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.

PRIMARY OBJECTIVES:

I. To compare overall survival (OS) between participants with de novo stage IV oligometastatic HER2+ breast cancer who experience at least a partial response (PR) after initial systemic therapy similar to those used in stage III disease with curative intent, and are randomized to a multimodality approach including definitive locoregional therapy with surgery and radiotherapy and ablative intent stereotactic radiotherapy to detectable metastatic lesions followed by additional HER2-directed systemic therapy, similar to those used for residual disease after neoadjuvant therapy, (Cohort A, Arm 1) versus those who are randomized to physician's choice standard of care HER2-directed systemic therapies without local and metastasis directed ablative therapies (Cohort A, Arm 2). (Randomized Cohort A) II. To evaluate the distribution of progression-free survival (PFS) and overall survival (OS) among participants with de novo stage IV oligometastatic HER2+ breast cancer who do not experience a response after systemic therapy. (Observational Cohort B)

SECONDARY OBJECTIVES:

I. To compare progression-free survival (PFS) in Cohort A, Arm 1 (randomized to multimodality therapy) versus Cohort A, Arm 2 (randomized to standard of care HER2-directed systemic therapy). (Randomized Cohort) II. To compare PFS in Cohort A, Arm 1 per protocol (received all multimodality therapy as planned) versus Cohort A, Arm 2. (Randomized Cohort) III. To compare OS in Cohort A, Arm 1 per protocol (received all multimodality therapy as planned) versus Cohort A, Arm 2. (Randomized Cohort) IV. To assess duration of standard of care first line systemic therapy received from time of response assessment in Cohort B. (Observational Cohort)

BANKING OBJECTIVE:

I. To bank specimens for future correlative studies.

OUTLINE:

STEP 1: Patients receive physician's choice of HER2-targeted systemic therapy according to National Comprehensive Cancer Network (NCCN)/American Society of Clinical Oncology (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 stereotactic radiosurgery (SRS)/stereotactic radiotherapy (SRT) at the discretion of the treating physician.

STEP 2: Patients with partial or complete response in the breast following completion of Step 1 are assigned to Cohort A. Patients with clinically stable or progressive disease following completion of Step 1 are assigned to Cohort B.

COHORT A: Patients are randomized to 1 of 2 arms.

ARM 1:

LOCOREGIONAL THERAPY: Patients undergo breast surgery (either breast conserving therapy or total mastectomy) within 4-6 weeks of completion of Step 1 systemic therapy. Within 8 weeks of breast surgery, patients undergo locoregional radiation therapy (RT) to the breast, with or without RT to the breast/chest wall and/or regional lymph nodes, over 5-16 fractions. Patients may undergo RT boost to the lumpectomy bed over 4-5 fractions at the discretion of the treating physician.

STEREOTACTIC BODY RADIATION THERAPY (SBRT): Within 4-6 weeks of completion of locoregional therapy, patients undergo SBRT, with or without concurrent adjuvant therapy (pertuzumab and trastuzumab, or trastuzumab emtansine [T-DM1], or trastuzumab deruxtecan [T-DXd] with or without pertuzumab), to all targetable metastatic lesions every other day for 1, 3, or 5 fractions over a maximum of 3 weeks.

POST-LOCOREGIONAL THERAPY AND SBRT: Following recovery from surgery, patients resume 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 who are estrogen receptor positive may also receive endocrine therapy, with or without CDK4/6 inhibitors, at the discretion of the treating physician for at least 5 years, in the absence of disease progression or unacceptable toxicity.

ARM 2: 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.

COHORT B: 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 echocardiography (ECHO), magnetic resonance imaging (MRI), mammography, ultrasound, computed tomography (CT), and/or positron emission tomography (PET)/CT throughout the trial. Patients may undergo optional biopsy and/or collection of blood samples throughout the trial.

After completion of study treatment, patients registered to Step 2 are followed up for 10 years.

Inclusion Criteria:

• 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

• Participants must be ≥ 18 years old at the time of registration

• Participants must have Zubrod performance status of 0-2

• Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration

• Participants must be able to safely receive the physician's choice of standard of care systemic HER2+ targeted treatment per the current Food and Drug Administration (FDA)-approved package insert(s), treating physician's discretion, and institutional guidelines

• Participants must be candidates for definitive surgical and radiotherapeutic management of locoregional disease opinion per the discretion of the treating physician

• Participants must be able to receive ablative dose stereotactic body radiation therapy (SBRT) to all metastatic lesions identified at baseline, in the opinion of the treating physician

• Participants must be offered the opportunity to participate in specimen banking

• NOTE: As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

  • Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and CIRB regulations

• REGISTRATION STEP 2 - COHORT ASSIGNMENT AND RANDOMIZATION:

• COHORT A: Participants must be registered to Step 2 within 14 days of staging scans performed after completing Step 1 systemic therapy

• COHORT A: Participants must have standard of care (SOC) staging scans and breast imaging performed following 12-24 weeks (minimum of 4 cycles) of initial systemic therapy and within 14 days prior to Step 2 registration

• COHORT A: Participants must have experienced partial or complete response in the breast (in the opinion of the treating physician) following 12-24 weeks of initial systemic therapy based on staging scans performed within 14 days prior to Step 2 registration

  • Participants with breast lesion(s) at diagnosis must have a clinical response on breast imaging per the treating physician
  • Metastatic lesions, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and bone response criteria, must have at least stable disease
  • Brain metastases treated with SRS/SRT must have at least stable disease as per Response Assessment in Neuro-Oncology Brain Metastases (RANO BM) and must not require steroid treatment
  • Participants with no known breast lesions at diagnosis must have at least partial response in the metastatic sites as assessed by RECIST and bone response criteria
  • NOTE: The same imaging modality must be used as in Step 1

• COHORT A: Participants must be eligible for definitive surgical and radiotherapeutic management of locoregional disease per the discretion of the treating physician

• COHORT A: Participants must not have metastatic lesions that are not amenable to ablative dose stereotactic body radiation therapy (SBRT)

  • Lung lesions that completely resolve after systemic therapy will not be targeted with SBRT, as it is not possible to achieve dose build-up
  • The development of new sclerotic bone lesions after systemic therapy is not to be interpreted as disease progression, and all such lesions should be targeted with SBRT

• COHORT B: Participants must be registered to Step 2 within 14 days of staging scans performed after completing Step 1 systemic therapy

• COHORT B: Participants must have standard of care (SOC) staging and breast imaging performed following 12-24 weeks (minimum of 4 cycles) of initial systemic therapy and within 14 days prior to Step 2 registration

• COHORT B: Participants must experience clinically stable disease or progression following 12-24 weeks (minimum of 4 cycles) of initial systemic therapy and within 14 days prior to Step 2 registration

  • Participants must have progression in metastatic lesions as assessed by RECIST and bone response criteria or may have stable disease in metastatic lesions by RECIST and bone response criteria if there is progression or no clinical response in the breast
  • Participants with known breast lesion must have progression or no clinical response on breast imaging as per the treating physician
  • NOTE: The same modality must be used as in Step 1