Vaccine Therapy With or Without Polysaccharide-K in Patients With Stage IV HER2 Positive Breast Cancer Receiving HER2-Targeted Monoclonal Antibody Therapy

This randomized phase I/II trial studies the side effects of vaccine therapy with or without polysaccharide-K and to see how well it works in treating patients with stage IV human epidermal growth factor receptor 2 (HER2) positive breast cancer who are receiving HER2-targeted monoclonal antibody therapy. Vaccines made from HER2 intracellular domain (ICD) peptide may help the body build an effective immune response to kill tumor cells that express HER2. Polysaccharide-K may stimulate the immune system in different ways and stop tumor cells from growing. It is not yet known whether vaccine therapy works better when given with or without polysaccharide-K in treating breast cancer.

PRIMARY OBJECTIVES:

I. To evaluate the safety of polysaccharide-K (PSK) when given with HER2-directed immunotherapy.

SECONDARY OBJECTIVES:

I. To evaluate the effect of PSK on natural killer (NK) cell functional activity when given with HER2-directed immunotherapy.

TERTIARY OBJECTIVES:

I. To investigate the effect of PSK when given with HER2-directed immunotherapy on: serum levels of pro-inflammatory cytokine and/or chemokines; intermolecular epitope spreading; serum transforming growth factor (TGF)-beta levels; progression free survival (PFS) and overall survival (OS).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive HER2 ICD peptide-based vaccine intradermally (ID) once monthly for 3 months, trastuzumab (or trastuzumab and pertuzumab) per standard of care, and placebo orally (PO) twice daily (BID) for 4 months.

ARM II: Patients receive HER2 ICD peptide-based vaccine ID and trastuzumab (or trastuzumab and pertuzumab) as in Arm I and polysaccharide-K PO BID for 4 months.

After completion of study treatment, patients are followed up for 9 months and then twice annually for 3 years.

Eligibility Criteria:
Inclusion Criteria:

* Patients with stage IV HER2+ breast cancer treated to:

  * No evidence of disease (NED), or
  * Stable bone only disease after definitive therapy
* HER2 overexpression by immunohistochemistry (IHC) of 2+ or 3+ in the primary tumor or metastasis; or documented gene amplification by fluorescent in situ hybridization (FISH) analysis; IHC =\< 2+ must have HER2 gene amplification documented by FISH
* Patients must continue HER2-targeted monoclonal antibody therapy dosing per standard of care through the entire study period (one year)

  * HER2-targeted monoclonal antibody therapy is defined as either trastuzumab monotherapy, or trastuzumab and pertuzumab combination therapy administered per standard of care
* Patients must be at least 21 days post cytotoxic chemotherapy prior to enrollment
* Patients must be at least 28 days post immunosuppressants prior to enrollment
* Patients must be at least 28 days from use of any mushroom supplements (examples: turkey tail, reishi, maitake, shiitake) and agree to withhold them for the entire study period (one year)
* Patients on bisphosphonates and/or endocrine therapy are eligible
* Patients who are having sex that could lead to pregnancy must agree to contraceptive use during the entire study period
* Patients must have Zubrod performance status score of =\< 2
* Patients must have recovered from major infections and/or surgical procedures, and in the opinion of the investigator, not have significant active concurrent medical illnesses precluding study treatment
* White blood cell (WBC) \>= 3000/mm\^3
* Hemoglobin (Hgb) \>= 10 g/dl
* Serum creatinine =\< 2.0 mg/dl or creatinine clearance \> 60 ml/min
* Total bilirubin =\< 1.5 mg/dl
* Serum glutamic oxaloacetic transaminase (SGOT) =\< 2.5 times the upper limit of normal
* Patients must have adequate cardiac function as demonstrated by normal left ventricular ejection fraction (LVEF) \>= the lower limit of normal for the facility on multi gated acquisition (MUGA) scan or echocardiogram (ECHO) within 3 months of enrollment

Exclusion Criteria:

* Patients with any of the following cardiac conditions:

  * Restrictive cardiomyopathy
  * Unstable angina within 6 months prior to enrollment
  * New York Heart Association functional class III-IV heart failure
  * Symptomatic pericardial effusion
* Patients with any contraindication to receiving rhu granulocyte macrophage colony stimulating factor (rhuGM-CSF) based products
* Patients with any clinically significant autoimmune disease requiring active treatment
* Patients receiving any concurrent immunosuppressants
* Patients who are pregnant or breast-feeding
* Patients who are simultaneously enrolled in other treatment studies
* Patients who have received a previous HER2 breast cancer vaccine
* Known hypersensitivity reaction to mushroom products