A Retrospective Analysis on Metastatic Rate of the Internal Mammary Lymph Node and Its Clinical Significance in Adjuvant Radiotherapy of Breast Cancer Patients

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We aimed to investigate the metastatic rate of IMNs and to provide recommendations on target volume delineation of IMNs for adjuvant radiotherapy in breast cancer patients. Methods : We retrospectively analyzed data from 114 breast cancer patients treated with surgery without adjuvant radiotherapy who developed local and/or regional lymph node recurrence/metastasis at our institute from January 2015 to January 2019. Patients with widely lung or pleural metastases were excluded. We first analyzed the recurrence rate with the chest wall, the metastatic rate of internal mammary/anterior mediastinal, ipsilateral axillary and supraclavicular lymph nodes, and then investigated the distribution of the IMNs. Results : Among the 114 included patients, the recurrence rate with the chest wall, metastatic rate of IMNs, IMNs/anterior mediastinal lymph nodes, ipsilateral axillary lymph nodes, and the ipsilateral supraclavicular lymph nodes was 43%, 37.7%, 59.6%, 12.3%, and 22.8%, respectively. The metastatic IMNs were mainly located from the first to the second intercostal space. However, metastatic lymph nodes could also be observed above the upper edge of the first rib. Conclusions : The metastatic rate is high in the IMNs and irradiation of the internal mammary lymphatic chain is required. It is suggested that the upper bound of the internal mammary lymphatic chain should be up to the subclavian vein with a 5-mm margin, thus connecting to the caudal border of supraclavicular clinical target volume in breast cancer patients at high risk of recurrence. Cancer Biology Oncology breast cancer the internal mammary lymph node metastasis radiotherapy Figures Figure 1 Figure 2 Figure 3 Background Breast cancer is the most common malignant tumor in women, and postoperative adjuvant radiotherapy is an important mode of treatment[1, 2]. Based on results from two clinical trials (MA.20 and EORTC 22922/10925)[3, 4], the 2016 National Comprehensive Cancer Network (NCCN) guidelines strongly recommend irradiation of internal mammary lymph nodes (IMNs) in patients with 1-3 positive axillary lymph nodes (ALNs) (category 2A), following mastectomy and lumpectomy[5]. This approach is recommended in addition to irradiation of the chest wall and supraclavicular lymph nodes in postoperative adjuvant radiotherapy. Nevertheless, controversies persist regarding the recommendation of IMNs irradiation in all patients with ALNs metastases[6, 7]. Opponents believe that the recurrence rate of IMNs is low, within 2%-5%, while irradiation of IMNs increases cardiac and pulmonary toxicity. Although the internal mammary lymphatic chain is the first-echelon nodal drainage site in breast cancer[8, 9], along with the axilla, the importance of its treatment has long been debated. The metastatic rate of IMNs was 33% after the extended mastectomy in breast cancer patients treated in the 1970s[10, 11], suggesting a discrepancy between clinical and pathologic findings. To examine this contradiction, we retrospectively analyzed data from 114 breast cancer patients treated only by surgery without adjuvant radiotherapy who developed local recurrence and regional lymph node metastases, while receiving care at our institute from January 2015 to January 2019. We aimed to investigate metastatic rate and provide recommendations on target volume delineation of IMNs for adjuvant radiotherapy in surgically treated breast cancer patients. Methods Patient selection This is the selection process of patients included in this study (Fig.1): 126 patients were initially identified as having chest-wall recurrence and regional lymph node metastases from January 2015 to January 2019. 12 patients were subsequently excluded for the following reasons: 1 patient was excluded with the reason that he was male breast cancer patient; 3 patients were excluded with the reason that the pathology was invasive lobular carcinoma; 8 patients had widely lung or pleural metastases, and therefore not included. The remaining 114 patients were included in this study. Diagnostic criteria Eligibility criteria included unilateral histologically confirmed invasive breast carcinoma of stage I, II, or III with any quadrant located primary tumor, irrespective of axillary involvement, eligible patients had undergone mastectomy or breast-conserving surgery and axillary dissection; exclusion criteria included patients that male breast cancer, bilateral breast cancer, and noninvasive breast carcinoma, patients with widely lung or pleural metastases were also excluded; the definition of hormone receptor-positive is estrogen and/or progesterone receptor positive (the positive rate is equal or greater than 1%), and the definition of HER2 positive is immunohistochemistry [IHC] 3+ or IHC2+/ in situ hybridization-positive. The definition of TNM stage is according to the 7th edition of AJCC cancer staging. The diagnosis of internal mammary/anterior mediastinal lymph node metastasis was mainly based on clinical symptoms, signs, and imaging modalities (mainly enhanced computed tomography [CT] of the chest). Under normal circumstances, the short diameter of IMNs on the enhanced CT is 2-5 mm. The definition of lymph node metastasis include that the internal mammary lymph nodes whose short diameter is more than 6mm, or the lymph node is tightly connected to the internal mammary blood vessels regardless of the short diameter, lymph node who meet one of the above conditions can be seen as metastatic lymph node; the anterior mediastinal lymph nodes whose short diameter were more than 10mm, or the lymph node is tightly connected to the blood vessels, or lymph node with ring-enhancement in contrast-enhanced CT images also can be seen as metastatic lymph node; and the hypermetabolism in PET-CT also be diagnosed as metastases even if the short diameter was less than 6mm or 10mm[12]. Statistical analysis We first analyzed the recurrence rate with the chest wall, the metastatic rate of internal mammary/anterior mediastinal, ipsilateral axillary and supraclavicular lymph nodes, and then investigated the distribution of the IMNs. In this cross-sectional study, the interval estimation of the population rate was based on approximate normal distribution method when nP and n(1-P) were both greater than five, otherwise look-up table method was used. Results Clinical characteristics of included patients The patients’ age at onset ranged from 31 to 77 years (median age 45 years old), and none of the included 114 patients had received postoperative adjuvant radiotherapy, patients with widely lung or pleural metastases were excluded. In the present study, most tumors (82.5%) were located at the lateral quadrant; the molecular subtype of Her2 negative (Hormone Receptor (HR)+), Her2 positive (HR+/-) and TNBC (triple negative breast cancer) are 30.7%, 34.2%, and 35.1% respectively; and the rate of tumor staging that under stage IIIA is 64.9% (Table 1). Clinical characteristics of patients with chest wall recurrence and regional lymph nodes metastases In the present study sample, there were 49 (43%) cases of chest wall recurrence, 43 (37.7%) cases of IMNs metastases only, and 68 (59.6%) cases of IMNs/anterior mediastinal lymph node metastases. There were also 14 (12.3%) cases of ipsilateral ALNs recurrence and 26 (22.8%) cases of ipsilateral supraclavicular lymph node recurrence (Table 2). Regardless of tumor location, molecular subtype, or tumor staging, the metastatic rate of IMNs/anterior mediastinal lymph nodes was higher than 40% (Table 3). Distribution of the metastatic internal mammary/anterior mediastinal lymph nodes Among the 43 patients, 45.4% of the metastatic IMNs were located at the first intercostal space, 36.4% at the second intercostal space, 9.1% at the third intercostal space, and 2.3% at the fourth intercostal space (Table 4). The IMNs were mainly located at the first to the second intercostal space (Fig.2 A-B), while the anterior mediastinal lymph nodes were mainly distributed in the region 3A and region 6 (Fig.2 C-D). Moreover, metastatic lymph nodes could also be observed above the upper edge of the first rib (Fig.3 A-B), with a metastatic rate of 7%. Discussion The 2016 NCCN guidelines strongly recommended irradiation of the IMNs as part of the postoperative adjuvant radiotherapy for patients with 1-3 positive ALNs, following mastectomy and lumpectomy (category 2A)[5]. However, changes to the guidelines did not eliminate the controversies regarding irradiation of the internal mammary lymphatic chain. The reason was probably that the recurrence rate was only 2% according to clinical reports[13], and the irradiation dose of cardiopulmonary was increased by irradiation of the internal mammary lymphatic chain[14, 15]. In this study, we retrospectively examined data from 114 patients with local and/or regional lymph node recurrence without adjuvant radiotherapy. The recurrence rates with the chest wall, supraclavicular, and axillary lymph nodes were 43%, 22.8%, and 12.3%, respectively, which is consistent with the literature[16]. However, the recurrence rate of IMNs was 37.7%, second to the recurrence of the chest wall, and higher than the recurrence rate with the supraclavicular region, in the present study. So the recurrence rate of IMNs was underestimated probably. The reason might be that IMNs tend to be small, with a diameter ranging from 2-5 mm. As a result, routine imaging examinations easily miss IMNs, whose short diameter in excess of 6 mm qualifies as metastasis, unless a huge mass is formed at a very late stage. In addition, IMNs recurrence rarely exists in isolation, often involving systemic metastases to the liver, lung, and other organs[17], while presenting without specific symptoms, leading physicians to focus on other recurrences. In this study, the patients enrolled didn’t undergo postoperative adjuvant radiotherapy owing to various reasons such as lack of indications of radiation therapy, poor economic conditions and so on, but most of the previous studies enrolled patients that underwent postoperative radiotherapy which may reduce the metastatic rate; secondly, the reason is perhaps that nearly 30% of the patients studied underwent PET-CT examination which could improve the detection