Exercise decreases Neuregulin-1 concentrations in HER2+ breast cancer patients

Exercise decreases Neuregulin-1 concentrations in HER2+ breast cancer patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Exercise decreases Neuregulin-1 concentrations in HER2+ breast cancer patients Quentin Jacquinot, Gaël Ennequin, Antoine Falcoz, Douglas Sawyer, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7242299/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Feb, 2026 Read the published version in Breast Cancer Research and Treatment → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose Trastuzumab used for the treatment of patients with HER2-positive breast cancer can induce cardiotoxicity. While the Nueregulin-1(NRG1)/HER pathway plays a central role in human cardiovascular physiology, the link between exercise, NRG1 and cardiotoxicity remains unclear The study aimed to assess the effect of a 12-week supervised exercise training on circulating NRG1 levels. A secondary objective was to assess the correlation between NRG1 level and cardiotoxicity. Methods Patients were randomized to receive either adjuvant trastuzumab in combination with a training 12-week supervised exercise program in a training group (training group, TG) or trastuzumab alone (control group, CG). Cardiorespiratory fitness test left ventricular ejection fraction and circulating level of NRG1 were assessed before, after and 3 months after training. Results Eighty-nine patients were randomized (TG; n = 46 ; CG; n = 43) with 76 having a baseline NRG1 concentration available. After the exercise program, plasma levels of NRG1 significantly decreased in the TG (mean difference − 0.20 ng/ml ; 95% CI, -0.32, -0.07) whereas they remained stable in the CG (mean difference − 0.05 ng/ml; 95% CI, -0.20, 0.10). NRG1 remain stable during follow up. However, no correlation was observed between NRG1 changes and either cardiorespiratory fitness (peak V̇O 2 ) and Left Ventricular Ejection Fraction (LVEF) (R = 0.087, p = 0.53; R =-0.157, p = 0.26 and R =-0.131, p = 0.33 respectively). Conclusion A 12-week interval training program significantly decreased NRG1 concentration in HER2-positive breast cancer patients treated with adjuvant trastuzumab therapy. This change was not associated with peak V̇O 2 nor LVEF. Trial registration: This trial was registered with ClinicalTrials.gov under the number NCT02433067. breast cancer HER2 overexpression cardiotoxicity supervised exercise program prevention supportive care Figures Figure 1 Introduction Breast cancer is one of the most diagnosed cancers worldwide. Recent report indicate that breast cancer accounts for almost one-third of newly diagnosed female cancer in the United States [ 1 ]. Moreover, the incidence rate of female breast cancer has been slowly increasing by approximately 0.5% per year since the mid-2000s, possibly due to a decline in the fertility rates and the rise in obesity [ 2 ]. Among patients with breast carcinoma, the human epidermal growth factor receptor 2 (HER2-positive) subtype is found in 15–20% of invasive breast cancers and is associated with a worse prognosis [ 3 ]. This subtype is characterized by overexpression of the HER2 (also known as ERBB2). Unlike other HER homologs [Epidermal Growth Factor Receptor (EGFR), HER3 and 4], HER2 does not directly bind to any known ligands. Neuregulin 1 (NRG1), encoded by the NRG1 gene, acts as a direct ligand for HER3 and HER4 tyrosine kinase receptors and can recruit both EGFR and HER2 co-receptors, leading to ligand-activated tyrosine phosphorylation. The NRG1/ERBB signaling pathway plays a complex role in the development and progression of breast cancer. Furthermore, circulating NRG1 has been reported to be elevated in breast cancer patients compared to healthy controls, serving as a prognostic and outcome indicator for breast cancer patients [ 4 ]. Consequently, targeting HER2 and the NRG1/HER pathway has been one of a leading area in breast cancer treatment development. Among available therapies, the anti-HER2 monoclonal antibody trastuzumab was the first molecularly targeted agent approved by the FDA for treating HER2-positive breast cancer. While adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer [ 5 , 6 ], this therapy can induce cardiac dysfunction and heart failure considered as cardiotoxicity [ 7 , 8 ]. Indeed, the NRG1/HER pathway plays a pivotal role in the human cardiovascular physiology [ 9 ]. It is now well established that regular exercise improves cardiovascular health [ 10 ]. Consequently, different pharmacological and non-pharmacological therapies, such as physical exercise, have been explored as preventive approaches against cardiotoxicity during breast cancer treatment [ 11 , 12 ]. However, studies investigating the effects of exercise training program on trastuzumab-induced cardiotoxicity are scarce [ 13 ]. We recently reported that a 12-week supervised exercise regimen was safe and improved the cardiopulmonary fitness in HER2-positive patients treated with adjuvant trastuzumab [ 14 ]. Moreover, the rate of patients free of cardiotoxicity was higher after training compared to that observed following standard care. However, the biological mechanisms involved in these findings remain to be explored. Therefore, the aim of this study was to assess the effect of a 12-week supervised exercise training on the circulating level of NRG1. A secondary objective was to evaluate the correlation between NRG1 level and cardiotoxicity. Materials and methods 1. Ethical approval The CARDAPAC study was conducted in compliance with the Declaration of Helsinki. It received approval from the Ethics Committee (Comité de Protection des Personnes Est-II), Besançon, France under the number P/2014/241 and from the National Health Products Safety Agency (N° ID RCB 2014-A01911-46). The trial was registered on ClinicalTrials.gov under the number NCT02433067. Financial support was provided by the “Conférence de Coordination Inter Régionale Est (CCIR-Est) de la Ligue contre le Cancer. 2. Study design CARDAPAC was a phase II, randomized, prospective, multicentre, non-comparative trial conducted from April 2015 to February 2020. The original CADAPAC protocol and results regarding the primary endpoint have been published [14, 15]. In the present paper, only data concerning neuregulin and cardiac parameters will be presented to better understand their roles and their link with cardiotoxicity. Briefly, women were recruited based on the eligibility criteria summarized in Supplementary Table S1. All participants provided written informed consent prior to enrolment. Patients were randomly assigned to receive adjuvant trastuzumab in combination with a supervised training exercise program (training group, TG) or trastuzumab alone without the exercise program (control group, CG) in a 1:1 ratio. Randomization was performed according to the minimization technique with stratification (eRandomisation software Tenalea ® ) by age (18–30 vs 30–50 vs 50–85 years) and global health score defined from a quality-of-life questionnaire [QLQ-C30 (0–30 vs 30–50 vs 50–70 vs >70)]. 