Patient must be >= 18 years of age

Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Patient must have histologically confirmed HER2-positive primary invasive breast carcinoma, determined by local testing. The tumor must have either HER2 immunohistochemistry (IHC) result of 3+ or HER2/CEP17 ratio >= 2 with >= 4.0 HER2 signals per cell by in situ hybridization (ISH). Tumors with HER2/CEP17 ISH ratio < 2 are ineligible, even if HER2 copy number is > 6, unless HER2 IHC result is 3+

Patients hormone receptor (ER and PR) status must be known and will be determined by local testing. Patients with either hormone receptor–positive or hormone receptor- negative HER2-positive breast cancer are eligible

Patients must have AJCC 8th edition stage II or IIIa according to anatomic staging table at diagnosis
* Patients without nodal involvement (cN0) are eligible if T size > 2.0 cm (T2-3)
** NOTE:	Cohort for patients with 2-3 cm, ER+ and node negative HER2-positive/ER-positive disease closed on July 27, 2022
* Patients with HER2-positive/ER-negative disease without nodal involvement (cN0) are eligible if T size > 2.0 cm (T2-3)
** NOTE: Cohort for HER2-postive/ER-negative patients closed on May 18, 2023
* Patients with HER2-positive/ER-positive disease without nodal involvement (cN0) are eligible if T size > 3.0 cm
* 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 receive standard adjuvant therapy, consisting of HER2-directed therapy, radiation (if indicated) and endocrine therapy (if ER+) if achieving pCR at surgery

Patient with bilateral invasive breast cancers are eligible if both cancers are HER2-positive at least one meets protocol eligibility and neither cancer renders the patient ineligible

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

Patients must not have impaired decision-making capacity

Patient must not have a history of any prior (ipsilateral or contralateral) invasive breast cancer
* One exception: a patient with a history of T1N0 triple negative breast cancer diagnosed 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 of microinvasion) are eligible. Current ipsilateral or contralateral DCIS (diagnosed at the time of the current invasive cancer) is permitted
* NOTE: Patients currently receiving endocrine therapy for prior contralateral DCIS are eligible

Patient must not have stage IV (metastatic) breast cancer
* Staging studies (CT chest/abdomen/pelvis and a bone scan or PET-CT scan) are required for stage III disease (according to AJCC cancer staging manual anatomic staging table, 8th edition) or those with abnormal baseline liver function tests (LFTs), symptoms (e.g., new bone pain) or abnormal physical exam findings (National Comprehensive Cancer 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, including surgery, chemotherapy, hormonal therapy, radiation or experimental therapy

Patients with a history of other non-breast malignancies are eligible if they have been disease-free for at least 5 years, and are deemed by the investigator to be at low risk for recurrence of that malignancy
* Patients with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, basal cell or squamous cell carcinoma of the skin, melanoma-in-situ and localized papillary or follicular thyroid cancer who have completed recommended treatment including surgery. Patients with any other cancers within the last 5 years are ineligible

Patents must have a left ventricular ejection fraction (LVEF) within normal institutional 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 the side of the cancer[s]) (with or without breast MRI) performed at screening. An axillary ultrasound on the side of the cancer(s) is also required. Comprehensive breast and axillary imaging must be performed within 60 days of registration (i.e. the patient’s mammogram/ breast ultrasound /axillary ultrasound OR their breast MRI). Either mammogram/ultrasound (including imaging of the ipsilateral axilla) or breast MRI must be performed within 60 days of registration

Baseline imaging of the ipsilateral axilla by ultrasound 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 the presence of metastatic disease in the lymph nodes. A clip must be placed in the involved axillary lymph node. (If there are more than 1 suspicious axillary nodes, only one clipped node is required). Alternatives to a clip that reliably mark the involved node for removal at surgery are acceptable (e.g., carbon tattooing, Savi scout, radiofrequency identification [RFID] etc.)