rate of metastatic lymph nodes probably; and thirdly, in our opinion, the internal mammary lymph node region and the anterior mediastinal lymph node region can be seen as an entirety (the reason could be explained below), so when the metastasis of the anterior mediastinal lymph node occures, we think that the internal mammary lymph node has a very high probability of metastasis even if the short diameter is less than 6mm. In the present study, the recurrence rate of IMNs was very high, which is consistent with the pathologic results reported for extended mastectomy[11, 18]. It answers the clinical problem that a discrepancy between clinical and pathologic findings, which have confused us for many years, and suggests the necessity of irradiation of the internal mammary lymphatic chain. Overall, these findings indicate that IMNs should be included in the target volume, now that the supraclavicular lymph nodes need to be irradiated. The IMNs receive lymphatic drainage from the medial and central parts of the breast and chest wall. The output tube is connected to the supraclavicular lymph nodes, leads to the anterior mediastinal lymph nodes, and enters the vein via the thoracic duct or the right lymphatic duct. Metastasis to the anterior mediastinal lymph node is not as rare as once thought. The anterior mediastinum is a stenotic region between the sternum, pericardium, and mediastinal pleura. Anatomically, the anterior mediastinal lymph nodes include the parasternal and anterior mediastinum group, while the parasternal group corresponds to the IMNs in breast cancer. The anterior mediastinum, which receives lymphatic drainage from the adjacent pleura, is not a region of high-risk lymph node metastasis even in lung cancer, except when there is pleural involvement or reflux of the enlarged mediastinal lymph node is formed. Anatomically, the anterior mediastinal metastatic lymph nodes should be derived from the internal mammary lymphatic chain, excluding widely lung or pleural metastases. Based on these considerations, we propose a concept of the extensive internal mammary lymph node region, which captures the internal mammary lymphatic chain and anterior mediastinal lymph node area (mainly region 3A and 6). While metastatic IMNs might be easily missed at routine imaging examinations, metastatic anterior mediastinal lymph nodes are larger and easier to identify on enhanced CT images therefore reducing the risk metastases being missed. Our results suggest that the metastatic rate to the anterior mediastinal lymph node is 50.9%. When the IMN and anterior mediastinum regions are combined, the recurrence rate increases to 59.6%. As such, we propose that irradiation of the internal mammary lymphatic chain is an indispensable part of adjuvant radiotherapy for breast cancer patients treated with surgery. This proposal is consistent with the NCCN guidelines[5]. Traditionally, the internal mammary lymphatic chain has been defined as the region between the first and third intercostal space[19]; however, metastatic lymph nodes could also be observed above the upper edge of the first rib. The internal mammary artery originates from the lower wall of the first segment of the subclavian artery, 1-2 cm down the lateral side of the sternum, divided into 2 branches (the superior epigastric and musculophrenic artery) until the sixth intercostal space, and accompanied by two veins. In our opinion, the internal mammary lymph node is consistent with the medial supraclavicular lymph node, once the metastases of the IMNs happened, it is easy to metastases to the medial supraclavicular region, so this is why we suggested that the upper bound of the internal mammary lymphatic chain should be up to the subclavian vein with 5mm margin, which is connected to the caudal board of the supraclavicular CTV in breast cancer patients with high risk of recurrence. Veronesi et al.[20] performed a follow-up study of 737 patients who had not undergone adjuvant radiotherapy and systemic therapy after radical mastectomy for thirty years. The prognosis for patients with IMNs metastases was similar to the prognosis of patients with ALNs metastases, with the 10-year disease-free survival at 59.6% and 62.4%, respectively. And both of IMNs and ALNs metastases having the worst prognosis, the 10-year disease-free survival was 37.3%. Once IMNs recurred, according to the poor prognosis of the follow-up of 6,000 breast cancer patients, IMN metastasis may indicate distant metastasis[17]. In a separate study from 2009, Heuts et al.[21] reported that, during a 46-month follow-up of 764 patients, the prognosis for patients with IMN metastasis was similar to the prognosis of patients with ALN metastasis, which improved due to better understanding of IMN metastasis. In the present retrospective study, 36 patients had both IMNs and distant metastases. This is likely because the output tube of IMN is located in the supraclavicular and anterior mediastinum region, entering the superior vena cava through the left and right jugular veins, thus increasing the risk of widely systemic metastases. Moreover, the metastatic rate of the extensive internal mammary lymph node exceeded 41.2%, regardless of the tumor location, molecular subtype, or tumor stage. IMNs cannot be removed during radical surgery or modified during radical mastectomy due to the abandon of the extended radical resection. As a result, active irradiation of the internal mammary lymphatic chain may reduce the risk of metastasis and recurrence of IMN, and improve the prognosis for breast cancer patients. Nevertheless, positive systemic therapy retains its important role in breast cancer treatment. Irradiation of IMNs is problematic because it might increase the cardiac dose, as well as the risk of morbidity and mortality. Recent advances in radiotherapy technology include sophisticated imaging integrated into planning systems with techniques that shield the heart or involve deep inspiration breath holding. Such approaches allow shaping or sculpting radiation doses to suit complex cancer volumes, while reducing treatment time to protect healthy organs. These advances have the potential to further increase the added benefit of radiotherapy beyond surgery and systemic therapy, increasing survival rates. Conclusions There were several limitations of this study. Firstly, this is a retrospective study, so there may exist selection bias; secondly, most of the patients did not undergo adjuvant radiotherapy owing to that most of them were treated in county hospitals before recurrence, and the others had no indications of radiotherapy according to guidelines at that time; thirdly, our study were mainly based on enhanced-CT, further studies should be done based on more accurate imageological examinations such as PET-CT and so on. In conclusion, the metastatic rate is high in the IMNs, suggesting that irradiation of the internal mammary lymphatic chain is indispensable. We propose that the upper bound of the internal mammary lymphatic chain should be the subclavian vein with a 5-mm margin, thus connecting to the caudal border of supraclavicular CTV in breast cancer patients at high risk of recurrence. Further high-quality prospective randomized trials are needed to validate this conclusion. List of abbreviations IMNs: Internal Mammary Lymph Nodes CTV: Clinical Target Volume NCCN: National Comprehensive Cancer Network ALNs: Axillary Lymph Nodes IHC: Immunohistochemistry CT: Computed Tomography PET/CT: Positron Emission Tomography/Computed Tomography HR: Hormone Receptor TNBC: Triple Negative Breast Cancer Declarations Ethics approval and consent to participate This study is in accordance with the Declaration of Helsinki and has been approved by the Ethics Committee of Zhongnan Hospital of Wuhan University. Due to the retrospective nature of the study, the informed consent requirement was waived. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported by the National Natural Science Foundation of China (Grant No. 81641116). The sponsor reviewed and approved the study protocol and the final version of the manuscript. All analytic decisions were made by the authors, and the final version of the manuscript was approved by all authors. Author’s contributions YZ conceived and designed the study, and critically revised the manuscript; LL performed the research and wrote the first draft; HZ and LW collected and analyzed the data; CX and YZ participated in paper writing and revised the manuscript. All authors have read and approved the manuscript. Acknowledgements Not applicable. Authors’ Information Affiliations Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University; Hubei Cancer Clinical Study Center; Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, People’s Republic of China Li Li, Hongyan Zhang, Linwei Wang, Conghua Xie, Yunfeng Zhou, Yahua Zhong References Zeng H, Zheng R, Zhang S, Zou X, Chen W. Female breast cancer statistics of 2010 in China: estimates based on data from 145 population-based cancer registries. J Thorac Dis. 2014; 6:466-70. Mcgale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, Gray R, Mannu G, Peto R, Whelan T. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014; 383:2127-35. Poortmans PM, Sandra C, Carine K, Erik VL, Volker B, Henk S, Laurence C, Alain F, Philippe M, Mariacarla VJNEJM. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med. 2015; 373:317-27. Whelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, Vallis KA, White JR, Rousseau P, Fortin A et al . Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med. 2015; 373:307-16. Gradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, Elias AD, Farrar WB, Forero A, Giordano SHJJotNCCNJ. Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016; 14:324-54. Hennequin C, Fourquet A. Controversy about internal mammary chain irradiation in breast cancer. Cancer Radiothérapie Journal De La Société Française De Radiothérapie Oncologique. 2014; 18:351-5. Hennequin C, Bossard N, Servagi-Vernat S, Maingon P, Dubois J-B, Datchary J, Carrie C, Roullet B, Suchaud J-P, Teissier E et al . Ten-Year Survival Results of a Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy. 