Internal mammary node failure in invasive breast-cancer patients who received post-operative radiotherapy without prophylactic internal mammary node irradiation

Internal mammary node failure in invasive breast-cancer patients who received post-operative radiotherapy without prophylactic internal mammary node irradiation | 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 Internal mammary node failure in invasive breast-cancer patients who received post-operative radiotherapy without prophylactic internal mammary node irradiation Yasushi Hamamoto, Kenji Makita, Kei Nagasaki, Hiromitsu Kanzaki, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6509075/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jul, 2025 Read the published version in Breast Cancer → Version 1 posted 5 You are reading this latest preprint version Abstract Background Breast-cancer (BC) patients who would benefit most from prophylactic internal mammary node (IMN) irradiation have not been clearly identified. Risk factors for ipsilateral IMN failure in BC patients who received post-operative radiotherapy (PORT) without prophylactic IMN irradiation were investigated. Methods Between January 2012 and March 2013, unilateral invasive BC patients who had no clinically positive IMN and received PORT without prophylactic IMN irradiation after breast-conserving surgery or mastectomy were retrospectively reviewed. At that time, prophylactic IMN irradiation was not recommended for clinically negative IMN by Japanese BC guidelines. For identification of risk factors of IMN failure, the following factors were assessed using univariate and multivariate analyses: primary tumor location, hormone receptor status, human epidermal growth factor receptor 2 (HER2), axillary node status, and administration of neoadjuvant chemotherapy (NAC). Results A total of 194 BC patients (median age, 53 years; pStage I, 97; pStage II, 59; pStage III, 21; received NAC, 37) were analyzed. Median follow-up time with CT and/or FDG-PET/CT was 110 months (range, 4-132 months). IMN failure-free rates were 99% at 5-year s and 98% at 10-year s . The 10-year overall survival rate was 93%. In multivariate analysis, hormone receptor negativity was the only significant unfavorable factor for IMN failure (Hazard ratio 20.389, [95% CI 1.601-259.610], p=0.0202). Conclusions Hormone receptor status may have a greater impact on IMN failure compared to the primary tumor location and axillary lymph-node status in the modern systemic therapy era. Because our study was a small retrospective study, further large-scale studies are needed. Breast cancer Internal mammary node Post-operative radiotherapy Prophylactic irradiation Figures Figure 1 Figure 2 Introduction Internal mammary node (IMN) metastases are not rare in patients with medial/central invasive breast cancer (BC) [1]. However, IMN failure after appropriate treatment is uncommon. IMN failure was observed in 2% or less of stage I-III BC after primary treatment, even when the IMN was not treated with surgery or radiotherapy [2-5]. Benefits of prophylactic IMN irradiation for patients with high-risk BC were assessed by two large randomized control studies conducted in France (French IMN study) and Korea (KROG 08-06) [6,7]. Both studies could not demonstrate survival benefit of prophylactic IMN irradiation. In addition, in EORTC 22922/10925 trial (including patients with positive axillary nodes [AxLNs] or medial/central BC) [8] and NCIC Clinical Trials Group MA.20 trial (including patients with node-positive BC or high-risk node-negative BC) [9], prophylactic irradiation to the regional nodes including the IMN region did not improve overall survival (OS). On the other hand, DBCG-IMN study, which was a prospective population-based cohort study conducted in Denmark, demonstrated that IMN irradiation improved OS with statistical significance in patients who had node-positive early BC [10]. Meta-analysis conducted by Japanese Breast Cancer Society (JBCS) guidelines also demonstrated survival benefit of prophylactic IMN irradiation [11]. Considering these results, JBCS guidelines published in 2022 weakly recommend prophylactic IMN irradiation for BC patients who need post-operative radiation therapy (PORT) to regional lympn-nodes. However, BC patients who would benefit most from prophylactic IMN irradiation in the era of modern systemic therapy have not been clearly identified. In this study, we investigated the risk factors for ipsilateral IMN failure when IMN irradiation was omitted in PORT. Material and methods Clinical records of female patients who had unilateral invasive BC (pStage I-III and ypStage 0-III) and received PORT in our institution between January 2012 and March 2013 were retrospectively reviewed. Prophylactic IMN irradiation was not performed in PORT for clinically negative IMN in this period because JBCS guidelines published in 2011 and 2013 did not recommend the prophylactic IMN irradiation for the patients without clinically positive IMN. In this study, patients who had clinically positive IMN before treatment were excluded from the analysis of risk factors for IMN failure, and the estimation of IMN-failure free survival rates and OS. Patients who received neoadjuvant chemotherapy (NAC) were included. Breast gadolinium-enhanced magnetic resonance imaging (Gd-MRI) and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) were performed routinely for staging before treatment. IMN failure and distant failure were diagnosed by follow-up CT and/or FDG-PET/CT. Post-operative Radiotherapy For patients who received breast conserving surgery, 50 Gy in 25 fractions were delivered to the whole breast. When a patient had four or more positive AxLNs, 50 Gy in 25 fractions were also delivered to the supraclavicular region at the discretion of radiation oncologists. For the patients who received mastectomy, post-mastectomy radiotherapy with 50 Gy in 25 fractions was delivered to the chest-wall and the supraclavicular region in principle when they had four or more clinically/pathologically positive AxLNs and/or had a T3-4 primary tumor. For the patients with positive or close surgical margins, boost irradiation of 10 