Competing risk analysis of cardiovascular death in breast cancer: evidence from the SEER database

Introduction

According to the 2020 cancer data, 19.3 million new cancers were diagnosed worldwide, among which women with breast cancer (BC) comprised 2.26 million. Female patients with BC contributed approximately 11.7% of all new cancer diagnoses and 24.5% of new cancer diagnoses in women, ranking first in terms of cancer incidence in women. Meanwhile, more than 680,000 people died from BC, accounting for approximately 6.9% of cancer deaths and 15.5% of all cancer deaths among women worldwide, making it the most life-threatening cancer among women globally (1). Along with medical advances, the majority of BC patients have achieved longer survival and even achieved clinical cures. According to the published literature (2), the 5-year survival rate for BC is as high as 90% and cancer-specific mortality is steadily decreasing, but the proportion of deaths from non-cancer causes among women with BC is increasing (3-5). Therefore, identifying high risk factors for non-cancer deaths such as cardiovascular disease (CVD) (3), infections (6), suicide (7), and diabetes (8) has become critical for BC patients.

CVDs are the leading cause of death globally, with a 21.1% increase in cardiovascular mortality (CVM) from 2007 to 2017 (9). Numerous studies have shown that the prevalence of CVDs is also higher in BC patients than in the general population, and that CVDs are the leading cause of death in BC patients relative to other non-cancer mortality factors (3-5). The American Heart Association (AHA) has reported the existence of several overlapping risk factors for BC and CVDs, such as smoking, poor dietary habits, sedentary lifestyle, diabetes, and obesity (10). The risk of CVD death in BC patients may also be increased by the cardiotoxic effects of treatment such as radiation and chemotherapy (11-13). The most common cardiotoxic effect during BC treatment is left ventricular dysfunction with or without heart failure (12). Especially in elderly patients, the threat of death from CVDs is higher than that of BC (14). Therefore, monitoring, prevention, and secondary management of cardiotoxicity during BC treatment is crucial. Any patients treated for BC, whether the patient has heart disease or not, should be aware of the potential effects of this treatment on their heart. Understanding the risk factors for CVDs in BC patients would play an invaluable role in monitoring and prevention.

To our knowledge, there are relatively few reports on the risk factors for the development of CVM in BC patients. Therefore, in this study, we evaluated the risk and identified independent predictors of CVM in BC patients. We sought to provide a reference for the prevention, monitoring, and management of CVM in patients with BC. We present this article in accordance with the TRIPOD reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1163/rc).

Methods

Data source

We collected data from the Surveillance, Epidemiology and End Results (SEER) database for all BC patients from 2010 to 2018 through the SEER∗Stat software (version 8.3.9.2; https://seer.cancer.gov/seerstat/). The SEER database is a U.S. population-based cancer registry system that includes incidence, survival, and mortality data. The study did not require ethical approval as the data used were from publicly available information on the SEER database. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Study population and design

Patients with pathological diagnosis of BC from 2010 to 2018 were obtained for this study. Patients who matched the following characteristics were included: (I) case selection (International Classification of Disease for Oncology/World Health Organization 2008) being ‘C500-C509’; (II) primary BC confirmed by puncture or surgical pathology; (III) specific cause of death diagnoses recorded in the SEER database; (IV) with eligible and complete data. The exclusion criteria were as follows: (I) untreated BC patients identified by autopsy or death certificate only; (II) unknown race, age, or sex; (III) unknown American Joint Committee on Cancer (AJCC) stage; (IV) unknown estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, and BC subtype; (V) no positive histology; (VI) unknown cause of death; (VII) unknown surgery.

Participant variables

Patient variables included age at diagnosis (0–60, 60+), race (White, Black, other), AJCC stage (0, I, II, III, IV), year of diagnosis (2010–2012, 2013–2015, 2016–2018), surgery (no, partial mastectomy, total mastectomy, modified radical mastectomy), ER (positive, negative), PR (positive, negative), HER2 (positive, negative), BC subtype [hormone receptor (HR)+/HER2− (luminal A), HR+/HER2+ (luminal B), HR−/HER2+ (HER2 enriched), HR−/HER2− (triple negative)], chemotherapy (yes, no), radiation therapy (yes, no), median household income (<$60,000, ≥$60,000), and cause of death.

We classified the causes of death in BC as CVD and non-CVD (BC, other cancer, and other non-cancer diseases) (Table 1). The main outcome of interest was CVM. CVM was defined as death due to CVD. The follow-up period was from the first diagnosis of BC to the patient’s death or the last follow-up.