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Tables Table 1 C linical characteristics of all patients Number(n=) Percent (%) Gender female 114 100 Age ＜ 45years 57 50 ≥ 45years 57 50 Tumor location medial/central 20 17.5 lateral 94 82.5 Molecular subtype ` Her2 negative (HR+) 35 30.7 Her2 positive (HR+/-) 39 34.2 TNBC 40 35.1 Tumor staging I 16 14.0 IIA 30 26.3 IIB 28 24.6 IIIA 17 14.9 IIIB 8 7.0 IIIC 15 13.2 HR: Hormone Receptor; TNBC: Triple Negative Breast Cancer Table 2 C linical characteristics of chest wall recurrence and RN metastasis Number (n=) Percent (%) Chest wall recurrence 49 43.0 IMNs metastasis 43 37.7 Anterior mediastinal lymph node metastasis 58 50.9 IMNs/anterior mediastinal lymph node metastasis 68 59.6 Ipsilateral supraclavicular lymph node recurrence 26 22.8 Ipsilateral axillary lymph node recurrence 14 12.3 RN: Regional Nodal ; IMNs: Internal Mammary Lymph Nodes Table 3 Clinical characteristics of IMNs/anterior mediastinal lymph nodes metastases IMNs/anterior mediastinal lymph node metastases (%) No IMNs/anterior mediastinal lymph node metastases (%) 95%CI Tumor location medial/central 14(70%) 6(30%) 49.92%, 90.08% lateral 52(55.3%) 42(44.7%) 45.27%, 65.37% Molecular subtype Her2 negative (HR+) 17(48.6%) 18(51.4%) 32.01%, 65.13% Her2 positive (HR+/-) 21(53.8%) 18(46.2%) 38.20%, 69.49% TNBC 28(70%) 12(30%) 55.80%, 84.20% Tumor staging I 10(62.5%) 6(37.5%) 38.78%, 86.22% IIA 18(60%) 12(40%) 42.47%, 77.53% IIB 16(57.1%) 12(42.9%) 38.81%, 75.47% IIIA 7(41.2%) 10(58.8%) 17.78%, 64.57% IIIB 6(75%) 2(25%) 47.00%, 100.00% IIIC 9(60%) 6(40%) 35.21%, 84.79% I MNs: Internal Mammary Lymph Nodes; CI: Confidence Interval; TNBC: Triple Negative Breast Cancer Table 4 Anatomic distribution of IMNs metastases Location of the metastatic IMNs Number(n=) Percent(%) The upper edge of the first rib 3 7 The first intercostal space 20 45.4 The second intercostal space 16 36.4 The third intercostal space 4 9.1 The fourth intercostal space 1 2.3 The fifth intercostal space 0 0 The sixth intercostal space 0 0 I MNs: Internal Mammary Lymph Nodes Supplementary Files STROBEchecklist.docx Cite Share Download PDF Status: Published Journal Publication published 24 Feb, 2020 Read the published version in BMC Cancer → Version 4 posted Review # 1 received at journal 31 Jan, 2020 Reviewer # 1 agreed at journal 30 Jan, 2020 Reviewers invited by journal 24 Jan, 2020 Editor assigned by journal 17 Jan, 2020 Editor invited by journal 16 Jan, 2020 Submission checks completed at journal 14 Jan, 2020 You are reading this latest preprint version Show more versions 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies 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-4541","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":296694,"identity":"7ab1bc29-e9e8-49d6-828c-3deb30e339c6","order_by":1,"name":"Li Li","email":"","orcid":"","institution":"Wuhan University Zhongnan Hospital Department of Chemotherapy and Radiation Therapy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Li","suffix":""},{"id":296695,"identity":"30b7a9c3-7a5e-4e5b-8cda-13d22735fe34","order_by":2,"name":"Hongyan Zhang","email":"","orcid":"","institution":"Wuhan University Zhongnan Hospital Department of Chemotherapy and Radiation Therapy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hongyan","middleName":"","lastName":"Zhang","suffix":""},{"id":296696,"identity":"2b2304cb-0bfc-401a-8c23-9cc9912726c6","order_by":3,"name":"Linwei Wang","email":"","orcid":"","institution":"Wuhan University Zhongnan Hospital Department of Chemotherapy and Radiation Therapy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Linwei","middleName":"","lastName":"Wang","suffix":""},{"id":296697,"identity":"dd033856-39f4-43f1-93b2-87a8f586fed2","order_by":4,"name":"Conghua xie","email":"","orcid":"","institution":"Wuhan University Zhongnan Hospital Department of Chemotherapy and Radiation Therapy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Conghua","middleName":"","lastName":"xie","suffix":""},{"id":296698,"identity":"06982842-d73d-4833-a552-fb328c022676","order_by":5,"name":"Yunfeng Zhou","email":"","orcid":"","institution":"Wuhan University Zhongnan Hospital Department of Chemotherapy and Radiation Therapy","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yunfeng","middleName":"","lastName":"Zhou","suffix":""},{"id":296699,"identity":"2d16f429-443b-4d71-ba3a-64379226126b","order_by":6,"name":"Yahua Zhong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYDCCA1DaQP75wQcJFTVEaWFsAGthyEk2eHDmGElaEswkH7YwE9bBd7z5+YOPe+oStzMcSKtIbGBj4G/vTsCrRfLMMcPGGc/YEnc2Nh67kbhDhkHizNkNeLUY3MhhbOY5wJO44TBD2o3EM2wMBhK5RGmRSNxwjMGsILGNmWgtBokbzjCYMRClBeSXmTMOJBhvuMGTLJFw5hgPQb8AQ+zBhw8H6mQ33GA/+PFHRY0cf3svfi0w4NgAZfAQpRwE7IlWOQpGwSgYBSMPAAB4zlLSejPjlgAAAABJRU5ErkJggg==","orcid":"","institution":"Wuhan University Zhongnan Hospital Department of Chemotherapy and Radiation Therapy","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yahua","middleName":"","lastName":"Zhong","suffix":""}],"badges":[],"createdAt":"2019-08-28 17:38:05","currentVersionCode":4,"declarations":"","doi":"10.21203/rs.2.13837/v4","doiUrl":"https://doi.org/10.21203/rs.2.13837/v4","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12885-020-6642-9","type":"published","date":"2020-02-24T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":372935,"identity":"4a809e1a-159d-4bfd-ae4f-da449a7c5ea2","added_by":"auto","created_at":"2020-01-16 15:33:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":551388,"visible":true,"origin":"","legend":"Flowchart representing selection process of patients included in this study.","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/68828e57-9c27-41fc-ade4-97d9c5f0b65e/v4/fig1.png"},{"id":372936,"identity":"f98fa4ec-42a2-4dd7-92cf-7c8b26fd5114","added_by":"auto","created_at":"2020-01-16 15:33:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":6684029,"visible":true,"origin":"","legend":"(A-B) metastatic internal mammary lymph nodes (white arrow); (C-D) metastatic anterior mediastinal lymph node (white arrow)","description":"","filename":"Fig2R2.jpg","url":"https://assets-eu.researchsquare.com/files/68828e57-9c27-41fc-ade4-97d9c5f0b65e/v4/Fig2-R2.jpg"},{"id":372937,"identity":"eb0aced0-75c3-404a-908b-7261b81d8a2c","added_by":"auto","created_at":"2020-01-16 15:33:36","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3756506,"visible":true,"origin":"","legend":"(A-B) metastatic lymph node above the upper edge of the first rib (white arrow).","description":"","filename":"Fig3R2.jpg","url":"https://assets-eu.researchsquare.com/files/68828e57-9c27-41fc-ade4-97d9c5f0b65e/v4/Fig3-R2.jpg"},{"id":13486152,"identity":"faf6e103-2146-409f-9f33-847855291b68","added_by":"auto","created_at":"2021-09-16 22:04:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":865784,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4541/v4/4367269b-6a75-4c94-8319-340f1636dcf6.pdf"},{"id":372934,"identity":"c82ea799-57cd-49cf-bb59-0072ba2080de","added_by":"auto","created_at":"2020-01-16 15:33:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":34053,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEchecklist.docx","url":"https://assets-eu.researchsquare.com/files/68828e57-9c27-41fc-ade4-97d9c5f0b65e/v4/STROBE_checklist.docx"}],"financialInterests":"","formattedTitle":"A Retrospective Analysis on Metastatic Rate of the Internal Mammary Lymph Node and Its Clinical Significance in Adjuvant Radiotherapy of Breast Cancer Patients","fulltext":[{"header":"Background","content":"\u003cp\u003eBreast cancer is the most common malignant tumor in women, and postoperative adjuvant radiotherapy is an important mode of treatment[1, 2]. Based on results from two clinical trials (MA.20 and EORTC 22922/10925)[3, 4], the 2016 National Comprehensive Cancer Network (NCCN) guidelines strongly recommend irradiation of internal mammary lymph nodes (IMNs) in patients with 1-3 positive axillary lymph nodes (ALNs) (category 2A), following mastectomy and lumpectomy[5]. This approach is recommended in addition to irradiation of the chest wall and supraclavicular lymph nodes in postoperative adjuvant radiotherapy.\u003c/p\u003e\n\u003cp\u003eNevertheless, controversies persist regarding the recommendation of IMNs irradiation in all patients with ALNs metastases[6, 7]. Opponents believe that the recurrence rate of IMNs is low, within 2%-5%, while irradiation of IMNs increases cardiac and pulmonary toxicity. Although the internal mammary lymphatic chain is the first-echelon nodal drainage site in breast cancer[8, 9], along with the axilla, the importance of its treatment has long been debated. The metastatic rate of IMNs was 33% after the \u0026nbsp;extended mastectomy in breast cancer patients treated in the 1970s[10, 11], suggesting a discrepancy between clinical and pathologic findings. To examine this contradiction, we retrospectively analyzed data from 114 breast cancer patients treated only by surgery without adjuvant radiotherapy who developed local recurrence and regional lymph node metastases, while receiving care at our institute from January 2015 to January 2019. We aimed to investigate metastatic rate and provide recommendations on target volume delineation of IMNs for adjuvant radiotherapy in surgically treated breast cancer patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePatient selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is the selection process of patients included in this study (Fig.1): 126 patients were initially identified as having chest-wall recurrence and regional lymph node metastases from January 2015 to January 2019. 