A Single Arm Phase II Study of ADjuvant Endocrine Therapy, Pertuzumab, and Trastuzumab for Patients With Anatomic Stage I Hormone Receptor-positive, HER2-positive Breast Cancer
A Single Arm Phase II Study of ADjuvant Endocrine Therapy, Pertuzumab, and Trastuzumab for Patients With Anatomic Stage I Hormone Receptor-positive, HER2-positive Breast Cancer
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.

 .
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 overall principal
 investigator will make the final determination as to eligibility. The
 investigator must document approval in the patient medical record.

 -  Patients who have an area of T1aN0, ER+ (defined as ≥ 10%), HER2-negative cancer
 in either 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, confirmed by central testing. See Appendix
 I for ASCO CAP 2018 HER2 testing guidelines.

 -  NOTE: DCIS components will not be counted in the determination of HER2 status

 -  NOTE: HER-2 status must be confirmed to be positive by central review prior to
 patient starting protocol therapy. Patients previously having had HER2 testing by
 NeoGenomics do not need to undergo retesting for central confirmation of HER2
 status. A pathology report documenting testing by NeoGenomics should be provided
 at time of patient registration.

 -  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, with the following exceptions: (1) central
 confirmation of HER2 status is needed only for any site of disease that is tested to
 be HER2-positive by local testing (unless original testing was done by NeoGenomics);
 (2) all areas that were locally tested for ER and PR status must be ER/PR positive (as
 defined above).

 -  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.

 -  ≤ 90 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.

 -  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.

 -  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.

 -  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 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.