This phase II trial studies how well Akt inhibitor MK2206 works in treating patients with breast cancer cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine whether v-akt murine thymoma viral oncogene (Akt) inhibitor MK2206 achieves objective tumor responses (complete response [CR], partial response [PR]) in advanced breast cancer patients who have a phosphoinositide-3-kinase, catalytic, alpha polypeptide (PIK3CA) or Akt mutation and/or phosphatase and tensin homolog (PTEN) loss or mutation.

SECONDARY OBJECTIVES:

I. To determine the 6 month progression-free survival on MK2206. II. To determine baseline molecular markers that may predict clinical outcome. III. To determine pharmacodynamic markers in blood and tumor tissue that may predict a decrease in proliferation-related Ki-67 antigen (Ki-67) and clinical outcome.

IV. To determine safety and tolerability of MK2206 in previously treated patients with advanced breast cancer.

V. To determine if decrease in Ki-67 at 2 weeks correlates with anti-tumor effect (CR, PR, or stable disease [SD] > 6 months).

VI. To determine concordance of PIK3CA and PTEN status between primary tumor and distant metastasis.

VII. To determine concordance of PIK3CA status of circulating free deoxyribonucleic acid (DNA) and distant metastasis.

OUTLINE:

Patients receive Akt Inhibitor MK-2206 orally (PO) on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 weeks.

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed breast cancer, with diagnosed or suspected metastatic, inoperable locally advanced breast cancer, or inoperable locally recurrent breast cancer
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan
• Patients who have failed to respond to at least one line of systemic therapy are eligible for MK2206 therapy; if the patient has a human epidermal growth factor receptor 2 (HER2) positive tumor, it is expected that they will have received at least one HER2-targeted therapy in the metastatic setting; if the patient has an estrogen receptor positive (ER+) tumor, it is expected that they will have received at least one ER-targeted therapy in the metastatic setting; patients can be enrolled for molecular screening while on another therapy if the patient is interested in MK2206 therapy upon progression
• Archived primary tumor biopsies or surgical specimens, or biopsies of recurrence or metastasis, will be available for PIK3CA/Akt mutational analysis and PTEN analysis; patients with surgical samples, or core/punch biopsies available, will be eligible for testing for PIK3CA/Akt status as well as PTEN testing; the most recent sample will be preferred (i.e. in patients with metastatic disease, metastases samples are preferred over archival primary tumor and in patients with local recurrences a biopsy of the recurrence is preferred over archival primary tumor); NOTE: PIK3CA or Akt mutation status can be determined on fine needle aspirate (FNA) samples, but PTEN status cannot as stroma and endothelial cells are used as internal controls and PTEN testing has not been validated on FNA samples; thus patients with only FNA samples and no tissue blocks available will be considered to be eligible for screening for PIK3CA/Akt mutations and will be enrolled onto the study only if they are found to have PIK3CA mutations or Akt mutations; patients whose tumors have already been tested in the Clinical Laboratory Improvement Amendments (CLIA) environment and have been found to have a PIK3CA mutation or Akt mutation or PTEN loss by immunohistochemistry (IHC) or PTEN mutation will be eligible for treatment; patients whose tumors have been tested in the research environment and found to have a PIK3CA mutation or Akt mutation or PTEN loss or PTEN mutation will have their marker status confirmed in the CLIA environment
• Patients whose tumors have already been tested in the CLIA environment and have been found to have a PIK3CA mutation or Akt mutation or PTEN loss or mutation will be eligible for treatment; patients whose tumors have been tested in the research environment and found to have a PIK3CA mutation or Akt mutation or PTEN loss or mutation will have their marker status confirmed in the CLIA environment.
• Patient will have a tumor suitable for FNA and/or core/punch biopsy for research purposes
• Patient must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count (ANC) >= 1,000/uL
• Platelets >= 100,000/uL
• Hemoglobin (Hgb) >= 9 g/dL
• Creatinine =< 1.5 X upper limit of normal (ULN)
• Prothrombin time (PT), partial thromboplastin time (PTT) =< 1.2 X ULN
• Total bilirubin =< 1.5 X ULN
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 X ULN
• Patients of childbearing potential must have a negative serum or urine pregnancy test beta-human chorionic gonadotropin (hCG) within 72 hours prior to study registration
• Women of childbearing potential and men must use two forms of contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and also for 4 weeks after the end of therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately
• Patient must have completed any systemic therapy regimens and therapeutic radiation a minimum of 21 days prior to initiation of study therapy
• Ability to understand and the willingness to sign a written informed consent document
• >= 6 months life expectancy as documented in patient records

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events to grade 1 or less due to agents administered more than 3 weeks earlier
• Patients may have received prior investigational therapies; however, they not be receiving any other investigational agents concurrent with MK2206; patients must have completed therapy a minimum of 21 days prior to initiation of study therapy
• Patients may not have received treatment with another inhibitor of phosphatidylinositol 3 kinase (PI3K), Akt or mammalian target of rapamycin (mTOR) in the neoadjuvant, adjuvant or metastatic setting with the exception of rapalogs; patients with metastatic breast cancer, who received PI3K/Akt/mTOR inhibitors on short preoperative window trials (treatment for 4 weeks or less), will be eligible if the treatment was over 6 months prior to registration; patients must have completed therapies a minimum of 21 days prior to initiation of study therapy
• Patients with known brain metastases should be excluded from this clinical trial; patients will not undergo pre-treatment imaging of the brain, unless clinically indicated
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK2206 or other agents used in the study
• Patients receiving any medications or substances that are potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP 450 3A4) are ineligible; however, patients will be permitted regular dietary consumption of caffeine; glyburide will be allowed for the treatment of hyperglycemia
• Patients with diabetes or in risk for hyperglycemia should not be excluded, but patients with poorly controlled diabetes (glycated hemoglobin [HBA1C] > 8%) should be excluded
• Baseline corrected QT by Fridericia's formula (QTcF) > 450 msec (male) or QTcF >b470 msec (female) will exclude patients from entry on study
• 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
• Baseline bradycardia related to cardiac disease, or significant bundle branch block
• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MK2206
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
• Patients at high risk for coagulopathy
• Liver disease burden greater or equal to 50 percent
• Need for blood or platelet transfusion within one month from baseline laboratory testing as well as within treatment initiation