Gy in five fractions was added to the tumor bed. For patients who had received NAC, PORT was performed with considering disease status before NAC. Adjuvant/neoadjuvant systemic therapy Appropriate standard systemic therapy was administered if deemed necessary. NAC was administered when breast surgeons deemed it necessary or beneficial considering the results of pretreatment examinations. In adjuvant systemic therapy, hormone therapy was performed on patients with positive hormone-receptor, and chemotherapy was performed on high-risk patients. Trastuzumab was administrated to patients with HER2 over-expression. Statistical analysis IMN-failure free survival rates and OS were estimated by the Kaplan-Meier method. The survival time and failure time were calculated from the start of PORT. In the analysis of risk factors for IMN failure, following factors were evaluated; primary tumor location, hormone receptor status, HER2 status, AxLN status (existence of high-risk AxLNs), and NAC administration. In this study, the high risk AxLN were defined as four or more positive AxLNs and/or AxLNs with remnant cancer cells after NAC. Although histological grades, nuclear grades, Ki67, and lympho-vascular invasion were important factors, detail information of these factors was not available in a significant proportion of patients. Therefore, these factors could not be evaluated in this study. Statistical differences of IMN-failure free survival rates and OS according to each risk factor were evaluated by the log-rank test. For multivariate analysis, Cox’s proportional hazard model was used. Statistical analysis was performed using StatView 5.0 software (SAS Institute Inc, NC). Ethical statement This study was conducted in compliance with ethical guidelines for medical research in Japan and the Declaration of Helsinki. As a retrospective observational study, patient consent was obtained through an opt-out approach. This study was approved by the institutional ethics committee (approval. no. 2021-71). Results Consecutive 220 patients received PORT for invasive BC in our institution between January 2012 and March 2013. Six patients who had concurrent bilateral invasive BC and 11 patients who were lost to follow-up immediately after completion of PORT were excluded from this study. Among remaining 203 patients, nine patients had clinically positive IMN before treatment. For the analysis of risk factors for IMN failure, these nine patients were excluded, and clinical data of the remaining 194 patients was used (Fig. 1). Regarding these 194 patients, median age was 53 years, and number of pStage I, II, and III were 97, 59, and 21, respectively. Thirty-seven patients received NAC. Table 1 shows patient characteristics. Median follow-up time for survival was 119 months (range 4-135 months). Median follow-up time for IMN failure (followed up by CT and/or FDG-PET/CT) was 110 months (range 4-132 months). The 5-year and 10-year OS rates were 96% and 93% respectively, and the 5-year and 10-year locoregional failure free rates were 98% and 95% respectively. (1) Ipsilateral IMN failure IMN failure free rates were 99% at 5-year s and 98% at 10-year s (Fig. 2). Among 94 patients who had medial/central BC, two patients (2.1%) experienced IMN failure. In 38 patients who received NAC, pretreatment pathological AxLN status could not be evaluated. Pretreatment pathological AxLN status could be evaluated in the remaining 166 patients. Among these 166 patients, two patients experienced IMN failure. Both patients had no pathologically positive AxLNs before treatment. Among 23 patients who had four or more pathologically positive AxLNs before treatment (including 11 patients with medial/central BC), no patient experienced IMN failure. (2) Risk factors for ipsilateral IMN failure Results of univariate and multivariate analysis were shown in Table 2. In univariate analysis, negativity of hormone receptor was the only statistically significant unfavorable factors for IMN failure (p=0.0012). In multivariate analysis, negativity of hormone receptor was the only significant unfavorable factor for IMN failure (HR 20.389 [95% CI; 1.601-259.610], p=0.0202). (3) Characteristics of the patients who had clinically positive IMN before treatment Nine patients had clinically positive IMNs diagnosed by pretreatment FDG-PET/CT before treatment. These nine patients also underwent gadolinium enhancement MRI (Gd-MRI) (± CT) before treatment. Pretreatment Gd-MRI (± CT) were able to diagnose IMN abnormalities in two of nine (22%) patients. In addition, majority of these nine patients had medial/central BC and/or pathologically positive AxLNs. Seven of nine patients (78%) had medial/central BC. After exclusion of two patients who received NAC and achieved ypN0 status, all seven patients had pathologically positive AxLNs. Discussion In this study, BC patients who received PORT between January 2012 and March 2013 were reviewed. At that time, taxane and anti-HER2 drugs had already been introduced, and the JBCS guidelines do not recommend prophylactic IMN irradiation for patients without clinically positive IMN. In our study, the 10-year IMN failure rate was 2%. Based on our study including not only node-positive BC and medial/central BC but also node-negative BC and lateral BC, hormone receptor negativity was the only significant independent factor for IMN failure among the assessed factors. Medial/central location of the primary tumor and AxLN status appeared to have a smaller impact on IMN failure than previously believed. On the other hand, majority of patients who had clinically positive IMNs before treatment had medial/central BC and/or positive AxLNs. Until now, two large randomized control studies were conducted in France (French IMN study) and Korea (KROG 08-06) to evaluate benefits of prophylactic IMN irradiation for patients with high-risk BC [6,7]. The French IMN study enrolled patients who had stage I-II BC with positive AxLN or a medial/central BC, and underwent a modified radical mastectomy with or without systemic therapy in 1991-1997. No statistically significant differences in OS rates were observed between the IMN-irradiated group and the