To the best of our knowledge, this represents the longest and largest epidemiological survey on ARCM in an Asian population of women with BC. In this study, we aimed to investigate the changes in ARCM after the therapeutic revolution by trastuzumab therapy in BC. This is because the prognosis of cardiomyopathy is significantly influenced by the prognosis of the underlying disease [23]. Furthermore, improved prognosis has changed not only in epidemiology but also in clinical practice in a community. The major findings of this study are as follows: (1) although the incidence of ARCM has decreased and is currently approximately 2% (Fig. 2), the number of survivors is increasing (Fig. 3). (2) The prognosis of ARCM was worse than that of non-ARCM (Fig. 4a); however, there has been an improvement trend since 2007 (Fig. 4b). (3) Since 2007, the survival rate of patients with ARCM treated with trastuzumab has been significantly better than that of patients with ARCM without trastuzumab. Nevertheless, the survival rate of patients with ARCM who did not receive trastuzumab has remained poor since 1990 (Fig. 5b, c). These findings suggest that the recent rise in HER2-positive ARCM cases treated with trastuzumab, along with their improved prognosis, likely contributes to more patients with BC and ARCM surviving.

The incidence of ARCM has decreased since 1990 (Fig. 2). We speculate that the decreased incidence of ARCM may be due to a decrease in the amount of anthracycline used in individual patients. Throughout the history of advances in chemotherapy, efforts have been made to reduce the use of anthracyclines [9, 10, 13, 14]. Notably, the amount of anthracycline used in the late phase was lower than that used in the early phase of ARCM (Table 1). In the early phase, anthracycline-based systemic treatments, which resulted in a substantial survival benefit but at the cost of cardiotoxicity, were widely adopted in our community. In the late phase, HER2-targeted therapies, including trastuzumab, have gained acceptance, enriching, and enhancing the integrated therapy options available for BC [24]. Consequently, HER2-positive patients become less dependent on anthracyclines in the late phase. The incidence of ARCM in previous reports varied according to the region, patient characteristics, chemotherapy regimens, and definitions of cardiac dysfunction in the research cohort. In a prospective study, Cardinale et al. found that 9.7% of 1344 patients with BC treated with anthracyclines had systolic dysfunction within 1 year [25]. In the Aphinity trial, 0.5% of patients developed symptomatic HF and 2.8% had subclinical left ventricular systolic dysfunction within 1 year [26]. These figures are lower in Japan than in other Western countries. In a claims-based data analysis in Japan, the incidence of HF was 1.0% over 18 months [27]. In a prospective observational study of trastuzumab-treated patients in Japan, encompassing 73% of anthracycline users, the 3-year cumulative incidence of Common Terminology Criteria for Adverse Events grade 3–4 cardiotoxicity was 0.54% [28]. Although exact comparisons cannot be made due to different conditions, in general, our incidence of ARCM in the late phase was higher than that in previous reports in Japan and close to that of the affinity trial [26] (Fig. S1).

Despite the decrease in incidence, the number of surviving patients with ARCM increased (Fig. 3b). We speculated that this increase was caused by an increase in the number of patients treated with anthracycline and improved prognosis. In fact, our number of patients treated with anthracycline increased more than before, and the majority of our patients survived (Fig. 3a). Because ARCM develops in these populations, an increase in the population leads to an increase in ARCM. The prognosis of ARCM patients was worse than that of patients with non-ARCM (Fig. 4). Compared with the National Clinical Database [15], our patients with ARCM had more metastases and more triple-negative histology (Table 1). Because both metastasis and triple-negative histology are poor prognostic factors, patients with ARCM might have a worse prognosis than patients without ARCM in our cohort. However, an improved prognosis was observed in the late phase (Fig. 4b). We observed a favorable prognosis in the ARCM subgroup of ARCM with trastuzumab (Fig. 5c). Trastuzumab therapy was an independent predictor of late-phase survival (Table 2b). A recent prognostic improvement in BC was reported by Caswell-Jin et al. in the US [6]. According to their simulations, the greatest change in survival after metastatic recurrence occurred between 2000 and 2019, from a mean of 1.9 years to a mean of 3.2 years. The median survival for estrogen receptor (ER)-positive/HER2-positive BC improved by 2.5 years, that for ER-negative/HER2-positive BC improved by 1.6 years, and that for ER-negative/HER2-negative BC improved by 0.5 years. Our findings regarding favorable survival in subgroups of patients with ARCM treated with trastuzumab are also consistent with their report. Patients with HER2-positive ARCM likely benefitted from trastuzumab, a more effective targeted therapy than anthracyclines, and the improved prognosis increased the number of survivors in our cohort.

