Risk factors associated with cardiac events among breast cancer survivors at a Saudi tertiary cancer center: a retrospective cohort study

Introduction

Breast cancer (BC) remains a remarkable health challenge worldwide, with over 2.3 million new cases and 685,000 deaths reported in 2020 (1). By 2040, the number of new cases is expected to increase to over 3 million, and the number of deaths to 1 million annually (1). BC is the most common cancer in Saudi Arabia, affecting both men and women, with incidence and mortality rates of 14.8% and 8.5%, respectively (2), and a calculated prevalence of 53%.

Globally, cardiovascular disease (CVD) is believed to be the primary cause of death, with a mortality rate of 31% (3). Gulf Council countries, including Saudi Arabia, face health concerns because of CVD (3). A nationwide survey revealed that the prevalence of coronary artery disease in Saudi Arabia is 5.5% (4), and it is estimated that CVD is responsible for over 45% of all deaths there (3).

Although advanced BC therapy has notably improved the survival of patients with BC (5), whether it contributes to cardiac complications and increased overall mortality has been questioned (5). BC therapy includes radiation, chemotherapy, and targeted treatments (6). The heart is thus potentially exposed to radiation and, as a result, the risk of CVD, including acute coronary syndrome, may be increased (5,7). In addition, chemotherapy has been associated with an increased risk of cardiac injury (5).

Studies have shown a directly proportional relationship between the risk of ischemic heart disease (IHD) and the mean whole-heart radiation dose (MWHD) (6). Moreover, it was found that cardiomyopathy caused by trastuzumab (a targeted cancer drug) does not depend on the total dose administered (8). Although human epidermal growth factor receptor 2 (anti-HER2) targeted therapies are highly effective for treating HER2-positive BC, they are also associated with a significant drawback: the potential to cause heart failure, particularly through a reduction in left ventricular ejection fraction (LVEF). As a result, cardiotoxicity is one of the most common and serious side effects of these treatments (8). Therefore, close monitoring of patients who are receiving treatment is essential (8). Much of the overlap between CVD and BC can be attributed to shared risk factors, such as age, tobacco use, diet, obesity, and physical inactivity (9).

There are limited data on the occurrence of CVD in BC survivors in Saudi Arabia, particularly regarding risk factors, the impact of treatment modalities, and their association with survival. Therefore, in this study, we aimed to provide a deeper understanding of these issues. We present this article in accordance with the STROCSS reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-78/rc).

Methods

Study design and patient selection

The method used in this retrospective descriptive study. It was conducted at King Abdulaziz University Hospital, a tertiary cancer center in Jeddah, Saudi Arabia, between January 1, 2008, and December 31, 2020. All adult women diagnosed with primary BC were included. Men with BC and patients with benign breast conditions were excluded from the study. Detailed patient selection and exclusion process is demonstrated in Figure 1. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Research Committee at the Unit of Biomedical Ethics at King Abdulaziz University Hospital (No. 113-24). Informed consent was not required because this was a retrospective study and data were collected from the hospital electronic system.

Figure 1 Flow chart illustrating patient inclusion and exclusion.

Data collection

Patient data were collected from the hospital’s electronic information system. Histopathology reports, operative reports, medications, admission episodes, and clinical notes were all reviewed.

We gathered information on demographics, body mass index, type of breast surgery, BC treatment, smoking status, and baseline chronic medical illnesses such as diabetes, hypertension, IHD, coronary artery bypass grafting, heart failure, peripheral vascular disease, dyslipidemia, and chronic kidney disease.

Cardiac events were defined as the occurrence of one or more of the following: myocardial infarction, heart failure, cardiac arrhythmias, cardiac death, and substantial asymptomatic worsening of the LVEF on echocardiogram throughout post-treatment follow-up. Clinically significant LVEF decline was defined as an absolute ≥10% drop in LVEF. Those outcomes were ascertained clinically, biochemically, ECG, admissions to CCU, and by cardiology consultation.

Statistical analysis

All data were analyzed by using SPSS software, version 25 (IBM Corp., Armonk, NY, USA). All qualitative variables are presented as frequency and percentages. The chi-squared test was used to determine the significant association among cardiac events, comorbidities, response to treatment, mortality, and recurrence. A P value of <0.05 was considered significant.