12 patients were subsequently excluded for the following reasons: 1 patient was excluded with the reason that he was male breast cancer patient; 3 patients were excluded with the reason that the pathology was invasive lobular carcinoma; 8 patients had widely lung or pleural metastases, and therefore not included. The remaining 114 patients were included in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnostic criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligibility criteria included unilateral histologically confirmed invasive breast carcinoma of stage I, II, or III with any quadrant located primary tumor, irrespective of axillary involvement, eligible patients had undergone mastectomy or breast-conserving surgery and axillary dissection; exclusion criteria included patients that male breast cancer, bilateral breast cancer, and noninvasive breast carcinoma, patients with widely lung or pleural metastases were also excluded; the definition of hormone receptor-positive is estrogen and/or progesterone receptor positive (the positive rate is equal or greater than 1%), and the definition of HER2 positive is immunohistochemistry [IHC] 3+ or IHC2+/ in situ hybridization-positive. The definition of TNM stage is according to the 7th edition of AJCC cancer staging. The diagnosis of internal mammary/anterior mediastinal lymph node metastasis was mainly based on clinical symptoms, signs, and imaging modalities (mainly enhanced computed tomography [CT] of the chest). Under normal circumstances, the short diameter of IMNs on the enhanced CT is 2-5 mm. The definition of lymph node metastasis include that the internal mammary lymph nodes whose short diameter is more than 6mm, or the lymph node is tightly connected to the internal mammary blood vessels regardless of the short diameter, lymph node who meet one of the above conditions can be seen as metastatic lymph node; the anterior mediastinal lymph nodes whose short diameter were more than 10mm, or the lymph node is tightly connected to the blood vessels, or lymph node with ring-enhancement in contrast-enhanced CT images also can be seen as metastatic lymph node; and the hypermetabolism in PET-CT also be diagnosed as metastases even if the short diameter was less than 6mm or 10mm[12].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe first analyzed the recurrence rate with the chest wall, the metastatic rate of internal mammary/anterior mediastinal, ipsilateral axillary and supraclavicular lymph nodes, and then investigated the distribution of the IMNs. In this cross-sectional study, the interval estimation of the population rate was based on approximate\u0026nbsp;normal\u0026nbsp;distribution\u0026nbsp;method when nP and n(1-P) were both greater than five, otherwise look-up table method was used.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinical characteristics of included patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patients\u0026rsquo; age at onset ranged from 31 to 77 years (median age 45 years old), and none of the included 114 patients had received postoperative adjuvant radiotherapy, patients with widely lung or pleural metastases were excluded. In the present study, most tumors (82.5%) were located at the lateral quadrant; the molecular subtype of Her2 negative (Hormone Receptor (HR)+), Her2 positive (HR+/-) and TNBC (triple negative\u0026nbsp;breast cancer) are 30.7%, 34.2%, and 35.1% respectively; and the rate of tumor staging that under stage IIIA is 64.9% (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical characteristics of patients with chest wall recurrence and regional lymph nodes metastases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the present study sample, there were 49 (43%) cases of chest wall recurrence, 43 (37.7%) cases of IMNs metastases only, and 68 (59.6%) cases of IMNs/anterior mediastinal lymph node metastases. There were also 14 (12.3%) cases of ipsilateral ALNs recurrence and 26 (22.8%) cases of ipsilateral supraclavicular lymph node recurrence (Table 2). Regardless of tumor location, molecular subtype, or tumor staging, the metastatic rate of IMNs/anterior mediastinal lymph nodes was higher than 40% (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDistribution of the metastatic internal mammary/anterior mediastinal lymph nodes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong the 43 patients, 45.4% of the metastatic IMNs were located at the first intercostal space, 36.4% at the second intercostal space, 9.1% at the third intercostal space, and 2.3% at the fourth intercostal space (Table 4). The IMNs were mainly located at the first to the second intercostal space (Fig.2 A-B), while the anterior mediastinal lymph nodes were mainly distributed in the region 3A and region 6 (Fig.2 C-D). Moreover, metastatic lymph nodes could also be observed above the upper edge of the first rib (Fig.3 A-B), with a metastatic rate of 7%.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe 2016 NCCN guidelines strongly recommended irradiation of the IMNs as part of the postoperative adjuvant radiotherapy for patients with 1-3 positive ALNs, following mastectomy and lumpectomy (category 2A)[5]. However, changes to the guidelines did not eliminate the controversies regarding irradiation of the internal mammary lymphatic chain. The reason was probably that the recurrence rate was only 2% according to clinical reports[13], and the irradiation dose of cardiopulmonary was increased by irradiation of the internal mammary lymphatic chain[14, 15]. In this study, we retrospectively examined data from 114 patients with local and/or regional lymph node recurrence without adjuvant radiotherapy. The recurrence rates with the chest wall, supraclavicular, and axillary lymph nodes were 43%, 22.8%, and 12.3%, respectively, which is consistent with the literature[16]. However, the recurrence rate of IMNs was 37.7%, second to the recurrence of the chest wall, and higher than the recurrence rate with the supraclavicular region, in the present study. So the recurrence rate of IMNs was underestimated probably. The reason might be that IMNs tend to be small, with a diameter ranging from 2-5 mm. As a result, routine imaging examinations easily miss IMNs, whose short diameter in excess of 6 mm qualifies as metastasis, unless a huge mass is formed at a very late stage. In addition, IMNs recurrence rarely exists in isolation, often involving systemic metastases to the liver, lung, and other organs[17], while presenting without specific symptoms, leading physicians to focus on other recurrences. In this study, the patients enrolled didn\u0026rsquo;t undergo postoperative adjuvant radiotherapy owing to various reasons such as lack of indications of radiation therapy, poor economic conditions and so on, but most of the previous studies enrolled patients that underwent postoperative radiotherapy which may reduce the metastatic rate; secondly, the reason is perhaps that nearly 30% of the patients studied underwent PET-CT examination which could improve the detection rate of metastatic lymph nodes probably; and thirdly, in our opinion, the internal mammary lymph node region and the anterior mediastinal lymph node region can be seen as an entirety (the reason could be explained below), so when the metastasis of the anterior mediastinal lymph node occures, we think that the internal mammary lymph node has a very high probability of metastasis even if the short diameter is less than 6mm. In the present study, the recurrence rate of IMNs was very high, which is consistent with the pathologic results reported for extended mastectomy[11, 18]. It answers the clinical problem that a discrepancy between clinical and pathologic findings, which have confused us for many years, and suggests the necessity of irradiation of the internal mammary lymphatic chain. Overall, these findings indicate that IMNs should be included in the target volume, now that the supraclavicular lymph nodes need to be irradiated.\u003c/p\u003e\n\u003cp\u003eThe IMNs receive lymphatic drainage from the medial and central parts of the breast and chest wall. The output tube is connected to the supraclavicular lymph nodes, leads to the anterior mediastinal lymph nodes, and enters the vein via the thoracic duct or the right lymphatic duct. Metastasis to the anterior mediastinal lymph node is not as rare as once thought. The anterior mediastinum is a stenotic region between the sternum, pericardium, and mediastinal pleura. Anatomically, the anterior mediastinal lymph nodes include the parasternal and anterior mediastinum group, while the parasternal group corresponds to the IMNs in breast cancer. The anterior mediastinum, which receives lymphatic drainage from the adjacent pleura, is not a region of high-risk lymph node metastasis even in lung cancer, except when there is pleural involvement or reflux of the enlarged mediastinal lymph node is formed. Anatomically, the anterior mediastinal metastatic lymph nodes should be derived from the internal mammary lymphatic chain, excluding widely lung or pleural metastases. Based on these considerations, we propose a concept of the extensive internal mammary lymph node region, which captures the internal mammary lymphatic chain and anterior mediastinal lymph node area (mainly region 3A and 6). While metastatic IMNs might be easily missed at routine imaging examinations, metastatic anterior mediastinal lymph nodes are larger and easier to identify on enhanced CT images therefore reducing the risk metastases being missed. Our results suggest that the metastatic rate to the anterior mediastinal lymph node is 50.9%. When the IMN and anterior mediastinum regions are combined, the recurrence rate increases to 59.6%. As such, we propose that irradiation of the internal mammary lymphatic chain is an indispensable part of adjuvant radiotherapy for breast cancer patients treated with surgery. This proposal is consistent with the NCCN guidelines[5].\u003c/p\u003e\n\u003cp\u003eTraditionally, the internal mammary lymphatic chain has been defined as the region between the first and third intercostal space[19]; however, metastatic lymph nodes could also be observed above the upper edge of the first rib. The internal mammary artery originates from the lower wall of the first segment of the subclavian artery, 1-2 cm down the lateral side of the sternum, divided into 2 branches (the superior\u0026nbsp;epigastric and musculophrenic artery) until the sixth intercostal space, and accompanied by two veins. In our opinion, the internal mammary lymph node is consistent with the medial supraclavicular lymph node, once the metastases of the IMNs happened, it is easy to metastases to the medial supraclavicular region, so this is why we suggested that the upper bound of the internal mammary lymphatic chain should be up to the subclavian vein with 5mm margin, which is connected to the caudal board of the supraclavicular CTV in breast cancer patients with high risk of recurrence.\u003c/p\u003e\n\u003cp\u003eVeronesi et al.[20] performed a follow-up study of 737 patients who had not undergone adjuvant radiotherapy and systemic therapy after radical mastectomy for thirty years. The prognosis for patients with IMNs metastases was similar to the prognosis of patients with ALNs metastases, with the 10-year disease-free survival at 59.6% and 62.4%, respectively. And both of IMNs and ALNs metastases having the worst prognosis, the 10-year disease-free survival was 37.3%. Once IMNs recurred, according to the poor prognosis of the follow-up of 6,000 breast cancer patients, IMN metastasis may indicate distant metastasis[17]. In a separate study from 2009, Heuts et al.