This phase I trial studies the side effects and best dose of multiantigen deoxyribonucleic acid (DNA) plasmid-based vaccine in treating patients with human epidermal growth factor receptor 2 (HER2)-negative stage III-IV breast cancer. Multiantigen DNA plasmid-based vaccine may target immunogenic proteins expressed in breast cancer stem cells which are the component of breast cancer that is resistant to chemotherapy and has the ability to spread. Vaccines made from DNA may help the body build an effective immune response to kill tumor cells.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 4 arms.

Arm 1: Patients receive CD105/Yb-1/SOX2/CDH3/MDM2-polyepitope plasmid DNA vaccine with recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) as 1 injection intradermally (ID) every 28 days for 3 months. Patients may also receive 2 additional booster STEMVAC vaccines at 3 and 9 months after the third vaccine in the absence of unacceptable toxicity or disease progression.

ARM 2: Patients receive CD105/Yb-1/SOX2/CDH3/M2-polyepitope plasmid DNA vaccine with rhuGM-CSF as 2 injections ID every 28 days for 3 months. Patients may also receive 2 additional booster STEMVAC vaccines at 3 and 9 months after the third vaccine in the absence of unacceptable toxicity or disease progression.

ARM 3: Patients receive CD105/Yb-1/SOX2/CDH3/MDM2-polyepitope plasmid DNA vaccine with rhuGM-CSF as 3 injections ID every 28 days for 3 months. Patients may also receive 2 additional booster STEMVAC vaccines at 3 and 9 months after the third vaccine in the absence of unacceptable toxicity or disease progression.

ARM 4: Patients receive CD105/Yb-1/SOX2/CDH3/MDM2-polyepitope plasmid DNA vaccine with rhuGM-CSF as 2 injections ID every 28 days for 3 months. Patients may also receive 1 additional STEMVAC vaccine at 3 months after the third vaccine in the absence of unacceptable toxicity or disease progression.

After completion of study treatment, patients are followed up twice yearly for up to 5 years.

Inclusion Criteria:

• Patients with stage III-IV HER2 negative breast cancer treated with primary or salvage therapy and now have:

  • No evidence of disease (NED), or
  • Stable bone only disease

• Patients who have completed standard of care and recovered with mild to no residual toxicity from recent therapy

• Patients must be at least 28 days post cytotoxic chemotherapy, and/or monoclonal antibody therapy (excluding bone-directed therapy), prior to enrollment

• Patients must be at least 28 days post systemic steroids prior to enrollment

• Patients on bisphosphonates, denosumab, and/or endocrine therapy are eligible

• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status score of =< 1

• Patients must have recovered from major infections and/or surgical procedures, and in the opinion of the investigator, not have any significant active concurrent medical illnesses precluding protocol treatment

• Estimated life expectancy of more than 6 months

• White blood cells (WBC) >= 3000/mm^3 (within 30 days of first vaccination)

• Lymphocyte count >= 800/mm^3 (within 30 days of first vaccination)

• Platelet count >= 75,000/mm^3 (within 30 days of first vaccination)

• Hemoglobin (Hgb) >= 10 g/dl (within 30 days of first vaccination)

• Serum creatinine <= 1.2 mg/dl or creatinine clearance > 60 ml/min (within 30 days of first vaccination)

• Total bilirubin <= 1.5 mg/dl (within 30 days of first vaccination)

• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) <= 2 times upper limit of normal (ULN) (within 30 days of first vaccination)

• Blood glucose < 1.5 ULN (within 30 days of first vaccination)

• All patients who are having sex that can lead to pregnancy must agree to contraception for the duration of study

Exclusion Criteria:

• Patients with any of the following cardiac conditions:

  • Symptomatic restrictive cardiomyopathy
  • Unstable angina within 4 months prior to enrollment
  • New York Heart Association functional class III-IV heart failure on active treatment
  • Symptomatic pericardial effusion

• Patients at risk for gastrointestinal bleeding (example: peptic ulcer disease, prolonged daily non-steroidal anti-inflammatory use)

• Patients with any seizure disorder

• Patients with any contraindication to receiving rhuGM-CSF based products

• Patients with any clinically significant autoimmune disease uncontrolled with treatment

• Patients who are simultaneously enrolled in any other treatment study

• Patients who are pregnant or breastfeeding