Results

Our study included 676 patients with BC. The median follow-up duration was 2.39 (1.21–4.59) years. Mean age was 49.73±12.22 years, and most patients (57.34%) were 41–60 years old, and more than half of them (58.28%) had undergone mastectomies. Among all patients included in our study, 6.07% had experienced cardiac events, and the incidence of cardiac events was higher among those aged >80 years. Tumor size, lymph nodes status, and metastasis were not significantly affecting cardiac events (Table 1). Detailed counts of cardiac event subtypes are presented in Table S1.

The most frequently observed morbidity was hypertension (20.12%), followed by diabetes mellitus (18.34%), dyslipidemia (8.31%), history of IHD/coronary artery bypass grafting (2.22%), heart failure (1.04%), and chronic kidney disease (1.04%). In addition, 3.55% of patients were smokers.

Among all patients, there was a significant association between cardiac events and diabetes, IHD, heart failure, peripheral vascular disease, and dyslipidemia (P<0.05). There was also a significant association between age and cardiac events (P=0.04). Table 1 presents the association between cardiac events and comorbidities among patients with BC.

Regarding treatment-related characteristics, approximately two-thirds of the patients (69.53%) received radiotherapy, more than half (52.81%) received adjuvant systemic therapy, 251 (37.13%) received neoadjuvant therapy, 395 (58.43%) received hormonal therapy, and 169 (25.0%) received anti-HER2 treatment. There was a significant association between receiving adjuvant chemotherapy or anti-HER2 treatment and cardiac events (P<0.05), the incidence of cardiac events being higher among those who received both adjuvant chemotherapy and anti-HER2 treatment. Table 2 shows the correlation between treatment modalities and cardiac events.

Mortality was reported for 109 patients, of whom 39 had cardiac events. Thus, there was a significant association between cardiac events and mortality among these patients (P<0.05). Table 3 shows the mortality associated with cardiac events among patients with BC.

Discussion

CVD continues to be the leading cause of death globally (3) and is also an important health concern for BC survivors (10). Although BC survival rates have improved for multiple reasons, including early detection and cutting-edge individualized treatment modalities (10), survivors of BC therapy often experience multiple long-term treatment-related complications, cardiac events being one of the most prominent (10). CVD accounts for 35% of non-cancer deaths in BC survivors aged 50 years and older, making it the leading cause of non-cancer-related deaths in this population (11). The type of BC therapy plays a crucial role in CVD in patients with BC. Another important factor to consider is the presence of comorbidities in patients before starting therapy.

In this retrospective study, we aimed to determine the overall incidence of cardiac events in our population of patients, as well as the predictors of these events. There was no significant association between radiation therapy and the occurrence of adverse cardiac events. Although our data did not include the MWHD, previous studies have demonstrated a linear dose-response relationship between the occurrence of myocardial infarction in patients with BC and the MWHD (6).

As established earlier, radiotherapy plays an important role in BC therapy. Those with left-sided BCs may be at a higher risk of developing cardiac effects due to the proximity to the heart (12). Nevertheless, some studies have found no significant difference in cardiac outcomes between patients who received right-sided versus left-sided radiotherapy (13,14). This may be because modern radiotherapy is a more targeted technique, which in turn makes it less cardiotoxic.

We observed that 169 patients in our study were administered the anti-HER2 drug trastuzumab, which has been associated with cardiac events. Huszno et al. (8) stated that trastuzumab treatment commonly causes cardiotoxicity, leading to heart failure and a decrease in the LVEF, which may be asymptomatic. We reported that of 357 patients who underwent adjuvant chemotherapy, 30 developed cardiac events (P<0.05). Mehta et al. (10) argued that the most monitored side effect of chemotherapy is left ventricle systolic dysfunction. Arrhythmias can result from BC treatment, including chemotherapy and radiation therapy, regardless of the presence of a concurrent cardiac disease.

