Increasing Survivors of Anthracycline-related Cardiomyopathy with Breast Cancer in Trastuzumab Era: Thirty-one-Year Trends in a Japanese Community

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However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We sought to update our knowledge of ARCM in the trastuzumab era. METHODS This was a retrospective observational cohort study. A total of 2,959 patients with BC treated with anthracyclines in three regional cancer centers in Niigata City between 1990 and 2020 were included. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post- 2007 (late phase), corresponding to before and during the trastuzumab era in Japan. RESULTS The incidence of ARCM peaked at 6% in the 1990s, decreased, and remained at 2% until the 2010s. Mean anthracycline use in the early and late phases was 525 mg/m 2 and 307 mg/m 2 (P<0.001), and the 5-year survival rates were 28% and 45% (P=0.058), respectively. Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in late phase was an independent predictor for mortality within 10 years (hazard ratio =0.24, 95% confidence interval: 0.10–0.56; P=0.001). At the end of the late phase, there were four times as many patients with ARCM as at the end of the early phase (twenty-six and six, respectively). Survivors of BC increased more rapidly in the late phase, though the rate of accumulation change was slight in the anthracycline-treated BC group and more pronounced in the ARCM group (P <0.001). CONCLUSIONS With increasing survivor with ARCM in the trastuzumab era, subtypes of HER2 positivity have gained significant importance in treating patients with ARCM in BC. cardiotoxicity anthracycline trastuzumab human epidermal growth factor receptor type 2 secular trend Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 INTRODUCTION Breast cancer (BC) is the most prevalent malignancy in Western countries, and its worldwide prevalence is expected to increase significantly in the future [1-3]. In East Asia, the incidence of BC has increased rapidly over the past few decades, making it the most common cancer in several countries, including Japan [4, 5]. Although its prognosis has improved [6], a significant risk of cancer treatment-related cardiac dysfunction (CTRCD) persists, which has been associated with potential treatment termination and lower therapeutic efficacy [7-12]. Therefore, cancer treatment-related cardiotoxicity is of significant concern. In patients with BC, anthracycline or trastuzumab is the most common cause of CTRCD. Anthracyclines induce myocardial damage and necrosis in a dose-dependent manner through oxidative stress and other mechanisms. Cardiomyocytes, being unable to repair or regenerate, undergo irreversible injury, leading to cardiotoxicity [7-10]. In contrast, trastuzumab, an anti-human epidermal growth factor receptor type 2 (HER2) antibody, can cause cardiomyocyte dysfunction, but not necrosis, and its induced cardiotoxicity is reversible [8-12]. CTRCD caused by these treatments increases the risk of death and symptomatic heart failure (HF) in the future. Considering the remarkably younger age at diagnosis in patients with BC compared to those with other malignancies, its social impact, defined by mortality and living with a disability, is also prominent. Although anthracycline doses have historically been restricted to avoid cardiotoxicity [9, 10, 13, 14], most patients receive anthracycline-containing chemotherapy as neoadjuvant or adjuvant therapy [12-15]. Patients with recurrent/metastatic BC have been forced to receive anthracycline up to the limits of its use [16]. In contrast, trastuzumab has shown high efficacy in patients with HER2-positive BC since its introduction in the early 2000s. Trastuzumab partially replaced traditional anthracycline-containing regimens in both early and advanced cancer and reduced anthracycline use by preventing recurrence/metastasis in the mid-2000s [6, 10, 12, 14, 16]. As a result, trastuzumab may have changed not only the cancer prognosis but also anthracycline-related cardiomyopathy (ARCM). However, the impact of this therapeutic revolution on ARCM remains unknown, particularly in the Asian community. To update our knowledge of ARCM in the trastuzumab era, we evaluated patients with BC and ARCM over the past 31 years in a local Japanese city. METHODS Design and study cohort This retrospective observational multicenter cohort study, based on clinical data, was performed in three designated cancer care hospitals in Niigata City (Niigata University Medical and Dental Hospital, Niigata Cancer Center Hospital, and Niigata City General Hospital). Hospital-based BC registries in Japan, designated for cancer care hospitals nationwide since 2004, collect information on therapies and prognoses for all cancer cases encountered in each hospital according to coding rules precisely defined by the Japanese Breast Cancer Society [17, 18]. These three local hospitals designated for cancer care have registered the medical information of 97% of the patients with BC in Niigata City. Data before 2004 were comprehensively collected from the information databases for cancer in each hospital. Consecutive patients diagnosed with BC and treated with two or more anthracycline treatments between January 1, 1990, and December 31, 2020, were identified. We investigated all echocardiography examinations performed after anthracycline treatment and defined ARCM as patients newly diagnosed with a left ventricular ejection fraction (LVEF) < 50% [19 20]. Patients with LVEF < 50% before BC therapy were excluded. To assess the impact of the recommended therapeutic strategies in the clinical practice guidelines, we divided the patients into two groups based on the phases of study enrollment: before 2007 (early phase) and after 2007 (late phase). Since 2007, Japanese BC clinical practice guidelines have recommended trastuzumab for HER2-positive patients in both early and advanced settings [21]. Therefore, the early and late phases were equivalent to before and in the trastuzumab era in Japan, respectively. Data collection Data on the baseline patient characteristics and treatments associated with BC and cardiomyopathy were collected. The cumulative anthracycline dose was calculated by converting the different anthracycline doses into doxorubicin equivalents [22]. The incidence of ARCM was calculated by dividing the number of patients with ARCM by the total number of patients treated with anthracyclines. Ethical considerations This study was approved by the institutional review board and independent ethics committee of each participating site. A waver of informed consent was approved. It was conducted in accordance with the principles of the Declaration of Helsinki and in compliance with the ethical guidelines for medical and health research involving human participants. This study was registered with the University Hospital Medical Information Network of Japan (registration number UMIN-000052011). Statistical analysis To calculate the significance of differences between the two groups, Student’s t-test was used for continuous variables, and Fisher's exact probability test was used for categorical variables. Values are reported as mean ± standard deviation and numbers (%). Linear regression analysis was used to examine the effect of de novo patient accumulation on the number of surviving patients. Survival curves and cumulative incidence rate curves were evaluated using the Kaplan–Meier method, and differences between groups were assessed using a log-rank test. Factors associated with death within 10 years were analyzed using Cox proportional hazards models. For the multivariable models, independent variables were selected from the variables that were significant in the crude models. IBM SPSS Statistics for Windows, version 27.0; (Armonk, NY, IBM Corp) was used for the statistical analyses, and the significance level was set at two-tailed P<0.05. RESULTS Number of patients treated with anthracyclines and patients diagnosed with