3. Study protocol At enrolment (T0), human Neuregulin 1 (NGR1) and cardiac parameters were evaluated, and measurements were repeated at the end of the 3-month supervised exercise program (T3) and 3 months after the end of training (T6). Between T0 and T3, both groups followed standard oncological care with (TG) or without (CG) the supervised (3 times/week) training program. Between T3 and T6, both groups had standard oncological care without supervised physical activity. Human NGR1 (Neuregulin 1) Blood samples were collected in the morning (8:00 to 10:00) after an overnight fast, by venous puncture. Plasma was collected using EDTA tubes. Samples were centrifuged (15 min at 3,500 rpm at 2-8°C). Supernatants were aliquoted and stored in cryotubes at −80°C until analysis. Samples were assayed for plasma NGR1 utilizing an indirect sandwich ELISA (NBP2-68069; R&D Systems). Following the manufacturer’s instructions, the absorbance of each well was assessed using a spectrophotometer at 450 nm. Other parameters LVEF was assessed by transthoracic Doppler echocardiography (Philips EPIQ7, Philips Healthcare, Andover, MA, USA) in the apical 4-chamber (4C) view using Simpson's biplane rule, according to the American Society of Echocardiography recommendations [16, 17]. GLS was assessed in the basal, mid-ventricular and apical segments in the 4-chamber view according to the European Society of Cardiology recommendations [18]. Maximal power (Watts) and peak V̇O 2 (ml.min -1 .kg -1 ) were measured during a maximal cardiorespiratory exercise test. Testing was conducted using a cyclo-ergometer (Ergoselect 200; Ergoline; Bitz, Germany) as already described in the design protocol [15]. Furthermore, two subgroups were defined: TOX and NoTOX according to the presence or absence of cardiotoxicity. Cardiotoxicity was defined as either a decrease of the LVEF under 50% at T3 (independently of the baseline value) or an absolute drop in LVEF of at least 10% from T0 to T3. Supervised training program The supervised training program, previously detailed by Jacquinot et al. (2017b) involved patients performing three 55-minute intermittent exercise sessions per week for 12 weeks, totaling 36 sessions. An exercise specialist supervised the program, which utilized an electromagnetically braked cycle ergometer based on the Square-Wave Endurance Exercise Test [20] to help motivate participants. During each session, heart rate (HR) was continuously displayed with a finger pulse oximeter (Onyx ® Vantage 9590, Nonin Medical, Inc., USA) at the end of each “base” and “pic” interval. Thus, the total physical work gradually and safely increased throughout the program to an optimal stimulation. Statistical analysis Qualitative variables were described as number and percentage, and quantitative variables as mean with standard deviation (SD) or median with interquartile range (IQR). Echocardiography variables and cardiorespiratory parameters at maximal exercise were described as mean ± standard deviation (SD) at T0, T3 and T6. Subgroup analyses of echocardiography variables and cardiorespiratory parameters at maximal exercise according to age were described using median with IQR. Violin plots were used to obtain a longitudinal representation of data during follow-up. Differences over time were described as the difference in means, with 95% confidence interval (CI). Spearman’s correlation coefficient was used to assess the association between changes in LVEF, peak V̇O 2 , maximal power and NGR1. Statistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R software version 4.0.3 (R Development Core Team, Vienna, Austria; http://www.r-project.org). p-values <0.05 were considered statistically significant and were given for exploratory purposes. All tests were two-sided. Results Population Between April 2015 and February 2020, 205 patients were screened and 89 were randomized: 46 patients (51.7%) were assigned to the TG and 43 patients (48.3%) to the CG. The baseline clinical characteristics of all participants and the primary endpoint have been published in a previous article [14]. NGR1 Seventy-six patients (85.4%) have a measurable NRG1 concentration at baseline (T0). The plasma levels of NGR1 decreased between T0 and T3 and remained stable between T3 and T6 in the global population (Table 1). The evolution of plasma levels of NGR1 between the two groups over time is presented in Table 2. At T3, plasma NGR1 levels significantly decreased in the TG (mean difference -0.19 ng/ml ; 95% CI, -0.31, -0.06) whereas they were not modified in the CG (mean difference -0.06 ng/ml ; 95% CI, -0.21, 0.08 ; Table 2). At T6, plasma NGR1 levels in both groups were unchanged compared to values measured at T3 (TG: mean difference 0.00 ng/ml ; 95% CI, -0.11, 0.11; CG : mean difference -0.04 ng/ml ; 95% CI, -0.17, 0.08 ; Table 2). Violin plots illustrate the changes in NGR1 between T0, T3, and T6, revealing heterogeneous individual trajectories in both groups (Figure 1). When considering only TG patients who presented cardiotoxicity at T3 (defined as LVEF < 50% at T3 or an absolute drop in LVEF of at least 10%; shown in red in Figure 1), NGR1 decreased in all three patients (Figure 1A). In the CG, NGR-1 decreased in two patients and increased in two patients. Other outcomes NGR1 levels were similar between the NoTOX and TOX group at T0 and T3 (Table 3). Levels of NGR1 were not correlated with peak V̇O 2 (R = 0.087, p = 0.53); maximal power (R =-0.157, p = 0.26) and LVEF changes (R =-0.131, p = 0.33 ; Table 4). Discussion Our major findings indicate that exercise training significantly reduces circulating NRG1 levels in HER2-positive breast cancer patients undergoing adjuvant trastuzumab therapy. However, modifications in NRG1 levels were not associated with changes in cardiotoxicity or physical fitness. The NRG1/ERRB pathways have been extensively studied for their role in the development and progression of breast cancer [21]. However, the role of NRG1 as a biomarker in breast cancer has been poorly investigated, and the available literature regarding NRG1 concentrations in humans is conflicting [22]. De luliis and collaborators reported a mean NRG1 concentration of 1.95 ng/mL in breast cancer patients [4]. Interestingly, NRG1 levels were significantly higher in HER2-negative patients compared to those HER2-positive. The mean value of NRG1 levels in HER2-positive patients was 0.98 ± 0.71 ng/mL which aligns with our present results. Conversely, Geisberg and colleagues reported higher NRG1 concentrations (9.0 ± 11.4 ng/mL) in a cohort of breast cancer patients [23]. It should be noted that HER2-positive patients represented only 37% of the subjects included and had a higher BMI. This difference might explain the lower NRG1 concentrations observed in our participants. Systemic levels of NRG1 has been proposed as biomarkers in various diseases, including cardiovascular disease [24], neurodegenerative disease [25] and cancer [4, 26]. Regarding breast cancer, Geisberg and colleagues investigated whether NRG1 could serve as a biomarker to identify breast cancer patients at risk for impaired cardiovascular function [23]. Their results showed that higher baseline NRG1 levels were observed in those with the greatest decline in LVEF. Furthermore,, De luliis and collaborators demonstrated a significant association between plasmatic NRG1 and prediction of 1-year mortality in breast cancer patients before treatment with anthracyclines and taxanes, with or without trastuzumab [4]. Altogether, further studies are warranted to determine whether NRG1 can be used as a biomarker to characterize breast cancer patient at risk for treatment-induced cardiovascular dysfunction or death. Breast cancer patient undergoing treatment can experience numerous and varied side effects, such as fatigue, body composition changes or a reduction in cardiorespiratory fitness [27, 28]. Consequently, many non-pharmacological strategies have been tested to limit these side effects and improve quality of life. There is currently a large body of evidence supporting that the benefit of regular physical exercise for breast cancer patients undergoing treatment [29]. Yet, the effect of regular exercise in patients at risk for cardiotoxicity is less investigated. We previously reported that a supervised exercise program improved cardiopulmonary fitness, particular l y peak V̇O 2 , in HER2-positive patients treated with adjuvant trastuzumab therapy, with a modest effect on cardiotoxicity [14]. Recently, Fernandez-Casas and collaborators assessed the cardioprotective effects of exercise training in women with breast cancer, both during and after treatments. While exercise training (aerobic alone or a combination of resistance and aerobic exercise) improves peak V̇O 2 in breast cancer patients, this type of intervention was not effective in improving cardiovascular function [30]. Similarly, Amin and colleagues reached the same conclusion regarding improvement in peak V̇O 2 but not cardiotoxicity in response to exercise training [12]. It should be noted that the significant heterogeneity in the field regarding breast cancer treatments, exercise program, primary cardiac outcomes or sample size warrants further studies. Interestingly, we observed here that exercise significantly decreases circulating NRG1 levels in HER2-positive breast cancer patients which persist during