[21] reported that, during a 46-month follow-up of 764 patients, the prognosis for patients with IMN metastasis was similar to the prognosis of patients with ALN metastasis, which improved due to better understanding of IMN metastasis. In the present retrospective study, 36 patients had both IMNs and distant metastases. This is likely because the output tube of IMN is located in the supraclavicular and anterior mediastinum region, entering the superior vena cava through the left and right jugular veins, thus increasing the risk of widely systemic metastases. Moreover, the metastatic rate of the extensive internal mammary lymph node exceeded 41.2%, regardless of the tumor location, molecular subtype, or tumor stage. IMNs cannot be removed during radical surgery or modified during radical mastectomy due to the abandon of the extended radical resection. As a result, active irradiation of the internal mammary lymphatic chain may reduce the risk of metastasis and recurrence of IMN, and improve the prognosis for breast cancer patients. Nevertheless, positive systemic therapy retains its important role in breast cancer treatment.\u003c/p\u003e\n\u003cp\u003eIrradiation of IMNs is problematic because it might increase the cardiac dose, as well as the risk of morbidity and mortality. Recent advances in radiotherapy technology include sophisticated imaging integrated into planning systems with techniques that shield the heart or involve deep inspiration breath holding. Such approaches allow shaping or sculpting radiation doses to suit complex cancer volumes, while reducing treatment time to protect healthy organs. These advances have the potential to further increase the added benefit of radiotherapy beyond surgery and systemic therapy, increasing survival rates.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThere were several limitations of this study. Firstly, this is a retrospective study, so there may exist selection bias; secondly, most of the patients did not undergo adjuvant radiotherapy owing to that most of them were treated in county hospitals before recurrence, and the others had no indications of radiotherapy according to guidelines at that time; thirdly, our study were mainly based on enhanced-CT, further studies should be done based on more accurate imageological examinations such as PET-CT and so on. In conclusion, the metastatic rate is high in the IMNs, suggesting that irradiation of the internal mammary lymphatic chain is indispensable. We propose that the upper bound of the internal mammary lymphatic chain should be the subclavian vein with a 5-mm margin, thus connecting to the caudal border of supraclavicular CTV in breast cancer patients at high risk of recurrence. Further high-quality prospective randomized trials are needed to validate this conclusion.\u003c/p\u003e"},{"header":"List of abbreviations","content":"\u003cp\u003eIMNs: Internal Mammary Lymph Nodes\u003c/p\u003e\n\u003cp\u003eCTV: Clinical Target Volume\u003c/p\u003e\n\u003cp\u003eNCCN: National Comprehensive Cancer Network\u003c/p\u003e\n\u003cp\u003eALNs: Axillary Lymph Nodes\u003c/p\u003e\n\u003cp\u003eIHC: Immunohistochemistry\u003c/p\u003e\n\u003cp\u003eCT: Computed Tomography\u003c/p\u003e\n\u003cp\u003ePET/CT: Positron Emission Tomography/Computed Tomography\u003c/p\u003e\n\u003cp\u003eHR: Hormone Receptor\u003c/p\u003e\n\u003cp\u003eTNBC: Triple Negative\u0026nbsp;Breast Cancer\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is in accordance with the Declaration of Helsinki and has been approved by the Ethics Committee of Zhongnan Hospital of Wuhan University. Due to the retrospective nature of the study, the informed consent requirement was waived.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (Grant No. 81641116). The sponsor reviewed and approved the study protocol and the final version of the manuscript. All analytic decisions were made by the authors, and the final version of the manuscript was approved by all authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYZ conceived and designed the study, and critically revised the manuscript; LL performed the research and wrote the first draft; HZ and LW collected and analyzed the data; CX and YZ participated in paper writing and revised the manuscript. All authors have read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAffiliations\u003c/p\u003e\n\u003cp\u003eDepartment of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University; Hubei Cancer Clinical Study Center; Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei, People\u0026rsquo;s Republic of China\u003c/p\u003e\n\u003cp\u003eLi Li, Hongyan Zhang, Linwei Wang, Conghua Xie, Yunfeng Zhou, Yahua Zhong\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZeng H, Zheng R, Zhang S, Zou X, Chen W. Female breast cancer statistics of 2010 in China: estimates based on data from 145 population-based cancer registries. J Thorac Dis. 2014; 6:466-70.\u003c/li\u003e\n\u003cli\u003eMcgale P, Taylor C, Correa C, Cutter D, Duane F, Ewertz M, Gray R, Mannu G, Peto R, Whelan T. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014; 383:2127-35.\u003c/li\u003e\n\u003cli\u003ePoortmans PM, Sandra C, Carine K, Erik VL, Volker B, Henk S, Laurence C, Alain F, Philippe M, Mariacarla VJNEJM. Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer. N Engl J Med. 2015; 373:317-27.\u003c/li\u003e\n\u003cli\u003eWhelan TJ, Olivotto IA, Parulekar WR, Ackerman I, Chua BH, Nabid A, Vallis KA, White JR, Rousseau P, Fortin A\u003cem\u003e et al\u003c/em\u003e. Regional Nodal Irradiation in Early-Stage Breast Cancer. N Engl J Med. 2015; 373:307-16.\u003c/li\u003e\n\u003cli\u003eGradishar WJ, Anderson BO, Balassanian R, Blair SL, Burstein HJ, Cyr A, Elias AD, Farrar WB, Forero A, Giordano SHJJotNCCNJ. Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2016; 14:324-54.\u003c/li\u003e\n\u003cli\u003eHennequin C, Fourquet A. Controversy about internal mammary chain irradiation in breast cancer. Cancer Radioth\u0026eacute;rapie Journal De La Soci\u0026eacute;t\u0026eacute; Fran\u0026ccedil;aise De Radioth\u0026eacute;rapie Oncologique. 2014; 18:351-5.\u003c/li\u003e\n\u003cli\u003eHennequin C, Bossard N, Servagi-Vernat S, Maingon P, Dubois J-B, Datchary J, Carrie C, Roullet B, Suchaud J-P, Teissier E\u003cem\u003e et al\u003c/em\u003e. Ten-Year Survival Results of a Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy. Int J Radiat Oncol. 2013; 86:860-6.\u003c/li\u003e\n\u003cli\u003eZhou ZR, Yang ZZ, Yu XL, Guo XM. Is internal mammary nodes irradiation as a part of breast cancer postoperative radiotherapy necessary? J Thorac Dis. 2016; 8:3427-30.\u003c/li\u003e\n\u003cli\u003eHeutsa EM, Meyenfeldt MFV, Voogd AC. Internal mammary lymph drainage and sentinel node biopsy in breast cancer \u0026ndash; A study on 1008 patients. Eur J Surg Oncol. 2009; 35:252-7.\u003c/li\u003e\n\u003cli\u003eVeronesi U, Zucali R, Luini A. Local control and survival in early breast cancer: the Milan trial. Int J Radiat Oncol Biol Phys. 1986; 12:717-20.\u003c/li\u003e\n\u003cli\u003eUrban JA, Marjani MA. Significance of internal mammary lymph node metastases in breast cancer. AJR Am J Roentgenol. 1971; 111:130-6.\u003c/li\u003e\n\u003cli\u003eGenereux GP, Howie JL. Normal mediastinal lymph node size and number: CT and anatomic study. AJR Am J Roentgenol. 1984; 6:1095-100.\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. 2000; 46:805-14.\u003c/li\u003e\n\u003cli\u003eLeung HW, Chan AL, Muo CH. Late cardiac morbidity of adjuvant radiotherapy for early breast cancer - A population-based study. J Cardiol. 2016; 67:567-71.\u003c/li\u003e\n\u003cli\u003eChoi J, Kim YB, Shin KH, Ahn SJ, Lee HS, Park W, Kim SS, Kim JH, Lee KC, Kim DWJJoBC. Radiation Pneumonitis in Association with Internal Mammary Node Irradiation in Breast Cancer Patients: An Ancillary Result from the KROG 08-06 Study. J Breast Canc. 2016; 19:275-82.\u003c/li\u003e\n\u003cli\u003eStrom EA, Woodward WA, Angela K, Buchholz TA, Perkins GH, Anuja J, Richard T, Eva S, Aysegul S, Mcneese MD. Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy. Int J Radiat Oncol. 2005; 63:1508-13.\u003c/li\u003e\n\u003cli\u003eSuzanne C, Sangen MJC, Van Der, Kuijt GP, Voogd AC. Diagnosis, treatment and prognosis of internal mammary lymph node recurrence in breast cancer patients. Breast Cancer Res Treat. 2005; 89:271-5.\u003c/li\u003e\n\u003cli\u003eCopelandiii EM. Halsted Radical Mastectomy. In: \u003cem\u003eEncyclopedia of Cancer.\u003c/em\u003e edn.: Springer Berlin Heidelberg; 2009.\u003c/li\u003e\n\u003cli\u003eColli F. The internal mammary lymphatic chain in breast carcinoma. Methods of verifying the metastatic invasion. Riv Patol Clin. 1960; 15:993-1002.\u003c/li\u003e\n\u003cli\u003eVeronesi U, Marubini E, Mariani L, Valagussa P, Zucali RJEJoC. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Eur J Cancer. 1999; 35:1320-5.\u003c/li\u003e\n\u003cli\u003eHeuts EM, Kw VDEF. Results of tailored treatment for breast cancer patients with internal mammary lymph node metastases. Breast. 2009; 18:254-8.