Assessment of Biosignature Classification of DCIS for RadioTherapy Benefit Post Lumpectomy (ABCD RT)

Inclusion Criteria: * The patient or a legally authorized representative must provide study-specific informed consent prior to Step 1/Registration and, for patients treated in the U.S., authorization permitting release of personal health information. Breast and Disease Assessment * The patient must be female and greater than or equal to 30 and less than or equal to 85 years of age. (Note: The DCISionRT test is validated only in women between the ages of 30 and 85.) * The patient must have a diagnosis of DCIS less than or equal to 6 cm. (Note: The DCISionRT test is validated only in women with DCIS less than or equal to 6 cm.) * The patient must have an ECOG performance status of less than or equal to 2 (or Karnofsky greater than or equal to 50%). * The patient must have had a bilateral mammogram within 6 months prior to registration. * The patient must have undergone breast conserving surgery with negative surgical margins (greater than or equal to 2 mm). Margin status is assessed on lumpectomy specimen and/or additional margins as determined by the local pathologist. If pathologic examination demonstrates DCIS less than 2 mm from resection edge, additional excisions may be performed to obtain clear margins. Patients with lobular carcinoma in situ (LCIS), atypical lobular hyperplasia (ALH), and/or atypical ductal hyperplasia (ADH) are eligible regardless of margins for these histologies. * The patient must have no suspicious unresected microcalcification, densities, or palpable abnormalities (in the ipsilateral or contralateral breast) unless biopsied and found to be benign. * The interval between the last surgery for DCIS (including re-excision of margins) and registration must be no more than 70 days * The following staging criteria must be met postoperatively according to AJCC 8th edition criteria: * Primary tumor must be pTis * Patients must be cN0 (by physical exam and/or imaging) * Axillary surgery staging with sentinel node biopsy and/or axillary node dissection is not required. If surgical axillary staging was performed, ipsilateral nodes must be pN0. (Patients with pathologic staging of pN0 (i+) or pN0)(mol+) are NOT eligible. * DCIS may be of any grade (1-3). * The DCIS must be tested for estrogen receptor (ER) and progesterone receptor (PgR) status, either on an initial core biopsy or surgical specimen, by current ASCO/CAP Guideline Recommendations for hormone receptor testing. Any ER and/or PgR receptor status is eligible. * Participants must have unilateral DCIS diagnosed within 4 months of registration without a history of prior ipsilateral or contralateral DCIS or invasive breast cancer. * DCISionRT result must have been either previously obtained or the patient has consented to submission of specimen for centralized testing by PreludeDx. * The patient must have recovered from surgery with the incision well healed and no signs of infection. * The patient must have no contraindications to standard-of-care breast radiotherapy (i.e., active collagen-vascular disease, scleroderma, prior breast/chest radiotherapy). Co-morbid and Other Conditions * Patients of childbearing potential must have a negative pregnancy test within 14 days of registration, have no intention of becoming pregnant for 120 days following registration and be willing to use highly effective contraception if randomized to RT from registration until 1 month after completion of RT. * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the treatment regimen are eligible for this trial. * If germ-line testing performed, results must be reviewed and indicate no pathogenic or likely pathogenic variants associated with increased breast cancer risk. (Variants of unknown significance are acceptable.) Medications * Patients must discontinue postmenopausal hormone replacement therapy, including estrogens or progesterone formulations prior to study entry. Low-dose vaginal estrogen creams, tablets, rings, or IUDs are allowed. For patients treated with anti-endocrine therapy as chemoprevention for the development of breast cancer, anti-endocrine therapy must have been discontinued greater than 6 months prior to the diagnosis of DCIS. * Adjuvant anti-endocrine therapy is a standard treatment option for ER or PgR positive DCIS. Patients may not have a history of taking oral anti-endocrine therapy (SERMS, SERDS, or aromatase inhibitors) prior to DCIS diagnosis. Adjuvant anti-endocrine therapy for DCIS may not be initiated prior to DCISion RT testing.