Surgery vs. No Surgery for Primary Tumor in De Novo Stage IV Breast Cancer With Solitary Bone Metastases (POSITIVE-Bone)

A National Multicenter, Prospective, Randomized Controlled Trial Comparing Primary Tumor Surgery Followed by Systemic Therapy With Systemic Therapy Alone in Patients With De Novo Stage IV Breast Cancer and Solitary Bone Metastases

This is a national multicenter, prospective, randomized controlled trial. The study aims to compare the 5-year overall survival (OS) between patients receiving primary tumor surgery followed by systemic therapy (surgery group) and those receiving systemic therapy alone (non-surgery group) in patients with de novo Stage IV breast cancer who have solitary bone metastases. Secondary objectives include comparing progression-free survival (PFS), breast cancer-specific survival (BCSS), local control rates, patient-reported outcomes (BREAST-Q, QLQ-C30), safety (surgical complications and systemic therapy toxicities), and cost-effectiveness.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; Bone Metastases; Stage IV Breast Cancer
• Intervention / Treatment: Procedure: Primary Tumor Resection; Other: Standard systemic therapy

Detailed Description

The value of primary tumor resection in de novo stage IV breast cancer (BC) remains debated. While early retrospective studies suggested a potential survival benefit, recent large-scale randomized controlled trials (e.g., JCOG1017, E2108) have shown no OS benefit for the overall stage IV BC population. However, exploratory subgroup analyses consistently point towards a potential benefit for patients with hormone receptor-positive (HR+) disease and low metastatic burden, such as solitary bone metastases.

Given the unique biological behavior of HR+ BC and the effectiveness of modern systemic therapies (e.g., endocrine therapy + CDK4/6 inhibitors), it is hypothesized that primary tumor surgery may provide an additional "consolidation" benefit in this specific subgroup by improving local control and potentially prolonging survival. To address this, our team has designed this national multicenter, prospective, randomized controlled trial.

This study will enroll patients with de novo stage IV BC confirmed to have only bone metastases. All participants will receive standard systemic therapy based on their molecular subtype. Participants will be randomized 1:1 to either undergo primary tumor surgery (mastectomy or breast-conserving surgery with or without immediate reconstruction) within 4 weeks of randomization, followed by continued systemic therapy, or to receive systemic therapy alone. Palliative radiotherapy for bone metastases is permitted in both arms. The primary endpoint is 5-year overall survival. Secondary endpoints include PFS, BCSS, local control rate, quality of life (BREAST-Q, QLQ-C30), surgical complication rates, and cost analysis. This study will provide high-level evidence to guide personalized treatment decisions for this specific patient subgroup in China.

• Study Type: Interventional
• Enrollment (Estimated): 216
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Zhenggui Du; Phone Number: +86 13880768222; Email: docduzg@163.com
• Study Contact Backup: Name: Liuying Li; Phone Number: +86 13678020999; Email: lliuying99@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female patients aged 18 to 70 years (inclusive);
• Histopathologically confirmed (by core needle biopsy) invasive breast cancer;
• Diagnosed with de novo Stage IV breast cancer with metastases confirmed to be limited to bone;
• Patients may be enrolled either at initial diagnosis or after receiving first-line systemic therapy;
• Willing and able to provide written informed consent.

Exclusion Criteria:

