given the significant association of subclinical LV systolic dysfunction with incident HF later in life,23 these findings suggest that cancer survivors could still be at increased risk of developing HF despite cardioprotective therapy. In the present study, 28.1% of the study population was treated with a non-AC/non-TZ regimen, and CTRCD occurred in 6.2% of them. High-dose cyclophosphamide is considered highly cardiotoxic and has been associated with a high incidence of CTRCD regardless of prior treatment with ACs.24 In this study, no one received high-dose cyclophosphamide, and the administration of cyclophosphamide was more common in the non-CTRCD group than in the CTRCD group. Considering the similar proportion of CV risk factors among the cancer therapy regimen groups (Supplementary Table 3), undetected CVD susceptible to cardiotoxicity related to cancer treatment may also exist in the non-AC/non-TZ regimen group. Nevertheless, the use of a non-AC/non-TZ regimen did not increase the risk of developing CTRCD under cardioprotective therapy.
Cancers and CVD have shared risk factors, and at the time of cancer diagnosis, many patients have preexisting chronic diseases, such as diabetes mellitus, hypertension, or dyslipidemia.25 These CVD comorbidities are common in breast cancer survivors, who are usually over than 50 years and in the postmenopausal status.26 Although these comorbidities have been associated with an increased risk of CV morbidity and mortality,27 earlier research in breast cancer survivors has focused primarily on cardiac dysfunction related to AC and/or TZ use or radiation-induced coronary artery disease.282930 In our study, 167 (28.9%) patients had at least one of these three comorbidities, and most CTRCD patients were on medications for each comorbidities at enrollment (diabetes mellitus 94.4% [in the CTRCD group] vs. 93.8% [in the non-CTRCD group], hypertension 82.6% vs. 76.8%, dyslipidemia 72.4% vs. 79.7%; P values = not significant). We found that hypertension status was an independent risk factor of CTRCD development regardless of baseline CV toxicity risk, even under cardioprotective therapy. Additional survival analyses also showed that patients with hypertension had a significantly lower CTRCD-free survival rate compared to those without hypertension not only in the overall population (log-rank P < 0.001, Supplementary Fig. 2A) but also in both the low- (log-rank P = 0.036, Supplementary Fig. 2B) and intermediate-to-high (log-rank P = 0.005, Supplementary Fig. 2C) CV toxicity groups. Previously, hypertension has been reported to significantly increase the risk of AC- or TZ-induced cardiomyopathy or HF in cancer patients.2831 Patients with hypertension have increased myocardial wall stress, which results in the release of growth factors or cytokines leading to cardiac remodeling or dysfunction. These hypertension-mediated cardiac damage together with the cytotoxic effects of AC accelerate the development of HF. Among patient receiving TZ, disruption of HER2/neuregulin pathway reduces NO bioavailability and concomitantly increases angiotensin-II and reactive oxygen species. These pathological processes induce endothelial dysfunction, along with myocardial stress underlying hypertension, which contribute to the development of HF.32 However, hypertensive patients with cancer have been traditionally excluded in the large hypertension trials, and optimal BP goals and treatment strategies for hypertension in this population remains unclear.32 Calip et al.33 reported a persistent, significant decline in adherence to diabetes medications, anti-hypertensive drugs and statins following breast cancer diagnosis and noted that appropriate pharmacotherapy for these comorbidities is often neglected during and after cancer therapy. The significant association between hypertension status and the risk of developing CTRCD may also be attributed to poor mediation adherence among cancer patients with hypertension. Additionally, in the low CV toxicity risk group, we found that higher BMI and diabetes mellitus were factors related to CTRCD risk. In the intermediate-to-high CV toxicity risk group, high-dose doxorubicin treatment was a risk factor for the development of CTRCD. The findings further suggest that assessing baseline CVD comorbidities may be important to predict CTRCD event, especially in low CV toxicity risk group.