the follow up. Unfortunately, this change was not associated with cardiovascular function or cardiorespiratory fitness. The literature reports that circulating NRG1 is associated with peak V̇O 2 values in healthy volunteers [31]. This discrepancy might be explained by the large range in circulating concentration between subjects (32 ng.mL -1 to 473 ng.mL -1 ) and the use of an in-house ELISA assay. In line with our results, Geisberg and colleagues did not report a significant association with baseline plasma NRG1 and self-reported physical fitness in breast cancer patients [23]. Importantly, those authors reported a small but statistically significant correlation between baseline circulating levels of NRG1 and maximal change in cardiac function. Moreover, it has been reported that NRG1 circulating levels were associated with 1-year mortality [4]. In others diseases such as heart failure, higher levels of NRG1 were associated with worse outcomes [32] Thus, a decrease in circulating NRG1 levels might represent a favorable outcome in patients with breast cancer. It is now important to determine whether exercise is one of the drivers leading to a decrease in circulating levels of NRG1. Our results show that NRG1 concentrations significantly decrease after the training program but not during the follow-up, suggesting that exercise can explain this adaptation. To date, no clinical study has investigated the effect of chronic exercise on systemic NRG1 levels in cancer patients. Only one study has investigated the impact of resistance training on NRG1 pathway in skeletal muscle of healthy volunteers [33]. Result showed no change in NRG1 expression in skeletal muscle in response to exercise. Yet, we cannot rule out the possibility that exercise training can impact other organs that highly express NRG1 protein and contribute to the circulating level. This study has some limitations that need to be highlighted and suggests avenues for further studies. First, as previously reported [14], the target number of subjects to meet the primary endpoint was not reached, and the overall population was likely too small to a significant association between NRG1 concentration and LEVF. Furthermore, other cardioprotective effects linked to exercise and NRG1 concentration, including anti-ischemic, anti-thrombotic, and anti-inflammatory status, were not assessed in this study. Moreover, it is important to elucidate whether a slight decrease in NRG1 concentration can have a significant clinical impact in breast cancer patients. Indeed, it is crucial to clarify whether a modification in NRG1 levels will lead to a decrease in mortality or recurrence in breast cancer patients. Similarly, further studies should determine if a decrease in NRG1 concentrations contributes to a systemic environment, unfavorable to cancer progression or recurrence. As such, we could determine the functional activity of circulating NRG-1 in blood plasma as previously reported by using a cell-based ELISA measuring phosphorylation of ErbB3 [34]. The biological relevance of NRG1 pathways for HER2-positivite breast cancer patients has been experimentally studied, yet we lack clinical evidence to support these findings. To conclude, a 12-week interval training program significantly decreases NRG1 concentration in HER2-positive breast cancer patients treated with adjuvant trastuzumab therapy. However, this change was not associated with peak V̇O 2 nor LEVF values. As cardiovascular health is a major concern in breast cancer patients during and after treatment, safe and adapted exercise training should be recommended, and its biological impact needs to be further determined. Declarations Funding The project was supported by a grant from “Conférence de Coordination Inter Régionale Est (CCIR-Est) de la Ligue contre le Cancer » (N°8FI11826PYRO). The study was approved by the French National Health Products safety agency (P/2014/241) and this trial was registered on the National Clinical Trials under the number NCT02433067. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Quentin Jacquinot and Antoine Falcoz. The first draft of the manuscript was written by Quentin Jaquinot, Gaël Ennequin, Fabienne Mougin-Mougin and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability The datasets generated during and/or analysed during the current study are not publicly available why data are not public but are available from the corresponding author on reasonable request. Ethics approval This study was conducted in compliance with the Declaration of Helsinki. It received approval from the Ethics Committee (Comité de Protection des Personnes Est-II), Besançon, France under the number P/2014/241 and from the National Health Products Safety Agency (N° ID RCB 2014-A01911-46). Consent to participate Written informed consent was obtained from the parents. Consent to publish The authors affirm that human research participants provided informed consent for publication Acknowledgements The authors are grateful to medical doctors and adapted physical activities educators of the technical rehabilitation platform of the Hospital Center "Haute-Comté" and Cardiac and Pulmonary Rehabilitation Center (Héricourt, Franois, France; Foundation "Arc-en-Ciel"). The authors gratefully acknowledge the medical doctors and nurses of the service of Physiology- Functional explorations of University Hospital (Besancon, France) for performing cardiorespiratory testing and for taking the blood samples, and Barbara Dehecq for the neuregulin dosages. The authors wish to thank all patients who participated in this study. References Siegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. 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Maturitas 183:107932. https://doi.org/10.1016/j.maturitas.2024.107932 Moondra V, Sarma S, Buxton T et al (2009) Serum Neuregulin-1β as a Biomarker of Cardiovascular Fitness. Open Biomark J 2:1–5. https://doi.org/10.2174/1875318300902010001 Hage C, Wärdell E, Linde C et al (2020) Circulating neuregulin1-β in heart failure with preserved and reduced left ventricular ejection fraction. ESC Heart Fail 7:445–455. https://doi.org/10.1002/ehf2.12615 LeBrasseur NK, Mizer KC, Parkington JD et al (2005) The expression of neuregulin and erbB receptors in human skeletal muscle: effects of progressive resistance training. Eur J Appl Physiol 94:371–375. https://doi.org/10.1007/s00421-005-1333-4 Boateng E, deKay JT, Peterson SM et al (2020) High ErbB3 activating activity in human blood is not due to circulating neuregulin-1 beta. Life Sci 251:117634. https://doi.org/10.1016/j.lfs.2020.117634 Tables Table 1 : Plasma levels of NRG1 in global population of the study (n=76) at T0, T3 and T6 T0 T3 T6 T3-T0 T6-T3 T6-T0 n Mean (SD) n Mean (SD) n Mean (SD) n Mean (IC95%) n Mean (IC95%) n Mean (IC95%) NRG1 (ng/ml) 76 1.12 (0.37) 61 1.02 (0.37) 56 1.03 (0.38) 58 -0.13 (-0.23, -0.04) 52 -0.02 (-0.10, 0.06) 52 -0.13 (-0.25, -0.01) NRG1 : Neuréguline-1 Table 2 : Plasma levels of NRG-1 in training group and control group at T0, T3 and T6 Training group (n=42) Control group (n=33) T0 T3 T6 T3-T0 T6-T3 T0 T3 T6 T3-T0 T6-T3 n Mean (SD) n Mean (SD) n Mean (SD) n Mean (95% CI) n Mean (95% CI) n Mean (SD) n Mean (SD) n Mean (SD) n Mean (95% CI) n Mean (95% CI) NRG1 ( ng/ml) 41 1.16 (0.38) 33 1.00 (0.35) 30 1.03 (0.37) 33 -0.19 (-0.31, -0.06) 27 0.00 (-0.11, 0.11) 35 1.08 (0.36) 28 1.05 (0.39) 26 1.02 (0.39) 25 -0.06 (-0.21, 0.08) 25 -0.04 (-0.17, 0.08) NRG1 : Neuréguline-1 Table 3 : Plasma levels of NRG1 according to toxicity group NoTOX group TOX group p n=65 n=10 NRG1 at T0 Median (IQR) 1.11 (0.85-1.36) 1.08 (0.82-1.64) 0.90 Missing 10 0 NRG1 at T3 Median (IQR) 0.95 (0.80-1.24) 0.96 (0.65-1.07) 0.41 Missing 14 3 Difference NRG1 T3-T0 Median (IQR) -0.16 (-0.36, 0.13) -0.15 (-0.51, 0.10) 0.94 Missing 16 3 Table 4 : Correlations matrix FEVG difference peak V̇O 2 difference Maximal power difference NRG1 difference -0.13102 0.08782 -0.15734 0.3358 0.5318 0.2653 Additional Declarations No competing interests reported. Supplementary Files SupplementaryTable1Inclusionandexclusioncriteria.docx Cite Share Download PDF Status: Published Journal Publication published 04 Feb, 2026 Read the published version in Breast Cancer Research and Treatment → Version 1 posted Editorial decision: Revision requested 03 Oct, 2025 Reviews received at journal 04 Sep, 2025 Reviewers agreed at journal 01 Sep, 2025 Reviewers invited by journal 04 Aug, 2025 Editor assigned by journal 30 Jul, 2025 Submission checks completed at journal 30 Jul, 2025 First submitted to journal 29 Jul, 2025 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. We do this by developing innovative software and high quality services for the global research community. 