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

Current DCIS treatment decisions rely on clinical-pathologic criteria that have remained unchanged for over 50 years. Even in favorable patients, RT provides an absolute benefit (\~8%), which is considered clinically meaningful. However, DCISionRT retrospective data suggests that approximately 37% of patients (Low Risk) may safely omit RT with less than 1% absolute difference in IBR. This could impact around 22,470 women annually in the US. Further, approximately one-third of Grade 3 DCIS patients (who have biosignature Low Risk scores) may also safely omit RT. From a number-needed-to-treat (NNT) perspective, RTOG 9804 results suggest that to prevent an IBR the NNT ≈ 13. In contrast, the DCISionRT data for biosignature Low Risk, the NNT ≈ 125. This represents a major shift in treatment value. In addition, shorter RT regimens have increased RT utilization, raising concerns about overtreatment. Biosignature-guided care could better balance overtreatment versus undertreatment. For high-risk DCIS, there have been no NCTN trials in over 20 years (last being ECOG 5194). NRG CC016 would be the first trial since then to include high-risk DCIS by both clinical-pathology and biosignature (score greater than 2.8 - Cohort B) criteria and determine the clinical utility of biosignature risk categorization over patient age and tumor grade, size and hormone receptor status. It will also prospectively assess outcomes for the subsets of Elevated Risk (\~40% of DCIS) and Residual Risk (\~20% of DCIS) patients treated with standard-of-care breast RT, with anticipated 10-year IBR rates of 5% and 15%, respectively. The study addresses multiple critical gaps: * First prospective assessment of a biosignature to determine its clinical utility in risk assessment for DCIS. * Determine if biosignature Low Risk patients gain no clinically meaningful benefit from RT. * Prospective assessment of outcomes in Elevated and Residual Risk groups. * Evaluation of boost benefit in higher-risk subgroups. * Evaluation of patient-reported outcomes including worry and quality of life (Section 11.1) for DCIS. This trial will randomize Low Risk biosignature patients to test the non-inferiority of RT-omission and prospectively determine outcomes in Elevated Risk and Residual Risk biosignature groups treated with RT. If published retrospective data are reproduced prospectively here, this would: * Redefine standard-of-care treatment for DCIS through use of a biosignature. * Enable safe omission of RT in selected patients (Low Risk) regardless of clinical-pathologic criteria with excellent outcomes. * Identify a subset of DCIS (Elevated Risk) with similar excellent outcomes following breast RT. * Identify a specific subset of DCIS (Residual Risk) in need of additional intervention. * Represent the first prospective assessment of a radiation-specific biosignature in oncology.