Inclusion Criteria:
* HER2-positive T1 histologically confirmed invasive carcinoma of the breast. Patients must have node-negative (N0) or micrometastases (N1mi) breast cancer according to the AJCC 8th edition anatomic staging table.
* If the patient has had a negative sentinel node biopsy, then no further axillary dissection is required, and the patient is determined to be node-negative. Axillary nodes with single cells or tumor clusters ≤ 0.2 mm by either H\&E or immunohistochemistry (IHC) will be considered node-negative.
* Any axillary lymph node with tumor clusters between 0.02 and 0.2cm is considered a micrometastasis. Patients with a micrometastasis are eligible. An axillary dissection is not required to be performed in patients with a micrometastasis found by sentinel node evaluation. In cases where the specific pathologic size of lymph node involvement is subject to interpretation, the Sponsor-Investigator will make the final determination as to eligibility. The investigator must document approval in the patient medical record.
* Patients who have one or more foci of T1aN0, ER+ (defined as \>10%), HER2-negative cancer in the ipsilateral breast, in addition to their primary HER2-positive tumor, are eligible.
* For unifocal disease, all invasive disease must have been tested for ER and PR (for multifocal disease, see below). Either ER or PR must be positive, defined as ER ≥10% or PR ≥10%. ER- and PR-assays should be performed by immunohistochemical methods according to the local institution standard protocol.
* HER2-positive by ASCO CAP 2018 guidelines.
* Bilateral breast cancers that individually meet eligibility criteria are allowed.
* Patients with multifocal or multicentric disease are eligible as long as each tumor individually meets eligibility criteria.
* Patients with a history of ipsilateral DCIS are eligible as long as the patient has not received prior hormonal therapy. Patients with a history of contralateral DCIS are not eligible unless contralateral DCIS was diagnosed at least 15 years ago
* ≤ 95 days between the date of protocol registration and the patient's most recent breast surgery for this breast cancer
* Patients must have undergone definitive breast surgery for the current malignancy. All tumor should be removed by either a modified radical mastectomy or a segmental mastectomy (lumpectomy), with either a sentinel node biopsy or axillary dissection
\-- All margins should be clear of invasive cancer or DCIS (i.e. no tumor on ink). The local pathologist must document negative margins of resection in the pathology report. If all other margins are clear, a positive posterior (deep) margin is permitted, provided the surgeon documents that the excision was performed down to the pectoral fascia and all tumor has been removed. Likewise, if all other margins are clear, a positive anterior (superficial; abutting skin) margin is permitted provided the surgeon documents that all tumor has been removed. Radiation therapy to the conserved breast is required.
* Patients may have received up to 8 weeks of hormonal therapy as adjuvant treatment for this cancer. Patients should otherwise not have received prior hormonal therapy with the exception that hormonal therapy administered for less than 8-week duration at least 15 years ago is allowed.
* Prior oophorectomy (including for cancer therapy) is allowed.
* Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy.
* Patients who have participated in a window study (treatment with an investigational agent prior to surgery for ≤2 weeks) are eligible. Patients must have discontinued the investigational agent at least 14 days before participation in this study.
* Men and women with any menopausal status ≥18 years of age
* ECOG Performance Status 0 or 1
* Participants must have normal organ and marrow function as defined below:
* ANC ≥ 1000/mm3
* hemoglobin ≥8 g/dl
* platelets ≥ 75,000/mm3
* AST and ALT both \<5x institutional ULN
* Total bilirubin ≤ 1.5 mg/dL. For patients with Gilbert syndrome, the direct bilirubin should be \<institutional ULN
* Serum creatinine ≤ 2.0 mg/dL OR calculated GFR ≥ 30mL/min
* Left ventricular ejection fraction (LVEF) ≥ 50%
* Post-menopausal patients must meet one of the following criteria:
* Prior bilateral ovariectomy/oophorectomy
* Age ≥ 60 years
* Age \< 60 years with intact uterus and amenorrhoeic for ≥ 12 consecutive months prior to chemotherapy and/or endocrine therapy exposure (medication-induced amenorrhea is not acceptable to meet this criterion)
* Age \< 60 years hysterectomized and FSH and plasma estradiol levels in the postmenopausal range according to local policies prior to chemotherapy and/or endocrine therapy exposure.
* Willingness to discontinue contraceptive hormonal therapy, e.g. birth control pills, prior to registration and while on study
* Premenopausal patients with intact uterus must have a negative serum or urine pregnancy test, including women who have had a tubal ligation and women less than 12 months from their last menstrual period.
* Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of nonhormonal contraception or two effective forms of nonhormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of antibody treatment and 3 months after the last dose of hormonal treatment.
* Patients must be willing and able to sign informed consent.
* Patients must be willing to provide archival tissue for research purposes.
* If patient is English-speaking, must be willing to fill out patient questionnaires.
Exclusion Criteria:
* Neoadjuvant or adjuvant chemotherapy for this breast cancer prior to enrollment is prohibited.
* Any of the following due to teratogenic potential of the study drugs:
* Pregnant women
* Nursing women
* Women of childbearing potential who are unwilling to employ adequate contraception (condoms, diaphragms, IUDS, surgical sterilization, abstinence, etc). Hormonal birth control methods are not permitted.
* Men who are unwilling to employ adequate contraception (condoms, surgical sterilization, abstinence, etc).
* Participants who are receiving any other investigational agents for treatment of breast cancer, unless specific approval is obtained from the Sponsor-Investigator.
* Locally advanced tumors at diagnosis, including tumors fixed to the chest wall, peau d'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawny cutaneous induration with an erysipeloid edge)
* Patients with a history of previous invasive breast cancer.
* Individuals with a history of a different malignancy are ineligible except for the following circumstances:
* Individuals with a history of other 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.
* individuals with the following cancer are eligible regardless of when they were diagnosed and treated: cervical cancer in situ, and non-melanoma cancer of the skin.
* Intercurrent illness including, but not limited to: ongoing or active, unresolved systemic infection, renal failure requiring dialysis, active cardiac disease, prior myocardial infarction (asymptomatic changes on EKG suggestive of old MI is not an exclusion), history of CHF, current use of any therapy specifically for CHF, uncontrolled hypertension, significant psychiatric illness, or other conditions that in the opinion of the investigator limit compliance with study requirements.
Time and Motion Substudy Eligibility:
* Participant must be enrolled at Dana-Farber Cancer Institute
* Participant must not have discontinued pertuzumab following treatment cycle 1
* Participant must be able to tolerate subcutaneous administration following cycle 1