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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-7242299","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":495480527,"identity":"80ee9fd9-15a7-44f4-b089-512c6c487c39","order_by":0,"name":"Quentin Jacquinot","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIiWNgGAWjYFCCAyBCAoiZDxxgsGFgYG9gYPhAnBY2toQDDGkMDDwHGBhnEGcbG48BA1Fa+A4efvjhbZtFHr98z8fDFQl2DDzsBxibK/BokTxwzFhybptEsWQb74aDZxKSGXh4Ehgbz+DRYnDggBkzb5tE4oZjQC2NPw7U75dgYH/YgFfL8W9QLTwPDjYAQ4BHgoGxEb+WMzBbeBiI0yJ54Eyx5JxzEokz29IMgFpAfklsxKuF78bxjR/elNUl9jMffvyxARxihw/i1cJw4wAwKlCFGPFqYGA434ChZRSMglEwCkYBKgAAck1UClBVOYgAAAAASUVORK5CYII=","orcid":"","institution":"Institut Régional Fédératif du Cancer de Franche-Comté","correspondingAuthor":true,"prefix":"","firstName":"Quentin","middleName":"","lastName":"Jacquinot","suffix":""},{"id":495480528,"identity":"b5e53b3a-f1d8-4175-83ae-f3ecd39abb63","order_by":1,"name":"Gaël Ennequin","email":"","orcid":"","institution":"Université de Clermont Auvergne, CRNH","correspondingAuthor":false,"prefix":"","firstName":"Gaël","middleName":"","lastName":"Ennequin","suffix":""},{"id":495480529,"identity":"d52e94c3-acb2-400f-886d-f1e53b5af60a","order_by":2,"name":"Antoine Falcoz","email":"","orcid":"","institution":"Unité de méthodologie et de qualité de vie en cancérologie","correspondingAuthor":false,"prefix":"","firstName":"Antoine","middleName":"","lastName":"Falcoz","suffix":""},{"id":495480530,"identity":"02d38317-3ad2-464a-9717-6dc9fabc47f6","order_by":3,"name":"Douglas Sawyer","email":"","orcid":"","institution":"MaineHealth Institue for Research","correspondingAuthor":false,"prefix":"","firstName":"Douglas","middleName":"","lastName":"Sawyer","suffix":""},{"id":495480531,"identity":"b9cc97a1-40b8-4bc5-96ad-407da4188f53","order_by":4,"name":"Nathalie Meneveau","email":"","orcid":"","institution":"Institut Régional Fédératif du Cancer de Franche-Comté","correspondingAuthor":false,"prefix":"","firstName":"Nathalie","middleName":"","lastName":"Meneveau","suffix":""},{"id":495480532,"identity":"624246c8-fef6-42cc-a591-1f694c455856","order_by":5,"name":"Fabienne Mougin","email":"","orcid":"","institution":"Université Marie et Louis Pasteur, UFR STAPS","correspondingAuthor":false,"prefix":"","firstName":"Fabienne","middleName":"","lastName":"Mougin","suffix":""}],"badges":[],"createdAt":"2025-07-29 10:38:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7242299/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7242299/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10549-026-07903-x","type":"published","date":"2026-02-04T15:57:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":88643493,"identity":"c225bc1c-7bc9-4b19-8887-3052356634eb","added_by":"auto","created_at":"2025-08-08 16:16:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":16846,"visible":true,"origin":"","legend":"\u003cp\u003eViolin plot for plasma levels of NRG1 in TG (A) and CG (B)\u003c/p\u003e","description":"","filename":"Figure1.ViolinplotforplasmalevelsofNRG1inCGB.png","url":"https://assets-eu.researchsquare.com/files/rs-7242299/v1/86be3f3478d57dc6295a8064.png"},{"id":102233988,"identity":"a5b40f3a-e669-4cd8-9d5d-8d85bfdb0f77","added_by":"auto","created_at":"2026-02-09 16:02:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":793049,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7242299/v1/bb4e65a3-1b43-48e8-ba06-6b020ccc6b2e.pdf"},{"id":88645330,"identity":"29c200d4-06ea-42e6-9b56-579ec09b4466","added_by":"auto","created_at":"2025-08-08 16:24:01","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":25459,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1Inclusionandexclusioncriteria.docx","url":"https://assets-eu.researchsquare.com/files/rs-7242299/v1/2e26eb03f058d91f02993e28.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Exercise decreases Neuregulin-1 concentrations in HER2+ breast cancer patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBreast cancer is one of the most diagnosed cancers worldwide. Recent report indicate that breast cancer accounts for almost one-third of newly diagnosed female cancer in the United States [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Moreover, the incidence rate of female breast cancer has been slowly increasing by approximately 0.5% per year since the mid-2000s, possibly due to a decline in the fertility rates and the rise in obesity [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Among patients with breast carcinoma, the human epidermal growth factor receptor 2 (HER2-positive) subtype is found in 15\u0026ndash;20% of invasive breast cancers and is associated with a worse prognosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This subtype is characterized by overexpression of the HER2 (also known as ERBB2). Unlike other HER homologs [Epidermal Growth Factor Receptor (EGFR), HER3 and 4], HER2 does not directly bind to any known ligands. Neuregulin 1 (NRG1), encoded by the \u003cem\u003eNRG1\u003c/em\u003e gene, acts as a direct ligand for HER3 and HER4 tyrosine kinase receptors and can recruit both EGFR and HER2 co-receptors, leading to ligand-activated tyrosine phosphorylation. The NRG1/ERBB signaling pathway plays a complex role in the development and progression of breast cancer. Furthermore, circulating NRG1 has been reported to be elevated in breast cancer patients compared to healthy controls, serving as a prognostic and outcome indicator for breast cancer patients [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Consequently, targeting HER2 and the NRG1/HER pathway has been one of a leading area in breast cancer treatment development. Among available therapies, the anti-HER2 monoclonal antibody trastuzumab was the first molecularly targeted agent approved by the FDA for treating HER2-positive breast cancer. While adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], this therapy can induce cardiac dysfunction and heart failure considered as cardiotoxicity [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Indeed, the NRG1/HER pathway plays a pivotal role in the human cardiovascular physiology [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIt is now well established that regular exercise improves cardiovascular health [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Consequently, different pharmacological and non-pharmacological therapies, such as physical exercise, have been explored as preventive approaches against cardiotoxicity during breast cancer treatment [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, studies investigating the effects of exercise training program on trastuzumab-induced cardiotoxicity are scarce [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. We recently reported that a 12-week supervised exercise regimen was safe and improved the cardiopulmonary fitness in HER2-positive patients treated with adjuvant trastuzumab [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Moreover, the rate of patients free of cardiotoxicity was higher after training compared to that observed following standard care. However, the biological mechanisms involved in these findings remain to be explored. Therefore, the aim of this study was to assess the effect of a 12-week supervised exercise training on the circulating level of NRG1. A secondary objective was to evaluate the correlation between NRG1 level and cardiotoxicity.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e\u003cem\u003e1.