CompassHER2-pCR: Decreasing Chemotherapy for Breast Cancer Patients After Pre-surgery Chemo and Targeted Therapy

Inclusion Criteria:

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance statusof 0 or 1

• Patient must have histologically confirmed HER2-positive primary invasive breastcarcinoma, determined by local testing. The tumor must have either HER2 IHC resultof 3+ or HER2/CEP17 ratio > 2 with > 4.0 HER2 signals per cell by ISH. Tumors withHER2/CEP17 ISH ratio < 2 are ineligible, even if HER2 copy number is > 6, unlessHER2 IHC result is 3+.

• Patients hormone receptor (estrogen receptor [ER] and progesterone receptor [PR])status must be known and will be determined by local testing. Patients with eitherhormone receptor -positive or hormone receptor- negative HER2-positive breast cancerare eligible

• Patients must have AJCC 8th Edition stage II or IIIa according to anatomic stagingtable at diagnosis

• Patients without nodal involvement (cN0) are eligible if T size > 2.0 cm (T2-3)

• Patients with nodal involvement (cN1-2) are eligible if T1-3

• Patients with clinical T4 or N3 disease are not eligible

• Patient must be willing and able (i.e., have no contraindication) to receivestandard adjuvant therapy, consisting of HER2-directed therapy, radiation (ifindicated) and endocrine therapy (if ER+) if achieving pCR at surgery

• Patient with bilateral invasive breast cancers are eligible if both cancers areHER2-positive (as defined in 3.1.3) at least one meets protocol eligibility andneither cancer renders the patient ineligible (i.e. per eligibility 3.1.5)

• Patients with multiple ipsilateral invasive tumors are eligible as long as alltumors are HER2-positive, and at least one tumor focus meets eligibility criteria (per eligibility 3.1.5). Multiple lesions that appear part of the same index tumordo not require additional biopsy/HER2 testing. Multiple lesions that appear part ofthe same index tumor do not require additional biopsy/HER2 testing. However, even ifbiopsy is not deemed necessary, consideration should be given to placing a clip inany lesion that is 1 cm or further from the primary tumor to ensure that all tumoris removed at surgery AND that the pathologist can locate all primary sites of tumorto assess pathologic response at surgery.

• Patients with a history of other non-breast malignancies are eligible if they havebeen disease-free for at least 5 years, and are deemed by the investigator to be atlow risk for recurrence of that malignancy.

• Patients with the following cancers are eligible if diagnosed and treatedwithin the past 5 years: cervical cancer in situ, basal cell or squamous cellcarcinoma of the skin, and localized papillary or follicular thyroid cancer whohave completed recommended treatment including surgery. Patients with any othercancers within the last 5 years are ineligible.

• Patents must have a left ventricular ejection fraction (LVEF) within normalinstitutional parameters (or > 50%)

• Patients must not have > grade 1 peripheral neuropathy of any etiology.

• Patients must have a bilateral mammogram and a diagnostic breast ultrasound [on theside of the cancer(s)] (with or without breast MRI) performed at screening. Anaxillary ultrasound on the side of the cancer(s) is also required. However, if apatient has a negative axillary physical exam and a baseline MRI without suspiciouslymph nodes performed before axillary ultrasound, axillary ultrasound may beomitted. Comprehensive breast and axillary imaging must be performed within 42 daysof registration (i.e. the patient's mammogram/ breast ultrasound /axillaryultrasound OR their breast MRI).

• Baseline imaging of the ipsilateral axilla by ultrasound or breast MRI is mandatory.For subjects with axillary lymph node(s) suspicious on clinical exam or imaging,patient must be willing to have a needle aspiration or core biopsy to determine thepresence of metastatic disease in the lymph nodes. A clip must be placed in theinvolved axillary lymph node. (If there are more than 1 suspicious axillary nodes,only one clipped node is required).

• Patient of childbearing potential and sexually active patients must use accepted andeffective method(s) of contraception or to abstain from sexual intercourse for theduration of their participation in the study and for 7 months after the last dose ofstudy treatment.

• Patient must be willing and able to sign informed consent

• Leukocytes >= 3,000/mcL (obtained =< 28 days prior to protocol registration)

• Absolute neutrophil count >= 1,500/mcL (obtained =< 28 days prior to protocolregistration)

• Platelets >= 100,000/mcL (obtained =< 28 days prior to protocol registration)

• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (obtained =< 28days prior to protocol registration)

• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (obtained =< 28 days prior to protocolregistration)

• Creatinine =< 1.5 x institutional ULN (obtained =< 28 days prior to protocolregistration)

• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviraltherapy with undetectable viral load within 6 months are eligible for this trial

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load

Exclusion Criteria:

• Patients must not have impaired decision-making capacity

• Patient must not have a history of any prior (ipsilateral or contralateral) invasivebreast cancer

• One exception: a patient with a history of T1N0 triple negative breast cancerdiagnosed more than 10 years earlier, who remains disease free is eligible

• Patient must not have prior ipsilateral ductal breast carcinoma in situ (DCIS).Patients with prior lobular breast carcinoma in situ (LCIS), atypical hyperplasia,other high risk benign lesions or contralateral DCIS (without evidence ofmicroinvasion) are eligible

• NOTE: Patients currently receiving endocrine therapy for prior contralateralDCIS are eligible

• Patient must not have stage IV (metastatic) breast cancer

• Staging studies (computed tomography [CT] chest/abdomen/pelvis and a bone scanor positron emission tomography [PET]-CT scan) are required for stage IIIdisease or those with abnormal baseline liver function tests (LFTs), symptoms (e.g. new bone pain) or abnormal physical exam findings (National ComprehensiveCancer Network [NCCN] guidelines version [V]1.2019)

• Patient must not have T4 and/or N3 disease, including inflammatory breast cancer

• Patient must not have any prior treatment for the current breast cancer, includingsurgery, chemotherapy, hormonal therapy, radiation or experimental therapy

• Patients must not have > grade 1 peripheral neuropathy of any etiology

• Patient must not have a concurrent serious medical condition that would precludecompletion of study therapy. For example, uncontrolled hypertension (systolic > 180mm Hg and/or diastolic > 100 mm Hg) or clinically significant (i.e. active)cardiovascular disease: cerebrovascular accident/stroke or myocardial infarctionwithin 6 months prior to registration, unstable angina, congestive heart failure (CHF) or serious cardiac arrhythmia requiring medication and other concurrentserious diseases that may interfere with planned treatment

• Patient must not be pregnant or breast-feeding due to the potential harm to anunborn fetus and possible risk for adverse events in nursing infants with thetreatment regimens being used. Patients must also not expect to conceive from thetime of registration, while on study treatment, and until at least 7 months afterthe last dose of study treatment. All patients of childbearing potential must have ablood test or urine study within 14 days prior to registration to rule out pregnancy

• All patients of childbearing potential is anyone, regardless of sexualorientation or whether they have undergone tubal ligation, who meets thefollowing criteria: 1) has achieved menarche at some point, 2) has notundergone a hysterectomy or bilateral oophorectomy; or 3) has not beennaturally postmenopausal for at least 24 consecutive months (i.e., has hadmenses at any time in the preceding 24 consecutive months)