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eTable\u0026nbsp;1 \u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003eC\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003elinical characteristics of all patients\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"margin-left: 5.4pt; border-collapse: collapse; border: none;\" width=\"548\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 17.4pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 17.4pt;\" width=\"185\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 17.4pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eNumber(n=)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 17.4pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003ePercent (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eGender\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003efemale\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e114\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e100\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eAge\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 10pt;\"\u003e＜\u003c/span\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif;\"\u003e45years\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e57\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e50\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 10pt;\"\u003e\u0026ge;\u003c/span\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif;\"\u003e45years\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e57\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e50\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eTumor location\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003emedial/central\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e20\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e17.5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003elateral\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e94\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e82.5\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eMolecular subtype\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e`\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; 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height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e30.7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eHer2 positive (HR+/-)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e39\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e34.2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eTNBC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e40\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e35.1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eTumor staging\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eI\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e16\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e14.0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIA\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e30\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e26.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIB\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e28\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e24.6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIIA\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e17\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e14.9\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIIB\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e7.0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 138.6pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"185\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIIC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e15\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 128.5pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"171\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e13.2\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 7.5pt;\"\u003eHR: \u003c/span\u003e\u003cspan style=\"font-size: 7.5pt;\"\u003eHormone Receptor; TNBC: Triple Negative\u0026nbsp;Breast Cancer\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; text-indent: 10.0pt; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003eTable\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003eC\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003elinical characteristics of chest wall recurrence and RN metastasis\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\" width=\"568\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 260.65pt; border-top: solid black 1.5pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"348\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border-top: solid black 1.5pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"123\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eNumber (n=)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.45pt; border-top: solid black 1.5pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"98\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003ePercent (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 260.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"348\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eChest wall recurrence\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"123\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e49\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.45pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"98\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e43.0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 260.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"348\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIMNs metastasis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"123\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e43\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.45pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"98\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e37.7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 260.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"348\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eAnterior mediastinal lymph node metastasis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"123\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e58\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.45pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"98\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e50.9\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 260.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"348\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIMNs/anterior mediastinal lymph node metastasis\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"123\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e68\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.45pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"98\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e59.6\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 260.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"348\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIpsilateral supraclavicular lymph node recurrence\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"123\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e26\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.45pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"98\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e22.8\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 260.65pt; border: none; border-bottom: solid black 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"348\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIpsilateral axillary lymph node recurrence\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 92.15pt; border: none; border-bottom: solid black 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"123\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e14\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.45pt; border: none; border-bottom: solid black 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"98\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e12.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 7.5pt;\"\u003eRN: \u003c/span\u003e\u003cspan style=\"font-size: 7.5pt;\"\u003eRegional Nodal\u003c/span\u003e\u003cspan style=\"font-size: 7.5pt;\"\u003e; IMNs: \u003c/span\u003e\u003cspan style=\"font-size: 7.5pt;\"\u003eInternal Mammary Lymph Nodes\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eTable\u0026nbsp;3\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003e\u0026nbsp;\u003c/span\u003e\u003cspan style=\"font-size: 10.0pt; line-height: 200%;\"\u003eClinical characteristics of IMNs/anterior mediastinal lymph nodes metastases\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\" width=\"540\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 52.75pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border-top: solid black 1.5pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 52.75pt;\" width=\"133\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: solid black 1.5pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 52.75pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIMNs/anterior mediastinal lymph node metastases (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: solid black 1.5pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 52.75pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif;\"\u003eNo \u003c/span\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif;\"\u003eIMNs/anterior mediastinal lymph node metastases (%)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: solid black 1.5pt; border-left: none; border-bottom: solid black 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 52.75pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e95%CI\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eTumor location\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: none; border-bottom: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border: none; border-bottom: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: none; border-bottom: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003emedial/central\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e14(70%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e6(30%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e49.92%, 90.08%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003elateral\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e52(55.3%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e42(44.7%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e45.27%, 65.37%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eMolecular subtype\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eHer2 negative (HR+)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e17(48.6%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border: solid white 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e18(51.4%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e32.01%, 65.13%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eHer2 positive (HR+/-)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e21(53.8%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e18(46.2%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e38.20%, 69.49%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eTNBC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e28(70%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e12(30%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e55.80%, 84.20%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eTumor