\u0026nbsp; \u0026nbsp;Ethical approval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe CARDAPAC study was conducted in compliance with the Declaration of Helsinki. It received approval from the Ethics Committee (Comit\u0026eacute; de Protection des Personnes Est-II), Besan\u0026ccedil;on, France under the number P/2014/241 and from the National Health Products Safety Agency (N\u0026deg; ID RCB 2014-A01911-46). The trial was registered on ClinicalTrials.gov under the number NCT02433067. Financial support was provided by the \u0026ldquo;Conf\u0026eacute;rence de Coordination Inter R\u0026eacute;gionale Est\u0026nbsp;(CCIR-Est) de la Ligue contre le Cancer.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e2.\u0026nbsp; \u0026nbsp;Study design\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCARDAPAC was a phase II, randomized, prospective, multicentre, non-comparative trial conducted from April 2015 to February 2020. The original CADAPAC protocol and results regarding the primary endpoint have been published\u0026nbsp;[14, 15]. In the present paper, only data concerning neuregulin and cardiac parameters will be presented to better understand their roles and their link with cardiotoxicity.\u003c/p\u003e\n\u003cp\u003eBriefly, women were recruited based on the eligibility criteria summarized in Supplementary Table S1. All participants provided written informed consent prior to enrolment. Patients were randomly assigned to receive adjuvant trastuzumab in combination with a supervised training exercise program (training group, TG) or trastuzumab alone without the exercise program (control group, CG) in a 1:1 ratio. Randomization was performed according to the minimization technique with stratification (eRandomisation software Tenalea\u003csup\u003e\u0026reg;\u003c/sup\u003e) by age (18\u0026ndash;30 vs 30\u0026ndash;50 vs 50\u0026ndash;85 years) and global health score defined from a quality-of-life questionnaire [QLQ-C30 (0\u0026ndash;30 vs 30\u0026ndash;50 vs 50\u0026ndash;70 vs \u0026gt;70)].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3. \u0026nbsp; Study protocol\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAt enrolment (T0), human Neuregulin 1 (NGR1) and cardiac parameters were evaluated, and measurements were repeated at the end of the 3-month supervised exercise program (T3) and 3 months after the end of training (T6). Between T0 and T3, both groups followed standard oncological care with (TG) or without (CG) the supervised (3 times/week) training program. Between T3 and T6, both groups had standard oncological care without supervised physical activity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHuman NGR1 (Neuregulin 1)\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood samples were collected in the morning (8:00 to 10:00) after an overnight fast, by venous puncture. Plasma was collected using EDTA tubes. Samples were centrifuged (15 min at 3,500 rpm at 2-8\u0026deg;C). Supernatants were aliquoted and stored in cryotubes at \u0026minus;80\u0026deg;C until analysis. Samples were assayed for plasma NGR1 utilizing an indirect sandwich ELISA (NBP2-68069; R\u0026amp;D Systems). Following the manufacturer\u0026rsquo;s instructions, the absorbance of each well was assessed using a spectrophotometer at 450 nm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOther parameters\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLVEF was assessed by transthoracic Doppler echocardiography (Philips EPIQ7, Philips Healthcare, Andover, MA, USA) in the apical 4-chamber (4C) view using Simpson\u0026apos;s biplane rule, according to the American Society of Echocardiography recommendations [16, 17].\u003c/p\u003e\n\u003cp\u003eGLS was assessed in the basal, mid-ventricular and apical segments in the 4-chamber view according to the European Society of Cardiology recommendations [18].\u003c/p\u003e\n\u003cp\u003eMaximal power (Watts) and peak V̇O\u003csub\u003e2\u0026nbsp;\u003c/sub\u003e(ml.min\u003csup\u003e-1\u003c/sup\u003e.kg\u003csup\u003e-1\u003c/sup\u003e) were measured during a maximal cardiorespiratory exercise test. Testing was conducted using a cyclo-ergometer (Ergoselect 200; Ergoline; Bitz, Germany) as already described in the design protocol [15].\u003c/p\u003e\n\u003cp\u003eFurthermore, two subgroups were defined: TOX and NoTOX according to the presence or absence of cardiotoxicity. Cardiotoxicity was defined as either a decrease of the LVEF under 50% at T3 (independently of the baseline value) or an absolute drop in LVEF of at least 10% from T0 to T3.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSupervised training program\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe supervised training program, previously detailed by Jacquinot et al. (2017b) involved patients performing three 55-minute intermittent exercise sessions per week for 12 weeks, totaling 36 sessions. An exercise specialist supervised the program, which utilized an electromagnetically braked cycle ergometer based on the Square-Wave Endurance Exercise Test [20] to help motivate participants.\u003c/p\u003e\n\u003cp\u003eDuring each session, heart rate (HR) was continuously displayed with a finger pulse oximeter (Onyx\u003csup\u003e\u0026reg;\u0026nbsp;\u003c/sup\u003eVantage 9590, Nonin Medical, Inc., USA) at the end of each \u0026ldquo;base\u0026rdquo; and \u0026ldquo;pic\u0026rdquo; interval. Thus, the total physical work gradually and safely increased throughout the program to an optimal stimulation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQualitative variables were described as number and percentage, and quantitative variables as mean with standard deviation (SD) or median with interquartile range (IQR). Echocardiography variables and cardiorespiratory parameters at maximal exercise were described as mean \u0026plusmn; standard deviation (SD) at T0, T3 and T6. Subgroup analyses of echocardiography variables and cardiorespiratory parameters at maximal exercise according to age were described using median with IQR. Violin plots were used to obtain a longitudinal representation of data during follow-up.\u0026nbsp;Differences over time were described as the difference in means, with 95% confidence interval (CI).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSpearman\u0026rsquo;s correlation coefficient was used to assess the association between changes in LVEF, peak V̇O\u003csub\u003e2\u003c/sub\u003e, maximal power and NGR1.\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA) and R software version 4.0.3 (R Development Core Team, Vienna, Austria; http://www.r-project.org). p-values \u0026lt;0.05 were considered statistically significant and were given for exploratory purposes. All tests were two-sided.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePopulation\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBetween April 2015 and February 2020, 205 patients were screened and 89 were randomized: 46 patients (51.7%) were assigned to the TG and 43 patients (48.3%) to the CG.\u0026nbsp;The baseline clinical characteristics of all participants and the primary endpoint have been published in a previous article\u0026nbsp;[14].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eNGR1\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSeventy-six patients (85.4%) have a measurable NRG1 concentration at baseline (T0). The plasma levels of NGR1 decreased between T0 and T3 and remained stable between T3 and T6 in the global population (Table 1). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe evolution of plasma levels of NGR1 between the two groups over time is presented in Table 2. At T3, plasma NGR1 levels significantly decreased in the TG (mean difference -0.19 ng/ml ; 95% CI, -0.31, -0.06) whereas they were not modified in the CG (mean difference -0.06 ng/ml ; 95% CI, -0.21, 0.08 ; Table 2). At T6, plasma NGR1 levels in both groups were unchanged compared to values measured at T3 (TG: mean difference 0.00 ng/ml ; 95% CI, -0.11, 0.11; CG : mean difference -0.04 ng/ml ; 95% CI, -0.17, 0.08 ; Table 2).\u003c/p\u003e\n\u003cp\u003eViolin plots illustrate the changes in NGR1 between T0, T3, and T6, revealing heterogeneous individual trajectories in both groups (Figure 1). When considering only TG patients who presented cardiotoxicity at T3 (defined as LVEF \u0026lt; 50% at T3 or an absolute drop in LVEF of at least 10%; shown in red in Figure 1), NGR1 decreased in all three patients (Figure 1A). In the CG, NGR-1 decreased in two patients and increased in two patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOther outcomes\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNGR1 levels were similar between the NoTOX and TOX group at T0 and T3 (Table 3). Levels of NGR1 were not correlated with peak V̇O\u003csub\u003e2\u003c/sub\u003e (R = 0.087, p = 0.53); maximal power (R =-0.157, p = 0.26) and LVEF changes (R =-0.131, p = 0.33 ; Table 4).