ARCM A total of 10, 189 women were diagnosed with BC between January 1990 and December 2020. Of these, 2,959 patients were treated at least twice with anthracyclines. Consequently, 75 patients (2.5%) were diagnosed with ARCM (Fig. S1). The incidence of ARCM calculated every three years was approximately 6% in the 1990s but subsequently decreased to approximately 2% in the 2010s (Fig. 1). The cumulative incidence of ARCM in all patients was 2.1% over 5 years and 3.2% over 10 years (Fig. S2-a). In the early phase, the incidence was 3.0% over 5 years and 4.7% over 10 years, whereas in the late phase, it was 1.8% and 2.7%, respectively (P=0.047) (Fig. S2-b). Among patients treated with anthracyclines, the cumulative number of survivors outnumbered the cumulative number of deaths since 2005 (Fig. 2-a). In contrast, among patients with ARCM, the cumulative number of survivors was lower than that of patients who died (Fig. 2-b). However, a rapid increase in the number of ARCM survivors was observed during the late phase. To evaluate whether this increase in the accumulation speed was affected solely by the increase in that of de novo patients, the regression coefficients of de novo patients predicting that of alive patients were compared between the two periods. In the anthracycline-treated patient group, the regression coefficients were significantly, but only slightly, elevated in the late phase than in the early phase (+0.010, P<0.001) (Table S1 and Fig. 3). However, the increase in the coefficients was much greater in the ARCM group than in the anthracycline-treated patient group (+0.110, P<0.001). Characteristics of patients with ARCM The characteristics of the 75 patients with ARCM are presented in Table 1. Fifty-seven percent of the patients had distant metastases, and 52% had HER2-positivity. Doxorubicin and epirubicin were the main drugs used for chemotherapy, with a mean doxorubicin-equivalent dose of 359 mg/m 2 . In the early phase, only 17 % of patients received trastuzumab, but in the late phase, 54% of patients received it. All but one of these trastuzumab-treated patients were HER2 positive. The mean duration from the last treatment to the diagnosis of ARCM was 28.4 months, and LVEF at that time was 41.9±7.8% and LVEF of 16 patients (21%) was less than 35%. Twenty-nine patients (39%) required hospitalization for HF after ARCM diagnosis. In the late-phase group, patients had fewer metastases, used more taxanes and trastuzumab, and were administered fewer anthracyclines than patients in the early phase group; furthermore, the late-phase group had more patients with HER2-positive tumors. Examination of plasma brain natriuretic peptide (BNP) levels and HF treatment with angiotensin-converting enzyme inhibitors (ACEIs) and beta blockers were more common in the late phase. No differences were observed in the duration until LVEF declined after anthracycline treatment, LVEF levels, or the frequency of hospitalization for congestive HF. Differences in prognosis between the phases of patient enrollment Survival rates after the first administration of anthracyclines were 71% and 79% at 5 years and 33% and 69% at 10 years in patients with ARCM and non-ARCM, respectively. (log-rank test, P<0.001) (Fig. 4). Prognostic differences were absent between patients in the early and late phases; however, the survival rate tended to improve in patients in the late phase (P=0.058) (Fig. 5-a). The 5-year survival rates in the early and late phases were 28% and 45%, respectively. Patients were divided according to the use of trastuzumab, and the prognostic impact of each phase was analyzed. Trastuzumab users had a better prognosis in the late phase (P=0.002) (Fig. 5-c). The 5-year survival rates were 64% and 26% in the trastuzumab and non-trastuzumab groups, respectively. Prognostic risk factors in patients with ARCM in multivariate analysis In all patients, HER2 positivity with trastuzumab therapy, body mass index, metastasis, and NT-proBNP level were positively associated with death according to the crude Cox proportional hazards models (Table 2-a). Multivariate analysis revealed that HER2 positivity with trastuzumab therapy, body mass index, and metastasis were independent risk factors for mortality within 10 years. In the late phase, trastuzumab administration and metastases were risk factors for mortality (Table 2-b). DISCUSSION To the best of our knowledge, this is 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 was because the prognosis of cardiomyopathy is greatly 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 the present study are as follows. (1) Although the incidence of ARCM has decreased and is currently approximately 2% (Fig. 1), the number of survivors is increasing (Fig. 2). (2) The prognosis of ARCM was worse than that of non-ARCM (Fig. 4); however, there has been an improvement trend since 2007 (Fig. 5-a). (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. 5-b, c). The incidence of ARCM has decreased since 1990 (Fig. 1). 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]. In fact, 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]. As a result, 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 a 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 (CTCAE) 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. S2). Despite the decrease in incidence, the number of surviving patients with ARCM increased (Fig. 2-b). 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. 2-a). 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, improved prognosis was observed in the late phase (Fig. 5-a). We observed a favorable prognosis in the ARCM subgroup of ARCM with trastuzumab (Fig. 5-c). Trastuzumab therapy was an independent predictor of late-phase survival (Table 2-b). 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] Study Limitations This study has several limitations. First, we could not confirm echocardiography before chemotherapy in six patients in the early phase. According to a survey conducted in Niigata City in the early phase, the prevalence of patients with LVEF < 50% among women aged 40–70 years was less than 1% [30]. Therefore, it is assumed that most women with BC have normal cardiac function prior to treatment. Second, our community does not have a systematic strategy for detecting asymptomatic ARCM. Because some patients were diagnosed with ARCM based on the symptoms of HF, there might be a tendency for the diagnosis to be delayed or for HF to progress. Consequently, our ARCM may not represent mildly symptomatic or asymptomatic ARCM. Third, some guidelines recommend echocardiography within 1 year of completion of anthracycline-containing regimen in the late phase [22] and the recommendation might increase the chances of detecting ARCM. However, adherence to this recommendation has not been evaluated in our community. CONCLUSION By integrating the BC registries of three cancer centers and observing them over a long period of time, we could detect the characteristic change of ARCM with BC in our community. The prognosis of ARCM was worse than that of non-ARCM; however, the prognosis of HER2 positive ARCM has improved, and the number of survivors has increased in the trastuzumab era. However, the prognosis for HER2 negative ARCM remained poor. A multidisciplinary team, including oncologists and cardiologists, should understand the importance of this subtype in the treatment of patients with BC and ARCM and support each individual patient. DECLARATIONS Acknowledgments We would like to thank Ms. Yoshiko Nakagawa and Ms. Chika Sekine for managing the database, and Drs. Tomoyasu Suzuki, Keisuke Suzuki, Yusuke Tamura, Manabu Oyamatsu, and Yoshinobu Okada for collecting patients’ data. Funding This study was funded by a Regional Medical Research Grant (GC03720223) from the Medical Association of Niigata City. The funders of the study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. This study was an investigator-initiated research conducted by Niigata Breast Cancer with