A Study of Skipping Radiation Therapy in People With Breast Cancer

Inclusion Criteria: A patient cannot be considered eligible for this study unless ALL of the following conditions are met. Please contact the study PI for exceptions, or if uncertainties arise. * The trial is open to female and male patients who have undergone breast conserving surgery and have received neoadjuvant\* or adjuvant systemic therapy with a HER2-targeted therapeutic regimen. * The maximum window between surgery (neoadjuvant cohort) or last chemotherapy (adjuvant cohort) and enrollment is 90 days. * While the standard duration of neoadjuvant or adjuvant systemic therapy is at least 12 weeks, patients will be eligible if they receive a minimum of 8 weeks of systemic therapy. Patients treated with an antibody-drug conjugate (ADC; eg. T-DM1 or T-DXd) must have received at least 6 cycles of this treatment. \*For the neoadjuvant cohort: Patients are eligible if they achieved pCR with HER2-targeted preoperative treatment. Pathologic complete response is defined as ypT0/TisN0 based on surgical pathology. Patients treated with and ADC must have received at least 6 cycles of this treatment. * The patient must be ≥18 years of age. * The patient must have an ECOG performance status of 0, 1, or 2/Karnofsky performance status above 60. * Histologically or cytologically confirmed invasive breast carcinoma. * The tumor must have been determined to be HER2-positive by current ASCO/CAP guidelines based on local testing results. * The tumor must have ER and PgR status assessed. * The following staging criteria must be met according to AJCC 8th edition criteria: Adjuvant cohort * Following resection, the patient's primary tumor must be ≤ 3 cm. * Surgical axillary evaluation via sentinel node biopsy or axillary dissection * 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 \<5 cm by imaging studies with negative axillary nodes (cN0) based on axillary U/S, CT, PET or MRI. Physical examination alone is not sufficient documentation of cN0 status. * The patient must have undergone surgical axillary nodal evaluation demonstrating ypN0 (eg. axillary node dissection, sentinel node biopsy with at least 3 sentinel lymph nodes removed, or sentinel node biopsy followed by axillary node dissection). * Must be ypT0/TisN0 at surgery (lumpectomy); patients with residual non invasive disease (DCIS) in the surgical specimen (ypTis), are only eligible if residual DCIS spans ≤1 cm, and surgical margins are negative for DCIS. * Bilateral mammogram or MRI within 52 weeks prior to enrollment. Exclusion Criteria: * Definitive clinical or radiologic evidence of metastatic disease. * On the Adjuvant cohort, patients with a primary tumor \>3 cm on pathologic examination of the surgical specimen. On the Neoadjuvant cohort, patients with a primary tumor \>5 cm or with abnormal or suspicious ipsilateral axillary nodes by pretreatment imaging, unless demonstrated to be negative by cytologic or histologic examination. * 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 histological confirmation that these nodes are negative for metastatic disease. * Suspicious microcalcifications, densities, or palpable abnormalities (in the ipsilateral or contralateral breast), or mass or non-mass enhancement on MRI (if performed) 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 or multifocal disease spanning \>4 cm. If multifocal, all foci should be confined to a maximum summed tumor extent of 3 cm determined by pathological assessment. * Paget's disease of the nipple. * Synchronous contralateral invasive breast cancer or DCIS or synchronous ipsilateral invasive breast cancer of a different histology. (Patients with synchronous and/or previous contralateral LCIS are eligible). * On the Adjuvant cohort, surgical margins that cannot be microscopically assessed or are positive at pathologic evaluation. (If surgical margins are rendered free of disease by re-excision, the patient is eligible). * Treatment plan that includes regional nodal irradiation. * Patients treated for a prior invasive breast malignancy are excluded. Contralateral DCIS ≥10 years prior to enrollment is permissible. * Patients on oral, transdermal, or subdermal estrogen replacement (including all estrogen only and estrogen-progesterone formulas) are not eligible unless discontinued prior to enrollment. * Use of any investigational product within 30 days prior to enrollment.