This phase II trial tests reduced post surgery (adjuvant) therapy for patients with early breast cancer who have confirmed that the disease has responded completely (pathologic complete response) after pre surgical treatment (neoadjuvant) therapy and do not have any tumor genetic material (molecular residual disease) circulating in their blood. Standard of care treatment after surgery consists of 1 year of pembrolizumab for patients with triple negative breast cancer or trastuzumab with or without pertuzumab to complete 1 year of treatment. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pertuzumab and trastuzumab are monoclonal antibodies and forms of targeted therapy that attach to a receptor protein called HER2. HER2 is found on some cancer cells. When pertuzumab or trastuzumab attach to HER2, the signals that tell the cells to grow are blocked and the tumor cell may be marked for destruction by the body's immune system. Lowering the total amount of cancer therapy after breast surgery, may continue to keep the great tumor response to treatment, and may help lower the amount of side effects patients have.

PRIMARY OBJECTIVES:

I. To determine the 3-year event free survival (EFS) after breast surgery in patients with early triple negative breast cancer (TNBC) that achieve a pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) with a pembrolizumab plus chemotherapy-based regimen and are minimal residual disease (MRD)-negative (negative circulating tumor deoxyribonucleic acid [ctDNA] with the NeXT Personal™ assay) at 4-6 weeks after breast surgery and discontinue standard of care (SOC) adjuvant pembrolizumab.

II. To determine the 3-year EFS after breast surgery in patients with early HER2+ breast cancer that achieve a pCR after NST with a trastuzumab and pertuzumab plus chemotherapy-based regimen and are MRD-negative (negative ctDNA with the NeXT Personal™ assay) at 4-6 weeks after breast surgery and discontinue SOC adjuvant trastuzumab and pertuzumab.

SECONDARY OBJECTIVES:

I. To estimate the rate of conversion from negative to positive ctDNA and time to conversion from negative to positive ctDNA among patients who undergo de-escalation of SOC adjuvant systemic therapy.

II. To establish the prevalence of patients with early TNBC or early HER2+ breast cancer who achieve a pCR after receiving NST and have a positive ctDNA with the NeXT Personal™ assay at 4-6 weeks after breast surgery.

III. To determine the 3-year EFS after breast surgery in patients with early HER2+ breast cancer or early TNBC that achieve a pCR after NST and have a positive ctDNA with the NeXT Personal™ assay at 4-6 weeks after breast surgery.

OUTLINE: Patients with triple negative breast cancer are assigned to cohort 1, patients with HER2 positive breast cancer are assigned to cohort 2.

COHORT 1: Patients may receive 1 to 3 cycles of standard of care treatment with pembrolizumab. Patients with a positive ctDNA test 4-6 weeks after surgery continue to receive standard of care treatment per their treating physician in the absence of disease progression or unacceptable toxicity. Patients with a negative ctDNA test will not receive further treatment with pembrolizumab and will undergo monitoring with ctDNA tests every 3 months for 3 years in the absence of disease progression.

COHORT 2: Patients may receive 1 to 3 cycles of standard of care treatment with trastuzumab with or without pertuzumab. Patients with a positive ctDNA test 4-6 weeks after surgery continue to receive standard of care treatment per their treating physician in the absence of disease progression or unacceptable toxicity. Patients with a negative ctDNA test will not receive further treatment with pembrolizumab and will undergo monitoring with ctDNA tests every 3 months for 3 years in the absence of disease progression. Patients may receive standard of care endocrine therapy per their treating physician throughout the study.