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur major findings indicate that exercise training significantly reduces circulating NRG1 levels in HER2-positive breast cancer patients undergoing adjuvant trastuzumab therapy. However, modifications in NRG1 levels were not associated with changes in cardiotoxicity or physical fitness.\u003c/p\u003e\n\u003cp\u003eThe NRG1/ERRB pathways have been extensively studied for their role in the development and progression of breast cancer [21]. However, the role of NRG1 as a biomarker in breast cancer has been poorly investigated, and the available literature regarding NRG1 concentrations in humans is conflicting [22]. De luliis and collaborators reported a mean NRG1 concentration of 1.95 ng/mL in breast cancer patients [4]. Interestingly, NRG1 levels were significantly higher in HER2-negative patients compared to those HER2-positive. The mean value of NRG1 levels in HER2-positive patients was 0.98\u0026nbsp;\u0026plusmn; 0.71 ng/mL which aligns with our present results. Conversely, Geisberg and colleagues reported higher NRG1 concentrations (9.0\u0026nbsp;\u0026plusmn; 11.4 ng/mL) in a cohort of breast cancer patients\u0026nbsp;[23]. It should be noted that HER2-positive patients represented only 37% of the subjects included and had a higher BMI. This difference might explain the lower NRG1 concentrations observed in our participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSystemic levels of NRG1 has been proposed as biomarkers in various diseases, including cardiovascular disease [24], neurodegenerative disease [25] and cancer [4, 26]. Regarding breast cancer, Geisberg and colleagues investigated whether NRG1 could serve as a biomarker to identify breast cancer patients at risk for impaired cardiovascular function [23]. Their results showed that higher baseline NRG1 levels were observed in those with the greatest decline in LVEF. Furthermore,, De luliis and collaborators demonstrated a significant association between plasmatic NRG1 and prediction of 1-year \u0026nbsp;mortality in breast cancer patients before treatment with anthracyclines and taxanes, with or without trastuzumab [4]. Altogether, further studies are warranted to determine whether NRG1 can be used as a biomarker to characterize breast cancer patient at risk for treatment-induced cardiovascular dysfunction or death.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBreast cancer patient undergoing treatment can experience numerous and varied side effects, such as fatigue, body composition changes or a reduction in cardiorespiratory fitness [27, 28]. Consequently, many non-pharmacological strategies have been tested to limit these side effects and improve quality of life. There is currently a large body of evidence supporting that the benefit of regular physical exercise for breast cancer patients undergoing treatment [29]. Yet, the effect of regular exercise in patients at risk for cardiotoxicity is less investigated. We previously reported that a supervised exercise program improved cardiopulmonary fitness, particular\u003cins cite=\"mailto:Gael%20ENNEQUIN\" datetime=\"2025-07-23T15:03\"\u003el\u003c/ins\u003ey peak V̇O\u003csub\u003e2\u003c/sub\u003e, in HER2-positive patients treated with adjuvant trastuzumab therapy, with a modest effect on cardiotoxicity [14]. \u0026nbsp;Recently, Fernandez-Casas and collaborators assessed the cardioprotective effects of exercise training in women with breast cancer, both during and after treatments. While exercise training (aerobic alone or a combination of resistance and aerobic exercise) improves peak V̇O\u003csub\u003e2\u0026nbsp;\u003c/sub\u003ein breast cancer patients, this type of intervention was not effective in improving cardiovascular function [30]. Similarly, Amin and colleagues reached the same conclusion regarding improvement in peak V̇O\u003csub\u003e2\u0026nbsp;\u003c/sub\u003ebut not cardiotoxicity in response to exercise training [12]. It should be noted that the significant heterogeneity in the field regarding breast cancer treatments, exercise program, primary cardiac outcomes or sample size warrants further studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInterestingly, we observed here that exercise significantly decreases circulating NRG1 levels in HER2-positive breast cancer patients which persist during the follow up. Unfortunately, this change was not associated with cardiovascular function or cardiorespiratory fitness. The literature reports that circulating NRG1 is associated with peak V̇O\u003csub\u003e2\u003c/sub\u003e values in healthy volunteers [31]. This discrepancy might be explained by the large range in circulating concentration between subjects (32 ng.mL\u003csup\u003e-1\u003c/sup\u003e to 473 ng.mL\u003csup\u003e-1\u003c/sup\u003e) and the use of an in-house ELISA assay. In line with our results, Geisberg and colleagues did not report a significant\u0026nbsp;association with baseline plasma NRG1 and self-reported physical fitness in breast cancer patients\u0026nbsp;[23]. Importantly, those authors reported a small but statistically significant correlation between baseline circulating levels of NRG1 and maximal change in cardiac function. Moreover, it has been reported that NRG1 circulating levels were associated with 1-year mortality\u0026nbsp;[4]. In others diseases such as heart failure, higher levels of NRG1 were associated with worse outcomes\u0026nbsp;[32]\u0026nbsp;Thus, a decrease in circulating NRG1 levels might represent a favorable outcome in patients with breast cancer. It is now important to determine whether exercise is one of the drivers leading to a decrease in circulating levels of NRG1. Our results show that NRG1 concentrations significantly decrease after the training program but not during the follow-up, suggesting that exercise can explain this adaptation. To date, no clinical study has investigated the effect of chronic exercise on systemic NRG1 levels in cancer patients. Only one study \u0026nbsp;has investigated the impact of resistance training on NRG1 pathway in skeletal muscle of healthy volunteers\u0026nbsp;[33]. Result showed no change in NRG1 expression in skeletal muscle in response to exercise. Yet, we cannot rule out the possibility that exercise training can impact other organs that highly express NRG1 protein and contribute to the circulating level.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study has some limitations that need to be highlighted and suggests avenues for further studies. First, as previously reported [14], the target number of subjects to meet the primary endpoint was not reached, and the overall population was likely too small to a significant association between NRG1 concentration and LEVF. Furthermore, other cardioprotective effects linked to exercise and NRG1 concentration, including anti-ischemic, anti-thrombotic, and anti-inflammatory status, were not assessed in this study. Moreover, it is important to elucidate whether a slight decrease in NRG1 concentration can have a significant clinical impact in breast cancer patients. Indeed, it is crucial to clarify whether a modification in NRG1 levels will lead to a decrease in mortality or recurrence in breast cancer patients. Similarly, further studies should determine if a decrease in NRG1 concentrations contributes to a systemic environment, unfavorable to cancer progression or recurrence. As such, we could determine the functional activity of circulating NRG-1 in blood plasma as previously reported by using a cell-based ELISA measuring phosphorylation of ErbB3 [34]. The biological relevance of NRG1 pathways for HER2-positivite breast cancer patients has been experimentally studied, yet we lack clinical evidence to support these findings.