Immunotherapy (NHS-IL12 & Bintrafusp Alfa) and Radiation Therapy for the Treatment of Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer, the REINA Trial

Is willing and able to provide written informed consent for the trial and has signed the appropriate written informed consent form, approved by the investigator's Institutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to the performance of any trial activities

Is age \>= 18 years at time of study entry

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

Women of childbearing potential must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 8 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. Men on study also must be using contraception. Women of childbearing potential (WOCBP) are women who have not been postmenopausal greater than 1 year or undergone a hysterectomy or bilateral oophorectomy

Has confirmed HR+ and HER2 negative breast cancer with known metastatic disease. Eligible patients must have estrogen receptor (ER) and/or progesterone (PR) expression 10% or greater by immunohistochemistry (IHC). HER2 negative or nonamplified is determined by the current American Society of Clinical Oncology- College of American Pathologists (ASCO-CAP) criteria which are as follows: HER2 testing by IHC as 0 or 1+. If HER2 is 2+, ISH (in situ hybridization) must be performed. HER2 is positive if:

* IHC 3+ based on circumferential membrane staining that is

* Complete, intense

* ISH positive based on:

* Single-probe average HER2 copy number \>= 6.0 signals/cell

* Dual-probe HER2/CEP17 ratio \>= 2.0 with an average HER2 copy number \>= 4.0 signals/cell

* Dual-probe HER2/CEP17 ratio \>= 2.0 with an average HER2 copy number \< 4.0 signals/cell

* Dual-probe HER2/CEP17 ratio \< 2.0 with an average HER2 copy number \>= 6.0 signals/cell

Has at least 2 identified sites of metastatic disease. This can include areas of metastatic disease to the bone, but one additional of the sites of metastatic disease must be amenable to biopsy

Has measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria

Has received no more than 5 previous lines of chemotherapy and has received at least one line of therapy with an endocrine therapy or endocrine therapy combination

Hemoglobin \>= 10.0 g/dL

Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L (\>= 1500 per mm\^3)

Platelet count \>= 100 x 10\^9/L (\>= 100,000 per mm\^3)

Serum bilirubin =\< 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only upon treating physician, principle investigator (PI) or co-PI approval

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =\< 5 x ULN

Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits, examinations, and assessments (including follow up)

Protocol participation is such that the treatment will be administered as an outpatient. Inpatient status is not required and change in status does not necessitate removal from protocol

Has not had major surgery within 28 days prior to starting study treatment. Central venous access surgeries and/or placements would not be considered as major surgery

What this study is about