The NILS study protocol - a retrospective validation study of a preoperative decision-making tool for non-invasive lymph node staging in women with primary breast cancer [ISRCTN14341750]

Background Routine preoperative axillary ultrasonography has proven insufficient for detecting low-burden nodal metastatic deposits. For the majority of newly diagnosed breast cancer patients presenting with clinical T1-T2 N0 disease, the standard axillary staging by sentinel lymph node biopsy is not therapeutic. The pilot non-invasive lymph node staging (NILS) artificial neural network (ANN) model to predict nodal status was published in 2019. The aim of the current study is to assess the performance measures of the model for the prediction of healthy lymph nodes in clinically N0 breast cancer patients at two breast cancer centers in Sweden. Methods This bicenter, observational, retrospective study has been designed to validate the NILS prediction model for nodal status using preoperatively collected clinicopathological and radiological data. A web-based implementation of the nodal status classifier has been developed and will be used in this study, resulting in an estimated probability of healthy lymph nodes for each study participant. Our primary endpoint is to report on the performance of the NILS prediction model to distinguish between healthy and metastatic lymph nodes (discrimination, N0 vs. N+) and compare the observed and predicted event rates of benign axillary nodal status (calibration). Discussion Internationally, there are numerous artificial intelligence projects involving non-invasive identification of N0 breast cancer. Here, we present a robust validation study based on external cohorts of our ANN model. Although validation is necessary to show generalizability, it is often overlooked. If the accuracy and discrimination reach a satisfactory level, our prediction tool can be implemented to assist medical professionals and breast cancer patients in shared decision-making on omitting sentinel node biopsy in patients predicted to be node-negative. In future, this may potentially save healthcare resources and reduce costs and adverse side effects. In addition, our study might prompt future studies of nodal metastases of malignancies in other organs, and thus might have implications beyond breast cancer. Trial registration This study has been prospectively registered in the ISRCTN registry, identification number: 14341750 ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from Lund University (Sweden), South Swedish Health Care Region (Sweden), Erling Persson Foundation (Sweden), Stig and Ragna Gorthon Foundation, and Vetenskapsradet (Swedish Research Council, Sweden) (external review). In this academic study, the funding sources had no role in the study design, data collection, analyses, data interpretation, writing of the manuscript, or the decision to submit the manuscript for publication. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Regional Ethics Committee in Lund, Sweden (committee reference number: 2021-00174). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes This is not applicable to the study protocol. Following the enrollment of participants, the raw datasets are kept with the corresponding author, and available on reasonable request due to restrictions, such as privacy and ethical restrictions. The data are not publicly available because of these restrictions. * BC : Breast Cancer ANN : Artificial Neural Network HER2 : Human Epidermal growth factor Receptor 2 The NILS protocol : The Non-Invasive Lymph node Staging protocol MRI : Magnetic Resonance Imaging AUC : Area Under the Curve