\u003c/p\u003e\n\u003cp\u003eTo conclude, a 12-week interval training program significantly decreases NRG1 concentration in HER2-positive breast cancer patients treated with adjuvant trastuzumab therapy. However, this change was not associated with peak V̇O\u003csub\u003e2\u0026nbsp;\u003c/sub\u003enor LEVF values. As cardiovascular health is a major concern in breast cancer patients during and after treatment, safe and adapted exercise training should be recommended, and its biological impact needs to be further determined.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe project was supported by a grant from \u0026ldquo;Conf\u0026eacute;rence de Coordination Inter R\u0026eacute;gionale Est\u0026nbsp;(CCIR-Est) de la Ligue contre le Cancer \u0026raquo; (N\u0026deg;8FI11826PYRO).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was approved by the French National Health Products safety agency (P/2014/241) and this trial was registered on the National Clinical Trials under the number NCT02433067.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Quentin Jacquinot and Antoine Falcoz. The first draft of the manuscript was written by Quentin Jaquinot, Ga\u0026euml;l Ennequin, Fabienne Mougin-Mougin and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are not publicly available why data are not public but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in compliance with the Declaration of Helsinki. It received approval from the Ethics Committee (Comit\u0026eacute; de Protection des Personnes Est-II), Besan\u0026ccedil;on, France under the number P/2014/241 and from the National Health Products Safety Agency (N\u0026deg; ID RCB 2014-A01911-46).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the parents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors affirm that human research participants provided informed consent for publication\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to medical doctors and adapted physical activities educators of the technical rehabilitation platform of the Hospital Center \u0026quot;Haute-Comt\u0026eacute;\u0026quot; and Cardiac and Pulmonary Rehabilitation Center (H\u0026eacute;ricourt, Franois, France; Foundation \u0026quot;Arc-en-Ciel\u0026quot;). The authors gratefully acknowledge the medical doctors and nurses of the service of Physiology- Functional explorations of University Hospital (Besancon, France) for performing cardiorespiratory testing and for taking the blood samples, and Barbara Dehecq for the neuregulin dosages. The authors wish to thank all patients who participated in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel RL, Miller KD, Wagle NS, Jemal A (2023) Cancer statistics, 2023. 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Eur J Appl Physiol 94:371\u0026ndash;375. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00421-005-1333-4\u003c/span\u003e\u003cspan address=\"10.1007/s00421-005-1333-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBoateng E, deKay JT, Peterson SM et al (2020) High ErbB3 activating activity in human blood is not due to circulating neuregulin-1 beta. Life Sci 251:117634. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.lfs.2020.117634\u003c/span\u003e\u003cspan address=\"10.1016/j.lfs.2020.117634\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"982\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"15\" style=\"width: 982px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 1 : Plasma levels of NRG1 in global population of the study (n=76) at T0, T3 and T6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 166px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 125px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 105px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 150px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3-T0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT6-T3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT6-T0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 32px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eMean (IC95%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003eMean (IC95%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003eMean (IC95%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNRG1\u0026nbsp;\u003c/strong\u003e(ng/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1.12 (0.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 32px;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e1.02 (0.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e1.03 (0.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e-0.13 (-0.23, -0.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e-0.02 (-0.10, 0.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e-0.13 (-0.25, -0.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 166px;\"\u003e\n \u003cp\u003e\u003cem\u003eNRG1 : Neur\u0026eacute;guline-1 \u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 43px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 166px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 33px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 78px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 30px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 75px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 32px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 43px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 118px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 43px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 137px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1063\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"25\" valign=\"top\" style=\"width: 1054px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 2\u0026nbsp;: Plasma levels of NRG-1 in training group and control group at T0, T3 and T6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 143px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 362px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTraining group\u0026nbsp;\u003c/strong\u003e(n=42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"14\" style=\"width: 496px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl group\u0026nbsp;\u003c/strong\u003e(n=33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 84px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 96px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3-T0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT6-T3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 64px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT6\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 106px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT3-T0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 118px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eT6-T3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 62px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003eMean\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003eMean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 24px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 90px;\"\u003e\n \u003cp\u003eMean\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 91px;\"\u003e\n \u003cp\u003eMean\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(95% CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNRG1\u0026nbsp;\u003c/strong\u003e \u003cem\u003e(\u003c/em\u003e\u003cem\u003eng/ml)\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e1.16 (0.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003e1.00 (0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\n \u003cp\u003e1.03 (0.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31px;\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\n \u003cp\u003e-0.19 (-0.31, -0.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\n \u003cp\u003e0.00 (-0.11, 0.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 60px;\"\u003e\n \u003cp\u003e1.08 (0.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\n \u003cp\u003e1.05 (0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\n \u003cp\u003e1.02 (0.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 24px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 90px;\"\u003e\n \u003cp\u003e-0.06 (-0.21, 0.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 91px;\"\u003e\n \u003cp\u003e-0.04 (-0.17, 0.