Abstract PO1-19-03: The T-REX trial: a randomized international non-inferiority trial on Tailored Regional EXternal beam radiotherapy in clinically node-negative breast cancer patients with 1-2 sentinel node macrometastases

Background: Modern systemic treatment has reduced the incidence of regional recurrences and improved survival in breast cancer (BC). It is thus questionable whether regional radiotherapy (RT) is still indicated in patients with sentinel lymph node (SLN) macrometastases. Postoperative regional RT is associated with an increased risk of arm morbidity, pneumonitis, cardiac disease, and secondary cancer. Therefore, there is a need to individualize the indication for regional RT in relation to risk of recurrence. Trial design: In this multicenter, prospective randomized phase 3 trial, eligible patients have a clinically node-negative, estrogen receptor-positive, HER2-negative BC with 1-2 SLN macrometastases, and have not undergone completion axillary lymph node dissection. Participants are randomly assigned to receive regional RT (standard arm) or not (intervention arm). Regional RT includes the axillary levels I-III and the supraclavicular fossa. Internal mammary nodes are targeted in selected patients. After breast-conserving surgery (BCS), RT to the remaining breast is given in both groups while after mastectomy, chest-wall RT is only given in the standard arm. In the intervention arm, chest wall RT may be indicated in selected cases with extensive multifocality, according to national guidelines. RT quality assurance is an integral part of the trial. In addition, material from the primary tumor, SLN metastases and any recurrences is subjected to gene expression analysis to identify both prognostic markers for locoregional recurrence and predictive markers for the benefit of regional RT. After confirmation of eligibility and written informed consent, patients are randomized 1:1 between the treatment arms. Allocation is stratified by trial site and breast surgery (BCS vs. mastectomy). Participation in T-REX should not affect decisions on systemic adjuvant treatment. Eligibility criteria: Trial inclusion and exclusion criteria are given in Table 1. Specific aims: The main aim of the trial is to investigate if the omission of regional RT is non-inferior to routine regional RT in clinically node-negative BC patients with estrogen receptor-positive, HER2-negative T1-2 tumors with 1-2 SLN macrometastases not receiving axillary lymph node dissection. Secondary aims are to investigate whether refraining from regional RT reduces arm morbidity and late RT side effects, and improves short- and long-term health-related quality of life. In addition, the use of genomic classifiers for the prognostication of locoregional recurrences and the prediction of a benefit from regional RT will be investigated. Statistical methods: Primary outcome is recurrence free survival (RFS) at five years. Non-inferiority will be declared if the outcome in the intervention arm is not more than 4.5 percentage units below the standard arm, corresponding to a hazard ratio of 1.41 assuming 88% 5-year RFS with standard treatment. Secondary outcomes include locoregional recurrence, overall survival, patient-reported arm morbidity, and health-related quality of life. Accrual: The trial will include 1350 patients in Sweden, Norway and Finland from April 2023 to December 2028. First sites have been opened in April 2023. Contact information: Primary Investigator: Sara Alkner, Skåne University Hospital, Lund University, sara.alkner@med.lu.se. Responsible for the biobank: Per Karlsson, Sahlgrenska University Hospital, Gothenburg University, per.karlsson@oncology.gu.se. Inclusion and exclusion criteria Citation Format: Sara Alkner, Jana de Boniface, Dan Lundstedt, Ingvil Mjaaland, Lisa Rydén, Johan vikström, Pär-Ola Bendahl, Erik Holmberg, Helena Sackey, Elinore Wieslander, Per Karlsson. The T-REX trial: a randomized international non-inferiority trial on Tailored Regional EXternal beam radiotherapy in clinically node-negative breast cancer patients with 1-2 sentinel node macrometastases [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-03.