Adding Surgery and Radiation to the Usual Treatment for HER2-Positive Breast Cancer That Had Already Spread at Diagnosis

NCT07578116 | Not Yet Recruiting Phase 3 DMC

• 3 other identifiers: S2511NCI-2026-02627U10CA180888
• Study Type: interventional
• Target: 562
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase III trial evaluates the effect of adding locoregional therapy (surgery and radiation) and metastasis-directed stereotactic body radiation therapy (SBRT) to standard systemic therapy following standard HER2-targeted systemic therapy, compared to standard systemic therapy alone, in treating patients with HER2-positive stage IV breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or to a limited number of sites (oligometastatic). The usual approach for patients with (oligo)metastatic HER2-positive breast cancer is systemic drug treatment, which means medicines that travel through the whole body to treat both the breast and any areas where the cancer has spread. There are a number of approved HER2-targeted systemic therapy regimens available to patients. These typically include immunotherapy and/or chemotherapy. Immunotherapy drugs may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Chemotherapy drugs work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Unlike systemic therapy, locoregional therapies like surgery and radiation are focused treatments at the site of disease, delivered with the intent of sparing healthy tissues. Breast surgeries such as breast conserving therapy or total mastectomy are procedures in which the cancerous breast tissue (and healthy breast tissue in the case of total mastectomy) are surgically removed from the body. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. SBRT is a type of external radiation therapy that uses special equipment to position a patient and precisely deliver radiation to tumors in the body (except the brain). The total dose of radiation is divided into smaller doses given over several days. This type of radiation therapy helps spare normal tissue. Adding locoregional therapy, as well as metastasis-directed SBRT, to standard systemic therapy may help patients with (oligo)metastatic, HER2-positive stage IV breast cancer live longer overall or before their cancer progresses, and may help more patients achieve no evidence of disease, when compared to standard systemic therapy alone.

Conditions

Anatomic Stage IV Breast Cancer AJCC v8; Metastatic HER2-Positive Breast Carcinoma; Oligometastatic Breast Carcinoma

Outcome Measures

Primary Outcomes (3)

• Overall survival (OS) (Cohort A)

  The primary analysis to evaluate the primary objective in the randomized cohort will be an intent-to treat (ITT) comparison of Arm 1 versus Arm 2 using a stratified log-rank test including all randomized, eligible participants. The hazard ratio and 95% confidence interval (CI) will be estimated by Cox regression including the stratification factors as variables in the model. Primary analyses will be repeated among individuals with brain metastases to understand whether the effect of the intervention differs in this subgroup.

  From date of Step 2 registration to date of death, assessed up to 10 years

• Progression-free survival (PFS) (Observational Cohort B)

  In the observational cohort, the primary objective will be evaluated by estimating 3- and 5-year survival and corresponding 95% CIs using the Kaplan-Meier estimator. All analyses in the observational cohort will be descriptive. Primary analyses will be repeated among individuals with brain metastases to understand whether the effect of the intervention differs in this subgroup.

  From date of Step 2 registration to date of first documentation of progression or recurrence or death, assessed at 3 and 5 years

• Overall survival (Observational Cohort B)

  In the observational cohort, the primary objective will be evaluated by estimating 3- and 5-year survival and corresponding 95% CIs using the Kaplan-Meier estimator. All analyses in the observational cohort will be descriptive. Primary analyses will be repeated among individuals with brain metastases to understand whether the effect of the intervention differs in this subgroup.

  From date of Step 2 registration to date of death, assessed at 3 and 5 years

Secondary Outcomes (3)

• Progression free survival (Cohort A)

  From date of Step 2 registration to date of first documentation of progression or recurrence or death, assessed at 3 and 5 years and then up to 10 years

• Overall survival (Cohort A)

  From date of Step 2 registration to date of death, assessed at 3 and 5 years and then up to 10 years

• Duration of standard of care first line systemic therapy (Cohort B)

  From time of response assessment at end of Step 1 up to 10 years

Other Outcomes (3)

• Primary outcome treatment effect by sex

  Up to 10 years

• Primary outcome treatment effect by race

  Up to 10 years

• Primary outcome treatment effect by ethnicity

  Up to 10 years

Study Arms (4)

Step 1 (HER2-targeted systemic therapy, STS/SRT)