non-IMN-irradiated group (62.6% vs. 59.3% at 10-years; p=0.8). The KROG 08-06 study enrolled BC patients who had positive AxLNs and underwent a modified radical mastectomy or breast-conserving surgery in 2008-2020. In this study, IMN irradiation did not improve disease-free survival at 7-years (85.3% vs. 81.9%; p=0.22) and OS at 7-years (89.4% vs. 88.2%, p=0.50). On the other hand, DBCG-IMN (a prospective population-based cohort study) including node-positive early BC patients treated between 2003 and 2007, demonstrated that patients who received IMN irradiation had a significantly higher 15-year OS rate than patients who did not receive IMN irradiation. (60.1% vs. 55.4%, P=0.007) [10]. One of the possible explanations for these inconsistent results in the previous studies is that IMN failure is relatively rare even when IMN irradiation is not performed. Because of the low incidence of IMN failure, the benefit of prophylactic IMN irradiation could not be detected in the single randomized control study. Although the incidence of IMN metastases is not rare especially in medial/central BC, the incidence of the IMN failure was rare [2-5]. Previous surgical series reported that 30% of BC patients had IMN metastasis, with a higher risk in patients with medial BC [1]. There are large discrepancy between the incidence of IMN metastases and the incidence of IMN failure after appropreate treatment without direct therapy (surgery or radiotherapy) to IMN. Although prophylactic IMN irradiation may be useful for properly selected BC patients, all BC patients do not need it. It has been believed that patients who had medial/central BC with AxLNs and BC with four or more positive AxLNs are the best candidates for prophylactic IMN irradiation due to the relatively high incidence of IMN metastases [11,12]. Indeed, an ad hoc subgroup analysis of KROG 08-06 limited to patients with medial/central BC showed significantly better disease-free survival rates and lower BC mortality rates in the IMN-irradiation group. However, contrary to expectations, location of the primary tumor (medial/central vs. lateral) and AxLN status did not appear to be significant factors for IMN failure in our study. Hormone receptor negativity appeared to have larger impact on IMN failure compared to location of BC and AxLN status in our study. There may be a possibility that the features of BC that are prone to IMN metastases and BC that are prone to IMN failure after appropriate treatment may differ considerably. BC that are prone to IMN metastasis are medial/central BC with or without positive AxLNs, whereas BC prone to IMN failure after appropriate systemic therapy and PORT without IMN irradiation may have refractory features to the standard systemic therapy. Because majority of our patients with clinically positive IMNs had medial/central BC and pathologically positive AxLNs, IMN metastases also appeared to be associated with medial/central BC and AxLN metastases in our patients. Another problem with studies of prophylactic IMN irradiation is the inaccuracy of diagnosing IMN metastasis before treatment. All our patients underwent FDG-PET/CT and Gd-MRI (± CT) before treatment, and IMN abnormalities were detected with FDG-PET/CT in nine patients. Of note, only FDG-PET/CT was able to detect IMN abnormalities in 78% (7/9) of these 9 patients. According to the previous studies, IMNs (including both normal and abnormal IMNs) could be observed in 42% of BC patients on CT and 54% of high risk BC patients on MRI. In addition, the size criteria for the diagnosis of abnormal IMNs has not been established [13]. It has been reported that FDG-PET/CT is more sensitive for IMN adenopathy compared to CT [13]. If FDG-PET/CT is not performed, some of clinically positive IMNs may be missed. In previous studies of prophylactic IMN irradiation, pretreatment FDG-PET/CT was often not routinely performed. Therefore, there is possibility that some clinically positive IMNs have been missed. Control of clinically positive IMN is likely to be more difficult for systemic therapy compared to the subclinical IMN metastases. When pretreatment FDG-PET/CT was not routinely performed, IMN failure is likely to be more frequent in patients with medial/central BC and/or multiple AxLN, in whom clinical IMN metastases occur more frequently. As a result, the benefit of prophylactic IMN irradiation may have been overestimated in patients who had medial/central BC and/or BC with multiple positive AxLNs. Hormone receptor negativity was the only statistically significant independent factor for IMN failure in our study. In the subgroup analysis of the KROG 08-06, prophylactic IMN irradiation tended to improve disease-free survival more after modified radical mastectomy in hormone receptor-negative BC compared with hormone receptor-positive BC [7]. In the subgroup analyses of MA.20, the effects of regional lymph-node (including IMN, supraclavicular lymph nodes, and AxLN) irradiation were larger for hormone receptor-negative (ER-negative or PR-negative) BC than for hormone receptor–positive BC [9]. Our results consistent with the results of the KROG 08-06 and the MA.20. Further studies are needed for confirmation of the significance of hormone receptor status. Pathological stage did not appear to have large impact on incidence of IMN failure from our results. Among the patients who did not receive NAC, the 10-year IMN failure free rates were 99%, 98%, and 100% for pStage I, II, and III, respectively. Differences in risk of IMN metastasis between stages may be reduced by appropriate adjuvant systemic therapy. In recent years, genomic analysis has been used for prediction of response to chemotherapy and patient prognosis. Personalized treatment based on risk assessment using genomic analysis is also being researched in BC. [14,15]. Genomic assay has potential to provide more accurate risk assessment for IMN metastases and IMN failure when it used in combination with classical clinical, pathological, and biologic features of BC. Further studies are needed to evaluate usefulness of genomic assay for risk assessment of IMN failure. There are some limitations of our study. Our study was a small