Regarding baseline comorbidities, we found that the most common in patients with BC were hypertension, diabetes mellitus, and dyslipidemia. Furthermore, we observed significant associations between cardiac events and comorbidities such as diabetes, IHD, heart failure, peripheral vascular disease, and dyslipidemia (P<0.05). The incidence of cardiac events among comorbid patients was higher than it was among non-comorbid patients. In addition, Liu et al. (15) reported that the predominant cardiovascular risk factor among patients with cancer was hypertension (10.8%), followed by diabetes mellitus (5.3%) and dyslipidemia (1.2%). The highest prevalence of CVD was associated with stroke (2.7%), coronary heart disease (1.7%), and heart failure (0.6%). However, Clark et al. (16) reported lower rates of CVD risk factors for diabetes (2.8%), hypertension (19.8%), and hypercholesterolemia (10%). Diabetes consistently correlates with poorer overall survival in patients with BC (17). Peairs et al. (18) reported that patients with diabetes may receive altered treatment regimens due to later-stage disease at BC diagnosis and greater risk of adverse effects.

Obesity has been directly linked to the occurrence of CVD (9). It is associated with several cardiovascular risk factors, such as hypertension, dyslipidemia, and diabetes mellitus, all of which increase the likelihood of cardiac events. In addition, obesity is a well-known risk factor for BC, particularly in postmenopausal women. Studies have demonstrated that excess body weight can lead to hormonal changes and inflammation, contributing to the development and progression of BC (9). Clark et al. (16) reported that obese BC survivors were more prone to developing cardiac complications due to preexisting cardiovascular risk factors and treatment-related cardiotoxicities. Nevertheless, in our study, we noted no significant association between a high body mass index and the occurrence of cardiac events. This discrepancy in findings highlights the need for further investigation to clarify the relationship between obesity, BC survival, and cardiovascular outcomes.

Among the 109 mortalities in our study, 39 patients experienced cardiac events before death, with a significant association between cardiac events and mortality (P<0.05).

Advancements in cancer treatments have significantly improved survival rates for patients with BC. However, these therapies have also led to an increased incidence of cardiovascular side effects. Our study thus underscores the importance of implementing cardiovascular screening both for patients undergoing BC treatment and for survivors.

In Saudi Arabia, a recent study assessing cardiotoxicity in patients receiving HER2-targeted therapies reported a 10.37% incidence of reduced LVEF, which is higher than what has been seen in previous studies (19). Another comprehensive retrospective analysis at Najran Cancer Center demonstrated that the most common type of cancer observed with cardiac toxicity was BC (27.6%), which resulted from several factors related to its different treatment modalities (20).

Our study reinforces the evidence that cardiac events are associated with different treatment modalities in BC, including trastuzumab, adjuvant chemotherapy, and radiotherapy, and have a strong correlation with cardiac outcomes. These findings are critical for developing strategies to counsel patients effectively, implementing tailored follow-up protocols, and refining treatment plans to mitigate risks. By addressing these challenges, our study provides actionable insights to improve care for BC survivors in Saudi Arabia.

Limitations of our study include its retrospective nature, which increases the risk of data being missing and loss of follow-up. Moreover, because the overall event rate was low, use of a more complicated regression analysis would not be statistically sound. Given the low rate of primary outcomes, multivariable analysis was not conducted and this limits the interpretation of study findings; therefore, a larger scale study that captures more patient events over extended follow-up periods would eliminate bias and corroborate our findings in a more robust fashion, and further larger studies with multivariate analysis should be done. Additionally, the relatively short duration of follow-up precluded assessment of long-term outcomes. Another limitation is that IHD and HF are progressive diseases that are likely to worsen by aging, so a decline in cardiac function might have been purely secondary to the nature of the disease rather than treatment effect. Lastly, BC laterality (right or left) was not specified or analyzed in the manuscript.

Conclusions

This study reveals a significantly higher mortality rate among patients with BC who experience cardiac events. Furthermore, a strong correlation exists between cardiac events and BC treatments, such as trastuzumab and adjuvant chemotherapy. Further research with larger cohorts is required to identify at-risk patients and develop effective preventative strategies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROCSS reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-78/rc

Data Sharing Statement: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-78/dss

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-78/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-2025-1-78/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethical approval was obtained from the Research Committee at the Unit of Biomedical Ethics at King Abdulaziz University Hospital (No. 113-24). Informed consent was not required because this was a retrospective study and data were collected from the hospital electronic system.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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