Genomically Directed Therapy with Capecitabine after Surgery for the Treatment of Residual Stage I-III Invasive Triple Negative Breast Cancer, PERSEVERE study

Inclusion Criteria

• Written informed consent and Health Insurance Portability and Accountability Act (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
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 21 days prior to study registration
• Must have clinical stage I-III at diagnosis (American Joint Committee on Cancer [AJCC] 8th edition) based on initial evaluation by physical examination and/or breast imaging prior to neoadjuvant chemotherapy
• Must have histologically or cytologically confirmed triple negative (estrogen receptor negative [ER-]/progesterone receptor negative [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 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 receiving pembrolizumab 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 assigned to Arm 2 and Arm 3 may continue pembrolizumab treatment during the study based on investigator discretion
• Must have significant residual invasive disease immediately prior to 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 ductal carcinoma in situ (DCIS) without invasion does not qualify as residual disease in the breast * Any macroscopic, >= 2 mm, 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. For those that do not require radiotherapy, the most recent surgery for breast cancer must have been completed no more than 84 days prior to study registration * 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 * 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 register no later than 84 days from the last local 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
• Hemoglobin (Hgb) >= 9.0 g/dL (within 21 days prior to study registration)
• Platelets >= 100 K/mm^3 (within 21 days prior to study registration)
• Absolute neutrophil count (ANC) >= 1.5 K/mm^3 (within 21 days prior to study registration)
• Calculated creatinine clearance of >= 50 cc/min using the Cockcroft-Gault formula (within 21 days prior to study registration)
• Bilirubin =< 1.5 x upper limit of normal (ULN) (except in participants with documented Gilbert’s disease, who must have a total bilirubin =< 3.0 mg/dL) (within 21 days prior to study registration)
• Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x ULN (within 21 days prior to study registration)
• Alanine aminotransferase (ALT, serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x ULN (within 21 days prior to study registration)
• Women of childbearing potential and their partners and male subjects and their partners must be willing to use effective contraception from the time consent is signed until after protocol therapy discontinuation based on package insert or investigator brochure guidelines
• Women of childbearing potential must have a negative 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
• ARM 1C ONLY: Fasting total glucose =< 126 mg/dL (within 21 days prior to study registration)
• ARM 1C ONLY: Glycosylated hemoglobin (HbA1C) =< 5.7% (within 21 days prior to study registration)
• ARM 1C ONLY: Cholesterol < 300 mg/dL; 10.34 mmol/L
• ARM 1C ONLY: Triglycerides < 300 mg/dL; 3.42 mmol/L

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
• Human immunodeficiency virus (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, the HBV viral load must be undetectable 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 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
• 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
• ARM 1C ONLY: Type 2 diabetes requiring ongoing systemic treatment at the time of study entry
• ARM 1C ONLY: 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
• ARM 1C ONLY: Symptomatic active lung disease, including pneumonitis
• ARM 1C ONLY: History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis). Patients currently receiving immunosuppressants for inflammatory bowel disease (e.g., sulfasalazine) are considered to have active disease and are therefore ineligible
• ARM 1C ONLY: Any active bowel inflammation (including diverticulitis)
• ARM 1C ONLY: Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy. Bisphosphonate and denosumab therapy for bone metastases or osteopenia/osteoporosis is allowed