retrospective study. Therefore, there may be some statistical uncertainty in the evaluation of risk factors for IMN failure. In addition, because this was a retrospective study, the available data for assessment of risk factors was limited. Some factors that should have been analyzed as potential risk factors such as lympho-vascular invasion, Ki-67, and histologic/nuclear grades could not be evaluated in this study. Further studies are needed to identify optimal candidates for prophylactic IMN irradiation. Conclusion Based on our study, hormone receptor negativity may have a greater impact on IMN failure compared with the location of the primary tumor and AxLN status in breast cancer patients who underwent PORT without prophylactic IMN irradiation after receiving appropriate systemic therapy as needed. Declarations Acknowledgements None. Author contributions Conceptualization: Yasushi Hamamoto; Methodology: Yasushi Hamamoto; Formal analysis and investigation: Yasushi Hamamoto; Writing—original draft preparation: Yasushi Hamamoto; Writing—review and editing: Yasushi Hamamoto, Kenji Makita, Hiromitsu Kanzaki, Kei Nagasaki, Mariko Kouchi, Midhiko Yamashita, Mina Takahashi, Daisuke Takabatake, Kenjiro Aogi Funding None. Data availability The dataset generated and analyzed during the current study are available from the corresponding author on reasonable request. The authors have no Conflict of interest. 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J Clin Oncol. 2023;41:1533-1540. https://doi.org/10.1200/JCO.22.00655 Tables Tables 1 and 2 are available in the Supplementary Files section Supplementary Files Table1.docx Table2.docx Cite Share Download PDF Status: Published Journal Publication published 30 Jul, 2025 Read the published version in Breast Cancer → Version 1 posted Editorial decision: Minor Revision 21 May, 2025 Reviewers agreed at journal 29 Apr, 2025 Reviewers invited by journal 29 Apr, 2025 Editor assigned by journal 24 Apr, 2025 First submitted to journal 22 Apr, 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-6509075","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":449617743,"identity":"e38ff2af-5c60-4c24-b5b8-55ecfdf8f893","order_by":0,"name":"Yasushi 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1","display":"","copyAsset":false,"role":"figure","size":23382,"visible":true,"origin":"","legend":"\u003cp\u003ePatient selection flowchart\u003c/p\u003e\n\u003cp\u003ePORT = post-operative radiotherapy\u003c/p\u003e\n\u003cp\u003eBC = breast cancer, IMN = internal mammary node\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6509075/v1/459ae5625a3b19c7e8c469c3.png"},{"id":82151710,"identity":"b609c013-5f84-479d-9c3e-11d2c57570cc","added_by":"auto","created_at":"2025-05-07 07:21:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10580,"visible":true,"origin":"","legend":"\u003cp\u003eInternal mammary-node failure free survival rate\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6509075/v1/7ef48e6b183da67e65347777.png"},{"id":88268391,"identity":"2d4921ca-73bb-4806-8aeb-eff9000d504a","added_by":"auto","created_at":"2025-08-04 16:51:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":374120,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6509075/v1/535e0746-cd46-4fef-adb4-f9fe795d15dc.pdf"},{"id":82154017,"identity":"390af0b2-af6f-423e-8803-26488a825563","added_by":"auto","created_at":"2025-05-07 07:29:40","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19691,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-6509075/v1/95183199920a2cdc1e3d87dc.docx"},{"id":82151726,"identity":"1152ecb6-271b-4aab-9783-1384ca15af64","added_by":"auto","created_at":"2025-05-07 07:21:43","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":20571,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-6509075/v1/1933cc3627ff0dc65280ebbf.docx"}],"financialInterests":"","formattedTitle":"Internal mammary node failure in invasive breast-cancer patients who received post-operative radiotherapy without prophylactic internal mammary node irradiation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eInternal mammary node (IMN) metastases are not rare in patients with medial/central invasive breast cancer (BC) [1]. However, IMN failure after appropriate treatment is uncommon. IMN failure was observed in 2% or less of stage I-III BC after primary treatment, even when the IMN was not treated with surgery or radiotherapy [2-5].\u003c/p\u003e\n\u003cp\u003eBenefits of prophylactic IMN irradiation for patients with high-risk BC were assessed by two large randomized control studies conducted in France (French IMN study) and Korea (KROG 08-06) [6,7]. Both studies could not demonstrate survival benefit of prophylactic IMN irradiation. In addition, in EORTC 22922/10925 trial (including patients with positive axillary nodes [AxLNs] or medial/central BC) [8] and NCIC Clinical Trials Group MA.20 trial (including patients with node-positive BC or high-risk node-negative BC) [9], prophylactic irradiation to the regional nodes including the IMN region did not improve overall survival (OS). On the other hand, DBCG-IMN study, which was a prospective population-based cohort study conducted in Denmark, demonstrated that IMN irradiation improved OS with statistical significance in patients who had node-positive early BC [10]. Meta-analysis conducted by Japanese Breast Cancer Society (JBCS) guidelines also demonstrated survival benefit of prophylactic IMN irradiation [11]. Considering these results, JBCS guidelines published in 2022 weakly recommend prophylactic IMN irradiation for BC patients who need post-operative radiation therapy (PORT) to regional lympn-nodes. However, BC patients who would benefit most from prophylactic IMN irradiation in the era of modern systemic therapy have not been clearly identified. In this study, we investigated the risk factors for ipsilateral IMN failure when IMN irradiation was omitted in PORT.