Abstract BACKGROUND. Advanced diagnostics such as magnetic resonance imaging (MRI) and gene-expression profiles are potentially useful to guide treatment in patients with ductal carcinoma in situ (DCIS). To evaluate these tests, we performed a prospective single arm multicenter study. We have previously reported the impact of MRI on surgical management of DCIS patients, and the effect of a 12-gene DCIS Score (DS) on radiotherapy (RT) use after wide local excision (WLE). We now report a pre-planned analysis of ipsilateral breast events (IBE) at 5-years. METHODS. Adult women with a core needle biopsy diagnosis of DCIS and eligible for WLE based on conventional imaging were registered following consent. All registered patients underwent breast MRI. Those still eligible, and willing, to receive WLE after appropriate follow-up biopsies underwent resection to free margins. DCIS sections were submitted to Exact Sciences for DS. Those with a low DS (< 39) were advised to omit RT; those with intermediate/high (inter/hi) DS (≥39) were advised to receive RT. All participants were monitored at 6-month intervals for any breast cancer event, and for survival. An IBE was defined as the first DCIS or invasive recurrence in the ipsilateral breast following the final WLE. Participants without IBE were censored by date of last contact or date of death for those who died. Follow-up was truncated at 5 years from WLE. Using data available as of 07-06-2023, Kaplan-Meier (K-M) curves were constructed to estimate the time-to-event distributions for subjects who received RT and for those who did not. The 5-year IBE rates and 95% confidence intervals (CIs) were estimated from K-M curves for all subjects with a DS (analogue of Intention to Treat [ITT] analysis), and for the subset who were compliant with their DS-based RT recommendation (Per Protocol analysis). The analyses were repeated for subgroups based on age at DCIS diagnosis (< 50 vs. ≥ 50). RESULTS. Of 339 women evaluable for the previously reported primary analysis (PMID 30653209), 171 (50.4%) underwent WLE with free surgical margins and had DS available for RT recommendations (ITT population). Of these, 7/82 low DS patients underwent RT, and 5/89 inter/hi DS patients declined RT; thus, the adherence to DS-based RT recommendations was 93%. At a median of 5 years of follow-up from final WLE, the ITT population experienced a total of eight IBE events (4.8%, 95% CI 2.4, 9.4) with 5-year IBE rates that were similar for participants with a low DS and for those with a inter/hi DS: 5.1% (95% CI: 1.9, 12.9) and 4.5% (95% CI 1.7, 11.7), respectively. Stratification by age did not alter these results: among women aged < 50 years (n=33), the IBE rate was 6.7% (95% CI 1.0, 38.7) for low DS and 5.6% (95% CI 0.8, 33.4) for inter/hi DS. Among women aged ≥ 50 years (n=138), the IBE rate was 4.7% (95% CI 1.5, 13.8) for low DS and 4.3% (95% CI 1.4, 12.7) for inter/hi DS. In the per-protocol analysis (N=159 adherent to RT recommendations), IBE rates were also similar for participants who had a low DS and no RT [5.5% (95% CI 2.1, 14.1)] and for those with inter/hi DS who received RT [4.8% (95% CI: 1.8% to 12.3%)]. Again, there was no discernible influence by age as categorized above. CONCLUSION. We report the first prospective data on use of DCIS Score for RT decisions, and 5-year IBE rates. We find that DS-based recommendations are followed by >90% of patients. Although the sample size is limited, the data are reassuring in that the IBE rate is similar between the low DS group treated with WLE alone and the inter/hi DS group treated with WLE and radiation, whereas prior studies have shown a marked difference in IBE rates by DS with excision alone. Therefore, this prospective trial provides strong evidence to support the omission of RT after surgery in DCIS patients with low DS, and its use in patients with intermediate/high DS. Citation Format: Seema Khan, Justin Romanoff, Constantine Gatsonis, Habib Rahbar, Ruth Carlos, Sunil Badve, Jean Wright, Constance Lehman, Worta McCaskill-Stevens, Ralph Corsetti, Derrick Spell, Kenneth Blankstein, Linda Han, Jennifer Sabol, John Bumberry, Ilana Gareen, Bradley Snyder, Lynne Wagner, Kathy Miller, Joseph Sparano, Christopher Comstock. Magnetic Resonance Imaging and a 12-Gene Expression Assay to Optimize Local Therapy for Ductal Carcinoma In Situ: 5-year clinical outcomes of E4112 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-01.