Abstract Background: BC is the most common malignancy diagnosed in AYAs. AYAs develop more biologically aggressive BC and present at more advanced stages, necessitating more intensive therapy with curative intent. While acute physical sequelae often resolve following initial treatment, the long-term physical and psychosocial impact of BC on a survivor’s life may worsen or emerge in survivorship. This impact includes symptoms (e.g., sexual problems, anxiety, fatigue, stress, sleep issues, hot flashes) as well as concerns unique to, or accentuated by, being young (e.g., fertility, genetics, childrearing, educational/work attainment). With provider attention to these issues often sub-optimal, strategies that empower patients have the potential to improve their well-being. To engage and activate AYA BC survivors, we developed YES, a web-based portal that leverages electronic patient-reported outcomes (ePROs) to facilitate self-monitoring and management of symptoms/AYA concerns. In contrast to ePRO models dependent on clinician interaction, our approach emphasizes self-management of chronic survivorship concerns outside of the clinic environment. This model is grounded in the reality that most clinicians have limited bandwidth to address these needs and considers that AYAs can have competing demands (e.g., missing work, child-care) that may make accessing in-person support challenging. Methods: The YES study is a randomized controlled trial of the YES intervention vs. usual care. YES supports participants to 1) self-monitor needs/symptoms; and 2) provides a repository for information and resources on self-management of symptoms/AYA concerns. Eligibility criteria include: female, age 15-39 years at diagnosis, stage 0-III BC, within 3 years of diagnosis, no recurrent/second primary BC, no other malignancy since BC diagnosis, and English speaking. Participants randomized to the YES arm are prompted through a monthly text or email to complete an ePRO assessment regarding current symptoms/AYA concerns. For each symptom/concern endorsed, information/resources to address the symptom/concern is automatically provided via the YES portal. The portal is monitored, and providers are contacted if participants report severe distress or suicidality. YES also provides peer support via a chat room and self-support through a journaling platform in the portal. Participants in the usual care group are offered access to YES for up to 3 months at the end of their 9-month study participation. All participants complete a REDCap survey with validated measures of quality of life (QOL), symptoms, and other PROs at baseline, 3, 6, and 9 months after randomization and provide a dried blood spot specimen via a self-administration kit at baseline and 6 months. The primary study aim is to determine the efficacy of YES vs. usual care in improving life quality measured by the QOL in Adult Cancer Survivors [QLACS] scale at 6 months post-randomization. With a planned sample size of 360 participants, the study will have ≥90% power to detect a 6-point mean change (6 months vs. baseline) in the cancer-specific QLACS score between arms. Secondary outcomes include efficacy of YES in reducing symptoms/AYA concerns at 6 months and sustainability of the effects of YES at 9 months. Repeated measures regression will be used with link functions selected based on the type of outcome data analyzed. Exploratory aims will evaluate moderators and mediators of intervention efficacy and the effects of YES on inflammatory biomarkers. At study completion, a subset of 30 participants diverse in age, race, ethnicity, and gender identity are invited to participate in an interview to understand their survivorship preferences/concerns and to understand how the portal supported their self-management. The YES trial opened to enrollment in 9/2021. As of 6/2023, 245 participants are enrolled. Clinical Trials Information: NCT04906200 Citation Format: Shoshana Rosenberg, Yue Zheng, Dawn Hershman, Craig Snow, Kate Dibble, Magnolia Contreras, Noel Roma, Nabihah Tayob, Michelle Naughton, Ann Partridge. Randomized controlled trial of Young, Empowered & Strong (YES), a web-based patient-reported symptom monitoring and self-management portal for adolescent and young adult (AYA) breast cancer (BC) survivors [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 PO4-18-10.