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cp\u003eClinical records of female patients who had unilateral invasive BC (pStage I-III and ypStage 0-III) and received PORT in our institution between January 2012 and March 2013 were retrospectively reviewed. Prophylactic IMN irradiation was not performed in PORT for clinically negative IMN in this period because JBCS guidelines published in 2011 and 2013 did not recommend the prophylactic IMN irradiation for the patients without clinically positive IMN. In this study, patients who had clinically positive IMN before treatment were excluded from the analysis of risk factors for IMN failure, and the estimation of IMN-failure free survival rates and OS. Patients who received neoadjuvant chemotherapy (NAC) were included.\u003c/p\u003e\n\u003cp\u003eBreast gadolinium-enhanced magnetic resonance imaging (Gd-MRI) and 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) were performed routinely for staging before treatment. IMN failure and distant failure were diagnosed by follow-up CT and/or FDG-PET/CT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePost-operative Radiotherapy\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor patients who received breast conserving surgery, 50 Gy in 25 fractions were delivered to the whole breast. When a patient had four or more positive AxLNs, 50 Gy in 25 fractions were also delivered to the supraclavicular region at the discretion of radiation oncologists. For the patients who received mastectomy, post-mastectomy radiotherapy with 50 Gy in 25 fractions was delivered to the chest-wall and the supraclavicular region in principle when they had four or more clinically/pathologically positive AxLNs and/or had a T3-4 primary tumor. For the patients with positive or close surgical margins, boost irradiation of 10 Gy in five fractions was added to the tumor bed. For patients who had received NAC, PORT was performed with considering disease status before NAC.\u003c/p\u003e\n\u003cp\u003eAdjuvant/neoadjuvant systemic therapy\u003c/p\u003e\n\u003cp\u003eAppropriate standard systemic therapy was administered if deemed necessary. NAC was administered when breast surgeons deemed it necessary or beneficial considering the results of pretreatment examinations. In adjuvant systemic therapy, hormone therapy was performed on patients with positive hormone-receptor, and chemotherapy was performed on high-risk patients. Trastuzumab was administrated to patients with HER2 over-expression.\u003c/p\u003e\n\u003cp\u003eStatistical analysis\u003c/p\u003e\n\u003cp\u003eIMN-failure free survival rates and OS were estimated by the Kaplan-Meier method. The survival time and failure time were calculated from the start of PORT.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In the analysis of risk factors for IMN failure, following factors were evaluated; primary tumor location, hormone receptor status, HER2 status, AxLN status (existence of high-risk AxLNs), and NAC administration. In this study, the high risk AxLN were defined as four or more positive AxLNs and/or AxLNs with remnant cancer cells after NAC. Although histological grades, nuclear grades, Ki67, and lympho-vascular invasion were important factors, detail information of these factors was not available in a significant proportion of patients. Therefore, these factors could not be evaluated in this study. Statistical differences of IMN-failure free survival rates and OS according to each risk factor were evaluated by the log-rank test. For multivariate analysis, Cox’s proportional hazard model was used. Statistical analysis was performed using StatView 5.0 software (SAS Institute Inc, NC).\u003c/p\u003e\n\u003cp\u003eEthical statement\u003c/p\u003e\n\u003cp\u003eThis study was conducted in compliance with ethical guidelines for medical research in Japan and the Declaration of Helsinki. As a retrospective observational study, patient consent was obtained through an opt-out approach. This study was approved by the institutional ethics committee (approval. no. 2021-71).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eConsecutive 220 patients received PORT for invasive BC in our institution between January 2012 and March 2013. Six patients who had concurrent bilateral invasive BC and 11 patients who were lost to follow-up immediately after completion of PORT were excluded from this study. Among remaining 203 patients, nine patients had clinically positive IMN before treatment. For the analysis of risk factors for IMN failure, these nine patients were excluded, and clinical data of the remaining 194 patients was used (Fig. 1). Regarding these 194 patients, median age was 53 years, and number of pStage I, II, and III were 97, 59, and 21, respectively. Thirty-seven patients received NAC. Table 1 shows patient characteristics. Median follow-up time for survival was 119 months (range 4-135 months). Median follow-up time for IMN failure (followed up by CT and/or FDG-PET/CT) was 110 months (range 4-132 months). The 5-year and 10-year OS rates were 96% and 93% respectively, and the 5-year and 10-year locoregional failure free rates were 98% and 95% respectively.\u003c/p\u003e\n\u003cp\u003e(1)\u0026nbsp;\u0026nbsp;Ipsilateral IMN failure\u003c/p\u003e\n\u003cp\u003eIMN failure free rates were 99% at 5-year\u003cs\u003es\u003c/s\u003e and 98% at 10-year\u003cs\u003es\u0026nbsp;\u003c/s\u003e(Fig. 2). Among 94 patients who had medial/central BC, two patients (2.1%) experienced IMN failure.\u003c/p\u003e\n\u003cp\u003e In 38 patients who received NAC, pretreatment pathological AxLN status could not be evaluated. Pretreatment pathological AxLN status could be evaluated in the remaining 166 patients. Among these 166 patients, two patients experienced IMN failure. Both patients had no pathologically positive AxLNs before treatment. Among 23 patients who had four or more pathologically positive AxLNs before treatment (including 11 patients with medial/central BC), no patient experienced IMN failure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e(2)\u0026nbsp;\u0026nbsp;Risk factors for ipsilateral IMN failure\u003c/p\u003e\n\u003cp\u003eResults of univariate and multivariate analysis were shown in Table 2. In univariate analysis, negativity of hormone receptor was the only statistically significant unfavorable factors for IMN failure (p=0.0012). In multivariate analysis, negativity of hormone receptor was the only significant unfavorable factor for IMN failure (HR 20.389 [95% CI; 1.601-259.610], p=0.0202).