In the strain surveillance of chemotherapy for improving cardiovascular outcomes (SUCCOUR) trial, in which 331 breast cancer patients were randomized to receive GLS- and an ejection fraction (EF)-guided cardioprotective therapy, patients in the 3D GLS-guided arm experienced a significantly lower reduction in LVEF than those in the EF-guided arm did. However, 2D LVEF was used if 3D measurements were not available; furthermore, the recently published 3-year results revealed no difference in LVEF changes between the patients in the two arms.3435 There is a paucity of long-term follow-up studies evaluating CTRCD with serial measurements of LVEF and LV GLS obtained from RT-3DE images. All of our study participants regularly underwent RT-3DE to measure 3D EF and 3D GLS even after completion of cancer therapy, and CTRCD was determined using either the EF (n = 20, 14.2%) or GLS (n = 142, 100%) criteria. This may explain why the incidence of CTRCD associated with the AC-based regimen was greater than that previously reported in other studies.22 Interestingly, we also found that patients with better baseline GLS were at a greater risk of developing CTRCD than were those with worse baseline GLS, which seems to be inconsistent with the findings of previous studies demonstrating good prognostic performance of worse GLS during cancer treatment for early prediction of subsequent CTRCD.36 However, most of them analyzed patients receiving various doses of cardiotoxic agents for various malignancies, and their researchers defined CTRCD as a clinically significant change in LVEF with or without new-onset HF symptoms. On the other hand, this study was conducted on breast cancer patients with a normal LVEF and no previous history of CVD or cardiotoxic cancer therapy, and CTRCD was further classified into asymptomatic CTRCD based on a reduction in LVEF and/or relative decline in GLS according to the 2022 ESC Cardio-Oncology guidelines. The patient baseline characteristics and new CTRCD diagnostic criteria may have contributed to the association between baseline GLS and CTRCD risk. Furthermore, we found that LVEF-based CTRCD group (n = 20) had a lower baseline LVEF compared with the no-CTRCD group (n = 435) or GLS-based CTRCD group (n = 142) (P < 0.001), whereas GLS-based CTRCD group showed a better baseline GLS value than not only LVEF-based CTRCD group but also no-CTRCD group (P < 0.001) (Supplementary Table 4). Unfortunately, we cannot explain the exact pathophysiology for this paradoxical association. However, it is speculated that, unlike LVEF, baseline GLS itself may not be a risk factor of CTRCD, and the degree of decline in GLS from baseline may be more important in determining CTRCD.
This study has several inherent limitations. First, it is a single-center study with potential selection biases that could influence the clinical outcome. However, all patients were treated with standardized protocols for the management of breast cancer, and echocardiographic images were obtained using a standardized method. Moreover, this was a prospective study involving a relatively large number of subjects and their clinical details during long-term follow-up. Second, the present study did not include a control group. In real clinical practice, due to the limited health insurance coverage before September 2021 in South Korea, serial echocardiographic examinations for assessing the development of CTRCD were not feasible in asymptomatic patients who were not enrolled in our study. Further randomized controlled trials including a placebo or untreated control group to evaluate the efficacy and safety of cardioprotective therapy for predicting CTRCD may be needed. Third, since we focused on the CTRCD risk related to cardiotoxic cancer treatment itself, patients with pre-existing CVD or a prior history of chemotherapy or radiation therapy that can affect myocardial function were excluded. For this reason, no patients at very-high risk were observed and the proportion of subjects with high risk was very low (n = 14, 3.4%) and therefore, we arbitrarily categorized patients into low and intermediate-to-high CV risk groups. Fourth, for patients with hypertension, detailed information regarding the duration of hypertension before enrollment, degree of BP control, and medication adherence was not available. Finally, we enrolled patients diagnosed with breast cancer from 2012 to 2021; therefore, data on cardiac biomarkers that have been recently incorporated in the diagnosis of CTRCD were not available. However, the best cutoff values for cardiac troponin I and T are not clearly defined, and in particular, the incidence of mild asymptomatic CTRCD has been reported to differ markedly depending on cardiac troponin assays and the use of sex-neutral or sex-specific upper reference limits.37
Among breast cancer patients receiving combination therapy with candesartan and carvedilol for the primary prevention of CTRCD, asymptomatic CTRCD was not uncommon, and previous hypertension, along with older age, lower LVEF and better GLS values at baseline, and cancer stage II or higher, was an independent predictor of CTRCD. Hypertension was a significant risk factor associated with the development of CTRCD in both the low- and intermediate-to-high CV toxicity risk groups. The use of high dose doxorubicin was associated with the CTRCD risk in intermediate-to-high risk group. In the low-risk group, higher BMI and previous diabetes mellitus were additional factors associated with the risk of developing CTRCD. Our findings indicate that hypertension is still a strong risk factor of CTRCD development among breast cancer patients and survivors under cardioprotective therapy, and highlight the importance of baseline assessment for underlying CVD comorbidities, particularly in the low CV toxicity risk group.