EXPERIMENTAL

Patients receive physician's choice of HER2-targeted systemic therapy according to NCCN/ASCO guidelines until completion of at least 12 weeks (4 cycles) or up to 24 weeks (8 cycles) of HER2-targeted therapy prior to Step 2 registration. Patients with brain metastases may also undergo SRS/SRT at the discretion of the treating physician. All patients also undergo ECHO, MRI, mammography, ultrasound, CT, and/or PET/CT throughout the trial. Patients may undergo optional biopsy and/or collection of blood samples throughout the trial.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Drug: HER2-targeted Therapy; Procedure: Magnetic Resonance Imaging; Procedure: Mammography; Procedure: Positron Emission Tomography; Radiation: Stereotactic Radiosurgery; Procedure: Ultrasound Imaging

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy)

EXPERIMENTAL

See Detailed Description.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Breast Conservation Treatment; Procedure: Computed Tomography; Drug: Cyclin-Dependent Kinase 4 Inhibitor; Drug: Cyclin-Dependent Kinase 6 Inhibitor; Procedure: Echocardiography Test; Drug: Hormone Therapy; Procedure: Magnetic Resonance Imaging; Procedure: Mammography; Biological: Pertuzumab; Procedure: Positron Emission Tomography; Radiation: Radiation Boost; Radiation: Radiation Therapy; Radiation: Stereotactic Body Radiation Therapy; Drug: Taxane Compound; Procedure: Total Mastectomy; Biological: Trastuzumab; Biological: Trastuzumab Deruxtecan; Biological: Trastuzumab Emtansine; Procedure: Ultrasound Imaging

Step 2 Cohort A, Arm 2 (systemic therapy)

EXPERIMENTAL

Patients continue systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines for at least 1 year in the absence of disease progression or unacceptable toxicity. Patients may receive locoregional therapy and/or SBRT according to standard of care only if required for palliative purposes. All patients also undergo ECHO, MRI, mammography, ultrasound, CT, and/or PET/CT throughout the trial. Patients may undergo optional biopsy and/or collection of blood samples throughout the trial.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Breast Conservation Treatment; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Procedure: Mammography; Biological: Pertuzumab; Procedure: Positron Emission Tomography; Radiation: Radiation Boost; Radiation: Radiation Therapy; Radiation: Stereotactic Body Radiation Therapy; Drug: Taxane Compound; Procedure: Total Mastectomy; Biological: Trastuzumab; Biological: Trastuzumab Deruxtecan; Biological: Trastuzumab Emtansine; Procedure: Ultrasound Imaging

Step 2 Cohort B (systemic therapy)

EXPERIMENTAL

Patients continue systemic therapy (T-DXd, or T-DM1, or T-DXd with or without pertuzumab, or taxane with trastuzumab and pertuzumab, or trastuzumab with pertuzumab) according to NCCN/ASCO guidelines in the absence of disease progression or unacceptable toxicity. All patients also undergo ECHO, MRI, mammography, ultrasound, CT, and/or PET/CT throughout the trial. Patients may undergo optional biopsy and/or collection of blood samples throughout the trial.

Procedure: Biopsy Procedure; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Echocardiography Test; Procedure: Magnetic Resonance Imaging; Procedure: Mammography; Biological: Pertuzumab; Procedure: Positron Emission Tomography; Biological: Trastuzumab; Biological: Trastuzumab Deruxtecan; Biological: Trastuzumab Emtansine; Procedure: Ultrasound Imaging

Interventions

Cyclin-Dependent Kinase 6 Inhibitor DRUG

Given CDK4/6 inhibitor

Also known as: CDK6 Inhibitor

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Step 1 (HER2-targeted systemic therapy, STS/SRT); Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Pertuzumab BIOLOGICAL

Given pertuzumab

Also known as: 2C4, 2C4 Antibody, BCD-178, EG1206A, HLX11, HS627, MoAb 2C4, Monoclonal Antibody 2C4, Omnitarg, Perjeta, Pertuzumab Biosimilar BCD-178, Pertuzumab Biosimilar EG1206A, Pertuzumab Biosimilar HLX11, Pertuzumab Biosimilar HS627, Pertuzumab Biosimilar TQB2440, Pertuzumab-dpzb, Poherdy, Rhumab 2C4, rhuMAb2C4, RO4368451, TQB 2440, TQB-2440, TQB2440

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Stereotactic Body Radiation Therapy RADIATION

Undergo SBRT

Also known as: SABR, SBRT, Stereotactic Ablative Body Radiation Therapy

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy)

