ATEMPT 2.0: Adjuvant T-DM1 vs TH

Inclusion Criteria:

• Patients must have HER2-positive Stage I histologically confirmed invasive carcinomaof the breast. Patients must have node-negative (N0) or micrometastases (N1mic)breast cancer according to the AJCC 8th edition anatomic staging table.

• If the patient has had a negative sentinel node biopsy, then no furtheraxillary dissection is required, and the patient is determined to benode-negative. If an axillary dissection without sentinel lymph node biopsy isperformed to determine nodal status, at least six axillary lymph nodes must beremoved and analyzed, and determined to be negative, for the patient to beconsidered node-negative. Axillary nodes with single cells or tumor clusters ≤ 0.2 mm by either H&E or immunohistochemistry (IHC) will be considerednode-negative.

• Any axillary lymph node with tumor clusters between 0.02 and 0.2 cm isconsidered a micrometastasis. Patients with a micrometastasis are eligible. Anaxillary dissection is not required to be performed in patients with amicrometastasis found by sentinel node evaluation. In cases where the specificpathologic size of lymph node involvement is subject to interpretation, theprincipal investigator will make the final determination as to eligibility. Theinvestigator must document approval in the patient medical record.

• Patients who have an area of a T1aN0, ER+ (defined as >10%), HER2-negativecancer in addition to their primary HER2-positive tumor are eligible.

• HER2-positive by ASCO CAP 2018 guidelines, confirmed by central testing. NOTE: HER-2status must be confirmed to be positive by central review by NeoGenomics prior topatient starting protocol therapy. Patients previously having had HER2immunohistochemical testing by NeoGenomics do not need to undergo retesting forcentral confirmation of HER2 status.

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

• ER/PR determination is required. ER and PR assays should be performed byimmunohistochemical methods according to the local institution standard protocol.

• Bilateral breast cancers that individually meet eligibility criteria are allowed.

• Patients with multifocal or multicentric disease are eligible, as long as each tumorindividually meets eligibility criteria. Central confirmation is needed for any siteof disease that is tested to be HER2-positive by local testing (unless testing waspreviously done by NeoGenomics).

• Patients with a history of ipsilateral DCIS are eligible if they were treated withwide excision alone, without radiation therapy, or treated with a mastectomy forthis current breast cancer. Patients with a history of contralateral DCIS are noteligible.

• ≤ 90 days between the planned treatment start date and the patient's most recentbreast surgery for this breast cancer

• ≥ 18 years of age with any menopausal status.

• ECOG Performance Status 0 or 1

• All tumor should be removed by either a modified radical mastectomy or a segmentalmastectomy (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 thepathology report. If all other margins are clear, a positive posterior (deep)margin is permitted, provided the surgeon documents that the excision wasperformed down to the pectoral fascia and all tumor has been removed. Likewise,if all other margins are clear, a positive anterior (superficial; abuttingskin) margin is permitted provided the surgeon documents that all tumor hasbeen removed.

• Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have anycontraindications to radiation therapy. Radiation to the conserved breast isrequired.

• Patients may have received up to 4 weeks of tamoxifen therapy, or other hormonaltherapy, for adjuvant therapy for this cancer. Patients cannot receive adjuvanthormonal therapy during protocol treatment for the first 12 weeks.

• Prior oophorectomy for cancer prevention is allowed.

• Patients who have undergone partial breast radiation (duration ≤ 14 days) prior toregistration are eligible. Partial breast radiation must be completed prior to 2weeks before starting protocol therapy. Patients who have undergone whole breastradiation are not eligible.

• Patients who have participated in a window study (treatment with an investigationalagent prior to surgery for ≤ 2 weeks) are eligible. Patients must have discontinuedthe investigational agent at least 14 days before participation.

• Adequate bone marrow function:

• ANC ≥ 1000/mm3,

• Hemoglobin ≥ 9 g/dl

• Platelets ≥ 100,000/mm3

• Adequate hepatic function:

• Total bilirubin ≤ 1.2mg/dL

• AST and ALT ≤ 1.5x Institutional ULN

• For patients with Gilbert syndrome, the direct bilirubin should be within theinstitutional normal range. Serum alkaline phosphatase should be ≤ 1.5xInstitutional ULN.

• Left ventricular ejection fraction (LVEF) ≥ 50%

• Premenopausal patients must have a negative serum or urine pregnancy test, includingwomen who have had a tubal ligation and for women less than 12 months after theonset of menopause.

• Women of childbearing potential and men with partners of childbearing potential mustbe willing to use one highly effective form of nonhormonal contraception or twoeffective forms of nonhormonal contraception by the patient and/or partner.Contraceptive use must be continued for the duration of the study treatment and for 7 months after the last dose of study treatment. Hormonal birth control methods arenot permitted.

• Patients should have tumor tissue available, and a tissue block of sufficient sizeto make 15 slides, which must be sent to DFCI for correlative research. If a tissueblock is unavailable, sites may send one H&E-stained slide and 15 unstained sectionsof paraffin-embedded tissue on uncharged slides. Slide sections should be 4-5microns in thickness. It is also acceptable to submit 2 cores from a block ofinvasive tissue using a 1.2 mm diameter coring tool. If tumor is not available, theinvestigator must document why tissue is not available in the patient medicalrecord, and that efforts have been made to obtain tissue.

• Willing and able to sign informed consent

• Must be able to read and understand English in order to participate in the qualityof life surveys. If patient does not read and understand English, the patient isstill eligible, but cannot participate in the quality of life surveys.

Exclusion Criteria:

• 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 adequatecontraception (condoms, diaphragms, IUDs, surgical sterilization, abstinence,etc.).

• Men who are unwilling to employ adequate contraception (condoms, surgicalsterilization, abstinence, etc.).

• Locally advanced tumors at diagnosis, including tumors fixed to the chest wall, peaud'orange, skin ulcerations/nodules, or clinical inflammatory changes (diffuse brawnycutaneous induration with an erysipeloid edge)

• Patients with a history of previous invasive breast cancer.

• History of prior chemotherapy in the past 5 years.

• History of paclitaxel therapy

• Patients with active liver disease, for example due to hepatitis B virus, hepatitisC virus, autoimmune hepatic disorder, or sclerosing cholangitis

• Individuals with a history of a different malignancy are ineligible except for thefollowing circumstances:

• Individuals with a history of other malignancies are eligible if they have beendisease-free for at least 5 years and are deemed by the investigator to be atlow risk for recurrence of that malignancy.

• Individuals with the following cancer are eligible regardless of when they werediagnosed and treated: cervical cancer in situ, and non-melanoma cancer of theskin.

• Intercurrent illness including, but not limited to: ongoing or active, unresolvedsystemic infection, renal failure requiring dialysis, active cardiac disease, priormyocardial infarction (asymptomatic changes on EKG suggestive of old MI is not anexclusion), history of CHF, current use of any therapy specifically for CHF,uncontrolled hypertension, significant psychiatric illness, or other conditions thatin the opinion of the investigator limit compliance with study requirements.