\u003c/p\u003e\n\u003cp\u003e(3)\u0026nbsp;\u0026nbsp;Characteristics of the patients who had clinically positive IMN before treatment\u003c/p\u003e\n\u003cp\u003eNine patients had clinically positive IMNs diagnosed by pretreatment FDG-PET/CT before treatment. These nine patients also underwent gadolinium enhancement MRI (Gd-MRI) (± CT) before treatment. Pretreatment Gd-MRI (± CT) were able to diagnose IMN abnormalities in two of nine (22%) patients.\u003c/p\u003e\n\u003cp\u003eIn addition, majority of these nine patients had medial/central BC and/or pathologically positive AxLNs. Seven of nine patients (78%) had medial/central BC. After exclusion of two patients who received NAC and achieved ypN0 status, all seven patients had pathologically positive AxLNs.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, BC patients who received PORT between January 2012 and March 2013 were reviewed. At that time, taxane and anti-HER2 drugs had already been introduced, and the JBCS guidelines do not recommend prophylactic IMN irradiation for patients without clinically positive IMN. In our study, the 10-year IMN failure rate was 2%. Based on our study including not only node-positive BC and medial/central BC but also node-negative BC and lateral BC, hormone receptor negativity was the only significant independent factor for IMN failure among the assessed factors. Medial/central location of the primary tumor and AxLN status appeared to have a smaller impact on IMN failure than previously believed. On the other hand, majority of patients who had clinically positive IMNs before treatment had medial/central BC and/or positive AxLNs.\u003c/p\u003e\n\u003cp\u003eUntil now, two large randomized control studies were conducted in France (French IMN study) and Korea (KROG 08-06) to evaluate benefits of prophylactic IMN irradiation for patients with high-risk BC [6,7]. The French IMN study enrolled patients who had stage I-II BC with positive AxLN or a medial/central BC, and underwent a modified radical mastectomy with or without systemic therapy in 1991-1997. No statistically significant differences in OS rates were observed between the IMN-irradiated group and the non-IMN-irradiated group (62.6% vs. 59.3% at 10-years; p=0.8). The KROG 08-06 study enrolled BC patients who had positive AxLNs and underwent a modified radical mastectomy or breast-conserving surgery in 2008-2020. In this study, IMN irradiation did not improve disease-free survival at 7-years (85.3% vs. 81.9%; p=0.22) and OS at 7-years (89.4% vs. 88.2%, p=0.50). On the other hand, DBCG-IMN (a prospective population-based cohort study) including node-positive early BC patients treated between 2003 and 2007, demonstrated that patients who received IMN irradiation had a significantly higher 15-year OS rate than patients who did not receive IMN irradiation. (60.1% vs. 55.4%, P=0.007) [10].\u0026nbsp;One of the possible explanations for these inconsistent results in the previous studies is that IMN failure is relatively rare even when IMN irradiation is not performed.\u0026nbsp;Because of the low incidence of IMN failure, the benefit of prophylactic IMN irradiation could not be detected in the single randomized control study. Although the incidence of IMN metastases is not rare especially in medial/central BC, the incidence of the IMN failure was rare [2-5]. Previous surgical series reported that 30% of BC patients had IMN metastasis, with a higher risk in patients with medial BC [1]. There are large discrepancy between the incidence of IMN metastases and the incidence of IMN failure after appropreate treatment without direct therapy (surgery or radiotherapy) to IMN. Although prophylactic IMN irradiation may be useful for properly selected BC patients, all BC patients do not need it. It has been believed that patients who had medial/central BC with AxLNs and BC with four or more positive AxLNs are the best candidates for prophylactic IMN irradiation due to the relatively high incidence of IMN metastases [11,12]. Indeed, an ad hoc subgroup analysis of KROG 08-06 limited to patients with medial/central BC showed significantly better disease-free survival rates and lower BC mortality rates in the IMN-irradiation group. However, contrary to expectations, location of the primary tumor (medial/central vs. lateral) and AxLN status did not appear to be significant factors for IMN failure in our study. Hormone receptor negativity appeared to have larger impact on IMN failure compared to location of BC and AxLN status in our study. There may be a possibility that the features of BC that are prone to IMN metastases and BC that are prone to IMN failure after appropriate treatment may differ considerably. BC that are prone to IMN metastasis are medial/central BC with or without positive AxLNs, whereas BC prone to IMN failure after appropriate systemic therapy and PORT without IMN irradiation may have refractory features to the standard systemic therapy. Because majority of our patients with clinically positive IMNs had medial/central BC and pathologically positive AxLNs, IMN metastases also appeared to be associated with medial/central BC and AxLN metastases in our patients.\u003c/p\u003e\n\u003cp\u003eAnother problem with studies of prophylactic IMN irradiation is the inaccuracy of diagnosing IMN metastasis before treatment. All our patients underwent FDG-PET/CT and Gd-MRI (\u0026plusmn; CT) before treatment, and IMN abnormalities were detected with FDG-PET/CT in nine patients. Of note, only FDG-PET/CT was able to detect IMN abnormalities in 78% (7/9) of these 9 patients. According to the previous studies, IMNs (including both normal and abnormal IMNs) could be observed in 42% of BC patients on CT and 54% of high risk BC patients on MRI. In addition, the size criteria for the diagnosis of abnormal IMNs has not been established [13]. It has been reported that FDG-PET/CT is more sensitive for IMN adenopathy compared to CT [13]. If FDG-PET/CT is not performed, some of clinically positive IMNs may be missed. In previous studies of prophylactic IMN irradiation, pretreatment FDG-PET/CT was often not routinely performed. Therefore, there is possibility that some clinically positive IMNs have been missed. Control of clinically positive IMN is likely to be more difficult for systemic therapy compared to the subclinical IMN metastases. When pretreatment FDG-PET/CT was not routinely performed, IMN failure is likely to be more frequent in patients with medial/central BC and/or multiple AxLN, in whom clinical IMN metastases occur more frequently. As a result, the benefit of prophylactic IMN irradiation may have been overestimated in patients who had medial/central BC and/or BC with multiple positive AxLNs.