Inclusion Criteria:
* Invasive adenocarcinoma of the breast diagnosed by core needle biopsy
* Breast cancer determined to be HER2-negative per current American Society of Clinical Oncologists/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) Guidelines (If IHC was performed, IHC 0 or 1+; if fluorescence in situ hybridization (FISH) or other in situ hybridization test, dual probe HER2/Chromosome 17 Centromere (CEP17) ratio \< 2.0 with an average HER2 copy number \< 4.0 signals/cell)
* Breast cancer determined to be hormone receptor-positive or hormone receptor-negative defined as follows:
* Hormone receptor-positive: ≥ 10% staining by IHC for either estrogen receptor (ER) or progesterone receptor (PgR)
* Hormone receptor-negative: \< 10% staining by IHC for both ER and PgR
* Locally advanced breast cancer defined as any of the following per American Joint Committee on Cancer (AJCC) Staging Criteria:
* T2 based on tumor measurements by physical examination or imaging and with clinically positive regional lymph nodes (cN1 or cN2), irrespective of hormone receptor status
* Hormone receptor-negative breast cancer patients with tumor size of 3-5 cm measured by physical examination or imaging with clinically negative regional lymph nodes (cN0)
* Any T3 based on tumor measurements by physical examination or imaging
* Any T4 (including inflammatory breast cancer), irrespective of hormone receptor status
* Ipsilateral axillary lymph nodes must be evaluated by MRI or ultrasound within 12 weeks prior to study registration to determine clinical nodal status. If imaging is suspicious or abnormal, a fine needle aspiration (FNA) or core biopsy of the questionable node(s) on imaging is required. Nodal status should be classified according to the following criteria:
* Nodal status - negative
* Imaging of the axilla is negative; OR
* Imaging of the axilla is suspicious or abnormal AND FNA or core biopsy is negative.
* Nodal status - positive
* FNA or core biopsy of node(s) is cytologically or histologically suspicious or positive
* Breast imaging performed prior to study registration as follows:
* Ipsilateral breast - within 12 weeks
* Contralateral breast - within 24 weeks
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Adequate bone marrow function as defined below:
* Absolute neutrophil count (ANC) ≥ 1,500/mm3
* Platelet count ≥ 100,000/mm3
* Hemoglobin ≥ 10.0 g/dL
* Adequate renal function as defined below:
* Serum creatinine ≤ upper limit of normal (ULN) for the lab or a calculated creatinine clearance ≥ 60 mL/min
* Adequate hepatic function as defined below:
* Total bilirubin ≤ ULN for the laboratory
* Aspartate aminotransferase (AST) ≤ 1.5 x ULN for the laboratory
* Alanine aminotransferase (ALT) ≤ 1.5 x ULN for the laboratory
* Alkaline phosphatase (ALP) ≤ 2.5 x ULN for the laboratory Note: If ALP is \> 1.5 x ULN, imaging to rule out bone and liver metastasis is required.
* Left ventricular ejection fraction (LVEF) assessment (ie, 2-D echocardiogram or multigated acquisition (MUGA) scan) performed within 12 weeks prior to study registration indicates an LVEF ≥ 50% regardless of the cardiac imaging facility's lower limit of normal
* Women who are not postmenopausal or have not undergone hysterectomy must have a documented negative serum pregnancy test within 72 hours prior to initiating study treatment.
Note: Postmenopausal is defined as any of the following:
* Age ≥ 60 years
* Age \< 60 years and amenorrheic for at least 1 year with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range
* Bilateral oophorectomy
* A female patient who is a woman of child-bearing potential (WCBP) and a male patient with a partner who is a WCBP must agree to use a medically accepted method for preventing pregnancy for the duration of immunotherapy and neoadjuvant chemotherapy and until after completion of breast surgery or, for patients who do not receive neoadjuvant chemotherapy, for a minimum of 6 months following the last dose of pembrolizumab or decitabine
* Ability to understand and willingness to sign the consent form
Exclusion Criteria:
* Breast cancer treatment for the currently diagnosed breast cancer including radiation therapy, chemotherapy, targeted therapy, or endocrine therapy prior to study registration
* Administration of a live vaccine within 30 days prior to initiating study treatment Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are permitted; however, intranasal influenza vaccines (eg, Flu-Mist) are live attenuated vaccines, and are not allowed.
* Administration of a monoclonal antibody within 4 weeks prior to initiating study treatment or has not recovered (ie, ≤ grade 1 or at baseline) from adverse events (AEs) due to a monoclonal antibody administered more than 4 weeks earlier
* Administration of any investigational agent within 4 weeks prior to initiating study treatment
* Evidence of metastatic disease that is extensive enough to preclude consideration of subsequent definitive surgery for the primary tumor
* History of ipsilateral invasive breast cancer or ipsilateral ductal carcinoma in situ (DCIS) Note: Patients with history of ipsilateral lobular carcinoma in situ (LCIS) are eligible.
* History of solid organ or allogeneic stem cell transplant
* Previous therapy for any malignancy with an anthracycline or taxane for Cohorts A and B and carboplatin for Cohort A
* Cardiac disease that would preclude administration of the drugs included in the study treatment regimen including, but not limited to:
* Angina pectoris that requires the current use of anti-anginal medication
* Ventricular arrhythmias except for benign premature ventricular contractions
* Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
* Conduction abnormality requiring a pacemaker
* Valvular disease with documented compromise in cardiac function; and symptomatic pericarditis
* Nervous system disorder (ie, paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) ≥ grade 2, per CTCAE v5.0
* Administration of or condition requiring administration of systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to initiating study treatment Exception: Patients with conditions that can be managed with steroids equivalent to or less than an oral prednisone dose of 10 mg daily would not be excluded from the study.
* Previous therapy for this cancer with an anti-anti-programmed death-1 (PD-1), anti-PD-L1, anti-PD-L2 agent, or any other immunomodulatory agent
* Known or presumed hypersensitivity to decitabine or pembrolizumab (or any of their excipients)
* Diagnosed immunodeficiency, eg, human immunodeficiency virus (HIV)
* Active autoimmune disease requiring systemic treatment within the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) or a documented history of clinically severe autoimmune disease or a syndrome that requires systemic steroids or immunosuppressive agents Note: Patients with the conditions or medical history listed below are NOT excluded from this study.
* Vitiligo
* Resolved childhood asthma/atopy
* Requirement for intermittent use of bronchodilators or local steroid injections or topical steroids
* Hypothyroidism stable on hormone replacement
* Sjogren's Syndrome
* Known history or evidence of interstitial lung disease or active, non-infectious pneumonitis
* Known history of active bacillus tuberculosis (TB)
* Active infection requiring systemic therapy
* Known active Hepatitis B or C
* Pregnancy or breastfeeding
* Diagnosis or treatment for another malignancy within 5 years prior to study registration, with the following exceptions: complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, and low-risk prostate cancer after curative therapy
* Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements
