Breast conservation therapy decreased heart-specific mortality in breast cancer patients compared with mastectomy

Aim To investigate the impacts of breast conservation therapy (BCT) and mastectomy on heart-specific mortality in breast cancer patients. Methods Patients with primary breast cancer registered in the Surveillance, Epidemiology, and End Results (SEER) database between Jan 1998 and Dec 2015 were included. Patients were divided into either breast conservation therapy or mastectomy group. To compare mortality caused by heart diseases in breast cancer patients with BCT or mastectomy, univariate and multivariate regression after propensity score matching (PSM) were performed. Kaplan-Meier analysis was also used to evaluate heart-specific survival between two groups. Results 132,616 patients with breast cancer were enrolled in this study. After PSM, four risk factors including age, race, marital status and types of surgery were identified significantly associated with death from heart diseases. Heart-specific survival analysis further showed that overall, BCT poses a lower risk to heart-specific mortality compared with mastectomy. Conclusion Compared with mastectomy, BCT significantly decreased heart-specific mortality in breast cancer patients.


Introduction
Breast cancer is currently the most common women's cancer, with an estimated 2 million new diagnosis in 2018 globally, and the fifth most common cause of mortality from cancer [1].Progress made in treatment of breast cancer has largely improved the prognosis in breast cancer.A 41% reduction of mortality rate compared with that in 1990s was reported for 2021 [2].However, despite cause of death, while breast cancer comes the second [8].There is also evidence suggesting that other than age, race and cancer stage are also risk factors associated with CVD mortality [9].
Currently, surgery including mastectomy and breast conserving therapy (BCT), with chemoradiotherapy, endocrine therapy and molecular targeted therapy, is the standard of care in treating breast cancer [10].Due to the development of radiotherapy, BCT is now more widely performed [11,12].No significant difference of prognosis, including overall survival and disease-free interval, was observed in previous studies, comparing BCT combining radiotherapy to mastectomy [13][14][15][16].Recent results also showed that BCT might be more beneficial in terms of overall survival [17,18].Therefore, it was suggested BCT might be preferred over mastectomy.However, whether BCT and mastectomy would impact on heart-specific mortality in breast cancer patients is still unclear.Here, using SEER database, we assess the death resulted from heart disease in breast cancer patients who had underwent either BCT or mastectomy, to further demonstrate if the BCT would outweigh mastectomy regarding heart-specific survival.

Patients
The data were derived from the SEER database between Jan 1998 and Dec 2015 using SEER*Stat v8.3.5 software.Only patients with primary breast cancer were selected.The criteria are as followed: age at diagnose, sex, race, marital status, type of surgery, American Joint Committee on Cancer (AJCC) stage, estrogen receptor (ER) and progestogen receptor(PR) status, laterality, cause of mortality, survival time.The flow chart for entry conditions were shown in Fig. 1.

Statistical analysis
The primary endpoint is heart-specific survival (HSS), defined as the time between confirmed heart diseases diagnosis to death from them or last follow up.The heart diseases were listed in Table 1.Kaplan-Meier analysis was performed to estimate HSS.Cox proportional-hazards models were used to estimate hazard ratio and 95% confidence intervals within the same subgroup.Competing risk model was developed in R v3.6.2 via using package "cmprsk", the primary endpoint of competing risk model is survival between the time at diagnosis of any diseases to death.The other analysis such as propensity score matching (PSM) were performed by SPSS 25.0.A p value less than 0.01 was considered significant.

Study population
A total of 132,616 patients were included in this study.The demographic and clinical characteristics were described in

Competing risk mortality
As shown in Fig. 2, heart-specific mortality was only second to breast cancer in terms of cause of mortality overall.Age-subgroup analysis further demonstrated that the risk of death from diseases of heart increased with age.In subgroup aged between 71 and 80, the mortality rate resulted from diseases of heart was higher than that caused by breast cancer after 13-year follow up.In subgroup aged 80 and over, after 8-year follow up, the heartspecific mortality rate was the leading cause of death, while breast cancer mortality ranked second.

Kaplan-Meier HSS in breast cancer patients
It showed that compared with HSS in mastectomy, HSS in BCT was significantly higher (P < 0.0001) (Fig. 3).

Risk factors for HSS identified by univariate and multivariate Cox analysis
As shown in Table 3,univariable analysis found that age, race, AJCC staging, ER and PR status, marital status, laterality and types of surgery were risk factors for HSS.Multivariable analysis was performed to further identify the variables mentioned above.Compared with patients aged no more than 50 at diagnosis, patients older than 50 were at a higher risk of heart-specific death (HR = 4.423, P < 0.0001).We also found that black populations had the highest risk of heart-specific mortality (HR = 1.647,P < 0.0001).Unsurprisingly, late stage posed a risk to death from heart disease (stage II: H = 1.348,P < 0.0001; stage III: HR = 1.935,P < 0.0001).No difference was observed between ER or PR status in heart-specific mortality.In terms of marital status, married patients were found to be less likely to die of heart-disease.Compared with BCT, mastectomy was significantly associated with higher risk of death from heart diseases(HR = 1.364,P < 0.0001).