Inclusion Criteria:

• EARLY HER2 POSITIVE (+) BREAST CANCER COHORT: Female or male with a diagnosis of biopsy proven invasive breast cancer HER2+, hormone (estrogen and progesterone)-receptor positive or negative. The HER2 status (following American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines) and hormone-receptor status will be determined according to institutional (local) guidelines
• EARLY TNBC COHORT: Female or male with a diagnosis of biopsy proven invasive TNBC (estrogen and progesterone receptor < 10%). The HER2 status (following ASCO/CAP guidelines) and hormone-receptor status will be determined according to institutional (local) guidelines
• FOR BOTH HER2+ AND TNBC COHORTS: Invasive breast cancer of any tumor histologic grade and/or nuclear grade, and any tumor histological subtype including but not limited to infiltrating ductal carcinoma, infiltrating lobular carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, and mixed histology
• FOR BOTH HER2+ AND TNBC COHORTS: Clinical tumor stage (per American Joint Committee on Cancer [AJCC] 8th edition): T1-4, N0-2a, M0. Patients who have a diagnosis of inflammatory breast cancer are eligible. Patients should not have clinical evidence of locoregional or distant metastatic breast cancer
• EARLY HER2+ BREAST CANCER COHORT: Have completed NST with a trastuzumab plus pertuzumab and chemotherapy-based regimen (for example, docetaxel plus minus carboplatin plus trastuzumab plus pertuzumab known as the docetaxel/pertuzumab/trastuzumab [THP]/carboplatin/paclitaxel/pertuzumab/trastuzumab [TCHP] regimens) followed by definitive breast surgery where the surgical pathology reports a pCR (ypT0-Tis, ypN0) and are willing to discontinue adjuvant trastuzumab plus pertuzumab
• EARLY TNBC COHORT: Have completed NST with a pembrolizumab plus chemotherapy-based regimen (for example, the KEYNOTE-522 regimen which is paclitaxel plus carboplatin plus pembrolizumab followed by doxorubicin plus cyclophosphamide plus pembrolizumab) followed by definitive breast surgery where the surgical pathology reports a pCR (ypT0-Tis, ypN0) and are willing to discontinue adjuvant pembrolizumab
• The surgical pathology report needs to show a pCR (ypT0-Tis, ypN0) for a patient to be able to participate in this study and all enrolled patients should be willing to discontinue standard adjuvant systemic therapy
• FOR BOTH HER2+ AND TNBC COHORTS: Adequate archival tumor tissue from the core diagnostic biopsy (per Personalis)
• FOR BOTH HER2+ AND TNBC COHORTS: Age ≥ 18 years
• FOR BOTH HER2+ AND TNBC COHORTS: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• FOR BOTH HER2+ AND TNBC COHORTS: Absolute neutrophil count ≥ 1,000/mcL
• FOR BOTH HER2+ AND TNBC COHORTS: Hemoglobin ≥ 9.0 g/dL
• FOR BOTH HER2+ AND TNBC COHORTS: Platelets ≥ 100,000/mcL
• FOR BOTH HER2+ AND TNBC COHORTS: Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN); patients with Gilbert's syndrome (if direct bilirubin <1.5 x institutional ULN)
• FOR BOTH HER2+ AND TNBC COHORTS: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × institutional ULN
• FOR BOTH HER2+ AND TNBC COHORTS: Creatinine ≤ 1.5 mg/dL
• FOR BOTH HER2+ AND TNBC COHORTS: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• FOR BOTH HER2+ AND TNBC COHORTS: 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, they are eligible if they have an undetectable HCV viral load
• FOR BOTH HER2+ AND TNBC COHORTS: Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible
• FOR BOTH HER2+ AND TNBC COHORTS: Pre- and postmenopausal women are eligible
• FOR BOTH HER2+ AND TNBC COHORTS: Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients with tumor stage of cN2b or cN3 are not eligible
• History of other malignancies besides breast cancer within the past 5 years, except cervical cancer in situ, melanoma in situ, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin
• Patients who are receiving any other anti-cancer investigational agents
• Patients with known cancer metastases from any site
• Patients with uncontrolled intercurrent illness including but not limited to active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic cardiac arrythmias
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Blood transfusion within 2 weeks before collection of blood for ctDNA testing
• Patients who have received 4 or more cycles of SOC adjuvant trastuzumab/pertuzumab (HER2+) or 4 or more cycles of SOC adjuvant pembrolizumab (TNBC)
• Pregnant women are not eligible to participate in this study