The use of RT has contributed to significant improvements in disease-specific survival among patients with early stage breast cancer [25]. The success of RT, used either alone or in combination with other modalities, has resulted in large cohorts of breast cancer survivors who are vulnerable to late complications such as RICT from RT [10, 26–31]. Awareness regarding the potential cardiotoxicity of RT has led to the application of improved RT techniques that minimize irradiation to the heart [27, 28]. In patients receiving RT for left-sided breast IDC, reducing the heart from the primary radiation beams is the preferred strategy, and DIBH is a particularly useful approach in this setting [22, 32–35]. Systematic cardiac blocking without DIBH often results in underdosage of portions of the breast, internal mammary nodes and thus may not be prudent. With DIBH, the heart is away from the left breast, and thus when the beams are shaped to exclude the heart, the amount of potential targets that are underdosed is reduced. Thus, DIBH can improve the therapeutic ratio of RT, and enable cardiac sparing with lesser impacts on target coverage [22, 32–35]. In our study, over 90% patients receiving adjuvant WBRT combined with DIBH techniques might be contributed to better survival benefits for breast cancer women with heart failure receiving adjuvant WBRT compared with those have no adjuvant WBRT (Table 1 and 2). Because dose constrains, RT techniques for cardiac protection and data on irradiation of the lymphatic drainage pathways were important factors of RICT [36] [22, 32–35], we added these covariates like heart-sparing RT techniques and treated clinical target volumes (breast only, breast and axillary lymph nodes, or breast, axillary and internal mammary chain) in Table 1. In our study, heart-sparing RT technique was associated with reduction of all-cause death and extensive RT field (including breast, axillary lymph nodes, and internal mammary chain) was associated with an increase if all-cause death (Table 2). The potential reasons of survival benefits in heart-sparing RT techniques and disadvantages of extensive RT might be contributed the higher heart irradiation dose-volume with more cardiac death in the women with HFrEF.
Anthracycline is among the chemotherapeutic agents implicated in cardiotoxicity, and irradiation combined with anthracycline-based chemotherapy was associated with substantially increased cardiotoxicity [37]. Thus, in a patient with normal baseline cardiac function, the benefits of anthracycline likely outweigh the risk, especially in patients higher risk breast cancers [38, 39]. In addition, trastuzumab-related cardiotoxicity is often manifested by an asymptomatic decrease in LVEF [40–42]. Thus, numerous treatment-related factors are responsible for cardiotoxicity in women with breast cancer [6, 38–46]. Therefore, decision-making regarding the use of adjuvant WBRT for women with left-side IDC and HFrEF receiving BCS is often a concern for physicians and patients irrespective of whether chemotherapy with antracycline-based regimens or trastuzumab is conducted. Thus, we conducted the study to determine the survival benefits offered by adjuvant WBRT in women with left-side IDC and HFrEF receiving BCS.
The recent decline in mortality in women with HF have been improving a lot [47, 48]. Therefore, adjuvant WBRT will be more worthy for the women with breast cancer and HF. Long-term mortality rates in patients with HF have improved over time [47, 48]. A decline in HF mortality was noted in an analysis by the Mayo Clinic that included 4537 patients, with the majority hospitalized around the time of diagnosis [47]. The two main causes of death in patients with HF are sudden death and progressive pump failure [49, 50]. However, patients with breast cancer might experience adverse effects from many cardiotoxic treatments such as adjuvant RT, anthracycline-based chemotherapy, or trastuzumab6, [6, 10, 26–31, 38–46]. Although cardiovascular diseases such as HF, heart attacks, and stroke remain the leading cause of death in women, many believe breast cancer to be more deadly [51]. In fact, the risk of RICT should be weighed against the potential benefits of adjuvant WBRT with respect to the patients’ prognosis and likely clinical benefit [10, 26–31]. Until now, no data have been available for the evaluation of oncologic outcomes of adjuvant WBRT in women with left-side breast IDC and HFrEF receiving BCS. This is the first study to explore the value of adjuvant WBRT for women with left-side breast IDC and HFrEF receiving BCS. As shown in Table 2, adjuvant WBRT resulted in better OS, LRR-free status, and DM-free status compared with no adjuvant WBRT in women with left-side breast IDC and HFrEF receiving BCS. The potential reasons might be the recent decline in mortality in women with HF [47, 48] and the advances in contemporary RT techniques with reduced irradiation volumes to the heart [2, 22, 27, 28].