Anthracycline-related Cardiomyopathy Investigators, independent of the funding source. Data availability The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request. COMPLIANCE WITH ETHICAL STANDARDS Conflict of Interest The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Consent to participate For this type of study formal consent is not required. Author contributions Conceptualization: Mitsuhiro Watanabe, Shinya Fujiki, Yuji Okura; Methodology: Mitsuhiro Watanabe, Shinya Fujiki, Yuji Okura; Formal analysis and investigation: Yuji Okura, Naohito Tanabe; Data curation: Eiko Sakata, Kazuki Moro, Naoki Kubota, Masato Moriyama, Keiichi Tsuchida; Writing - original draft preparation: Shinya Fujiki; Writing - review and editing: Yuji Okura, Takeshi Kashimura; Funding acquisition: Takayuki Inomata, Kazuyuki Ozaki, Nobuaki Sato, Yasuo Saijo; Resources: Chie Toshikawa, Mayuko Ikarashi, Chizuko Kanbayashi, Koji Kaneko; Supervision: Yu Koyama, Toshifumi Wakai; Validation: Akira Kikuchi; Project administration: Takayuki Inomata, Yuji Okura All authors read and approved the final manuscript. REFERENCES Giaquinto AN, Sung H, Miller KD, Kramer JL, Newman LA, Minihan A, et al. Breast Cancer Statistics, 2022. CA Cancer J Clin. 2022;72:524-541. Heer E, Harper A, Escandor N, Sung H, McCormack V, Fidler-Benaoudia MM. Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study. Lancet Glob Health. 2020;8:e1027-e1037. Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 2022;66:15-23. Yap YS, Lu YS, Tamura K, Lee JE, Ko EY, Park YH, et al. Insights Into Breast Cancer in the East vs the West: A Review. JAMA oncol. 2019;5:1489-1496. Katanoda K, Hori M, Saito E, Shibata A, Ito Y, Minami T, et al. Updated Trends in Cancer in Japan: Incidence in 1985-2015 and Mortality in 1958-2018-A Sign of Decrease in Cancer Incidence. J Epidemiol. 2021;31:426-450. Caswell-Jin JL, Sun LP, Munoz D, Lu Y, Li Y, Huang H, et al. Analysis of Breast Cancer Mortality in the US-1975 to 2019. JAMA. 2024;331:233-241. Jensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002;13:699-709. Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol. 2015;12:547-58. Padegimas A, Clasen S, Ky B. Cardioprotective strategies to prevent breast cancer therapy-induced cardiotoxicity. Trends Cardiovasc Med. 2020;30:22-28. Popat S, Smith IE. Therapy Insight: anthracyclines and trastuzumab--the optimal management of cardiotoxic side effects. Nature clinical practice Oncology 2008;5:324-35. Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol. 2005;23:2900-2. Onitilo AA, Engel JM, Stankowski RV. Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics, and risk factors. Ther Adv Drug Saf. 2014;5:154-66. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials. Lancet. 2023;401:1277-1292. Curigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700-1712. Tada K, Kumamaru H, Miyata H, Asaga S, Iijima K, Ogo E, et al. Characteristics of female breast cancer in japan: annual report of the National Clinical Database in 2018. Breast Cancer. 2023;30:157-166. Cardoso F, Paluch-Shimon S, Senkus E, Curigliano G, Aapro MS, André F, Barrios CH, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020;31:1623-1649. Saji S, Hiraoka M, Tokuda Y, Fukui N, Ikeda T. Trends in local therapy application for early breast cancer patients in the Japanese Breast Cancer Society Breast Cancer Registry during 2004-2009. Breast Cancer. 2012;19:1-3. Anazawa T, Miyata H, Gotoh M. Cancer registries in Japan: National Clinical Database and site-specific cancer registries. Int J Clin Oncol. 2015;20:5-10. Onishi T, Fukuda Y, Miyazaki S, Yamada H, Tanaka H, Sakamoto J, et al. Practical guidance for echocardiography for cancer therapeutics-related cardiac dysfunction. J Echocardiogr. 2021;19:1-20. Čelutkienė J, Pudil R, López-Fernández T, Grapsa J, Nihoyannopoulos P, Bergler-Klein J, et al. Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC). Eur J Heart Fail. 2020:1504-1524. The Japanese Breast Cancer Society. The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer 2007: KANEHARA & CO., LTD. Tokyo, 2007. (Japanese) Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:2768-2801. Felker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342:1077-1084. Swain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2023;22:101-126. Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-8. de Azambuja E, Agostinetto E, Procter M, Eiger D, Pondé N, Guillaume S, et al. Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab in early HER2-positive breast cancer in the APHINITY trial. ESMO Open. 2023;8:100772. Ohtsu H, Shimomura A, Miyazaki S, Yonemoto N, Ueda S, Shimizu C, et al. Cardiotoxicity of adjuvant chemotherapy with trastuzumab: a Japanese claim-based data analysis. Open Heart. 2022;9:e002053. Yamshiro H, Iwata H, Masuda N, Yamamoto N, Nishimura R, Ohtani S, et al. Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients. Int J Clin Oncol. 2015; 20: 709-722. Banke A, Fosbøl EL, Ewertz M, Videbæk L, Dahl JS, Poulsen MK, et al. Long-Term Risk of Heart Failure in Breast Cancer Patients After Adjuvant Chemotherapy With or Without Trastuzumab. JACC Heart Fail. 2019;7:217-224. Ramadan MM, Ohno Y, Okura Y, Tanabe N, Suzuki K, Abe A, et al. Systolic dysfunction in urban Japan. Circ J. 2008;72:349-57. Tables Tables 1 and 2 are available in the Supplementary Files section. Supplementary Files Table1BCCardiomyopathyTrendsinJapan.pdf Table 1. Patient characteristics Table2BCCardiomyopathyTrendsinJapan.pdf Table 2. Cox proportional hazards models for factors associated with death within 10 years a. Crude hazard ratios for death associated with trastuzumab on HER2 (+) and other prognostic factors related to BC and HF b. Adjusted hazard ratios for death associated with trastuzumab on HER2 (+) and possible confounding factors ACEIs, angiotensin-converting-enzyme inhibitors; ARBs, angiotensin receptor blockers; BC, breast cancer; BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; HER2, human epidermal growth factor receptor type2; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide Fig.S1BCCardiomyopathyTrendsinJapan.pdf Fig. S1 Patient flow chart for the study Fig.S2BCCardiomyopathyTrendsinJapan.pdf Fig. S2 Cumulative incidence rate curves for ARCM from the start of anthracycline administration The curve of incidence from 1990 to 2020 is shown in (a), and the curves of incidence divided into 1990–2006 (early phase) and 2007–2020 (late phase) are shown in (b). Statistically significant differences were determined using the log-rank test. TableS1BCCardiomyopathyTrendsinJapan.pdf Table S1. Regression coefficients that predict the number of patients alive based on the cumulative number of de novo patients, calendar year phase, and ARCM status Cite Share Download PDF Status: Published Journal Publication published 13 Aug, 2024 Read the published version in Breast Cancer → Version 1 posted Editorial decision: Major Revision 03 Jun, 2024 Reviewers agreed at journal 29 Apr, 2024 Reviewers invited by journal 22 Apr, 2024 Editor assigned by journal 22 Apr, 2024 First submitted to journal 18 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4291232","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":294281405,"identity":"10f99b66-3f24-44b7-999f-55e3a4cd30fb","order_by":0,"name":"Mitsuhiro Watanabe","email":"","orcid":"","institution":"Niigata University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mitsuhiro","middleName":"","lastName":"Watanabe","suffix":""},{"id":294281406,"identity":"05ded5a9-48a3-4bbb-a351-b4cc328ad829","order_by":1,"name":"Shinya Fujiki","email":"","orcid":"","institution":"Niigata University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Shinya","middleName":"","lastName":"Fujiki","suffix":""},{"id":294281407,"identity":"4a49d1a6-599e-4dd5-a35f-464c801aa7db","order_by":2,"name":"Yuji