The researchers are doing this study to see if the combination of surgery, locoregional radiation therapy, SBRT (stereotactic body radiation therapy), and the usual approach is more effective in treating oligometastatic HER2-positive breast cancer than the usual approach alone. The researchers will also study the side effects of the study treatment.

Prior to randomization, patients will receive standard of care first-line systemic therapy as defined by NCCN guidelines (paclitaxel, trastuzumab and pertuzumab at the time of study activation). Following a 3-12 month period without evidence of progression as determined by the treating clinician, patients may be registered and then randomly assigned in 1:1 fashion to one of two study arms. All patients will be followed until progression of disease or 3 years after randomization, whichever comes first. All HER2-directed agents are FDA-approved and administered per standard of care practice.

Inclusion Criteria:

• Age ≥ 18 years.
• Pathologically-confirmed metastatic breast cancer.
• Oligometastatic breast cancer (≤5 discrete metastatic lesions) without CNS involvement; as seen on standard imaging during initial workup and monitoring prior to registration.
• HER2-positive breast cancer per CAP/ASCO guidelines as determined by staff pathologist (any estrogen or progesterone receptor status).
• Based on size and location, all metastatic sites can be safely treated with either SBRT or resection.
• Enrolled at least 3 months (and up to 12 months) after initiation of first-line systemic therapy AND without evidence of progression as determined by treating clinician (whether clinically or radiographically) during this window. (ie. in the judgement of the treating clinician, based on standard evaluations, all known disease must be controlled prior to enrollment).
• ECOG performance status 0-2; KPS 60-100

Exclusion Criteria:

• Any foci of disease progression during initial 3-12 months of first-line systemic therapy (as determined by treating clinician)
• Escalation of systemic therapy line due to progressive disease (i.e. initiated second-line therapy prior to enrollment).
• Comorbidities precluding receipt of radiotherapy, surgery or standard systemic therapy.
• Intracranial or intrathecal/intramedullary spinal disease (ie. CNS involvement is excluded from the study; epidural/vertebral disease is permitted)
• Prior cancer history requiring chemotherapy within the past 10 years (ie. prior cancers are permitted provided no chemotherapy was administered).

Inclusion of Underrepresented Populations

• Individuals of all races and ethnic groups are eligible for this trial. There is no bias towards age or race in the clinical trial outlined. This trial is open to the accrual of men and women.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org