K-M survival analysis and multivariable analysis after propensity score matching (PSM)
To adjust the imbalance between groups, PSM was performed to age, race, AJCC staging, ER and PR status, marital status and laterality (Table 4).Survival analysis after PSM showed HSS was significantly higher in BCT group compared with mastectomy (P = 0.0009) (Fig. 4).The same result was also observed after adjusting for the other variables (HR = 1.311,P < 0.001).In addition, age over 50 (HR = 4.001, p < 0.0001) and black population (HR = 1.855, p < 0.0001) were also found as risk factors for heart-specific death (Table 5), while being married was protective.

Discussion
To provide a high-quality and patient-centered care, more attention should also be paid to health issues beyond breast cancer during treatment.This study is a large retrospective cohort study.In this study, we identified that heart-specific mortality is high in breast cancer patients, only second to breast cancer itself.It was reported that the confirmation and treatment of breast cancer would induce posttraumatic stress disorder (PTSD), which has been known highly associated with death from coronary heart diseases and cardiovascular events [19][20][21][22][23][24].That is, breast cancer could have a negative impact on cardiovascular health.
In line with previous studies [25][26][27], older breast cancer patients were more likely to die of heart diseases rather than breast cancer, and such risk increased with age.Previously, Safford et al. showed that compared with  others (e.g., white, Asian and Hispanic women), black women experienced a higher risk of death from heart diseases [28].The mortality rate was also higher in black females after taking treatment into account [29].In this study, we also found the black women had a higher heartspecific mortality than the others.There might be several reasons for that, such as lower social-economic status.
In terms of marital status, married women had the lowest risk.As reported by Dupre et al. [30], among patients with acute myocardial infarction, married patients had the lowest risk of death compared with other marital statuses.Schaal S et al. [31]suggested that widowhood could cause depression combined with PTSD which has been deemed a risk factor for coronary heart disease [23].
Besides, McGarry Kathleen et al. found that the number of widowhood below the poverty threshold was three times that of matrimony, which retained them from seeking better medical treatment [32,34].Therefore, lack of both psychological and financial support from partners also could pose a higher risk to heart-specific death.In this study, patients with BCT were found to have a lower risk of death from heart diseases than patients with mastectomy.It might because BCT is less traumatic and takes a shorter recovery time postoperatively.A study by Šimunović, M. et al. suggested that patients who underwent BCT had lower trauma stress response scores [33].It might also easier for BCT patients to return to normal life as less changes would be made to breast.A study including 3233 women with breast cancer by Flanagan, M. R. et al. showed that compared with patients with mastectomy, BCT patients had a higher satisfaction rate and higher quality of life [34,13].
Regarding the surgical aspect, studies are not conclusive as to the improved survival rates in metastatic breast cancer patients undergoing resection [35].In this study, the risk of death attributable to heart diseases was higher in late stage breast cancer.That might be due to more chemoradiotherapy and higher doses they had received, leading to more iatrogenic cardiotoxicity, and more PTSD as well.
Interestingly, while it has been recognized that estrogen has a protective effect on cardiovascular system and anti-estrogen therapy may thus negatively impact on that [36,37], It was also reported correlations between endocrine pathologies as negative prognostic factors both for breast cancer progression and survival [38],our study showed no significant difference in the risk of death from heart diseases between ER or PR positive and negative subgroups.More research may be required to clarify the underlying mechanisms.
This study also has some limitations.First, this study is a retrospective study so the data quality and reliability may be limited.Second, it is confirmed that chemotherapy and targeted therapy can cause either early or delayed  cardiotoxicity, especially anthracyclines and Trastuzumab.However, due to lack of data about chemotherapy regimens and use of Trastuzumab in SEER database, we were not able to further explore the effect of chemotherapeutics and Trastuzumab on heart-specific mortality [39][40][41][42][43][44].What's more, while comorbidities such as diabetes and hypertension that could also contribute to heart diseases, our study didn't include these preexisting conditions because of insufficient data from SEER.

Conclusion
To conclude, our study showed that compared with mastectomy, BCT posed a significantly lower risk of heartspecific mortality.Age, race, stage and marital status were also important risk factors of death caused by heart diseases .

Fig. 2 A
Fig. 2 A. Overall competing risk analysis.B, C, D, E and F. Age-subgroup analysis of risk of heart-related death

Fig. 3
Fig. 3 Kaplan-Meier curve of HSS in BCT group and mastectomy group.It indicated that BCT had a lower risk of developing heart-specific death compared with mastectomy (P < 0.0001)

Fig. 4
Fig.4 Kaplan-Meier curve of HSS in BCT group and mastectomy group after PSM.It indicated that BCT had a significantly lower risk of developing heart-specific death compared with mastectomy (P = 0.0009)

Table 1
Heart-specific causes of death encoded with International Classification of Diseases 10 (ICD-10)

codes in SEER database Causes of Death SEER Code Medical Term ICD-10 Code
2% of the patients were at either stage I or stage II when first diagnosed.More than half of patients were either ER or PR positive.

Table 2
Baseline of patients characteristics a, other includes Latinos, Alaskan native, Asian, American Indian and Pacific Islander.b, others includes divorced, single and unmarried

Table 3
Cox proportional-hazards models of HSS a, other includes Latinos, Alaskan native, Asian, American Indian and Pacific Islander.b, others includes divorced, single and unmarried