Okura","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYDACHjBpw8DGjBBLIEZLGkTLARK0HIZwDhDjLn6eM2Yffradz+NjZ7/4+UMNgzx/A8OzB/i0SPb2GM/sbbtdzMbMUyxx4BiD4YwDDOkG+LQYnOcxZuBtu53YxsyTIHGA7X8CUHmaBCEtjH/bzoG0JP848I+BCC1ne4yZedsOALWwH5M42EaEFsmeY8XMMueSQbawWZztA/rlMAG/8PMkb2Z8U2aXOL//+OMbFd+AIdbek/YAnxYwYGQDkTxQs5l50gjqYGD4AyLYYWazHyNCyygYBaNgFIwgAAD6VkP6LSUxlwAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-4268-4730","institution":"Niigata Cancer Center Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yuji","middleName":"","lastName":"Okura","suffix":""},{"id":294281408,"identity":"7ab34464-be34-4120-8775-453bc877d2c8","order_by":3,"name":"Chie Toshikawa","email":"","orcid":"","institution":"Niigata City General Hospital: Niigata Shimin Byoin","correspondingAuthor":false,"prefix":"","firstName":"Chie","middleName":"","lastName":"Toshikawa","suffix":""},{"id":294281409,"identity":"aa704c7b-b74a-43ec-b1ca-1da62a7a4f16","order_by":4,"name":"Mayuko Ikarash","email":"","orcid":"","institution":"Niigata Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mayuko","middleName":"","lastName":"Ikarash","suffix":""},{"id":294281410,"identity":"1ce137f9-a0e7-496e-ba24-fb0e04337e0e","order_by":5,"name":"Chizuko Kanbayashi","email":"","orcid":"","institution":"Niigata Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Chizuko","middleName":"","lastName":"Kanbayashi","suffix":""},{"id":294281411,"identity":"45784cf8-b919-42e2-a33d-9e481b79f5a8","order_by":6,"name":"Kaneko Koji","email":"","orcid":"","institution":"Niigata Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kaneko","middleName":"","lastName":"Koji","suffix":""},{"id":294281412,"identity":"2c041024-06d6-43a0-a371-e6f8cab1d406","order_by":7,"name":"Akira Kikuchi","email":"","orcid":"","institution":"Niigata Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Akira","middleName":"","lastName":"Kikuchi","suffix":""},{"id":294281413,"identity":"4a9dddc6-1f5f-478d-9a5b-09af824b2466","order_by":8,"name":"Eiko Sakata","email":"","orcid":"","institution":"Niigata City General Hospital: Niigata Shimin Byoin","correspondingAuthor":false,"prefix":"","firstName":"Eiko","middleName":"","lastName":"Sakata","suffix":""},{"id":294281414,"identity":"f9249af6-a3e6-4028-b800-3ea59061ac19","order_by":9,"name":"Keiichi Tsuchida","email":"","orcid":"","institution":"Niigata City General Hospital: Niigata Shimin Byoin","correspondingAuthor":false,"prefix":"","firstName":"Keiichi","middleName":"","lastName":"Tsuchida","suffix":""},{"id":294281415,"identity":"c1d3459c-96d7-4db5-a633-3a1229c0c334","order_by":10,"name":"Kazuyuki Ozaki","email":"","orcid":"","institution":"Niigata City General Hospital: Niigata Shimin Byoin","correspondingAuthor":false,"prefix":"","firstName":"Kazuyuki","middleName":"","lastName":"Ozaki","suffix":""},{"id":294281416,"identity":"8b24a31d-3f7d-4cfc-89b6-0ab4ba1e2e62","order_by":11,"name":"Kazuki Moro","email":"","orcid":"","institution":"Niigata University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Kazuki","middleName":"","lastName":"Moro","suffix":""},{"id":294281417,"identity":"d947a738-2793-415b-9a1c-ab3aedeb6f3e","order_by":12,"name":"Naoki Kubota","email":"","orcid":"","institution":"Niigata Unicersity Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Naoki","middleName":"","lastName":"Kubota","suffix":""},{"id":294281418,"identity":"1fe17737-0cb3-4c13-993e-a4338c29ed13","order_by":13,"name":"Takeshi Kashimura","email":"","orcid":"","institution":"Niigata Unicersity Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Kashimura","suffix":""},{"id":294281419,"identity":"e058b272-9ed8-4e54-8520-1855288a36f9","order_by":14,"name":"Masato Moriyama","email":"","orcid":"","institution":"Niigata University of Pharmacy and Medical and Life Science","correspondingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Moriyama","suffix":""},{"id":294281420,"identity":"71c45101-1d6f-4920-858b-b3ad4c3fcb43","order_by":15,"name":"Nobuaki Sato","email":"","orcid":"","institution":"Niigata Cancer Center Hospital","correspondingAuthor":false,"prefix":"","firstName":"Nobuaki","middleName":"","lastName":"Sato","suffix":""},{"id":294281421,"identity":"d26b9528-ce1d-4cf1-a36c-e030cbd85f5c","order_by":16,"name":"Naohito Tanabe","email":"","orcid":"","institution":"University of Niigata Prefecture: Niigata Kenritsu Daigaku","correspondingAuthor":false,"prefix":"","firstName":"Naohito","middleName":"","lastName":"Tanabe","suffix":""},{"id":294281422,"identity":"865c0e63-e9cd-4498-86d1-1c5cc8655bff","order_by":17,"name":"Yu Koyama","email":"","orcid":"","institution":"Niigata University Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Koyama","suffix":""},{"id":294281423,"identity":"5bcb691d-6b20-472f-9934-7b063f2bd3de","order_by":18,"name":"Toshifumi Wakai","email":"","orcid":"","institution":"Niigata University Graduate School of Medical and Dental Science","correspondingAuthor":false,"prefix":"","firstName":"Toshifumi","middleName":"","lastName":"Wakai","suffix":""},{"id":294281424,"identity":"138392d1-ca55-4463-897a-f38dafc4f8f5","order_by":19,"name":"Yasuo Saijo","email":"","orcid":"","institution":"Niigata University Graduate School of Medical and Dental Science","correspondingAuthor":false,"prefix":"","firstName":"Yasuo","middleName":"","lastName":"Saijo","suffix":""},{"id":294281425,"identity":"d59251da-f2a4-408a-bab7-a8d1a8b2605f","order_by":20,"name":"Takayuki Inomata","email":"","orcid":"","institution":"Niigata Unicersity Graduate School of Medical and Dental Sciences","correspondingAuthor":false,"prefix":"","firstName":"Takayuki","middleName":"","lastName":"Inomata","suffix":""}],"badges":[],"createdAt":"2024-04-19 06:34:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4291232/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4291232/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12282-024-01623-0","type":"published","date":"2024-08-13T15:57:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55552053,"identity":"0f255463-bbc4-4020-bad5-ff77baa605ee","added_by":"auto","created_at":"2024-04-29 22:12:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1191404,"visible":true,"origin":"","legend":"\u003cp\u003eIncidence of ARCM in anthracycline-treated patients\u003c/p\u003e\n\u003cp\u003eThe incidence was calculated by dividing the number of patients who developed ARCM later by the number of patients who started anthracyclines each year. Black bars indicate patients treated with trastuzumab; grey bars indicate patients not treated with trastuzumab. The line graph shows the incidence of ARCM every three years.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/4f2c9771aca6a9a4006d9b64.jpg"},{"id":55552054,"identity":"aa1b0e9d-b43a-4fd3-b2f9-8c48d8414b54","added_by":"auto","created_at":"2024-04-29 22:12:06","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1066395,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative number of BC patients treated with anthracycline and ARCM\u003c/p\u003e\n\u003cp\u003e(a) Cumulative number of BC patients treated with anthracycline from January 1, 1990, to December 31, 2020. The number of patients was counted based on the date of first anthracycline administration.\u003c/p\u003e\n\u003cp\u003e(b) Cumulative number of patients with ARCM from January 1, 1990, to December 31, 2021. The number of patients was counted based on the date of diagnosis of ARCM.\u003c/p\u003e\n\u003cp\u003eThe blue line represents \u003cem\u003ede novo\u003c/em\u003e cancer patients, green line represents living patients, and orange line represents deceased patients.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/4219c03e9b77c63413e84543.jpg"},{"id":55552055,"identity":"bee1e334-387f-4f7c-98d4-6e5031f23f5a","added_by":"auto","created_at":"2024-04-29 22:12:06","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1022161,"visible":true,"origin":"","legend":"\u003cp\u003eScattergrams and regression lines between the cumulative number of patients with BC or ARCM in the early or late phases\u003c/p\u003e\n\u003cp\u003eThe regression equations are indicated for each of the four groups.