Trastuzumab Emtansine BIOLOGICAL

Given T-DM1

Also known as: Ado Trastuzumab Emtansine, ADO-Trastuzumab Emtansine, Kadcyla, PRO 132365, PRO-132365, PRO132365, RO5304020, T-DM1, TDM1, Trastuzumab-DM1, Trastuzumab-MCC-DM1, Trastuzumab-MCC-DM1 Antibody-Drug Conjugate, Trastuzumab-MCC-DM1 Immunoconjugate

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Ultrasound Imaging PROCEDURE

Undergo ultrasound

Also known as: 2-Dimensional Grayscale Ultrasound Imaging, 2-Dimensional Ultrasound Imaging, 2D-US, Ultrasonography, Ultrasound, Ultrasound Test, Ultrasound, Medical, US

Step 1 (HER2-targeted systemic therapy, STS/SRT); Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Biopsy Procedure PROCEDURE

Undergo biopsy

Also known as: Biopsy, BIOPSY_TYPE, Bx

Step 1 (HER2-targeted systemic therapy, STS/SRT); Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Biospecimen Collection PROCEDURE

Undergo collection of blood samples

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Step 1 (HER2-targeted systemic therapy, STS/SRT); Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Breast Conservation Treatment PROCEDURE

Undergo breast conserving therapy

Also known as: BCS, BCT, Breast Conserving Surgery/Lumpectomy, Breast-Conserving Surgery, breast-sparing surgery

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy)

Computed Tomography PROCEDURE

Undergo CT and/or PET/CT

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography

Step 1 (HER2-targeted systemic therapy, STS/SRT); Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Cyclin-Dependent Kinase 4 Inhibitor DRUG

Given CDK4/6 inhibitor

Also known as: CDK4 Inhibitor

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy)

Echocardiography Test PROCEDURE

Undergo ECHO

Also known as: EC, Echocardiography

Step 1 (HER2-targeted systemic therapy, STS/SRT); Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

HER2-targeted Therapy DRUG

Receive HER2-targeted systemic therapy

Step 1 (HER2-targeted systemic therapy, STS/SRT)

Hormone Therapy DRUG

Given endocrine therapy

Also known as: Chemotherapy-Hormones/Steroids, Endocrine Therapy, Hormonal, Hormonal Therapy, Hormonal Treatment, hormone treatment, Hormones

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy)

Mammography PROCEDURE

Undergo mammography

Also known as: MG

Step 1 (HER2-targeted systemic therapy, STS/SRT); Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Positron Emission Tomography PROCEDURE

Undergo PET/CT

Also known as: Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT

Step 1 (HER2-targeted systemic therapy, STS/SRT); Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Radiation Boost RADIATION

Undergo RT boost

Also known as: BOOST, Boost Radiation, Boost Radiation Therapy, Boost Radiotherapy, Radiation Therapy Boost, Radiotherapy Boost

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy)

Radiation Therapy RADIATION

Undergo RT

Also known as: Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy)

Stereotactic Radiosurgery RADIATION

Undergo SRS/SRT

Also known as: SRS, Stereotactic External Beam Irradiation, stereotactic external-beam radiation therapy, Stereotactic Radiation Therapy, Stereotactic Radiotherapy, stereotaxic radiation therapy, stereotaxic radiosurgery

Step 1 (HER2-targeted systemic therapy, STS/SRT)

Taxane Compound DRUG

Given taxane therapy

Also known as: taxane, Taxanes

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy)

Total Mastectomy PROCEDURE

Undergo total mastectomy

Also known as: Simple Mastectomy

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy)

Trastuzumab BIOLOGICAL

Given trastuzumab

Also known as: ABP 980, ALT02, Biceltis, CANMab, CT-P06, CT-P6, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, Hercessi, Herclon, Hertraz, Herwenda, Herzuma, HLX 02, HLX-02, HLX02, Kanjinti, Ogivri, Ontruzant, PF 05280014, PF-05280014, PF05280014, QL 1701, QL-1701, QL1701, rhuMAb HER2, RO0452317, SB3, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar ALT02, Trastuzumab Biosimilar CT-P6, trastuzumab biosimilar EG12014, Trastuzumab Biosimilar HLX02, Trastuzumab Biosimilar PF-05280014, Trastuzumab Biosimilar QL1701, Trastuzumab Biosimilar SB3, Trastuzumab Biosimilar SIBP-01, Trastuzumab-anns, Trastuzumab-dkst, Trastuzumab-dttb, Trastuzumab-herw, Trastuzumab-pkrb, Trastuzumab-qyyp, Trastuzumab-strf, Trastuzumab-zerc, Trazimera, Zercepac