Felker et al. reported that the prognosis of secondary cardiomyopathy varies depending on the underlying disease [23]. In this study, we revealed that prognosis differs depending on the subtype of the underlying disease. HER2 negative BC with metastasis has poor prognosis in ARCM. Most patients had been treated with anthracyclines; the cumulative dose was nearly the upper limit, and few alternative treatments remained. In contrast, HER2-positive BC treated with trastuzumab has a favorable prognosis for ARCM. Notably, nearly half of the patients enrolled in the late phase were HER2-positive and treated with trastuzumab. The cumulative dose of anthracyclines decreased significantly during the late phase. Ewer et al. described cardiac dysfunction caused by anthracycline as Type I CTRCD, and cardiac dysfunction caused by trastuzumab as Type II CTRCD [11]. In other words, our patients with ARCM in the early phase may have mainly had Type I CTRCD, and in the late phase, hybrids of types I and II may have been prevalent. The increase in patients with ARCM in our community during the trastuzumab era confirms previous reports that the addition of trastuzumab to anthracyclines leads to an increased risk of HF but is significantly outweighed by the benefits of improved cancer survival with trastuzumab [24, 29].

Our median time from the last dose of anthracycline to ARCM was 14.3 months (Table 1), which exceeds durations reported previously [25, 26]. The interval depends on echocardiography frequency and follow-up duration. Active surveillance with echocardiography every few months [25, 26] detects cardiac dysfunction earlier than biennial [30] or random surveillance [29]. Long-term studies reveal both early- and late-ARCM, demonstrating a cumulative increase in ARCM over time [7, 25, 26, 29, 30]. Including more cases of late-onset ARCM extends the interval from the last dose of anthracycline to ARCM. For example, a recent US study with a median follow-up of 9.9 years reported a median interval of 6.6 years from BC therapy to cardiac dysfunction [30]. Given methodological variations across studies, caution is necessary for when comparing results.

Although our study is large, multicenter, and long term, it also has limitations. First, our community lacked a systematic strategy for detecting asymptomatic ARCM. Therefore, echocardiography was performed at the discretion of individual physicians when heart failure was suspected. The average number of echocardiography performed before diagnosing ARCM was low, with 0.7 in the early phase and 2.0 in the late phase. Patients with late-phase ARCM underwent baseline evaluation and one assessment until detecting LVEF < 50%. Although the difference in echocardiography frequency between early and late phases was minimal, more frequent testing might have detected milder cardiac dysfunction and improved survival in the late phase. Second, we could not update the echocardiographic definition of cardiac dysfunction to include modern criteria like global longitudinal strain, as these data were not uniformly available for all patients. Consequently, we relied solely on LVEF. Nevertheless, overall, 77% of our cases met the IC-OS 2021 Consensus CTRCD definition (32 moderate cases and 26 severe cases) [31]. Third, baseline evaluation was not performed in half of the patients in early ARCM. A survey in Niigata City during the early phase indicated that the prevalence of women aged 40–70 years with LVEF < 50% was < 1% [32]. Hence, it is presumed that most women with BC had normal cardiac function before treatment. Fourth, although some guidelines recommend echocardiography within 1 year after completing an anthracycline-containing regimen in the late phase [22], adherence to this recommendation was not evaluated in our community. No existing guidelines in Japan recommended regular echocardiography monitoring throughout the observation period. As most patients appeared to be diagnosed with ARCM based on HF symptoms, there may be a tendency for delayed diagnosis or progression of HF. Consequently, our ARCM cases may not represent mildly symptomatic or asymptomatic ARCM.