\u003c/p\u003e\n\u003cp\u003ea. Patients treated with anthracycline\u003c/p\u003e\n\u003cp\u003eb. Patients diagnosed with ARCM\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/50ba84d47a54435a5271c710.jpg"},{"id":55552059,"identity":"efc9897a-ccaf-458f-95ac-a61e2634aaed","added_by":"auto","created_at":"2024-04-29 22:12:06","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":839527,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of overall survival in patients with BC with or without ARCM from the first day of anthracycline administration\u003c/p\u003e\n\u003cp\u003eThe blue line represents patients without ARCM and the red line represents patients with ARCM. Statistically significant differences were determined using the log-rank test.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/ce49243d0cd87a00d490fa07.jpg"},{"id":55552057,"identity":"a540cfb0-d29e-4212-9e3d-14fd5794a18f","added_by":"auto","created_at":"2024-04-29 22:12:06","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":30096,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier estimates of overall survival in BC patients with ARCM\u003c/p\u003e\n\u003cp\u003e(a) Kaplan–Meier estimates according to two phases. The early and late phases are indicated by the green and orange lines, respectively.\u003c/p\u003e\n\u003cp\u003e(b, c) Kaplan–Meier estimates according to trastuzumab therapy. The early and late phases are shown in (b) and (c), respectively. Patients with ARCM treated with or without trastuzumab are shown as dotted and solid lines, respectively. Statistically significant differences were determined using the log-rank test.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/70da2d9d85205cd6b60d4727.png"},{"id":63071220,"identity":"f87be47a-9f32-4589-88c2-6a96a822d069","added_by":"auto","created_at":"2024-08-22 20:04:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4609039,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/9b66ddde-d55a-468a-bde9-bc38e36df3e1.pdf"},{"id":55553161,"identity":"8ebf41e4-631e-4a40-bdae-294ac2a04f23","added_by":"auto","created_at":"2024-04-29 22:20:06","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":344730,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 1. \u003c/strong\u003ePatient characteristics\u003c/p\u003e","description":"","filename":"Table1BCCardiomyopathyTrendsinJapan.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/4e20ecc4e549929da83eb9fb.pdf"},{"id":55552060,"identity":"e0bce79b-6954-4eb3-a9c0-ce36851e2eef","added_by":"auto","created_at":"2024-04-29 22:12:06","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":235448,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 2. \u003c/strong\u003eCox proportional hazards models for factors associated with death within 10 years\u003c/p\u003e\n\u003cp\u003ea. Crude hazard ratios for death associated with trastuzumab on HER2 (+) and other prognostic factors related to BC and HF\u003c/p\u003e\n\u003cp\u003eb. Adjusted hazard ratios for death associated with trastuzumab on HER2 (+) and possible confounding factors\u003c/p\u003e\n\u003cp\u003eACEIs, angiotensin-converting-enzyme inhibitors; ARBs, angiotensin receptor blockers; BC, breast cancer; BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtration rate; HER2, human epidermal growth factor receptor type2; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide\u003c/p\u003e","description":"","filename":"Table2BCCardiomyopathyTrendsinJapan.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/3827e5613c566bbfc7fa2e57.pdf"},{"id":55552061,"identity":"fbc1eabd-c292-447e-814c-100e219809f6","added_by":"auto","created_at":"2024-04-29 22:12:06","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":58305,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFig. S1 \u003c/strong\u003ePatient flow chart for the study\u003c/p\u003e","description":"","filename":"Fig.S1BCCardiomyopathyTrendsinJapan.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/cb71dab55b86f71ee136cd12.pdf"},{"id":55552062,"identity":"98c0d085-edca-4315-9f65-8a6da94d9e57","added_by":"auto","created_at":"2024-04-29 22:12:06","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":77131,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFig. S2 \u003c/strong\u003eCumulative incidence rate curves for ARCM from the start of anthracycline administration\u003c/p\u003e\n\u003cp\u003eThe curve of incidence from 1990 to 2020 is shown in (a), and the curves of incidence divided into 1990–2006 (early phase) and 2007–2020 (late phase) are shown in (b). Statistically significant differences were determined using the log-rank test.\u003c/p\u003e","description":"","filename":"Fig.S2BCCardiomyopathyTrendsinJapan.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/6df47d0d9b96f3d54eac7384.pdf"},{"id":55552063,"identity":"2c2e27e6-3538-48b8-b5cd-ecb77ad7f109","added_by":"auto","created_at":"2024-04-29 22:12:06","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":195496,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S1. \u003c/strong\u003eRegression coefficients that predict the number of patients alive based on the cumulative number of de novo patients, calendar year phase, and ARCM status\u003c/p\u003e","description":"","filename":"TableS1BCCardiomyopathyTrendsinJapan.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4291232/v1/7cd439dce567cefd23af25a9.pdf"}],"financialInterests":"","formattedTitle":"Increasing Survivors of Anthracycline-related Cardiomyopathy with Breast Cancer in Trastuzumab Era: Thirty-one-Year Trends in a Japanese Community","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eBreast cancer (BC) is the most prevalent malignancy in Western countries, and its worldwide prevalence is expected to increase significantly in the future [1-3]. In East Asia, the incidence of BC has increased rapidly over the past few decades, making it the most common cancer in several countries, including Japan [4, 5]. Although its prognosis has improved [6], a significant risk of cancer treatment-related cardiac dysfunction (CTRCD) persists, which has been associated with potential treatment termination and lower therapeutic efficacy [7-12]. Therefore, cancer treatment-related cardiotoxicity is of significant concern.\u003c/p\u003e\n\u003cp\u003eIn patients with BC, anthracycline or trastuzumab is the most common cause of CTRCD. Anthracyclines induce myocardial damage and necrosis in a dose-dependent manner through oxidative stress and other mechanisms. Cardiomyocytes, being unable to repair or regenerate, undergo irreversible injury, leading to cardiotoxicity [7-10]. In contrast, trastuzumab, an anti-human epidermal growth factor receptor type 2 (HER2) antibody, can cause cardiomyocyte dysfunction, but not necrosis, and its induced cardiotoxicity is reversible [8-12]. CTRCD caused by these treatments increases the risk of death and symptomatic heart failure (HF) in the future. Considering the remarkably younger age at diagnosis in patients with BC compared to those with other malignancies, its social impact, defined by mortality and living with a disability, is also prominent.\u003c/p\u003e\n\u003cp\u003eAlthough anthracycline doses have historically been restricted to avoid cardiotoxicity [9, 10, 13, 14], most patients receive anthracycline-containing chemotherapy as neoadjuvant or adjuvant therapy [12-15]. Patients with recurrent/metastatic BC have been forced to receive anthracycline up to the limits of its use [16]. In contrast, trastuzumab has shown high efficacy in patients with HER2-positive BC since its introduction in the early 2000s. Trastuzumab partially replaced traditional anthracycline-containing regimens in both early and advanced cancer and reduced anthracycline use by preventing recurrence/metastasis in the mid-2000s [6, 10, 12, 14, 16]. As a result, trastuzumab may have changed not only the cancer prognosis but also anthracycline-related cardiomyopathy (ARCM). However, the impact of this therapeutic revolution on ARCM remains unknown, particularly in the Asian community. To update our knowledge of ARCM in the trastuzumab era, we evaluated patients with BC and ARCM over the past 31 years in a local Japanese city.