Statistical analysis

Standardized mortality ratio (SMR) was defined as the ratio of the number of observed deaths in BC patients divided by the expected number of deaths in the general U.S. population during the same time frame. For all SMR calculations, a latency exclusion period of 2 months was allowed. The exact method was used to calculate the 95% confidence interval (95% CI) for all SMRs. CVM was the primary endpoint of the study, and competing events were considered other causes of patient death from non-CVD. Multivariate competing risk survival analyses was used to determine the independent predictors of CVM. All data analyses were performed using R software (version 4.1.1; The R Foundation for Statistical Computing, Vienna, Austria) and Microsoft Excel 2019 (Microsoft, Redmond, WA, USA). All statistical tests were 2-sided, and P values <0.05 were considered statistically significant.

Results

Patient demographics

Figure 1 shows the diagram of study flow and selection of patients for inclusion. From 2010 to 2018, a total of 56,943 BC patients were excluded due to the initial exclusion/inclusion criteria, and a total of 399,014 BC patients were finally included for the analysis from the SEER database. Meanwhile, 46,390 (11.6%) deaths occurred during follow-up, with the largest number of deaths due to BC (n=28,035 patients), occurring mainly during the 1–5-year follow-up period. This was followed by 9,742 patients who died from other non-cancer diseases, 7,023 patients who died from CVD, and 1,590 patients who died from other cancers. The baseline characteristics are shown in Table 2 and Figure 2. The majority of BC patients were over 60 years old (56.0%), ER positive (ER+; 83.2%), PR positive (PR+; 72.6%), HER2 negative (HER2–; 85.0%), AJCC stage I (48.7%), no chemotherapy (86.6%), and no radiation therapy (71.8%). The predominant ethnicity was White (79.8%), Black (13.9%), and other races (5.2%). Other races include American Indian, Alaska Native, Asian or Pacific Islander, which are collectively referred to as other races due to their small numbers. The subtypes of BC consisted of HR positive (HR+)/HER2– (73.7%), HR+/HER2 positive (HER2+) (10.5%), HR–/HER2+ (4.5%), HR negative (HR–)/HER2– (11.3%). The vast majority of patients underwent surgical treatment, including partial mastectomy (52.3%), total mastectomy (24.7%), modified radical mastectomy (15.5%), and a small number of patients did not undergo surgical treatment. The proportion of risk associated with death from BC gradually decreased during the follow-up period, while the proportion of risk associated with death from other causes gradually increased (Figure 2).

Figure 1 The diagram of study flow and selection of patients for inclusion. SEER, Surveillance, Epidemiology, and End Results; AJCC, American Joint Committee on Cancer; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; CVM, cardiovascular mortality; CVD, cardiovascular disease; SMR, standardized mortality ratio.

Figure 2 Causes of death in each latency period following breast cancer diagnosis.

Among the 7,023 patients who died from CVD, the leading cause was disease of the heart (73.2%), followed by cerebrovascular disease, hypertension without heart disease, aortic aneurysm and dissection, other diseases of arteries, arterioles and capillaries, and atherosclerosis. The percentage of deaths due to various CVD is shown in Figure 3.

Figure 3 The percentage of deaths due to various cardiovascular disease.

The CVD risk in BC patients

The overall SMR for CVM was significantly higher in BC patients compared to the general population (SMR =4.84, 95% CI: 4.72–4.95). Further, CVD-related SMR were increased 57.03-fold (SMR =57.03, 95% CI: 52.52–61.83) in BC patients under 60 years of age, 16.05-fold (SMR =16.05, 95% CI: 15.05–17.10) in BC patients with AJCC stage IV, and 17.13-fold (SMR =17.13, 95% CI: 15.90–18.44) in BC patients diagnosed from 2016 to 2018. Table 2 shows the subgroup analyses stratified by different variables.

The SMRs of the 6 causes of CVM in BC patients are shown in Table 3. The highest SMR was aortic aneurysm and dissection (SMR =6.56, 95% CI: 5.17–8.21), followed by other diseases of the arteries, arterioles, and capillaries (SMR =5.24, 95% CI: 4.12–6.57), atherosclerosis (SMR =4.88, 95% CI: 3.59–6.46), diseases of the heart (SMR =4.84, 95% CI: 4.71–4.97), cerebrovascular diseases (SMR =4.82, 95% CI: 4.56–5.08), and hypertension without heart disease (SMR =4.53, 95% CI: 4.08–5.02).

Figure 4A shows that the SMR of all causes of death gradually decreased with increasing follow-up time, whereas the SMR of BC was always the highest. Figure 4B shows that the SMR in all causes of CVM of BC patients decreased with increasing follow-up time.

Figure 4 SMR for breast cancer patients at follow-up time. (A) SMR stratified by four causes of death. (B) SMR in cardiovascular disease stratified by all causes of cardiovascular mortality. SMR, standardized mortality rate.

Figure 5A shows that the SMR of all causes of death progressively increased with year of diagnosis. Figure 5B shows that the SMR in all causes of CVM of BC patients increased with year of diagnosis.