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

Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive from the time of registration, while on study treatment, and until at least 7 months after the last dose of study treatment.
* All patients of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy. If the pregnancy test (e.g., human chorionic gonadotropin [HCG] level) is abnormal but is felt to represent a false positive test for pregnancy (e.g., due to treatments being administered for egg harvesting, or because of recent miscarriage), a note by the treating gynecologist explaining why the team is confident the woman is not pregnant is required
* A patient of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Patient of childbearing potential and sexually active patients must use accepted and effective method(s) of contraception or to abstain from sexual intercourse for the duration of their participation in the study and for 7 months after the last dose of study 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 protocol registration)

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

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

Creatinine =< 1.5 x institutional ULN (obtained =< 28 days prior to protocol registration)

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

For 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, they are eligible if they have an undetectable HCV viral load

PRIMARY OBJECTIVES:
I. To determine if 3-year recurrence-free survival (RFS) is greater than 92% among clinical stages II or IIIa patients (by American Joint Committee on Cancer [AJCC] cancer staging manual anatomic staging table, 8th edition) with HER2-positive/estrogen receptor (ER)-positive breast cancer who achieve pathologic complete response (pCR) (ypT0/is ypN0) after preoperative therapy with 12 weeks of a taxane, trastuzumab (or Food and Drug Administration [FDA] approved biosimilar) and pertuzumab (THP x 12). Post-operatively, patients will receive standard of care adjuvant locoregional therapy, plus completion of 12 months of HER2-targeted therapy (and standard adjuvant endocrine therapy for patients with estrogen receptor-positive disease).
II. To determine if 3-year recurrence-free survival (RFS) is greater than 92% among clinical stages II or IIIa patients (by AJCC cancer staging manual anatomic staging table, 8th edition) with HER2-positive/ER-negative breast cancer who achieve pCR (ypT0/is ypN0) after preoperative therapy with 12 weeks of a taxane, trastuzumab (or FDA approved biosimilar) and pertuzumab (THP x 12). Post-operatively, patients will receive standard of care adjuvant locoregional therapy, plus completion of 12 months of HER2-targeted therapy (and no adjuvant endocrine therapy for patients with estrogen receptor-negative disease).

SECONDARY OBJECTIVES:
I. To determine 3-year IDFS (invasive disease-free survival), DDFS (distant disease-free survival), DRFS (distant relapse-free survival), RFI (recurrence-free interval), OS (overall survival) and breast cancer-specific survival in patients who achieve pCR (and by pretreatment clinical stage). (Secondary Clinical Objective)
II. To determine 3-year EFS (event-free survival) in all patients from time of study registration. (Secondary Clinical Objective)
III. To evaluate safety and tolerability for all patients during the pre-operative phase and for patients who attain pCR and de-escalate therapy (Arm A) until the completion of post-surgery protocol assigned therapy (i.e., until the end of trastuzumab and pertuzumab [HP] therapy). (Secondary Clinical Objective)
IV. To evaluate the association of ER status in the untreated primary tumor with pathologic response and with long-term survival outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Secondary Correlative Objective)
V. To evaluate the associations of detection of circulating tumor cells (CTCs) in the blood at baseline with pCR. (Secondary Correlative Objective)
VI. To evaluate the association of detection of CTCs in the blood at baseline, after 3 weeks of THP, after 12 weeks of THP (before surgery), after surgery before any additional therapy, and after completion of HER2-targeted therapy with RFS in patients who achieve pCR or not. (Secondary Correlative Objective)
VII. To determine if breast magnetic resonance imaging (MRI) radiomics signatures reflecting intratumor heterogeneity and microenvironment at baseline are predictive of pCR. (Secondary Correlative Objective)
VIII. To evaluate the association between tumor infiltrating lymphocytes (TILs) in the baseline tumor and 3-yr RFS in all patients. (Secondary Correlative Objective)
IX. To evaluate the associations between TILs in the baseline tumor with pCR in all patients. (Secondary Correlative Objective)
X. To evaluate the association between HER2DX risk score in the baseline tumor and RFS in patients who achieved pCR after neoadjuvant THP therapy (i.e., arm A). (Secondary Correlative Objective)
XI. To evaluate the association between HER2DX risk score in the baseline tumor and RFS in patients who had residual disease after neoadjuvant THP therapy (i.e., arm B). (Secondary Correlative Objective)
XII. To evaluate the associations between HER2DX pCR likelihood score in the baseline tumor with pCR in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease, separately. (Secondary Correlative Objective)