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003e\u003cstrong\u003eDesign and study cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective observational multicenter cohort study, based on clinical data, was performed in three designated cancer care hospitals in Niigata City (Niigata University Medical and Dental Hospital, Niigata Cancer Center Hospital, and Niigata City General Hospital). Hospital-based BC registries in Japan, designated for cancer care hospitals nationwide since 2004, collect information on therapies and prognoses for all cancer cases encountered in each hospital according to coding rules precisely defined by the Japanese Breast Cancer Society [17, 18]. These three local hospitals designated for cancer care have registered the medical information of 97% of the patients with BC in Niigata City. Data before 2004 were comprehensively collected from the information databases for cancer in each hospital.\u003c/p\u003e\n\u003cp\u003eConsecutive patients diagnosed with BC and treated with two or more anthracycline treatments between January 1, 1990, and December 31, 2020, were identified. We investigated all echocardiography examinations performed after anthracycline treatment and defined ARCM as patients newly diagnosed with a left ventricular ejection fraction (LVEF) \u0026lt; 50% [19 20]. Patients with LVEF \u0026lt; 50% before BC therapy were excluded.\u003c/p\u003e\n\u003cp\u003eTo assess the impact of the recommended therapeutic strategies in the clinical practice guidelines, we divided the patients into two groups based on the phases of study enrollment: before 2007 (early phase) and after 2007 (late phase). Since 2007, Japanese BC clinical practice guidelines have recommended trastuzumab for HER2-positive patients in both early and advanced settings [21]. Therefore, the early and late phases were equivalent to before and in the trastuzumab era in Japan, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData on the baseline patient characteristics and treatments associated with BC and cardiomyopathy were collected. The cumulative anthracycline dose was calculated by converting the different anthracycline doses into doxorubicin equivalents [22]. The incidence of ARCM was calculated by dividing the number of patients with ARCM by the total number of patients treated with anthracyclines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the institutional review board and independent ethics committee of each participating site. A waver of informed consent was approved. It was conducted in accordance with the principles of the Declaration of Helsinki and in compliance with the ethical guidelines for medical and health research involving human participants. This study was registered with the University Hospital Medical Information Network of Japan (registration number UMIN-000052011).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo calculate the significance of differences between the two groups, Student\u0026rsquo;s t-test was used for continuous variables, and Fisher\u0026apos;s exact probability test was used for categorical variables. Values are reported as mean \u0026plusmn; standard deviation and numbers (%). Linear regression analysis was used to examine the effect of de novo patient accumulation on the number of surviving patients.\u003c/p\u003e\n\u003cp\u003eSurvival curves and cumulative incidence rate curves were evaluated using the Kaplan\u0026ndash;Meier method, and differences between groups were assessed using a log-rank test. Factors associated with death within 10 years were analyzed using Cox proportional hazards models. For the multivariable models, independent variables were selected from the variables that were significant in the crude models. IBM SPSS Statistics for Windows, version 27.0; (Armonk, NY, IBM Corp) was used for the statistical analyses, and the significance level was set at two-tailed P\u0026lt;0.05.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eNumber of patients treated with anthracyclines and patients diagnosed with ARCM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 10, 189 women were diagnosed with BC between January 1990 and December 2020. Of these, 2,959 patients were treated at least twice with anthracyclines. Consequently, 75 patients (2.5%) were diagnosed with ARCM (Fig. S1). The incidence of ARCM calculated every three years was approximately 6% in the 1990s but subsequently decreased to approximately 2% in the 2010s (Fig. 1). The cumulative incidence of ARCM in all patients was 2.1% over 5 years and 3.2% over 10 years (Fig. S2-a). In the early phase, the incidence was 3.0% over 5 years and 4.7% over 10 years, whereas in the late phase, it was 1.8% and 2.7%, respectively (P=0.047) (Fig. S2-b).\u003c/p\u003e\n\u003cp\u003eAmong patients treated with anthracyclines, the cumulative number of survivors outnumbered the cumulative number of deaths since 2005 (Fig. 2-a). In contrast, among patients with ARCM, the cumulative number of survivors was lower than that of patients who died (Fig. 2-b). However, a rapid increase in the number of ARCM survivors was observed during the late phase. To evaluate whether this increase in the accumulation speed was affected solely by the increase in that of de novo patients, the regression coefficients of de novo patients predicting that of alive patients were compared between the two periods. In the anthracycline-treated patient group, the regression coefficients were significantly, but only slightly, elevated in the late phase than in the early phase (+0.010, P\u0026lt;0.001) (Table S1 and Fig. 3). However, the increase in the coefficients was much greater in the ARCM group than in the anthracycline-treated patient group (+0.110, P\u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCharacteristics of patients with ARCM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe characteristics of the 75 patients with ARCM are presented in Table 1. Fifty-seven percent of the patients had distant metastases, and 52% had HER2-positivity. Doxorubicin and epirubicin were the main drugs used for chemotherapy, with a mean doxorubicin-equivalent dose of 359 mg/m\u003csup\u003e2\u003c/sup\u003e. In the early phase, only 17 % of patients received trastuzumab, but in the late phase, 54% of patients received it. All but one of these trastuzumab-treated patients were HER2 positive. The mean duration from the last treatment to the diagnosis of ARCM was 28.4 months, and LVEF at that time was 41.9\u0026plusmn;7.8% and LVEF of 16 patients (21%) was less than 35%. Twenty-nine patients (39%) required hospitalization for HF after ARCM diagnosis. In the late-phase group, patients had fewer metastases, used more taxanes and trastuzumab, and were administered fewer anthracyclines than patients in the early phase group; furthermore, the late-phase group had more patients with HER2-positive tumors. Examination of plasma brain natriuretic peptide (BNP) levels and HF treatment with angiotensin-converting enzyme inhibitors (ACEIs) and beta blockers were more common in the late phase. No differences were observed in the duration until LVEF declined after anthracycline treatment, LVEF levels, or the frequency of hospitalization for congestive HF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDifferences in prognosis between the phases of patient enrollment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSurvival rates after the first administration of anthracyclines were 71% and 79% at 5 years and 33% and 69% at 10 years in patients with ARCM and non-ARCM, respectively. (log-rank test, P\u0026lt;0.001) (Fig. 4). Prognostic differences were absent between patients in the early and late phases; however, the survival rate tended to improve in patients in the late phase (P=0.058) (Fig. 5-a). The 5-year survival rates in the early and late phases were 28% and 45%, respectively. Patients were divided according to the use of trastuzumab, and the prognostic impact of each phase was analyzed. Trastuzumab users had a better prognosis in the late phase (P=0.002) (Fig. 5-c). The 5-year survival rates were 64% and 26% in the trastuzumab and non-trastuzumab groups, respectively.