Figure 5 SMR for breast cancer patients at different years of diagnosis. (A) SMR stratified by four causes of death. (B) SMR in cardiovascular disease stratified by all causes of cardiovascular mortality. SMR, standardized mortality rate.

Predictors of death from CVD

As shown in Table 4, multivariate competing risk models were used to identify predictors of CVM. The following indicators were identified as being independently associated with higher risks of CVM: age over 60 years [hazard ratio (HR) =5.56, 95% CI: 5.03–6.01, P<0.05], diagnosed between 2016 and 2018 (HR =1.21, 95% CI: 1.16–1.26, P<0.05), underwent partial mastectomy (HR =1.55, 95% CI: 1.43–1.65, P<0.05), HR−/HER2− subtype (HR =1.48, 95% CI: 1.01–1.92, P<0.05). Meanwhile, the following indicators were independently associated with lower risks: other race (HR =0.88, 95% CI: 0.79–0.94, P<0.05), AJCC stage IV (HR =0.05, 95% CI: 0.03–0.10, P<0.05), ER negative (ER–; HR =0.49, 95% CI: 0.38–0.61, P<0.05), PR negative (PR–; HR =0.66, 95% CI: 0.61–0.70, P<0.05), HER2 negative (HER2–; HR =0.62, 95% CI: 0.45–0.81, P<0.05), HR+/HER2+ subtype (HR =0.43, 95% CI: 0.33–0.61, P<0.05), no chemotherapy (HR =0.85, 95% CI: 0.38–1.25, P<0.05), no radiation therapy (HR =0.81, 95% CI: 0.37–1.26, P<0.05), and median household income ≥$60,000 (HR =0.89, 95% CI: 0.81–1.01, P<0.05).

Discussion

For the vast majority of cancer patients, CVD is a major factor in non-cancer mortality (15). In BC patients who are elderly or have underlying disease, CVD is the leading factor in patient mortality (14). By analyzing a large number of BC patients in the SEER database, our findings showed that BC patients had a higher risk of CVM during follow-up compared to the general population (SMR =4.84, 95% CI: 4.72–4.95). The proportion of deaths due to CVD in BC patients gradually increased with increasing follow-up time. Furthermore, we identified age, race, AJCC stage, year of diagnosis, ER status, PR status, HER2 status, median household income, BC subtype, chemotherapy, radiation therapy, and surgery as independent predictors of CVM in BC patients.

Our study found that the risk of CVM was highest in BC patients with less than 1 year of follow-up, as also mentioned in a recent study published in the European Heart Journal (SMR =3.93, 95% CI: 3.89–3.97) (16). The main reason for this may be that BC patients face the challenge of not only the cancer itself, but also the psychological blow of reduced body image due to the absence of the breast/s, which has a serious physical and psychological impact on the patients and aggravates negative emotional reactions such as anxiety, depression, fear, and despair. Some studies have found that CVD such as coronary heart disease, hypertension, and arrhythmia are closely related to psychosocial factors, such as anxiety, depression, and other related adverse emotions (17-19). Interestingly, in our study, we also found that the SMR of CVM gradually increased with increasing year to diagnosis, and we speculate that the reason for this is mainly due to the increasing number of novel drugs and chemotherapeutic agents for the treatment of BC with the development of science, such as trastuzumab, tucatinib, talazoparib, everolimus, abemaciclib (20-22), and Keytruda. The use of these novel drugs may increase the incidence of CVD in BC patients.

Multivariate competing risk regression analysis was used to determine independent predictors of CVM in BC patients. Our results showed a higher risk of CVM in older BC patients compared to younger BC patients (HR =5.53, 95% CI: 5.11–5.98), but interestingly, the SMR was higher in younger BC patients (HR =57.03, 95% CI: 52.52–61.83), which was also confirmed in the study by Zaorsky et al. (23). Our study also found that other races had lower CVM. Firstly, compared to the White race, other races generally had lower economic and living standards (24), resulting in detection and treatment of BC at a later stage, and thus a higher AJCC stage, with limited treatment options for BC and at a greater risk of death from BC, therefore, not having enough survival time for CVD to be developed or detected.

In addition, our study also found that CVM was lowest in patients with AJCC stage IV and non-operated BC; a possible reason for this is that the vast majority of non-operated BC patients have advanced tumors and their survival time is not long enough to experience CVM. The most recent study reported that the 5-year survival rate for BC patients with AJCC stage I is close to 100%, but only 28% for BC patients with AJCC stage IV (25). At the same time, our study showed that the probability of CVM was lower with increasing year to diagnosis, which may be due to a better understanding of the relationship between CVD and BC and a more focused interest in the prevention and treatment of CVD as society progresses. In our study, patients from low-income families were generally at higher risk of developing CVM, consistent with previous findings (26).

