Testing Radiation and HER2-targeted Therapy Versus HER2-targeted Therapy Alone for Low-risk HER2-positive Breast Cancer

Inclusion Criteria:

• The patient or a legally authorized representative must provide study-specificinformed consent prior to study entry and, for patients treated in the U.S.,authorization permitting release of personal health information.

• female and male patients who have undergone breast conserving surgery and completeda minimum of 4 cycles (12 weeks) of neoadjuvant or adjuvant chemotherapy incombination with HER2-targeted therapy.

-≥ 40 years of age

• ECOG performance status of 0 ,1, or 2/Karnofsky performance status above 60

• Histologically or cytologically confirmed invasive breast carcinoma.

• tumor must have been determined to be HER2-positive by current ASCO/CAP guidelinesbased on local testing results.

• Patient must have undergone axillary staging, either sentinel node biopsy (SNB) oraxillary lymph nodal dissection (ALND). In neoadjuvant patients, SNB followingneoadjuvant therapy is strongly recommended. SNB prior to neoadjuvant therapy isdiscouraged, but patients are permitted if node negative (pN0).

• The following staging criteria must be met according to AJCC 8th edition criteria:

Adjuvant cohort : By pathologic evaluation, the patient's primary tumor must be </= 2 cm and ipsilateral nodes must be pN0. Surgical lumpectomy margins must be negative for invasive cancer and ductal carcinoma in situ (no ink on tumor).

Neoadjuvant cohort: Prior to neoadjuvant therapy, the patient's primary tumor must be < 3 cm by imaging studies, with negative axillary nodes (cN0) based on axillary U/S, CT, PET or MRI. Physical examination is not sufficient documentation of cN0 status; • Must be ypT0N0 at surgery (lumpectomy); patients with residual non-invasive disease (DCIS) in the surgical specimen (ypTis), are NOT eligible.

• For the Adjuvant cohort, adjuvant therapy must have consisted of a minimum of 4cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.

• For the Neoadjuvant cohort, neoadjuvant therapy must have consisted of a minimum of 4 cycles (12 weeks) of chemotherapy in combination with HER2-targeted therapy.- ;Patients who did not receive chemotherapy in the neoadjuvant setting are noteligible, even if they achieved pCR with their preoperative treatment; nor wouldthese patients become eligible by receiving chemotherapy after surgery.

• In patients assigned to radiation therapy, treatment should start ≤ 12 weeks fromsurgery on the Neoadjuvant cohort and ≤ 8 weeks from the completion of chemotherapyon the Adjuvant cohort. Patients should continue HER2-targeted therapy duringassigned study treatment (radiation or observation).

• Bilateral mammogram or MRI within 52 weeks prior to randomization.

• HIV-infected patients on effective anti-retroviral therapy with undetectable viralload within 6 months of randomization are eligible for this trial.

Exclusion Criteria:

• Definitive clinical or radiologic evidence of metastatic disease.

• On the Adjuvant cohort, patients with a primary tumor >2 cm on pathologicexamination of the surgical specimen. On the Neoadjuvant cohort, patients with aprimary tumor > 3 cm or with abnormal or suspicious ipsilateral axillary nodes bypretreatment imaging, unless demonstrated to be negative by cytologic or histologicexamination.

• Pathologically positive axillary nodes at any time including of pN0(i+) or pN0(mol+)ypN0(i+) or ypN0(mol+) disease.

• Patient planning for or status-post mastectomy.

• Radiographically suspicious ipsilateral or contralateral axillary, supraclavicular,infraclavicular, or internal mammary lymph nodes, unless there is histologicalconfirmation that these nodes are negative for metastatic disease.

• Suspicious microcalcifications, densities, or palpable abnormalities (in theipsilateral or contralateral breast), or mass or non-mass enhancement on MRI (ifperformed) aside from the known cancer, unless biopsied and found to be benign.

• Non-epithelial breast malignancies such as sarcoma or lymphoma.

• Multicentric carcinoma (invasive cancer or DCIS) in more than one quadrant orseparated by > 4 centimeters. If multifocal, all foci should be confined to amaximum tumor bed of 3 cm determined by pathological assessment.

• Paget's disease of the nipple.

• Synchronous (unilateral or bilateral) invasive breast cancer or DCIS. (Patients withsynchronous and/or previous contralateral LCIS are eligible.)

• On the Adjuvant cohort, surgical margins that cannot be microscopically assessed orare positive at pathologic evaluation. (If surgical margins are rendered free ofdisease by re-excision, the patient is eligible).

• Treatment plan that includes regional nodal irradiation.

• Patients treated for a prior invasive breast malignancy are excluded. ContralateralDCIS ≥ 10 years prior to enrollment is permissible.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

• Patients on oral, transdermal, or subdermal estrogen replacement (including allestrogen only and estrogen-progesterone formulas) are not eligible unlessdiscontinued prior to randomization.

• Prior ipsilateral breast or thoracic RT for any condition (contralateral RT for DCIS ≥ 10 years prior to randomization is permitted).

• Active collagen vascular disease, specifically dermatomyositis with a CPK levelabove normal or with an active systemic lupus erythematosus, or scleroderma.

• Clinicians should consider whether any conditions would make this protocolunreasonably hazardous for the patient.

• Pregnancy or lactation at the time of randomization or intention to become pregnantduring treatment. (Note: Pregnancy testing according to institutional standards forpatients of childbearing potential must be performed within 14 days prior torandomization.)

• Use of any investigational product within 30 days prior to randomization.