staging\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eI\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e10(62.5%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border: solid white 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e6(37.5%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-left: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e38.78%, 86.22%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIA\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e18(60%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e12(40%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e42.47%, 77.53%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIB\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e16(57.1%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e12(42.9%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e38.81%, 75.47%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIIA\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e7(41.2%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e10(58.8%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e17.78%, 64.57%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIIB\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border: solid white 1.0pt; border-top: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e6(75%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e2(25%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid white 1.0pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e47.00%, 100.00%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 100.05pt; border: none; border-bottom: solid black 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"133\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eIIIC\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: solid white 1.0pt; border-bottom: solid black 1.5pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e9(60%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 106.35pt; border-top: none; border-left: none; border-bottom: solid black 1.5pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"142\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt; vertical-align: middle;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003e6(40%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 99.2pt; border-top: none; border-left: none; border-bottom: solid black 1.5pt; border-right: solid white 1.0pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"132\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e35.21%, 84.79%\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 7.5pt;\"\u003eI\u003c/span\u003e\u003cspan style=\"font-size: 7.5pt;\"\u003eMNs: Internal Mammary Lymph Nodes; CI: Confidence Interval; TNBC: Triple Negative\u0026nbsp;Breast Cancer\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eTable\u0026nbsp;4\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"font-size: 10pt; line-height: 200%; color: #000000;\"\u003eAnatomic distribution of IMNs metastases\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 161.35pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"215\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003eLocation of the metastatic IMNs\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 126.65pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"169\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003eNumber(n=)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.0pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp style=\"margin: 0in; margin-bottom: .0001pt;\"\u003e\u003cspan style=\"font-size: 10pt; font-family: 'Times New Roman', serif; color: #000000;\"\u003ePercent(%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 161.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"215\"\u003e\n\u003cp style=\"margin-right: -30.0pt;\"\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003eThe upper edge of the first rib\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 126.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"169\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e7\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 161.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"215\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003eThe first intercostal space\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 126.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"169\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e20\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e45.4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 161.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"215\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003eThe second intercostal space\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 126.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"169\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e16\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e36.4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 161.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"215\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003eThe third intercostal space\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 126.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"169\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e4\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e9.1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 161.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"215\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003eThe fourth intercostal space\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 126.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"169\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e1\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e2.3\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 161.35pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"215\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003eThe fifth intercostal space\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 126.65pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"169\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 19.85pt;\"\u003e\n\u003ctd style=\"width: 161.35pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"215\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003eThe sixth intercostal space\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 126.65pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"169\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 2.0in; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 19.85pt;\" width=\"192\"\u003e\n\u003cp\u003e\u003cspan style=\"font-size: 10pt; color: #000000;\"\u003e0\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"text-align: justify; text-justify: inter-ideograph; line-height: 200%;\"\u003e\u003cspan style=\"color: #000000;\"\u003e\u003cspan style=\"font-size: 7.5pt; line-height: 200%;\"\u003eI\u003c/span\u003e\u003cspan style=\"font-size: 7.5pt; line-height: 200%;\"\u003eMNs: Internal Mammary Lymph Nodes\u003c/span\u003e\u003c/span\u003e\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":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"breast cancer, the internal mammary lymph node, metastasis, radiotherapy","lastPublishedDoi":"10.21203/rs.2.13837/v4","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.13837/v4","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground : There is a discrepancy about the metastatic rate of internal mammary lymph nodes (IMNs) between clinical and pathologic findings. We aimed to investigate the metastatic rate of IMNs and to provide recommendations on target volume delineation of IMNs for adjuvant radiotherapy in breast cancer patients. \u003c/p\u003e\u003cp\u003eMethods : We retrospectively analyzed data from 114 breast cancer patients treated with surgery without adjuvant radiotherapy who developed local and/or regional lymph node recurrence/metastasis at our institute from January 2015 to January 2019. Patients with widely lung or pleural metastases were excluded. We first analyzed the recurrence rate with the chest wall, the metastatic rate of internal mammary/anterior mediastinal, ipsilateral axillary and supraclavicular lymph nodes, and then investigated the distribution of the IMNs. \u003c/p\u003e\u003cp\u003eResults : Among the 114 included patients, the recurrence rate with the chest wall, metastatic rate of IMNs, IMNs/anterior mediastinal lymph nodes, ipsilateral axillary lymph nodes, and the ipsilateral supraclavicular lymph nodes was 43%, 37.7%, 59.6%, 12.3%, and 22.8%, respectively. The metastatic IMNs were mainly located from the first to the second intercostal space. However, metastatic lymph nodes could also be observed above the upper edge of the first rib. \u003c/p\u003e\u003cp\u003eConclusions : The metastatic rate is high in the IMNs and irradiation of the internal mammary lymphatic chain is required. It is suggested that the upper bound of the internal mammary lymphatic chain should be up to the subclavian vein with a 5-mm margin, thus connecting to the caudal border of supraclavicular clinical target volume in breast cancer patients at high risk of recurrence.\u003c/p\u003e","manuscriptTitle":"A Retrospective Analysis on Metastatic Rate of the Internal Mammary Lymph Node and Its Clinical Significance in Adjuvant Radiotherapy of Breast Cancer Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":4,"date":"2020-01-16 15:33:35","doi":"10.21203/rs.2.13837/v4","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-01-31T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"reviewerAgreed","content":"","date":"2020-01-30T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-01-24T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-01-17T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-01-16T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-01-14T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":3,"date":"2019-12-19 16:24:29","doi":"10.21203/rs.2.13837/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-01-07T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-12-28T12:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-12-28T12:00:00+00:00","index":3,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n* Are the methods appropriate and well described?: **Yes**\n* Does the work include the necessary controls?: **No**\n* Are the conclusions drawn adequately supported by the data shown?: **No**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I recommend additional statistical review**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that i have no competing interests**\n\nComments to Author:\n---\n\nLine 31/33 \"metastatic lymph nodes could also be observed above the upper edge of the first rib (Fig.2 EF), with a metastatic rate of 7%\" . In this sentence, we don't know whether the metastatic lymph nodes is belong to internal mammary node or supraclavicular node. If they were supraclavicular node, these could be from axillary lymph node chain . And, based on this point, we couldn't conclude \"It is suggested that the upper bound of the internal mammary lymphatic chain should be up to the subclavian vein with a 5-mm margin, thus connecting to the caudal border of supraclavicular clinical target volume in breast cancer patients at high risk of recurrence\". From the authors's logistic, Maybe anterior medialstinal lymph node should be included in the radiation field. So, this study just showed us that the recurrence rate of IMNs could be underestimated.