Systemic Therapy With or Without Upfront Surgery in Metastatic Breast Cancer

Study Overview
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Brief Summary
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SUBMIT is a clinical trial that intends to answer the question whether up front breast surgery in patients with primary distant metastatic breast cancer will result in an improvement of the 2-year survival compared to the survival achieved with systemic therapy and delayed local treatment or systemic therapy alone. Randomization will take place immediately after the diagnosis of primary distant metastatic breast cancer. Patients either randomize for up front surgery of the breast tumor (UFS) followed by systemic therapy or for systemic therapy (ST) potentially followed by delayed local treatment of the breast tumor. The primary endpoint of this trial is the 2-years survival. Quality of life is one of the most important secondary endpoints.

Detailed Description
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In the Netherlands approximately one out of eight women will be diagnosed with breast cancer; 5% have metastatic disease at presentation. Because metastatic breast cancer is considered to be an incurable disease, it is only treated with a palliative intent. Recent retrospective studies have demonstrated that (complete) resection of the primary tumor significantly improves the outcome of patients with primary metastatic breast cancer. However, other studies showed that the survival benefit in patients who underwent surgery is caused by selection bias. SUBMIT is a clinical trial that intends to answer the question whether up front breast surgery in patients with primary distant metastatic breast cancer will result in an improvement of the 2-year survival compared to the survival achieved with systemic therapy and delayed local treatment or systemic therapy alone. Patients to submit in this study are patients with primary distant metastatic breast cancer, with no prior treatment of the breast cancer, who are 18 years or older and fit enough to undergo surgery and systemic therapy. Exclusion criteria are: history of breast cancer, other malignancy within the last 10 years, surgical treatment or radiotherapy of this breast tumor before randomization, irresectable T4 tumor or synchronous bilateral breastcancer. Randomization will take place immediately after the diagnosis of primary distant metastatic breast cancer. Patients either randomize for up front surgery of the breast tumor (UFS) followed by systemic therapy or for systemic therapy (ST) potentially followed by delayed local treatment of the breast tumor. The primary endpoint of this trial is the 2-years survival. Quality of life is one of the most important secondary endpoints.

Official Title
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Systemic Therapy With or Without Up Front Surgery of the Primary Tumor in Breast Cancer Patients With Distant Metastases at Initial presenTation

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Procedure: upfront breast surgery
* Other: systemic therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed primary distant metastatic breast cancer (M1) Anticipated survival of at least 6 months Histologically proven breast cancer Hormonal and HER2Neu status should be known T1-T3, resectable T4 status, N0-N3 Performance status of the patient should allow surgery / systemic therapy Co-morbidity of the patient should allow surgery / systemic therapy Age > 18 years Written informed consent Exclusion Criteria: Primary invasive breast cancer in medical history Other malignancy within the last 10 years, besides basal cell carcinoma of the skin or early stage cervical cancer Surgical treatment / radiotherapy of this breast tumor before randomization Irresectable T4 breast tumor Synchronous bilateral breast cancer

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 |
| --- | --- |
| Experimental: Upfront surgery<br>Upfront surgery followed by systemic treatment | Procedure: upfront breast surgery<br>* surgery of primary tumor, lumpectomy or mastectomy<br>|
| Other: Systemic therapy<br>Systemic therapy possibly followed by local treatment of the breast tumor | Other: systemic therapy<br>* chemotherapy, immunotherapy or endocrine therapy (possibly followed by local surgery of the breast)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Survival is defined in months from the time of randomization until death. Overall survival will be expressed as the median survival in months. | participants will be followed until death (expected median survival 31 months for surgery group) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of Life | The EORTC QLQ - C30 and BR23 questionnaires will be used for the measurement of the quality of life. The quality of life will be assessed at 3, 6, 12, 18 months and 2,3,4,5 years after randomisation | 5 years after randomisation | 
| Two year survival | The percentage of patients who survive two years after randomization will be determined. | 2 yrs after randomisation | 
| Number of unplanned local therapies | The number of patients who will receive local treatment at another point than scheduled | 5-6 months after randomisation | 
| Difference in systemic therapy given | register which patients receive what treatments | 6 months after randomisation | 
| Determination of pathological resection margin | The definition of a complete resection in this trial means free resection margins for the invasive component. | Pathological report approximately 1 day after surgery | 
| Number of treatments of the axillary lymph nodes | register which patients receive these treatments | 6 months after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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survival, systemic therapy, upfront surgery