In this study, we included the factors of ER status, PR status, and HER2 status of patients as investigation targets. Multivariate competing risk regression analysis showed that CVM was lower in ER–, PR–, and HER2– BC patients. It is well known that endocrine therapy is the basic adjuvant therapy for patients with HR+ BC. Abnormalities in lipid metabolism have been found in many women using tamoxifen, which may be a preclinical manifestation in patients with atherosclerosis (27). In some early large clinical trials comparing the adverse effects between tamoxifen and letrozole, it was shown that women utilizing letrozole were more likely to develop atherosclerosis than those using tamoxifen (28). Atherosclerosis can lead to thickening and hardening of the arterial walls and narrowing of the lumen, which can further develop into CVD. Trastuzumab is a monoclonal antibody targeting agent mainly used to treat HER2+ BC. Its cardiotoxicity may be related to inhibition of the neuregulin-1/erb-b2 receptor tyrosine kinase signaling pathway, which mainly causes alterations in myocardial contractile proteins and mitochondrial structure and function, and rarely myocardial necrosis, usually manifesting as non-dose-related, reversible cardiac insufficiency (29). Study has shown a 12.1% incidence of heart failure in BC patients when treated with trastuzumab alone (10).

We also found that patients with HR+/HER2+ subtype had lower CVM than patients with HR+/HER2– subtype. The main reason for this may be that HR+/HER2– subtype chemotherapy causes a greater cardiovascular risk. Anthracyclines, the most commonly used chemotherapeutic agents for BC, can directly affect cardiac function and can cause type I cardiotoxicity, which is irreversible. However, trastuzumab monoclonal antibody can cause type II cardiotoxicity, which is different from type I cardiotoxicity, and with early detection and early intervention, cardiotoxicity is expected to be reversible. The 8-year follow-up results of the HERA trial suggest that among patients who had cardiovascular events during 1 year of trastuzumab treatment, 79.5% of cardiac function returned to early standards after ending treatment, indicating that cardiovascular damage caused by trastuzumab is reversible (30). However, either anthracyclines or trastuzumab monoclonal antibody can trigger heart failure in some cases. According to recent research (31), statins work not just to lower cholesterol, but also to reduce oxidative stress and free radical production in heart cells, and the risk of heart failure was significantly lower in women who took statins while receiving anthracycline or trastuzumab monoclonal antibody therapy compared with those who did not take statins prior to cancer treatment. At the same time, we also found that BC patients who received radiotherapy and chemotherapy had higher CVM, which is consistent with the results of many studies (32,33).

In summary, the prognosis of BC patients depends on the cardiovascular health of patients during the whole treatment process. Monitoring changes in patients’ cardiac function during the course of treatment can help guide the clinical use of drugs and optimize the treatment plan. For asymptomatic patients who have already received cardiotoxic drugs and have normal cardiac function, regular follow-up of cardiac markers, cardiac ultrasound, and other examinations should be conducted 6–12 months and 2 years after treatment. Patients who experience CVD after treatment should be given long-term treatment with drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, as well as regular cardiac examinations (34). Meanwhile, the AHA guideline also puts forward the ABCDE 5-step approach to prevent CVD in BC patients (35), advocating the “7 Simple Lives”: increasing physical activity, healthy weight, healthy diet, avoiding tobacco, and maintaining normal blood pressure, blood glucose, and blood lipids, which can significantly reduce the risk of CVD and lower the incidence of BC.

There are some limitations in this study. First, due to database limitations, we were unable to obtain data on smoking, alcohol consumption, body mass index, specific chemotherapy regimens, and whether or not statins were taken to prevent CVD, which had an impact on our study. Secondly, the retrospective database-based non-randomized design of this study may have introduced selection bias for patients. Third, although the SEER database includes nearly 30% of the US population, it is still not representative of the entire population, and we need a large follow-up cohort study to validate our findings.

Conclusions

Compared to the general population, BC patients had a higher risk of CVM during follow-up. Patients who were diagnosed over 60 years of age, of other races, AJCC stage 0, diagnosed between 2016 and 2018, undergoing partial mastectomy, ER+, PR+, HER2+, HR–/HER2– subtype, receiving chemotherapy or radiation therapy, and median household income <$60,000, had a significantly increased risk of CVM. Our findings suggest that close attention should be paid to cardiovascular adverse events associated with BC treatment. Early detection and intervention of cardiovascular risk factors or CVD can improve the quality of life of BC patients.

Acknowledgments

The authors would like to thank all working group members for their contribution to this study.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1163/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1163/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-23-1163/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 (as revised in 2013). The study did not require ethical approval as the data used were from publicly available information on the SEER database.

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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