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrognostic risk factors in patients with ARCM in multivariate analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn all patients, HER2 positivity with trastuzumab therapy, body mass index, metastasis, and NT-proBNP level were positively associated with death according to the crude Cox proportional hazards models (Table 2-a). Multivariate analysis revealed that HER2 positivity with trastuzumab therapy, body mass index, and metastasis were independent risk factors for mortality within 10 years. In the late phase, trastuzumab administration and metastases were risk factors for mortality (Table 2-b).\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eTo the best of our knowledge, this is 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 was because the prognosis of cardiomyopathy is greatly 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 the present study are as follows. (1) Although the incidence of ARCM has decreased and is currently approximately 2% (Fig. 1), the number of survivors is increasing (Fig. 2). (2) The prognosis of ARCM was worse than that of non-ARCM (Fig. 4); however, there has been an improvement trend since 2007 (Fig. 5-a). (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. 5-b, c).\u003c/p\u003e\n\u003cp\u003eThe incidence of ARCM has decreased since 1990 (Fig. 1). 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]. In fact, 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]. As a result, 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 \u003cem\u003eet al\u003c/em\u003e. found that 9.7% of 1344 patients with BC treated with anthracyclines had systolic dysfunction within a 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 (CTCAE) grade 3\u0026ndash;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. S2).\u003c/p\u003e\n\u003cp\u003eDespite the decrease in incidence, the number of surviving patients with ARCM increased (Fig. 2-b). 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. 2-a). 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, improved prognosis was observed in the late phase (Fig. 5-a). We observed a favorable prognosis in the ARCM subgroup of ARCM with trastuzumab (Fig. 5-c). Trastuzumab therapy was an independent predictor of late-phase survival (Table 2-b). A recent prognostic improvement in BC was reported by Caswell-Jin \u003cem\u003eet al\u003c/em\u003e. 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.\u003c/p\u003e\n\u003cp\u003eFelker \u003cem\u003eet al\u003c/em\u003e. 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 \u003cem\u003eet al\u003c/em\u003e. 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]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has several limitations. First, we could not confirm echocardiography before chemotherapy in six patients in the early phase. According to a survey conducted in Niigata City in the early phase, the prevalence of patients with LVEF \u0026lt; 50% among women aged 40\u0026ndash;70 years was less than 1% [30]. Therefore, it is assumed that most women with BC have normal cardiac function prior to treatment. Second, our community does not have a systematic strategy for detecting asymptomatic ARCM. Because some patients were diagnosed with ARCM based on the symptoms of HF, there might be a tendency for the diagnosis to be delayed or for HF to progress. Consequently, our ARCM may not represent mildly symptomatic or asymptomatic ARCM. Third, some guidelines recommend echocardiography within 1 year of completion of anthracycline-containing regimen in the late phase [22] and the recommendation might increase the chances of detecting ARCM. However, adherence to this recommendation has not been evaluated in our community.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eBy integrating the BC registries of three cancer centers and observing them over a long period of time, we could detect the characteristic change of ARCM with BC in our community. The prognosis of ARCM was worse than that of non-ARCM; however, the prognosis of HER2 positive ARCM has improved, and the number of survivors has increased in the trastuzumab era. However, the prognosis for HER2 negative ARCM remained poor. A multidisciplinary team, including oncologists and cardiologists, should understand the importance of this subtype in the treatment of patients with BC and ARCM and support each individual patient.\u003c/p\u003e"},{"header":"DECLARATIONS","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Ms. Yoshiko Nakagawa and Ms. Chika Sekine for managing the database, and Drs. Tomoyasu Suzuki, Keisuke Suzuki, Yusuke Tamura, Manabu Oyamatsu, and Yoshinobu Okada for collecting patients\u0026rsquo; data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by a Regional Medical Research Grant (GC03720223) from the Medical Association of Niigata City. The funders of the study had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. This study was an investigator-initiated research conducted by Niigata Breast Cancer with Anthracycline-related Cardiomyopathy Investigators, independent of the funding source.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCOMPLIANCE WITH ETHICAL STANDARDS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor this type of study formal consent is not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Mitsuhiro Watanabe, Shinya Fujiki, Yuji Okura; Methodology: Mitsuhiro Watanabe, Shinya Fujiki, Yuji Okura; Formal analysis and investigation: Yuji Okura, Naohito Tanabe; Data curation: Eiko Sakata, Kazuki Moro, Naoki Kubota, Masato Moriyama, Keiichi Tsuchida; Writing - original draft preparation: Shinya Fujiki; Writing - review and editing: Yuji Okura, Takeshi Kashimura; Funding acquisition: Takayuki Inomata, Kazuyuki Ozaki, Nobuaki Sato, Yasuo Saijo; Resources: Chie Toshikawa, Mayuko Ikarashi, Chizuko Kanbayashi, Koji Kaneko; Supervision: Yu Koyama, Toshifumi Wakai; Validation: Akira Kikuchi; Project administration: Takayuki Inomata, Yuji Okura\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"REFERENCES","content":"\u003col\u003e\n\u003cli\u003eGiaquinto AN, Sung H, Miller KD, Kramer JL, Newman LA, Minihan A, et al. Breast Cancer Statistics, 2022. CA Cancer J Clin. 2022;72:524-541.\u003c/li\u003e\n\u003cli\u003eHeer E, Harper A, Escandor N, Sung H, McCormack V, Fidler-Benaoudia MM. Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study. Lancet Glob Health. 2020;8:e1027-e1037.\u003c/li\u003e\n\u003cli\u003eArnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 2022;66:15-23.\u003c/li\u003e\n\u003cli\u003eYap YS, Lu YS, Tamura K, Lee JE, Ko EY, Park YH, et al. Insights Into Breast Cancer in the East vs the West: A Review. JAMA oncol. 2019;5:1489-1496.\u003c/li\u003e\n\u003cli\u003eKatanoda K, Hori M, Saito E, Shibata A, Ito Y, Minami T, et al. Updated Trends in Cancer in Japan: Incidence in 1985-2015 and Mortality in 1958-2018-A Sign of Decrease in Cancer Incidence. J Epidemiol. 2021;31:426-450. \u003c/li\u003e\n\u003cli\u003eCaswell-Jin JL, Sun LP, Munoz D, Lu Y, Li Y, Huang H, et al. Analysis of Breast Cancer Mortality in the US-1975 to 2019. JAMA. 2024;331:233-241.\u003c/li\u003e\n\u003cli\u003eJensen BV, Skovsgaard T, Nielsen SL. Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients. Ann Oncol. 2002;13:699-709. \u003c/li\u003e\n\u003cli\u003eEwer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol. 2015;12:547-58.\u003c/li\u003e\n\u003cli\u003ePadegimas A, Clasen S, Ky B. Cardioprotective strategies to prevent breast cancer therapy-induced cardiotoxicity. Trends Cardiovasc Med. 2020;30:22-28.\u003c/li\u003e\n\u003cli\u003ePopat S, Smith IE. Therapy Insight: anthracyclines and trastuzumab--the optimal management of cardiotoxic side effects. Nature clinical practice Oncology 2008;5:324-35.