EXPLORATORY OBJECTIVES:
I. To determine 3-year RFS, IDFS (invasive disease-free survival), DDFS (distant disease-free survival), DRFS (distant relapse-free survival), RFI (recurrence-free interval), OS (overall survival) and breast cancer-specific survival in patients who do not achieve pCR (and by pretreatment clinical stage). (Exploratory Clinical Objective)
II. To determine the pathologic response to THP neoadjuvant therapy, as assessed by residual cancer burden (RCB). (Exploratory Clinical Objective)
III. To determine the association between residual cancer burden (RCB) and all described standardized definitions for efficacy end points (STEEP) criteria outcomes. (Exploratory Clinical Objective)
IV. To determine the false negative rate (FNR) of limited staging procedures (defined as sentinel lymph node biopsy [SLNB] plus removal of clipped node) in patients who undergo such procedures with a planned axillary lymph node dissection (ALND). (Exploratory Clinical Objective)
V. To determine axillary pCR rates as a function of the burden of disease at presentation as determined on pre-treatment ultrasound (US) and the axillary staging technique (SLNB plus ensuring removal of clipped node versus ALND). (Exploratory Clinical Objective)
VI. To evaluate the associations between plasma tumor cell-free deoxyribonucleic acid (DNA) (cfDNA) tumor-specific mutations (baseline and after therapy) with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Exploratory Correlative Objective)
VII. To evaluate the associations between tumor infiltrating lymphocytes (TILs) in the baseline tumor with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival), and in the residual tumor with long-term outcomes. (Exploratory Correlative Objective)
VIII. To evaluate the associations between immune activation gene signatures in the baseline tumor and pathologic response as well as outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival). (Exploratory Correlative Objective)
IX. To evaluate the association of intrinsic subtype at baseline with outcomes (pathologic response and survival). (Exploratory Correlative Objective)
X. To determine the frequency of change in intrinsic subtype between pretreatment tumor specimen and residual disease at the time of surgery and to evaluate any association with survival. (Exploratory Correlative Objective)
XI. To evaluate the associations between DNA copy number, DNA mutations, ribonucleic acid (RNA) expression and protein expression in the baseline tumor and changes from baseline to post-THP therapy with pathologic response and long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS, and breast cancer-specific survival). (Exploratory Correlative Objective)
XII. To determine if functional dynamic contrast-enhanced (DCE)-MRI markers (e.g., functional tumor volume, signal enhancement ratio) reflecting tumor vascularity at baseline are predictive of treatment outcome (pCR and EFS). (Exploratory Correlative Objective)
XIII. To determine if breast MRI radiomics signatures at post-treatment/presurgery are predictive of treatment outcome (pCR and EFS). (Exploratory Correlative Objective)
XIV. To investigate the performance of combined modeling incorporating radiomics and other prognostic markers (e.g., ER, progesterone receptor [PR], intrinsic subtype, tumor infiltrating lymphocytes [TILs] levels) to predict treatment response in women with HER2+ breast cancer. (Exploratory Correlative Objective)
XV. To evaluate the association between TILs in the baseline tumor with pCR and 3-yr RFS in patients with HER2-positive/ER-positive breast cancer and in patients with HER2-positive/ER-negative breast cancer, separately. (Exploratory Correlative Objective)
XVI. To evaluate the association between TILs in the baseline tumor with 3-yr RFS in patients in Arm A (i.e., patients who have pCR) and those in Arm B (i.e., no pCR), separately. (Exploratory Correlative Objective)
XVII. To evaluate the associations between TILs in the residual tumor with 3-yr RFS in patients in Arm B. (Exploratory Correlative Objective)
XVIII. To evaluate the association between TILs in the baseline tumor with other long-term outcomes (including EFS, IDFS, DDFS, DRFS, RFI, OS and Breast Cancer-Specific Survival) in all patients and separately in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease. This association will also be evaluated separately for patents in Arm A and Arm B. (Exploratory Correlative Objective)
XIX. To evaluate the associations between changes in TILs in the baseline tumor and residual cancer at surgery with long-term outcomes (including RFS, EFS, IDFS, DDFS, DRFS, RFI, OS and Breast Cancer-Specific Survival), for patients in Arm B. (Exploratory Correlative Objective)
XX. To evaluate the associations between TILs in the baseline tumor and RCB score in all patients, and separately in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease. (Exploratory Correlative Objective)
XXI. To evaluate the association between HER2DX risk score in the baseline tumor and RFS in patients who achieved pCR after neoadjuvant THP therapy (i.e., arm A) in HER2-positive/ER-positive breast cancer and HER2-positive/ER-negative breast cancer, separately. (Exploratory Correlative Objective)
XXII. To evaluate the association between HER2DX risk score in the baseline tumor and RFS in patients who had residual disease after neoadjuvant THP therapy (i.e., arm B) in HER2-positive/ER-positive breast cancer and HER2-positive/ER-negative breast cancer, separately. (Exploratory Correlative Objective)
XXIII. To evaluate the association between HER2DX risk score in the baseline tumor with other long-term outcomes (including EFS, IDFS, DDFS, DRFS, RFI, OS and breast cancer-specific survival) for patents in arm A and arm B, separately. (Exploratory Correlative Objective)
XXIV. To evaluate the associations between HER2DX pCR likelihood score in the baseline tumor and RCB score in all patients, and separately in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease. (Exploratory Correlative Objective)
XXV. To evaluate the discrimination and calibration performance of HER2DX pCR likelihood score in terms of pCR in all patients, and separately in patients with HER2-positive/ER-positive disease and in patients with HER2-positive/ER-negative disease. (Exploratory Correlative Objective)
XXVI. To evaluate the discrimination and calibration performance of HER2DX risk score in terms of RFS in arm A patients. (Exploratory Correlative Objective)
XXVII. To evaluate the discrimination and calibration performance of HER2DX risk score in terms of RFS in arm B patients. (Exploratory Correlative Objective)
XXVIII. To evaluate the association of CTCs and change at 3 weeks and 12 weeks with pCR. (Exploratory Correlative Objective)
XXIX. To evaluate the association of change in CTCs with RFS. (Exploratory Correlative Objective)
XXX. To evaluate the association of CTC phenotype and change with pCR and RFS. (Exploratory Correlative Objective)