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"26\" style=\"width: 1063px;\"\u003e\n \u003cp\u003e\u003cem\u003eNRG1 : Neur\u0026eacute;guline-1 \u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 23px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 24px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 39px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 36px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 60px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 31px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 92px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 34px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 89px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 3px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 64px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 28px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 57px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 16px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 90px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 1px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 27px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 82px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 9px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"630\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 630px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 3\u0026nbsp;: Plasma levels of NRG1 according to toxicity group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNoTOX group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTOX group\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 68px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003en=65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003en=10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNRG1 at T0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e1.11 (0.85-1.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e1.08 (0.82-1.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.90\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Missing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNRG1 at T3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e0.95 (0.80-1.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e0.96 (0.65-1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Missing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDifference NRG1 T3-T0\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e-0.16 (-0.36, 0.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e-0.15 (-0.51, 0.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Missing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 180px;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 161px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"4\" style=\"width: 425px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTable 4\u0026nbsp;: Correlations matrix\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFEVG\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e\u003cstrong\u003epeak V̇O\u003csub\u003e2\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003edifference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMaximal power difference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNRG1 difference\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e-0.13102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e0.08782\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e-0.15734\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 104px;\"\u003e\n \u003cp\u003e0.3358\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 109px;\"\u003e\n \u003cp\u003e0.5318\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 108px;\"\u003e\n \u003cp\u003e0.2653\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"breast cancer, HER2 overexpression, cardiotoxicity, supervised exercise program, prevention, supportive care","lastPublishedDoi":"10.21203/rs.3.rs-7242299/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7242299/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eTrastuzumab used for the treatment of patients with HER2-positive breast cancer can induce cardiotoxicity. While the Nueregulin-1(NRG1)/HER pathway plays a central role in human cardiovascular physiology, the link between exercise, NRG1 and cardiotoxicity remains unclear The study aimed to assess the effect of a 12-week supervised exercise training on circulating NRG1 levels. A secondary objective was to assess the correlation between NRG1 level and cardiotoxicity.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003ePatients were randomized to receive either adjuvant trastuzumab in combination with a training 12-week supervised exercise program in a training group (training group, TG) or trastuzumab alone (control group, CG). Cardiorespiratory fitness test left ventricular ejection fraction and circulating level of NRG1 were assessed before, after and 3 months after training.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eEighty-nine patients were randomized (TG; n\u0026thinsp;=\u0026thinsp;46 ; CG; n\u0026thinsp;=\u0026thinsp;43) with 76 having a baseline NRG1 concentration available. After the exercise program, plasma levels of NRG1 significantly decreased in the TG (mean difference \u0026minus;\u0026thinsp;0.20 ng/ml ; 95% CI, -0.32, -0.07) whereas they remained stable in the CG (mean difference \u0026minus;\u0026thinsp;0.05 ng/ml; 95% CI, -0.20, 0.10). NRG1 remain stable during follow up. However, no correlation was observed between NRG1 changes and either cardiorespiratory fitness (peak V̇O\u003csub\u003e2\u003c/sub\u003e) and Left Ventricular Ejection Fraction (LVEF) (R\u0026thinsp;=\u0026thinsp;0.087, p\u0026thinsp;=\u0026thinsp;0.53; R =-0.157, p\u0026thinsp;=\u0026thinsp;0.26 and R =-0.131, p\u0026thinsp;=\u0026thinsp;0.33 respectively).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eA 12-week interval training program significantly decreased NRG1 concentration in HER2-positive breast cancer patients treated with adjuvant trastuzumab therapy. This change was not associated with peak V̇O\u003csub\u003e2\u003c/sub\u003e nor LVEF.\u003c/p\u003e\u003ch2\u003eTrial registration:\u003c/h2\u003e\u003cp\u003eThis trial was registered with ClinicalTrials.gov under the number NCT02433067.\u003c/p\u003e","manuscriptTitle":"Exercise decreases Neuregulin-1 concentrations in HER2+ breast cancer patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-08 16:15:56","doi":"10.21203/rs.3.rs-7242299/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-03T18:44:45+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-04T12:24:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"334340961247362834724947936267390078282","date":"2025-09-01T08:00:34+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-04T14:04:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-30T04:21:28+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-30T04:21:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer Research and Treatment","date":"2025-07-29T10:32:51+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer-research-and-treatment","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brea","sideBox":"Learn more about [Breast Cancer Research and Treatment](https://www.springer.com/journal/10549)","snPcode":"10549","submissionUrl":"https://submission.nature.com/new-submission/10549/3","title":"Breast Cancer Research and Treatment","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"aa3ceb3b-260e-43ac-b90c-8026dc503177","owner":[],"postedDate":"August 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:00:41+00:00","versionOfRecord":{"articleIdentity":"rs-7242299","link":"https://doi.org/10.1007/s10549-026-07903-x","journal":{"identity":"breast-cancer-research-and-treatment","isVorOnly":false,"title":"Breast Cancer Research and Treatment"},"publishedOn":"2026-02-04 15:57:29","publishedOnDateReadable":"February 4th, 2026"},"versionCreatedAt":"2025-08-08 16:15:56","video":"","vorDoi":"10.1007/s10549-026-07903-x","vorDoiUrl":"https://doi.org/10.1007/s10549-026-07903-x","workflowStages":[]},"version":"v1","identity":"rs-7242299","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7242299","identity":"rs-7242299","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}