\u003c/li\u003e\n\u003cli\u003eEwer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol. 2005;23:2900-2.\u003c/li\u003e\n\u003cli\u003eOnitilo AA, Engel JM, Stankowski RV. Cardiovascular toxicity associated with adjuvant trastuzumab therapy: prevalence, patient characteristics, and risk factors. Ther Adv Drug Saf. 2014;5:154-66.\u003c/li\u003e\n\u003cli\u003eEarly Breast Cancer Trialists\u0026rsquo; Collaborative Group (EBCTCG). Anthracycline-containing and taxane-containing chemotherapy for early-stage operable breast cancer: a patient-level meta-analysis of 100 000 women from 86 randomised trials. Lancet. 2023;401:1277-1292. \u003c/li\u003e\n\u003cli\u003eCurigliano G, Burstein HJ, Winer EP, Gnant M, Dubsky P, Loibl S, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen International Expert Consensus Conference on the Primary Therapy of Early Breast Cancer 2017. Ann Oncol. 2017;28:1700-1712. \u003c/li\u003e\n\u003cli\u003eTada K, Kumamaru H, Miyata H, Asaga S, Iijima K, Ogo E, et al. Characteristics of female breast cancer in japan: annual report of the National Clinical Database in 2018. Breast Cancer. 2023;30:157-166. \u003c/li\u003e\n\u003cli\u003eCardoso F, Paluch-Shimon S, Senkus E, Curigliano G, Aapro MS, Andr\u0026eacute; F, Barrios CH, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). Ann Oncol. 2020;31:1623-1649.\u003c/li\u003e\n\u003cli\u003eSaji S, Hiraoka M, Tokuda Y, Fukui N, Ikeda T. Trends in local therapy application for early breast cancer patients in the Japanese Breast Cancer Society Breast Cancer Registry during 2004-2009. Breast Cancer. 2012;19:1-3. \u003c/li\u003e\n\u003cli\u003eAnazawa T, Miyata H, Gotoh M. Cancer registries in Japan: National Clinical Database and site-specific cancer registries. Int J Clin Oncol. 2015;20:5-10. \u003c/li\u003e\n\u003cli\u003eOnishi T, Fukuda Y, Miyazaki S, Yamada H, Tanaka H, Sakamoto J, et al. Practical guidance for echocardiography for cancer therapeutics-related cardiac dysfunction. J Echocardiogr. 2021;19:1-20.\u003c/li\u003e\n\u003cli\u003eČelutkienė J, Pudil R, L\u0026oacute;pez-Fern\u0026aacute;ndez T, Grapsa J, Nihoyannopoulos P, Bergler-Klein J, et al. Role of cardiovascular imaging in cancer patients receiving cardiotoxic therapies: a position statement on behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC). Eur J Heart Fail. 2020:1504-1524.\u003c/li\u003e\n\u003cli\u003eThe Japanese Breast Cancer Society. The Japanese Breast Cancer Society Clinical Practice Guidelines for Breast Cancer 2007: KANEHARA \u0026amp; CO., LTD. Tokyo, 2007. (Japanese)\u003c/li\u003e\n\u003cli\u003eZamorano JL, Lancellotti P, Rodriguez Mu\u0026ntilde;oz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: \u0026ensp;The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37:2768-2801.\u003c/li\u003e\n\u003cli\u003eFelker GM, Thompson RE, Hare JM, Hruban RH, Clemetson DE, Howard DL, et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000;342:1077-1084.\u003c/li\u003e\n\u003cli\u003eSwain SM, Shastry M, Hamilton E. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2023;22:101-126.\u003c/li\u003e\n\u003cli\u003eCardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-8. \u003c/li\u003e\n\u003cli\u003ede Azambuja E, Agostinetto E, Procter M, Eiger D, Pond\u0026eacute; N, Guillaume S, et al. Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab in early HER2-positive breast cancer in the APHINITY trial. ESMO Open. 2023;8:100772.\u003c/li\u003e\n\u003cli\u003eOhtsu H, Shimomura A, Miyazaki S, Yonemoto N, Ueda S, Shimizu C, et al. Cardiotoxicity of adjuvant chemotherapy with trastuzumab: a Japanese claim-based data analysis. Open Heart. 2022;9:e002053.\u003c/li\u003e\n\u003cli\u003eYamshiro H, Iwata H, Masuda N, Yamamoto N, Nishimura R, Ohtani S, et al. Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients. Int J Clin Oncol. 2015; 20: 709-722.\u003c/li\u003e\n\u003cli\u003eBanke A, Fosb\u0026oslash;l EL, Ewertz M, Videb\u0026aelig;k L, Dahl JS, Poulsen MK, et al. Long-Term Risk of Heart Failure in Breast Cancer Patients After Adjuvant Chemotherapy With or Without Trastuzumab. JACC Heart Fail. 2019;7:217-224.\u003c/li\u003e\n\u003cli\u003eRamadan MM, Ohno Y, Okura Y, Tanabe N, Suzuki K, Abe A, et al. Systolic dysfunction in urban Japan. Circ J. 2008;72:349-57.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e "}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"cardiotoxicity, anthracycline, trastuzumab, human epidermal growth factor receptor type 2, secular trend","lastPublishedDoi":"10.21203/rs.3.rs-4291232/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4291232/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBACKGROUND\u003c/p\u003e\n\u003cp\u003eTrastuzumab has improved breast cancer (BC) prognosis and reduced anthracycline use. However, the characteristic changes of anthracycline-related cardiomyopathy (ARCM) in patients with BC remain unclear. We sought to update our knowledge of ARCM in the trastuzumab era.\u003c/p\u003e\n\u003cp\u003eMETHODS\u003c/p\u003e\n\u003cp\u003eThis was a retrospective observational cohort study. A total of 2,959 patients with BC treated with anthracyclines in three regional cancer centers in Niigata City between 1990 and 2020 were included. Seventy-five patients (2.5%) developed ARCM and were categorized into two groups: pre- 2007 (early phase) and post- 2007 (late phase), corresponding to before and during the trastuzumab era in Japan.\u003c/p\u003e\n\u003cp\u003eRESULTS\u003c/p\u003e\n\u003cp\u003eThe incidence of ARCM peaked at 6% in the 1990s, decreased, and remained at 2% until the 2010s. Mean anthracycline use in the early and late phases was 525 mg/m\u003csup\u003e2\u003c/sup\u003e and 307 mg/m\u003csup\u003e2\u003c/sup\u003e (P\u0026lt;0.001), and the 5-year survival rates were 28% and 45% (P=0.058), respectively. Human epidermal growth factor receptor type 2 (HER2) positivity with trastuzumab therapy in late phase was an independent predictor for mortality within 10 years (hazard ratio =0.24, 95% confidence interval: 0.10–0.56; P=0.001). At the end of the late phase, there were four times as many patients with ARCM as at the end of the early phase (twenty-six and six, respectively). Survivors of BC increased more rapidly in the late phase, though the rate of accumulation change was slight in the anthracycline-treated BC group and more pronounced in the ARCM group (P \u0026lt;0.001).\u003c/p\u003e\n\u003cp\u003eCONCLUSIONS\u003c/p\u003e\n\u003cp\u003eWith increasing survivor with ARCM in the trastuzumab era, subtypes of HER2 positivity have gained significant importance in treating patients with ARCM in BC.\u003c/p\u003e","manuscriptTitle":"Increasing Survivors of Anthracycline-related Cardiomyopathy with Breast Cancer in Trastuzumab Era: Thirty-one-Year Trends in a Japanese Community","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-29 22:12:01","doi":"10.21203/rs.3.rs-4291232/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2024-06-03T18:22:01+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-04-29T07:55:01+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-22T23:02:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-22T11:17:02+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer","date":"2024-04-19T02:34:20+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"fbc615f1-a146-4e39-9cb2-fc268c641925","owner":[],"postedDate":"April 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-08-22T19:32:45+00:00","versionOfRecord":{"articleIdentity":"rs-4291232","link":"https://doi.org/10.1007/s12282-024-01623-0","journal":{"identity":"breast-cancer","isVorOnly":false,"title":"Breast Cancer"},"publishedOn":"2024-08-13 15:57:26","publishedOnDateReadable":"August 13th, 2024"},"versionCreatedAt":"2024-04-29 22:12:01","video":"","vorDoi":"10.1007/s12282-024-01623-0","vorDoiUrl":"https://doi.org/10.1007/s12282-024-01623-0","workflowStages":[]},"version":"v1","identity":"rs-4291232","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4291232","identity":"rs-4291232","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}