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Trastuzumab Deruxtecan BIOLOGICAL

Given T-DXd

Also known as: DS-8201, DS-8201a, Enhertu, Fam-trastuzumab Deruxtecan-nxki, T-DXd, WHO 10516

Step 2 Cohort A, Arm 1 (locoregional, SBRT, systemic therapy); Step 2 Cohort A, Arm 2 (systemic therapy); Step 2 Cohort B (systemic therapy)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• REGISTRATION STEP 1 - SCREENING \& INITIAL TREATMENT:
• Participants must have histologically confirmed de novo metastatic (i.e. American Joint Committee on Cancer \[AJCC\] stage IV, no prior history of breast cancer) HER2+ breast cancer with 1 to 5 distant metastatic lesions (oligometastatic). Metastatic breast cancer must be histologically confirmed through biopsy of a distant metastatic lesion unless it is not feasible or safe to biopsy a metastatic lesion, then there must be unequivocal evidence of metastasis on imaging and laboratory studies. HER2+ status must be confirmed in the breast tumor and distant metastatic site as defined per NCCN guidelines version 4.2025
• NOTE: If HER2 positivity at metastatic site is equivocal due to limitations in HER2 analysis in bone, or it is not feasible or safe to biopsy the metastatic lesion, then HER2 positivity based on breast tumor only is acceptable. If there is no breast lesion, HER2+ must be confirmed in at least one metastatic site
• Participants with brain metastases are eligible if they meet all of the following criteria at baseline:
• There are 5 or fewer intracranial lesions
• Each intracranial lesions is no larger than 2cm in longest dimension
• NOTE: The brain is counted as 1 distant site towards the oligometastatic definition. Brain imaging is not required for participants who have no neurological signs or symptoms suggestive of central nervous system (CNS) involvement; however, assessment of neurological symptoms and brain MRI is strongly encouraged to rule out CNS disease
• Participants must have no known leptomeningeal disease
• Participants must meet one of the following criteria prior to Step 1 registration:
• Treatment naïve and planning to initiate standard of care systemic HER2+ targeted treatment OR
• Have already initiated standard of care systemic HER2+ targeted treatment and have completed at least one (≥ 1) but no more than three (≤ 3) cycles prior to enrollment, without progression
• NOTE: Standard of care scans for baseline disease assessment must have been performed within 28 days prior to initiation of treatment
• Participants must not be receiving or planning to receive any investigational systemic therapy during study before disease progression
• Participants must not have received whole brain irradiation
• NOTE: Participants with up to five brain metastases may have received SRS/SRT either before or after initiation of systemic therapy. If lesions are small and asymptomatic and the participant is receiving CNS penetration they may be managed with observation

Sponsors & Collaborators

• SWOG Cancer Research Network: lead
• National Cancer Institute (NCI): collaborator

MeSH Terms

Interventions

Biopsy; Specimen Handling; Mastectomy, Segmental; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p18; Steroids; Hormones; Magnetic Resonance Spectroscopy; pertuzumab; 2C4 antibody; Radiotherapy; Radiation; Radiosurgery; Taxoids; taxane; Mastectomy, Simple; Trastuzumab; CT-P6; PF-05280014; trastuzumab biosimilar HLX02; Ogivri; Ontruzant; trastuzumab deruxtecan; Ado-Trastuzumab Emtansine; High-Energy Shock Waves

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Mastectomy; Cyclin-Dependent Kinase Inhibitor Proteins; Intracellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Cell Cycle Proteins; Proteins; Tumor Suppressor Proteins; Neoplasm Proteins; Fused-Ring Compounds; Polycyclic Compounds; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses; Spectrum Analysis; Chemistry Techniques, Analytical; Therapeutics; Physical Phenomena; Stereotaxic Techniques; Neurosurgical Procedures; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Maytansine; Macrolides; Lactones; Lactams, Macrocyclic; Macrocyclic Compounds; Ultrasonic Waves; Sound; Radiation, Nonionizing

Study Officials

• Mariya Rozenblit

  SWOG Cancer Research Network

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Model Details: Patients are sequentially assigned to Step 1 and Step 2 and then assigned to Cohort A or B in parallel.

Study Record Dates

• First Submitted: May 4, 2026
• First Posted: May 11, 2026
• Study Start (Estimated): March 9, 2027
• Primary Completion (Estimated): May 31, 2032
• Study Completion (Estimated): May 31, 2033
• Last Updated: May 11, 2026

Record last verified: 2026-05