OUTLINE:

PRE-OPERATIVE/NEOADJUVANT THERAPY: Patients receive either paclitaxel or nab-paclitaxel intravenously (IV) on days 1, 8 and 15, or docetaxel IV on day 1 at the discretion of the treating oncologist. Patients also receive trastuzumab IV on day 1 and weekly thereafter, and pertuzumab IV on day 1. Patients may substitute trastuzumab-hyaluronidase subcutaneously (SC) over 2-5 minutes on day 1 in place of trastuzumab or pertuzumab-trastuzumab-hyaluronidase SC over 8 minutes on day 1 of cycle 1 and over 5 minutes on day 1 of cycles 2-4 in place of trastuzumab and pertuzumab. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. However, if surgery occurs later than 21 days after the 4th cycle of trastuzumab and pertuzumab, patients receive an additional cycle of trastuzumab and pertuzumab before surgery.

SURGERY: Within 126 days (18 weeks) after the first dose of neoadjuvant therapy, patients undergo standard of care lumpectomy and/or mastectomy.

POST-OPERATIVE/ADJUVANT THERAPY: Patients are assigned to 1 of 2 arms.

ARM A: Patients with pCR after surgery receive trastuzumab and pertuzumab IV on day 1. Patients may substitute trastuzumab-hyaluronidase SC over 2-5 minutes on day 1 in place of trastuzumab or pertuzumab-trastuzumab-hyaluronidase SC over 5 minutes on day 1 in place of trastuzumab and pertuzumab. Treatment repeats every 21 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. Patients may also undergo standard of care radiation therapy and receive hormone therapy if appropriate.

ARM B: Patients with remaining tumor after surgery receive standard of care trastuzumab emtansine for 14 doses in the absence of disease progression or unacceptable toxicity. Patients may also receive additional standard of care chemotherapy, as well as hormone therapy if appropriate.

All patients undergo echocardiogram (ECHO) or multigated acquisition scan (MUGA) during screening and then every 3 months during pre-operative and post-operative therapy. Patients undergo mammogram and ultrasound with or without MRI during screening, and up to one week before cycle 4 day 1. Patients may undergo mammogram annually for 15 years. Patients undergo collection of blood cycle 1 day 1, cycle 2 day 1, pre-surgery, post-surgery, on the day of the first post-surgery systemic therapy, and after completion of all HER2-targeted therapy. Patients may undergo computed tomography (CT) and bone scan or positron emission tomography (PET)/CT during screening.

After completion of study treatment, patients are followed up every 3 months for 12 months, every 6 months for 1-5 years, then annually for 5-15 years from date of surgery.