Copanlisib, Letrozole, and Palbociclib in Treating Patients With Hormone Receptor Positive HER2 Negative Stage I-IV Breast Cancer

Inclusion Criteria:

* Post-menopausal (if female) defined as: 1) prior bilateral oophorectomy, 2) age 60 or over, or 3) \< 60 years and amenorrheic for at least 12 months with follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range per institutional parameters); use of luteinizing hormone-releasing hormone (LHRH) agonists to induce chemical ovarian ablation will not be allowed for this study
* Tumor is hormone receptor (HR)+ (estrogen receptor and/or progesterone receptor positive with at least 10% expression of either receptor by local immunohistochemical staining) and HER2 negative based on local assessment
* FOR PHASE Ib PORTION OF THE STUDY:
* Locally advanced/non-operable or metastatic breast cancer that has not been previously treated in the metastatic setting with systemic therapy (i.e. first line treatment)
* Measurable disease per RECIST 1.1
* FOR PHASE II PORTION OF THE STUDY:
* Clinical stage I (breast tumor \>= 1.0 cm in diameter), stage II or stage III breast cancer (according to the American Joint Committee on Cancer \[AJCC\] Staging Manual, 7th Edition, 2010); multifocal disease is allowed if confined to 1 breast, as long as one tumor is at least 1 cm and meets all of the other inclusion criteria
* Breast cancer suitable for mandatory baseline core biopsy
* No prior systemic therapy or radiotherapy for currently-diagnosed invasive or noninvasive breast cancer
* FOR ALL PHASES (Ib AND II):
* Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L
* Platelets \> 100 x 10\^9/L
* Hemoglobin \>= 8 g/dL (phase Ib) or \>= 10 g/dL (for phase II portion)

  * For phase Ib portion only: patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator; however, initial study drug treatment must not begin earlier than the day of the erythrocyte transfusion
* Bilirubin =\< 1.5 times the upper limit of normal (ULN)
* Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3.0 times ULN
* Subjects with Gilbert's syndrome, confirmed by genotyping or Invader UGTIA1 molecular assay prior to study entry, must have total bilirubin \< 3.0 times ULN
* Serum creatinine =\< 1.5 times ULN
* Lipase =\< 1.5 x ULN
* International normalized ratio (INR) and partial thromboplastin time (PTT) \< 1.5 x ULN
* Left ventricular ejection fraction (LVEF) \>= 50%
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Exclusion Criteria:

* FOR PHASE Ib ONLY:
* Early stage (curable) breast cancer
* FOR PHASE II ONLY:
* Metastatic breast cancer (local spread to axillary or internal mammary lymph nodes is permitted)
* Prior systemic therapy for invasive or non-invasive (DCIS) breast cancer
* Prior radiotherapy to the ipsilateral chest wall or breast for any malignancy
* Bilateral invasive breast cancer
* FOR ALL PHASES (Ib AND II): Inflammatory breast cancer
* FOR ALL PHASES (Ib AND II): Concurrent therapy with any other non-protocol anti-cancer therapy
* FOR ALL PHASES (Ib AND II): History of any other malignancy within the past 5 years, with the exception of non-melanoma skin cancer or carcinoma-in-situ of the cervix
* FOR ALL PHASES (Ib AND II): Concurrent diagnosis of pheochromocytoma
* FOR ALL PHASES (Ib AND II): Current therapy with raloxifene, tamoxifen, aromatase inhibitor, or other selective estrogen receptor modulator (SERM), either for osteoporosis or prevention of breast cancer; subjects must have discontinued therapies for at least 28 days prior to first baseline biopsy
* FOR ALL PHASES (Ib AND II): Concurrent treatment with postmenopausal hormone replacement therapy; prior treatment must be stopped for at least 28 days prior to first baseline biopsy
* FOR ALL PHASES (Ib AND II): Type I diabetes or patients on insulin therapy are not allowed; uncontrolled type II diabetes not allowed (glycosylated hemoglobin \[HbA1c\] \> 7.5)
* FOR ALL PHASES (Ib AND II): Proteinuria of \>= Common Terminology Criteria for Adverse Events (CTCAE) grade 3 as estimated by urine protein : creatinine ratio \> 3.5 on a random urine sample
* FOR ALL PHASES (Ib AND II): Uncontrolled arterial hypertension despite optimal medical management
* FOR ALL PHASES (Ib AND II): Hepatitis B (HBV) or hepatitis C (HCV); all patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel
* FOR ALL PHASES (Ib AND II): Known history of human immunodeficiency virus (HIV) infection
* FOR ALL PHASES (Ib AND II): Uncontrolled infection; active, clinically serious infections (\> CTCAE grade 2)
* FOR ALL PHASES (Ib AND II): History of significant cardiac disease:

  * Congestive heart failure \> New York Heart Association (NYHA) class 2
  * Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
  * Myocardial infarction less than 6 months before start of test drug
  * Anti-arrhythmic therapy (beta blockers or digoxin are permitted)
* FOR ALL PHASES (Ib AND II): Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication
* FOR ALL PHASES (Ib AND II): Participants receiving anticoagulation therapy are not allowed
* FOR ALL PHASES (Ib AND II): Patients with evidence or history of bleeding diathesis; any hemorrhage or bleeding event \>= CTCAE grade 3 within 4 weeks of start of study medication
* FOR ALL PHASES (Ib AND II): Blood or platelet transfusion within 7 days prior to treatment start
* FOR ALL PHASES (Ib AND II): Non-healing wound or ulcer
* FOR ALL PHASES (Ib AND II): History of, or current autoimmune disease
* FOR ALL PHASES (Ib AND II): Major surgical procedure or significant traumatic injury (as judged by the investigator) within 28 days before start of study medication, open biopsy within 7 days before start of study medication
* FOR ALL PHASES (Ib AND II): Patients with seizure disorder requiring medication
* FOR ALL PHASES (Ib AND II): Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
* FOR ALL PHASES (Ib AND II): Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not allowed; patients may be using topical or inhaled corticosteroids; previous corticosteroid therapy must be stopped or reduced to the allowed dose at least 7 days prior to the first study drug administration; if a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose after the patient has signed the consent document
* FOR ALL PHASES (Ib AND II): History of having received an allogeneic bone marrow or organ transplant
* FOR ALL PHASES (Ib AND II): Chronic oxygen therapy