Circulating Tumor DNA Enriched, Genomically Directed Post-neoadjuvant Trial for Patients With Residual Triple Negative Breast Cancer

General Inclusion Criteria

* Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or may be obtained separately.
* Age ≥ 18 years at the time of consent.
* ECOG Performance Status 0 or 1 within 28 days prior to study registration.
* Must have histologically or cytologically confirmed triple negative (ER-/PR-/HER2-) invasive breast cancer per pathology report. NOTE: ER and PR will be considered negative if ≤ 10% of cells stain weakly positive. HER2 will be considered negative if scored 0 or 1+ by immunohistochemistry (IHC) or 2+ by IHC associated with a fluorescence in situ hybridization (FISH) ratio of \< 2.0 or \< 6 copies per cell.
* Must have clinical stage I-III at diagnosis (AJCC 8th edition) based on initial evaluation by physical examination and/or breast imaging prior to neoadjuvant chemotherapy.
* Must have completed preoperative (neoadjuvant) chemotherapy for this index case. NOTE: Acceptable preoperative regimens include an anthracycline or a taxane, or both. Participants who received preoperative therapy as part of a clinical trial may enroll. Participants may not have received adjuvant chemotherapy after surgery prior to registration. Bisphosphonate use is allowed.
* Subjects who received pembrolizumab in the neoadjuvant setting are eligible and may continue treatment during the screening process. Subjects assigned to Arm 1 will require a 3 week wash out period prior to initiation of study treatment. Subjects may resume pembrolizumab to complete the planned year of therapy (17 cycles) after completion of study therapy based on investigator discretion. Subjects assigned to Arm 2 and Arm 3 may continue pembrolizumab treatment during the study based on investigator discretion. Total duration of pembrolizumab treatment should not be extended beyond 17 cycles.
* Must have significant residual invasive disease at the time of definitive surgery following preoperative chemotherapy. Significant residual disease is defined as at least one of the following:

  * Residual invasive disease in the breast measuring at least 1 cm. The presence of DCIS without invasion does not qualify as residual disease in the breast.
  * Any macroscopic, (≥ 2mm) residual, lymph node involvement regardless of primary tumor site involvement (includes no residual disease in the breast).
  * Residual cancer burden (RCB) score 2 or 3.
* Must have completed definitive resection of primary tumor. Participants must begin assigned arm therapy no later than 96 days from the last local therapy. NOTE: Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however participants with positive margins may enroll if the study site treatment team believes no further surgery is possible and participant has received radiotherapy. Participants with margins positive for lobular carcinoma in situ (LCIS) are eligible. Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable.
* Breast Radiotherapy

  * Radiotherapy is required for participants who underwent breast-conserving therapy, including lumpectomy or partial mastectomy unless deemed inappropriate by the treating provider.
  * Post mastectomy radiation is at the discretion of the treating physician.
  * If radiation was given prior to surgery, additional radiation after surgery is not required.
  * In all cases participants must begin arm assigned therapy no later than 96 days from the last local therapy
  * Any acute toxicity must have resolved to grade \< 2 prior to starting arm specific therapy.
* Must consent to allow submission of blood and archived tumor tissue sample from definitive surgery for next generation sequencing of the tumor. Tumor block is preferred however 14 slides + 1H\&E can be submitted if necessary. NOTE: Due to possible false positives, ctDNA should not be drawn before completing radiation or less than 14 days from surgery if radiation is not required.
* Adequate laboratory values must be obtained within 28 days prior to study registration.

  * Hemoglobin (Hgb) ≥ 9.0 g/dL
  * Platelets ≥ 100 K/mm3
  * Absolute neutrophil count (ANC) ≥ 1.5 K/mm3
  * Calculated creatinine clearance of ≥ 50 cc/min using the Cockcroft-Gault formula
  * Bilirubin ≤ 1.5 ULN (except in participants with documented Gilbert's disease, who must have a total bilirubin ≤ 3.0 mg/dL)
  * Aspartate aminotransferase (AST, SGOT) ≤ 2.5 ULN
  * Alanine aminotransferase (ALT, SGPT) ≤ 2.5 ULN
* Women of childbearing potential and their partners and male subjects and their partners must be willing to use effective contraception (as outlined in protocol) from the time consent is signed until after protocol therapy discontinuation based on package insert or investigator brochure guidelines (See protocol for timeframes).
* Women of childbearing potential must have a negative urine or serum pregnancy test at screening and within 7 days prior to study registration. Women should be counseled regarding acceptable birth control methods to utilize. If prior to treatment after discussion with the subject it is felt by the treating physician there is a possibility the subject is pregnant a pregnancy test should be repeated. NOTE: Women are considered not of childbearing potential if they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or they are postmenopausal for at least 12 consecutive months.
* Women must not be breastfeeding from the time of treatment initiation until the number of days after protocol therapy discontinuation based on package insert or investigator brochure guidelines (See protocol for timeframes).

Inclusion Criteria for Patients Assigned to Arm 1c ONLY

-Adequate laboratory values must be obtained within 21 days prior to starting arm therapy.

* Fasting total glucose ≤ 126 mg/dL
* HbA1C ≤ 5.7%
* Cholesterol \< 300 mg/dL; 10.34 mmol/L
* Triglycerides \< 300 mg/dL; 3.42 mmol/L

General Exclusion Criteria

* Clinically significant infections as judged by the treating physician.
* Stage IV (metastatic) disease, however no specific staging studies are required in the absence of symptoms or physical exam findings that would suggest distant disease.
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial. NOTE: Patients without a known history of being HIV positive do not require testing at screening. Patients who are known to be HIV positive will require testing as described to be eligible for this trial. Testing should be considered standard of care.
* Patients with evidence of chronic hepatitis B virus (HBV) infection, with undetectable HBV viral load within 6 months of registration are eligible for this trial. They should be on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable within 6 months of registration to be eligible for this trial. NOTE: Patients without a known history of being hepatitis positive do not require testing at screening. Patients who are known to be hepatitis positive will require testing as described to be eligible for this trial. Testing should be considered standard of care.
* Participants with unstable angina or a myocardial infarction within 12 months of study registration.
* Active second malignancy (except non-melanomatous skin cancer or incidental prostate cancer found on cystectomy): Active second malignancy is defined as a current need for cancer therapy or a high possibility (\> 30%) of recurrence during the study. Previous contralateral breast cancer is allowable unless it meets "active" criteria as stated above.
* Inability to swallow pills.
* Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol, safety of participation, or interpretation of results. This includes significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome) or any other serious medical condition or abnormality in clinical laboratory tests that meet these criteria in the investigator's opinion.
* History of severe allergic, anaphylactic, or other hypersensitivity reactions to any of the study medications being used in this study.
* Treatment with any investigational agent within 30 days prior to study registration.

Exclusion Criteria for Patients Assigned to Arm 1c ONLY

* Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition.
* Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes.
* Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmune-associated uveitis in either eye.
* Symptomatic active lung disease, including pneumonitis
* History of or active inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis). Patients currently receiving immunosuppressants for inflammatory bowel disease (e.g., sulfasalazine) are considered to have active disease and are therefore ineligible.
* Any active bowel inflammation (including diverticulitis)
* Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy. Bisphosphonate and denosumab therapy for bone metastases or osteopenia/osteoporosis is allowed.