The propensity score is defined as a subject's probability of adjuvant WBRT selection, conditional on the observed baseline covariates [24]. Weighting subjects through IPTW creates a synthetic sample in which treatment assignment is independent of the measured baseline covariates [24]. IPTW with the propensity score helped us obtain unbiased estimates of average treatment effects such as OS, breast cancer death, LRR, and DM (Tables 1-3). The use of IPTW has increased rapidly in recent years, but a majority of recent studies have not formally examined whether the weighting balanced the measured covariates between treatment groups [24]. In addition, extreme weights at the tails of the propensity score distribution increase the variance and decrease the balance between covariates [52]. Thus, further trim patients with extreme scores (i.e., remove them from the weighted analysis in our study). and multivariate analysis of propensity score–weighted population could be still necessary [52]. Finally, the standardized differences for all covariates in our study were smaller than 0.1, which means the weighted covariates were balanced between the adjuvant WBRT and no adjuvant WBRT groups (Table 1). Moreover, the factors affecting the mortality due to HF such as age, sex (all enrolled patients were women with breast IDC), race (all enrolled patients were Asian), smoking habits, ischemic heart disease, heart valvular disease, cardiomyopathy, hypertension, diabetes, and arrhythmias and conduction disorders were weighted through IPTW by using the propensity score (Table 1). In addition, all risk factors for all-cause death for patients with breast cancer receiving BCS, such as age, diagnosis year, CCI score, differentiation, pT, pN, heart-sparing RT techniques, treated clinical target volumes, smoking habits, hormone receptor status, nodal surgery, hospital level, and income, were also weighted using IPTW using the propensity score (Table 1).. Preexisting cardiovascular disease [4], age at the time of radiation and presence of other cardiac risk factors such as hypertension, diabetes, coronary artery disease, smoking habits also increase the risk of RICT [53]. The aforementioned risk factors for cardiotoxicity in the women with breast cancer receiving BCS related to treatments use were also weighted through IPTW by using the propensity score (Table 1). The homogenous covariates between adjuvant WBRT and no adjuvant WBRT after IPTW by using the propensity score may have been crucial in estimating causal treatment effects in our observational study. Thus, we believe that adjuvant WBRT is beneficial for favorable oncologic outcomes compared with no adjuvant WBRT after IPTW by using the propensity score (Tables 1 and 2). Our follow-up time (median follow-up durations were 6.96 and 5.09 years for adjuvant WBRT and no adjuvant WBRT, respectively) was also sufficient to estimate the significant differences in OS, breast cancer death, LRR, and DM between adjuvant WBRT and no adjuvant WBRT in women with left-side breast IDC and HFrEF receiving BCS.
According to our literature review, this is the first study to estimate the oncologic outcomes of adjuvant WBRT among women with left-side breast IDC and HFrEF receiving BCS. No consensus or evidence for the use of adjuvant WBRT in women with left-side breast IDC and HFrEF receiving BCS is present. In the IPTW-adjusted models, adjuvant WBRT was associated with a decrease in the risk of all-cause death, breast cancer death, LRR, and DM among women with left-side breast IDC and HFrEF receiving BCS (Table 2 and 3). The improvement in contemporary RT techniques with decreased irradiation doses and decreased volumes to the heart and the long-term improvement in mortality rates in patients with HFrEF over time might have caused the significant beneficial oncologic outcomes of adjuvant WBRT in women with left-side breast IDC and HFrEF receiving BCS [2, 27, 28]. Our study is the first to demonstrate that the potential benefits of adjuvant WBRT with contemporary RT techniques outweigh the risk of RICT given the patients' prognosis and likely long-term OS, breast cancer death, LRR, and DM benefits (Table 2 and 3). According to our findings, we strongly suggested that women with left-side breast IDC and HFrEF receiving BCS should also receive adjuvant WBRT to decrease the risk of all-cause death, breast cancer death, LRR, and DM.