\n\nFigure 2 E-F is not suitable in the title \"Distribution of the metastatic internal mammary/anterior mediastinal lymph nodes\"\n\n"},{"type":"editorInvitedReview","content":"","date":"2019-12-20T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n* Are the methods appropriate and well described?: **Yes**\n* Does the work include the necessary controls?: **Yes**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I am able to assess the statistics**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n\nComments to Author:\n---\n"},{"type":"reviewerAgreed","content":"","date":"2019-12-18T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-12-18T12:00:00+00:00","index":2,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n* Are the methods appropriate and well described?: **Yes**\n* Does the work include the necessary controls?: **No**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **Not relevant to this manuscript**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I have no COI**\n\nComments to Author:\n---\nI will accept the paper for publication without further revision."},{"type":"reviewersInvited","content":"","date":"2019-12-16T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-12-16T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2019-12-15T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-12-14T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2019-12-14T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2019-12-10 16:11:20","doi":"10.21203/rs.2.13837/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revise before sending to peer reviewers","date":"2019-11-29T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-11-28T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-11-27T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2019-11-27T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-08-31 04:40:55","doi":"10.21203/rs.2.13837/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2019-10-28T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-10-23T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reject\nForm responses:\n---\n* Are the methods appropriate and well described?: **No**\n* Does the work include the necessary controls?: **No**\n* Are the conclusions drawn adequately supported by the data shown?: **No**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I recommend additional statistical review**\n* Quality of written English: **Not suitable for publication unless extensively edited**\n* Declaration of competing interests: **I have no competing interests**\n\nComments to Author:\n---\nThe authors retrospectively analyzed 114 patients with breast cancer to investigate the metastatic rate of IMNs and also to provide recommendation target delineation of IMNs for radiotherapy.\nThe indication of radiotherapy to IMNs needs special consideration especially for the patients with high risk of cardiac function. Therefore, to determine the group which can be de-escalate the therapy is highly demanded.\nMajor revision\n1. The definition of adjuvant radiotherapy in the article is unclear. Does it mean radiotherapy to remnant breast or regional LN?\n2. The authors should describe a reason why the patients didn't receive radiotherapy. 35.1% of the patients is TNBC and most of cases was advanced. Is it because poor PS? Age? or any other reason? All clinical factors which possibly contributed to the decision should described in background table.\n3. The authors should describe detail of imaging analysis and clear definition of LN metastasis in method section and statistical considerations.\n4. The authors should show flow chart how you selected the patients.\n\nMinor revision\n1. Authors should show the anatomical location of LNs in figure because most of the readers are not radiologist.\n2. Language editing service is needed throughout the paper.\n"},{"type":"editorInvitedReview","content":"","date":"2019-10-22T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n* Are the methods appropriate and well described?: **No**\n* Does the work include the necessary controls?: **Yes**\n* Are the conclusions drawn adequately supported by the data shown?: **Yes**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I am able to assess the statistics**\n* Quality of written English: **Acceptable**\n* Declaration of competing interests: **I have no competing interests' below.**\n\nComments to Author:\n---\nThe present investigated the metastatic rate of internal mammary lymph nodes (IMNs) and to providerecommendations on target volume delineation of IMNs for adjuvant radiotherapy of breast cancer patients. The results showed that the metastatic rate is high in the IMNs and we think that irradiation of the internal mammary lymphatic chain is indispensable. It is suggested that the upper bound of the internal mammary lymphatic chain should be up to the subclavian vein with 5 mm margin, thus connecting to the caudal border of supraclavicular CTV in breast cancer patients with high risk of recurrence. This study has important guiding value for the target volume contouring of breast cancer.\n\nI have the following comments:\n1. Methods: More detials should be included in the Methods including enrolled and exclusion criteria; the definition of hormone receptor positive and HER2; the definition of TMN stage;\n2. Results: It is appreciated to assess the risk factors related to IMN recurrence;\nThe stage IIIA is 71.9%, However, only 14.9% of patients were stage IIIA in Table 1.\n3. Discussion: The incidence of IMN recurrence was significantly higher than previous studies. More discussion should be performed the association and difference to the previous studies.\n4. Limitation: Limitation should be added in this study.\n5. Abbreviations: Lack of partial abbreviation such as HR, et al.\n"},{"type":"editorInvitedReview","content":"","date":"2019-10-22T12:00:00+00:00","index":3,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n* Are the methods appropriate and well described?: **No**\n* Does the work include the necessary controls?: **No**\n* Are the conclusions drawn adequately supported by the data shown?: **No**\n* Are you able to assess any statistics in the manuscript or would you recommend an additional statistical review?: **I recommend additional statistical review**\n* Quality of written English: **Not suitable for publication unless extensively edited**\n* Declaration of competing interests: **I declare that I have no competing interests**\n\nComments to Author:\n---\nGeneral comments\nThis study is to analyze the loco regional recurrent pattern of breast cancer. In highly selected patients, the internal mammary node (IMN) recurrence rate is higher than other studies (9.5% in KJ, Born, et al. Int J Rad Onc Bio Phy.2018; 32.5% in Carl Deselm, et al. Int J Rad Onc Bio Phy. 2018 ). In addition, they thought the anterior mediastinal lymph node metastasis belong to IMN mets which they called extensive IMN metastasis. Although from anatomy, the anterior mediastinal region is close to sternum, the authors need to prove that anterior mediastinal node metastasis is not part of extensive multisite metastasis which could come from the blood circulation.\n\nSpecific revision:\nTitle:\nThe title need to be reorganized because it doesn't accurately depict the content in this paper.\nAbstract:\nthe highlight of this paper is to redefine the IMN metastasis, but in the methods, we couldn't find it.\nMethod\nP 2. Line 32 \"first\" should be \"firstly\"\nP 3. Line 16 French trial should be cited\nP 3. Line 26 \" to explain this contradiction\", your study is just the composition rate of the IMN Mets in 114 patients, not the incidence of IMN mets in BC patients.\nP3. Method\nWhen these patients were treated in your center. Whether this study was approved by the ethic committee.\nResults:\nP 4.Line 44 Fig (1E-F) this figure demonstrated medial supraclavicular node metastasis. Maybe it is not related to IMN metastasis.\n"},{"type":"reviewerAgreed","content":"","date":"2019-10-17T12:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-10-12T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2019-10-11T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-10-11T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2019-09-16T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-08-28T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2019-08-28T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-08-10T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"69a5d9b3-d1f7-4ebc-aab3-b22d66841403","owner":[],"postedDate":"January 16th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":44082,"name":"Cancer Biology"},{"id":44083,"name":"Oncology"}],"tags":[],"updatedAt":"","versionOfRecord":{"articleIdentity":"rs-4541","link":"https://doi.org/10.1186/s12885-020-6642-9","journal":{"identity":"bmc-cancer","isVorOnly":false,"title":"BMC Cancer"},"publishedOn":"2020-02-24 12:00:00","publishedOnDateReadable":"February 24th, 2020"},"versionCreatedAt":"2020-01-16 15:33:35","video":"","vorDoi":"10.1186/s12885-020-6642-9","vorDoiUrl":"https://doi.org/10.1186/s12885-020-6642-9","workflowStages":[]},"version":"v4","identity":"rs-4541","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-4541","version":["v4"]},"buildId":"omnImTCwR2MFx8CMYfrG7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}