MARGetuximab Or Trastuzumab (MARGOT)

Inclusion Criteria:

• Stage II or III (according to AJCC cancer staging manual anatomic staging table, 8thedition) histologically confirmed invasive carcinoma of the breast. A minimum tumorsize of 1.5 cm (in breast mass or axillary lymph node) determined by physical examor imaging (whichever is larger) is required. Patients with inflammatory breastcarcinoma (T4d) are NOT eligible.

• Centrally confirmed to have a low affinity CD16 germline genotype (FF or FV)

• HER-2 positive by 2018 American Society of Clinical Oncology/College of AmericanPathologists criteria, as assessed by standard institutional guidelines (centraltesting is not required).

• ER/PR determination is required. ER- and PR-assays should be performed byimmunohistochemical methods according to standard institutional guidelines

• Bilateral breast cancers are allowed as long as both cancers are HER2-positive (asdefined in 3.1.2), or the contralateral cancer is a <1 cm, ER+ tumor.

• Patients with multifocal or multicentric disease are eligible if the treatinginvestigator hasdetermined the patient should be treated as HER2-positive.

• Breast imaging should include dedicated ultrasound of the ipsilateral axilla. Forsubjects with a clinically positive axilla based on exam or imaging, a fine needleaspiration or core biopsy procedure will be performed to determine the presence ofmetastatic disease in the lymph nodes (though lymph node sampling procedure need notbe resulted prior to patient's registration on trial, as long as all othereligibility are met).

• Men and women (with any menopausal status) ≥18 years of age are eligible.

• ECOG performance status 0 or 1

• Required laboratory values demonstrating adequate organ function:

• ANC ≥ 1000/mm3

• Hemoglobin ≥ 9 g/dl

• Platelets ≥ 100,000/mm3

• Serum creatinine < 1.5 x ULN (institutional) OR calculated GFR ≥ 60mL/min

• Total bilirubin ≤ 1.5 x ULN (institutional). For patients with GilbertSyndrome, the direct bilirubin should be within the institutional normal rangeOR total bilirubin ≤ 2.0 mg/dL.

• AST and ALT ≤ 2.5x ULN (institutional) Left ventricular ejection fraction (LVEF) ≥ 50%.

• Women of childbearing potential must have a negative serum pregnancy test within 14days of treatment start. Childbearing potential is defined as: those who have notbeen surgically sterilized and/or have had a menstrual period in the past 12 months

• Women of childbearing potential and men with partners of childbearing potential mustbe willing to use one highly effective form of non-hormonal contraception or twoeffective forms of non-hormonal contraception by the patient and/or partner andcontinue its use for the duration of the study treatment and for 7 months after thelast dose of study treatment.

• Patients with a history of ipsilateral or contralateral DCIS or LCIS are eligible.

• Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have anycontraindications to radiation therapy.

• Non-English-speaking patients are eligible but will be exempt from patient-completedquestionnaires.

• Willing and able to sign informed consent.

• Willing to undergo breast biopsy for research purposes.

Exclusion Criteria:

• Pregnant or nursing women due to the teratogenic potential of the study drugs.

• Active, unresolved infection requiring intervention

• Receipt of intravenous antibiotics for infection within 7 days prior toregistration.

• Uncontrolled hypertension (systolic >180 mm Hg and/or diastolic >100 mm Hg) orclinically significant (i.e. active) cardiovascular disease: cerebrovascularaccident/stroke or myocardial infarction within 6 months prior to first studymedication, unstable angina, congestive heart failure (CHF) of New York HeartAssociation (NYHA) Class II or higher, or serious cardiac arrhythmia requiringmedication.

• Significant symptoms (Grade ≥ 2) from peripheral neuropathy.

• Other concurrent serious diseases that may interfere with planned treatment,including severe pulmonary conditions/illness, uncontrolled infections, uncontrolleddiabetes.

• Any prior treatment for the current breast cancer, including chemotherapy, hormonaltherapy, radiation, or experimental therapy.

• Patients with any prior history of invasive breast cancer within the past 5 yearsare not eligible. Non-metastatic invasive breast cancers diagnosed more than 5 yearsago and any other type of prior non-metastatic cancer is allowed.