\u003c/p\u003e\n\u003cp\u003eHormone receptor negativity was the only statistically significant independent factor for IMN failure in our study. In the subgroup analysis of the KROG 08-06, prophylactic IMN irradiation tended to improve disease-free survival more after modified radical mastectomy in hormone receptor-negative BC compared with hormone receptor-positive BC [7]. In the subgroup analyses of MA.20, the effects of regional lymph-node (including IMN, supraclavicular lymph nodes, and AxLN) irradiation were larger for hormone receptor-negative (ER-negative or PR-negative) BC than for hormone receptor\u0026ndash;positive BC [9]. Our results consistent with the results of the KROG 08-06 and the MA.20. Further studies are needed for confirmation of the significance of hormone receptor status.\u003c/p\u003e\n\u003cp\u003ePathological stage did not appear to have large impact on incidence of IMN failure from our results. Among the patients who did not receive NAC, the 10-year IMN failure free rates were 99%, 98%, and 100% for pStage I, II, and III, respectively. Differences in risk of IMN metastasis between stages may be reduced by appropriate adjuvant systemic therapy.\u003c/p\u003e\n\u003cp\u003eIn recent years, genomic analysis has been used for prediction of response to chemotherapy and patient prognosis. Personalized treatment based on risk assessment using genomic analysis is also being researched in BC. [14,15]. Genomic assay has potential to provide more accurate risk assessment for IMN metastases and IMN failure when it used in combination with classical clinical, pathological, and biologic features of BC. Further studies are needed to evaluate usefulness of genomic assay for risk assessment of IMN failure.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere are some limitations of our study. Our study was a small retrospective study. Therefore, there may be some statistical uncertainty in the evaluation of risk factors for IMN failure. In addition, because this was a retrospective study, the available data for assessment of risk factors was limited. Some factors that should have been analyzed as potential risk factors such as lympho-vascular invasion, Ki-67, and histologic/nuclear grades could not be evaluated in this study. Further studies are needed to identify optimal candidates for prophylactic IMN irradiation.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on our study, hormone receptor negativity may have a greater impact on IMN failure compared with the location of the primary tumor and AxLN status in breast cancer patients who underwent PORT without prophylactic IMN irradiation after receiving appropriate systemic therapy as needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgements None.\u003c/p\u003e\n\u003cp\u003eAuthor contributions\u003c/p\u003e\n\u003cp\u003eConceptualization: Yasushi Hamamoto; Methodology: Yasushi Hamamoto; Formal analysis and investigation: Yasushi Hamamoto; Writing—original draft preparation: Yasushi Hamamoto; Writing—review and editing: Yasushi Hamamoto, Kenji Makita, Hiromitsu Kanzaki, Kei Nagasaki, Mariko Kouchi, Midhiko Yamashita, Mina Takahashi, Daisuke Takabatake, Kenjiro Aogi\u003c/p\u003e\n\u003cp\u003eFunding None.\u003c/p\u003e\n\u003cp\u003eData availability The dataset generated and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eThe authors have no Conflict of interest.\u003c/p\u003e\n\u003cp\u003eInformed consent: Patient consent was obtained through an opt-out approach\u003c/p\u003e\n\u003cp\u003eResearch involving human participants and/or animals: All procedures performed in studies involving human subjects 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"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSugarbaker ED. Radical mastectomy combined with in-continuity resection of the homolateral. Internal Mammary Node Chain. Cancer. 1953;6:969-79. https://doi.org/10.1002/1097-0142(195309)6:5\u0026lt;969::aid-cncr2820060516\u0026gt;3.0.co;2-5.\u003c/li\u003e\n \u003cli\u003eFreedman GM, Fowble BL, Nicolaou N, Sigurdson ER, Torosian MH, Boraas MC, Hoffman JP. Should internal mammary lymph nodes in breast cancer be a target for the radiation oncologist? Int J Radiat Oncol Biol Phys. 2000;46:805-14. https://doi.org/10.1016/s0360-3016(99)00481-2.\u003c/li\u003e\n \u003cli\u003eXie L, Higginson DS, Marks LB. Elective regional nodal irradiation in patients with early-stage breast cancer. Semin Radiat Oncol. 2011;21:66\u0026ndash;78. https://doi.org/10.1016/j.semradonc.2010.08.006\u003c/li\u003e\n \u003cli\u003ePoortmans PM, Collette S, Kirkove C, Van Limbergen E, Budach V, Struikmans H, et al. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373:317\u0026ndash;27. https://doi.org/10.1056/NEJMoa1415369.\u003c/li\u003e\n \u003cli\u003evan Loevezijn AA, Bartels SAL, van Duijnhoven FH, Heemsbergen WD, Bosma SCJ, Elkhuizen PHM, et al. Internal mammary chain sentinel nodes in early-stage breast cancer patients: toward selective removal. Ann Surg Oncol. 2019;26:945\u0026ndash;53. https://doi.org/10.1245/s10434-018-7058-5.\u003c/li\u003e\n \u003cli\u003eHennequin C, Bossard N, Servagi-Vernat S, Maingon P, Dubois JB, Datchary J, et al. Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy. Int J Radiat Oncol Biol Phys. 2013;86:860-6. https://doi.org/10.1016/j.ijrobp.2013.03.021.\u003c/li\u003e\n \u003cli\u003eKim YB, Byun HK, Kim DY, Ahn SJ, Lee HS, Park W, et al. Effect of elective internal mammary node irradiation on disease-free survival in women with node-positive breast cancer: a randomized phase 3 clinical trial. JAMA Oncol. 