• Disease progression (per RECIST 1.1 criteria) in the primary tumor, regional lymph nodes, or bone metastases after first-line systemic therapy;
• Presence of other primary malignancies;
• Severe comorbidities that would preclude surgery or safe administration of systemic therapy (e.g., severe cardiopulmonary disease, uncontrolled diabetes, long-term smoking history with poor pulmonary function, immunodeficiency);
• Current participation in another clinical trial that would interfere with the outcomes of this study;
• Refusal to provide informed consent.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Surgery Group; Patients undergo primary tumor surgery (total mastectomy or breast-conserving surgery with sentinel lymph node biopsy or axillary lymph node dissection, with or without immediate breast reconstruction) within 4 weeks after randomization, followed by continued standard systemic therapy.	Procedure: Primary Tumor Resection; Surgical removal of the primary breast tumor. The procedure type (mastectomy or breast-conserving surgery) is determined by tumor size, location, and patient preference, and is performed by experienced breast surgeons following national guidelines. Axillary staging (sentinel node biopsy or dissection) is performed concurrently. Immediate breast reconstruction (prosthesis or autologous tissue) may be performed when indicated.
Active Comparator: Non-Surgery Group; Patients receive standard systemic therapy alone based on their molecular subtype (e.g., HR+/HER2-: endocrine therapy ± CDK4/6 inhibitor; HER2+: anti-HER2 therapy + chemotherapy; Triple-negative: chemotherapy ± immunotherapy). Palliative local therapy (e.g., radiotherapy) for bone metastases or for managing severe local complications from the primary tumor (e.g., uncontrolled ulceration, bleeding) is permitted but not elective curative-intent primary tumor surgery.	Other: Standard systemic therapy; Systemic treatment administered according to the patient's molecular subtype (HR+, HER2+, or Triple-negative) based on Chinese and international clinical guidelines. Regimens include, but are not limited to, endocrine therapy (e.g., letrozole, exemestane) with or without CDK4/6 inhibitors (e.g., palbociclib) for HR+/HER2- disease; anti-HER2 targeted therapy (e.g., trastuzumab, pertuzumab) combined with chemotherapy for HER2+ disease; and chemotherapy (e.g., taxanes, anthracyclines) with or without immunotherapy (e.g., pembrolizumab) for triple-negative disease. All patients with bone metastases routinely receive bone-modifying agents (zoledronic acid or denosumab).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Time from randomization to death from any cause.	5 years post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Time from randomization to death from any cause.	3 and 10 years post-randomization
Progression-Free Survival (PFS)	Time from randomization to first documented disease progression (local progression, regional recurrence, or new/ progressive distant metastases) or death from any cause.	Up to 10 years post-randomization
Breast Cancer-Specific Survival (BCSS)	Time from randomization to death due to breast cancer.	Up to 10 years post-randomization
Patient-Reported Outcomes (PROs)	Quality of life measured by the EORTC QLQ-C30 (global health status/QoL).	Baseline, 6 months, 5 years, and 10 years post-randomization.
Patient-Reported Outcomes (PROs)	Quality of satisfaction measured by the BREAST-Q (psychosocial well-being, sexual well-being, and chest physical well-being) questionnaires.	Baseline, 6 months, 5 years, and 10 years post-randomization.

Collaborators and Investigators

• Sponsor: West China Hospital
• Collaborators: Shanxi Province Cancer Hospital; Hunan Cancer Hospital; Hebei General Hospital; The Affiliated Hospital of Qingdao University; The First Affiliated Hospital of Zhengzhou University; The First Hospital of Jilin University; Hebei Medical University Fourth Hospital; General Hospital of Ningxia Medical University; Zhejiang Provincial People's Hospital; Tangshan People's Hospital; Anyang Tumor Hospital; Guangdong Women and Children Hospital; Cancer Hospital of Guangxi Medical University; Suzhou Municipal Hospital; The First Affiliated Hospital of Hunan University of Traditional Chinese Medicine; Baotou Cancer Hospital; The Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine; Lanzhou University Second Hospital; Shanxi Bethune Hospital; Xinjiang Medical University Cancer Hospital; The First Hospital of Lanzhou University, Gansu, China; Nanchang People's Hospital; Union Hospital, Tongji Medical College, Huazhong University of Science and Technology; The Nineth Hospital of Shenzhen, Longgang Center Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2031
• Study Completion (Estimated): December 31, 2036

Study Registration Dates

• First Submitted: June 24, 2026
• First Submitted That Met QC Criteria: June 29, 2026
• First Posted (Actual): July 7, 2026

Study Record Updates

• Last Update Posted (Actual): July 7, 2026
• Last Update Submitted That Met QC Criteria: June 29, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Breast Cancer; Bone Metastasis; Stage IV
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms
• Other Study ID Numbers: 2026(194)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data via the request portal. All IPD requests should be emailed to Dr. Zhenggui Du, the general project leader, and will be evaluated by Dr. Du and the head of the collaborating organization to decide whether to approve.
• IPD Sharing Time Frame: After publication of relevant research outputs, such as academic papers and books.
• IPD Sharing Access Criteria: When a request has been approved, the investigator will provide access to the de-identified individual patient-level data in the data management platform (Electronic Data Capture, EDC). A signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing the requested information. Additionally, all users will need to accept the terms and conditions of the data management platform to gain access.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No