The T-REX Trial: Tailored Regional External Beam Radiotherapy in Clinically Node-negative Breast Cancer Patients With 1-2 Sentinel Node Macrometastases.

Study Overview
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Brief Summary
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T-REX is a randomized multicenter, non-inferiority trial. Aim: To evaluate whether regional radiotherapy may safely be omitted in clinically node negative breast cancer patients with one or two sentinel node macrometastases and an estrogen receptor positive, HER2-negative tumor. Leading to an improved quality of life and reduced side effects, without worsening recurrence free survival at five years. Intervention: Patients will be randomized to locoregional radiotherapy towards the breast/chestwall and regional lymph nodes vs. to a de-escalated radiotherapy. In the intervention arm no lymph node irradiation will be given. Radiotherapy is still given to the remaining breast after breast conserving surgery, but no radiotherapy is given after mastectomy. Sample size: 1350 patients Primary end-point: Recurrence free survival at five years. Gene expression analysis: For all patients gene expression analysis for the gene signatures ARTIC, POLAR and OncotypeDX will be performed in collaboration with Exact Sciences, and related to risk of recurrence and benefit of adjuvant radiotherapy.

Detailed Description
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In this multicenter, prospective randomized trial clinically node-negative breast cancer patients with 1-2 macrometastases in their sentinel lymph node biopsy, and an estrogen receptor positive, HER2-negative tumor, will be randomly assigned to either receive adjuvant locoregional radiotherapy, or no regional radiotherapy. The main aim is to evaluate whether regional radiotherapy may safely be omitted in patients with limited lymph node metastasis and an estimated low risk of locoregional recurrence. Recurrence free survival after five years is the primary outcome, which for non-inferiority should not worsen more than 4.5 percentage units. Secondary outcomes are locoregional recurrence, regional nodal recurrence, new contralateral BC, distant recurrence free survival, overall survival, non-breast malignancies, cardiac disease, arm morbidity, and health-related quality of life. Target volumes include: Standard arm - The remaining breast/chest wall, axillary lymph node levels I-III, the supraclavicular lymph nodes (level IV), the interpectoral lymph nodes and in patients with a medial/central tumor also the internal mammary lymph nodes. Intervention arm - The remaining breast after breast conserving surgery. No radiotherapy after mastectomy

Official Title
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The T-REX-Trial: Tailored Regional External Beam Radiotherapy in Clinically Node-negative Breast Cancer Patients With 1-2 Sentinel Node Macrometastases; an Open, Multicenter, Randomized Non-inferiority Phase 3-trial.

Conditions
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Breast Cancer

Intervention / Treatment
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* Radiation: De-escalation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary unifocal or multifocal invasive breast cancer T1-T2. Clinically N0. Macrometastasis (≥2mm) in 1-2 lymph nodes at sentinel node biopsy. Oral and written consent. Age ≥ 18 years. All resection margins are tumor free (no tumor on ink). Primary tumor ER-positive, HER2-negative. Exclusion Criteria: Regional or distant metastases outside the ipsilateral axilla. Previous RT towards the planned target area, i.e. the ipsilateral chest/lymph nodes. Neoadjuvant systemic therapy. Axillary lymph node dissection or other previous axillary surgery on the affected side. Prior history of invasive breast cancer. Pregnancy. Bilateral invasive breast cancer. Contraindication for radiotherapy or systemic treatment. Inability to absorb or understand the contents of the informed consent form; for example, through disability, inadequate language skills or dementia. Other invasive cancer within 5 years prior to breast cancer diagnosis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard<br>Radiotherapy to the remaining breast after breast conserving surgery or chest wall after mastectomy, and regional axillary lymph node levels I-IV. Internal mammary nodes are included in the target volume if the tumor has a central/medial localization in the breast. | |
| Experimental: Intervention<br>No regional radiotherapy. Radiotherapy is given to the remaining breast after breast conserving surgery, while mastectomy patients do not receive any radiotherapy at all. | Radiation: De-escalation<br>* No regional radiotherapy. Radiotherapy towards the remaining breast after breast conserving surgery, but no radiotherapy at all after mastectomy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence Free Survival |  | Five years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Locoregional recurrence |  | Five years | 
| Regional nodal recurrence |  | Five years | 
| New contralateral breast cancer |  | Five years | 
| Distant recurrence free survival |  | Five years | 
| Overall survival |  | Five years | 
| Arm morbidity | Assessed by questionnaires completed by study participants digitally or on paper between randomization and start of RT, and after 1, 3, and 5 years. The questionnaire used is the Lymphedema Functioning, Disability and Health Questionnaire (Lymph-ICF) developed by Devoogdt in 2011. | Five years | 
| Health-related quality of life | Assessed by the questionnaire EORTC QLQ-C-30 completed by study participants between randomization and RT, and after 1, 3, and 5 years. | Five years | 
| Health-related quality of life | Assessed by the questionnaire BR-23 completed by study participants between randomization and RT, and after 1, 3, and 5 years. | Five years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, radiotherapy, gene expression analysis, adjuvant breast cancer treatment, regional breast cancer treatment