2022;8:96-105. https://doi.org/10.1001/jamaoncol.2021.6036.\u003c/li\u003e\n \u003cli\u003ePoortmans PM, Weltens C, Fortpied C, Kirkove C, Peignaux-Casasnovas K, Budach V, et al. Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial. Lancet Oncol. 2020;21:1602-1610. https://doi.org/10.1016/S1470-2045(20)30472-1.\u003c/li\u003e\n \u003cli\u003eWhelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, et al; MA.20 Study Investigators. Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med. 2015 Jul 23;373:307-16. https://doi.org/10.1056/NEJMoa1415340.\u003c/li\u003e\n \u003cli\u003eThorsen LBJ, Overgaard J, Matthiessen LW, Berg M, Stenbygaard L, Pedersen AN, et al. Internal mammary node irradiation in patients with node-positive early breast cancer: Fifteen-year results from the Danish Breast Cancer Group Internal Mammary Node Study. J Clin Oncol. 2022;40:4198-4206. https://doi.org/10.1200/JCO.22.00044\u003c/li\u003e\n \u003cli\u003eYoshimura M, Yamauchi C, Sanuki N, Hamamoto Y, Hirata K, Kawamori J, et al. The Japanese breast cancer society clinical practice guidelines for breast cancer screening and diagnosis, 2022 edition. Breast Cancer. 2024;31:347-357. https://doi.org/10.1007/s12282-023-01521-x\u003c/li\u003e\n \u003cli\u003eHuang O, Wang L, Shen K, Lin H, Hu Z, Liu G, et al. Breast cancer subpopulation with high risk of internal mammary lymph nodes metastasis: analysis of 2,269 Chinese breast cancer patients treated with extended radical mastectomy. Breast Cancer Res Treat. 2008;107:379-87. https://doi.org/10.1007/s10549-007-9561-4.\u003c/li\u003e\n \u003cli\u003eUrano M, Denewar FA, Murai T, Mizutani M, Kitase M, Ohashi K, et al. Internal mammary lymph node metastases in breast cancer: what should radiologists know? Jpn J Radiol. 2018;36:629-640. https://doi.org/10.1007/s11604-018-0773-9\u003c/li\u003e\n \u003cli\u003eJagsi R, Griffith KA, Harris EE, Wright JL, Recht A, Taghian AG, et al. Omission of Radiotherapy after Breast-conserving surgery for women with breast cancer with low clinical and genomic risk: 5-year outcomes of IDEA. J Clin Oncol. 2024;42:390-398. https://doi.org/10.1200/JCO.23.02270\u003c/li\u003e\n \u003cli\u003eSj\u0026ouml;str\u0026ouml;m M, Fyles A, Liu FF, McCready D, Shi W, Rey-McIntyre K, et al. Development and validation of a genomic profile for the omission of local adjuvant radiation in breast cancer. J Clin Oncol. 2023;41:1533-1540. https://doi.org/10.1200/JCO.22.00655\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":"Breast cancer, Internal mammary node, Post-operative radiotherapy, Prophylactic irradiation","lastPublishedDoi":"10.21203/rs.3.rs-6509075/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6509075/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\n\u003cp\u003eBreast-cancer (BC) patients who would benefit most from prophylactic internal mammary node (IMN) irradiation have not been clearly identified. Risk factors for ipsilateral IMN failure in BC patients who received post-operative radiotherapy (PORT) without prophylactic IMN irradiation were investigated.\u003c/p\u003e\n\u003cp\u003eMethods\u003c/p\u003e\n\u003cp\u003eBetween January 2012 and March 2013, unilateral invasive BC patients who had no clinically positive IMN and received PORT without prophylactic IMN irradiation after breast-conserving surgery or mastectomy were retrospectively reviewed. At that time, prophylactic IMN irradiation was not recommended for clinically negative IMN by Japanese BC guidelines. For identification of risk factors of IMN failure, the following factors were assessed using univariate and multivariate analyses: primary tumor location, hormone receptor status, human epidermal growth factor receptor 2 (HER2), axillary node status, and administration of neoadjuvant chemotherapy (NAC).\u003c/p\u003e\n\u003cp\u003eResults\u003c/p\u003e\n\u003cp\u003eA total of 194 BC patients (median age, 53 years; pStage I, 97; pStage II, 59; pStage III, 21; received NAC, 37) were analyzed. Median follow-up time with CT and/or FDG-PET/CT was 110 months (range, 4-132 months). IMN failure-free rates were 99% at 5-year\u003cdel\u003es\u003c/del\u003e and 98% at 10-year\u003cdel\u003es\u003c/del\u003e. The 10-year overall survival rate was 93%. In multivariate analysis, hormone receptor negativity was the only significant unfavorable factor for IMN failure (Hazard ratio 20.389, [95% CI 1.601-259.610], p=0.0202).\u003c/p\u003e\n\u003cp\u003eConclusions\u003c/p\u003e\n\u003cp\u003eHormone receptor status may have a greater impact on IMN failure compared to the primary tumor location and axillary lymph-node status in the modern systemic therapy era. Because our study was a small retrospective study, further large-scale studies are needed.\u003c/p\u003e","manuscriptTitle":"Internal mammary node failure in invasive breast-cancer patients who received post-operative radiotherapy without prophylactic internal mammary node irradiation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 07:21:35","doi":"10.21203/rs.3.rs-6509075/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor Revision","date":"2025-05-21T09:19:33+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-04-29T11:12:37+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-29T10:11:38+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-24T06:16:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer","date":"2025-04-23T01:32:47+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":"7b8464ce-aacb-472a-9522-f73522feb2f0","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-04T16:45:30+00:00","versionOfRecord":{"articleIdentity":"rs-6509075","link":"https://doi.org/10.1007/s12282-025-01746-y","journal":{"identity":"breast-cancer","isVorOnly":false,"title":"Breast Cancer"},"publishedOn":"2025-07-30 16:21:39","publishedOnDateReadable":"July 30th, 2025"},"versionCreatedAt":"2025-05-07 07:21:35","video":"","vorDoi":"10.1007/s12282-025-01746-y","vorDoiUrl":"https://doi.org/10.1007/s12282-025-01746-y","workflowStages":[]},"version":"v1","identity":"rs-6509075","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6509075","identity":"rs-6509075","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}