This phase II trial studies how well nelipepimut-S plus GM-CSF vaccine therapy or sargramostim works in treating patients with breast cancer. Vaccines made from peptide or antigen and/or a person's white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells that express breast cancer antigens. It is not yet known whether nelipepimut-S plus GM-CSF vaccine or sargramostim is more effective in treating patients with breast cancer.

PRIMARY OBJECTIVE:

I. Evaluate for nelipepimut-S-specific cytotoxic T lymphocyte (CTL; cluster of differentiation [CD]8+ T cell) response in patients receiving NeuVax (nelipepimut-S plus GM-CSF [sargramostim]) compared to patients receiving GM-CSF alone (control).

SECONDARY OBJECTIVES:

I. Toxicity profile and frequency of adverse events in women with ductal carcinoma in situ (DCIS) of the breast receiving nelipepimut-S vaccine as compared to women receiving GM-CSF alone.

II. Presence of DCIS at resection. III. Difference in HER2 expression in the biopsy and the surgical specimen excised post-vaccination.

IV. Histologic responses:

IVa. Degree of lymphocyte infiltration determined on hematoxylin and eosin (H&E) stained slides and immune infiltration as determined by multiplex immunofluorescence staining for markers including but not limited to CD3, CD4 and CD8.

IVb. Immune infiltrates in normal tissue maximally distant from the tumor (in mastectomy samples).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nelipepimut-S plus GM-CSF vaccine intradermally (ID) on days 0 and 14 and then undergo surgery on day 28.

ARM II: Patients receive sargramostim ID on days 0 and 14 and then undergo surgery on day 28.

After completion of study treatment, patients are followed up at 1 and 3 months.

Inclusion Criteria:

• Participants must be pre- or post-menopausal
• Participants must have a diagnosis of DCIS made by core needle biopsy
• Participants must be human leukocyte antigen (HLA)-A2 positive
• Eastern Cooperative Oncology Group (ECOG) performance status must be 0 or 1 (Karnofsky >= 60%)
• Clinical chemistry less than 2 x normal upper limit of normal range
• Platelets >= 100,000/mm^3
• Hemoglobin >= 10 g/dL
• Blood urea nitrogen < 2 x upper limit of normal (ULN)
• Alkaline phosphatase < 2 x ULN
• Lactate dehydrogenase < 2 x ULN
• Creatinine < 2 x ULN
• Bilirubin < 2 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2 x ULN
• A normal ejection fraction, as defined by the participant's institution; only limited echocardiograms (ECHOs) will be used as cardiac evaluation; no other tests are allowed; ECHO is to be done only in HLA-A2 positive participants; if ECHO has been done within 30 days prior to randomization and results showing a normal ejection fraction have been obtained prior to randomization, an additional ECHO is not needed at baseline
• Willingness to comply with all study interventions and follow-up procedures
• The ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

• Invasive breast cancer; areas of microinvasion or suspicious for microinvasion on the core biopsy is allowed
• History of prior breast cancer treated within the past two years; patients completing all breast cancer-specific treatment over two years prior to the current diagnosis are eligible
• History of prior ductal carcinoma in situ (DCIS) treated within the past two years; patients completing all treatment for a previous diagnosis of DCIS over two years prior to the current diagnosis are eligible
• Prior lobular carcinoma in situ (LCIS) is allowed
• Pregnant, unwilling to use adequate contraception during study treatment duration or breastfeeding; the effects of NeuVax on the developing human fetus are unknown; for this reason and because NeuVax may be teratogenic, pregnant women will be excluded; all heterosexually active women who may become pregnant must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation OR be post-menopausal defined as any one of the following 1) prior hysterectomy, 2) absence of menstrual period for 1 year in the absence of prior chemotherapy or 3) absence of menstrual period for 2 years in women with a prior history of chemotherapy exposure who were pre-menopausal prior to chemotherapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
• Any autoimmune disease or other medical condition that, in the opinion of the investigator, would compromise the subject's safety
• Immune deficiency diseases such as immunoglobulin deficiency or immunosuppressive therapy that might interfere with appropriate immune response
• Known history of or known active infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C
• Patients on chronic steroid therapy or other immunosuppressive therapy except for topical or inhaled steroids known to have low systemic absorption
• Patients with a known hypersensitivity to GM-CSF, yeast-derived products, or any component of the GM-CSF product (e.g., mannitol)
• Concurrent treatment with other investigational agent
• History of non-breast malignancy within 5 years prior to randomization, except curatively treated superficial bladder cancer, carcinoma in situ of the cervix (stage 0-1), and basal cell or squamous cell carcinoma of the skin
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to NeuVax
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• No recent or planned immunotherapy