As shown in Table 2 and 3, adjuvant WBRT was a significant prognostic factor for OS, breast cancer death, LRR, and DM compared with no adjuvant WBRT in women with left-side IDC and HFrEF receiving BCS; moreover, old age (>65 years), CCI ≥ 1, advanced pT stages (pT2–4), advanced pN stages (pN1–3), extensive RT field [54], hormone receptor negative status, and differentiation Grade II–III were significant prognostic factors for OS, compatible with findings of previous studies [16, 17, 55–59]. Moreover, advanced pN stages (pN1–3)., hormone receptor negative status, no heart-sparing RT technique [54], and differentiation Grade II–III were significant poor prognostic factors for LRR and DM in women with left-side breast IDC and HFrEF receiving BCS, which is also compatible with findings of previous studies [16, 17, 55–59]. Our findings of prognostic factors for OS, breast cancer death, LRR, and DM in women with IDC and HFrEF receiving BCS are similar with those of previous studies [16, 17, 55–59], and no additional prognostic factor has been identified in previous studies other than the ones determined in the current study irrespective of whether underlying HFrEF was present.
A strength of our study was that it was the first long-term follow-up cohort study to estimate the survival outcomes of adjuvant WBRT or no adjuvant WBRT among women with left-side IDC and HFrEF receiving BCS. The covariates between the adjuvant WBRT and no adjuvant WBRT groups were homogenous for women with left-side IDC and HFrEF receiving BCS, with no selection bias (Table 1). No study has estimated the effect of adjuvant WBRT on women with left-side IDC and HFrEF receiving BCS. In our study, the poor prognostic factors for OS in women with left-side IDC and HFrEF receiving BCS were old age, CCI ≥ 1, advanced pT stages (pT2–4), advanced pN stages (pN1–3), extensive RT field, no heart-sparing RT techniques, hormone receptor negative status, and differentiation Grade II–III of (Table 2), which are consistent with factors in women with breast cancer without HFrEF reported in previous studies [54, 58, 59]. Furthermore, our study is the first to demonstrate the benefits of adjuvant WBRT with contemporary RT techniques (over 90% combined with DIBH) for OS, breast cancer death, LRR, and DM in women with left-side IDC and HFrEF receiving BCS. Our findings should be considered in future clinical practice and prospective clinical trials. We suggest that adjuvant WBRT is valuable to achieving better outcomes of OS, breast cancer death, LRR, and DM in women with left-side IDC and HFrEF receiving BCS.
This study has some limitations. First, because all women with left-side breast IDC and HFrEF were enrolled from an Asian population, the corresponding ethnic susceptibility compared with the non-Asian population remains unclear; hence, our results should be cautiously extrapolated to non-Asian populations. However, no evidence exists as to the differences in oncologic outcomes in Asian versus non-Asian patients with breast IDC and HFrEF receiving BCS. Second, irradiation does-volume is very important for heart and left anterior descending artery [60–63]. However, most observational studies from database have no detail dose-volume to the heart and left anterior descending artery [10, 26–31], not only our study. This is the major limitation in our study and aforementioned observational studies. Nevertheless, our study having more detail characteristics of TNM stages and molecular expression, endpoints including breast cancer-specific survival and overall survival comrade with other observational studies [10, 26–31]. Our findings is also the first to examine the effect of adjuvant WBRT on detail oncologic outcomes such as all-cause death, breast cancer death, LRR, and DM in women with left-side breast IDC and HFrEF receiving BCS. Third, the diagnoses of all comorbid conditions were based on ICD-10-CM codes. However, the combination of Taiwanese TCRD and National Health Insurance Research Database appears to be a valid resource for population research on cardiovascular diseases, stroke, or chronic comorbidities [64–66]. Moreover, the Taiwan Cancer Registry Administration randomly reviews charts and interviews patients to verify the accuracy of the diagnoses, and hospitals with outlier chargers or practices may be audited and subsequently be heavily penalized if any malpractice or discrepancy is detected. Accordingly, to obtain crucial information on population specificity and disease occurrence, a large-scale randomized trial comparing carefully selected patients undergoing suitable treatments is essential. Finally, the TCRD does not contain information regarding dietary habits or body mass index, which may be risk factors for mortality. Nevertheless, considering the magnitude and statistical significance of the observed effects in this study, these limitations are unlikely to affect the conclusions.