This research study is studying a combination of HER2-directed therapies (trastuzumab and pertuzumab) and hormonal therapy as a treatment after surgery for hormone receptor positive breast cancer.

The study drugs involved in this study are:

• A combination of trastuzumab and pertuzumab given as an injection under the skin (PHESGO)
• Hormonal (endocrine) Treatment

The research study procedures include screening for eligibility and study treatment including laboratory evaluations, physical exams, questionnaires, and follow up visits.

• Participants will receive HER2-directed treatment for 1 year and hormonal therapy for approximately 5 years.
• It is expected that about 375 people will take part in this research study.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug works in treating a specific disease. "Investigational" means that the drug combination is being studied.

The drugs trastuzumab and pertuzumab are both monoclonal antibodies, which are disease-fighting proteins made by cloned immune cells. The U.S. Food and Drug Administration (FDA) has approved trastuzumab, pertuzumab, and trastuzumab + pertuzumab subcutaneous fixed dose combination (PHESGO) as treatment for HER2 positive breast cancer. The FDA has also approved hormonal therapies as treatment for hormone receptor positive breast cancer.

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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 \

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to Sponsor Investigator or designee. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Data can be shared no earlier than 1 year following the date of publication

DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu