Abstract Background: Recurrent breast cancers arise from minimal residual disease (MRD): the pool of disseminated and circulating tumor cells (DTCs and CTCs) that survive in their host following treatment of primary breast cancer. Detection of DTCs in the bone marrow (BM) after treatment is strongly associated with an increased risk of recurrence. Through the analysis of novel genetically-engineered mouse models, we have generated a substantial body of evidence that autophagy and mTOR signaling play key roles in the survival of DTCs. Moreover, administration of agents that block these pathways in mice harboring MRD reduces DTC burden and concomitantly reduces tumor recurrence, providing the rationale for translating these findings to patients (pts). Trial Design: The PENN-SURMOUNT screening study uses a clinically validated IHC assay (DTC-IHC) to identify at-risk pts who harbor DTCs. DTC+ pts are eligible for enrollment on the CLEVER trial, which will determine the feasibility, safety and efficacy of administering hydroxychloroquine (HCQ) and/or everolimus (EVE) in DTC+ patients to target MRD and prevent recurrence. PENN-SURMOUNT is single center, prospective cohort study of pts who have completed therapy for primary breast cancer, are within 5 yrs of diagnosis and are at increased risk for relapse by virtue of nodal positivity, triple negative disease, ER+/Oncotype DX RS ≥ 25, or residual disease after neoadjuvant therapy. Pts undergo screening BM aspirate to test for DTCs following completion of adjuvant chemo and radiotherapy. The primary objective of the study is to determine the incidence and frequency of MRD in pts who have completed primary treatment for breast cancer and to ascertain eligibility for the CLEVER recurrence prevention trial. CLEVER is a randomized, controlled, open label phase II pilot trial. Target enrollment is 60 pts, with 15 pts allocated to each of 4 treatment arms: HCQ (600 mg BID), EVE (10mg daily), combination HCQ/EVE, or control/observation. A cycle is 28 days of continuous dosing. After a 3-month observation period, control pts will be offered HCQ/EVE therapy for 6 cycles; thus, the control group is actually a delayed treatment group and all pts will receive treatment. Pts who demonstrate persistent DTCs after 6 cycles will continue on combination therapy for an additional 6 cycles. The primary endpoint is feasibility of administering HCQ, EVE or the combination in this population. Secondary objectives include safety, efficacy (DTC reduction), and 3-year RFS. The principal translational objective is to assess the utility of a novel DTC assay, "DTC-Flow", for more sensitive detection and response to study therapy, compared to DTC-IHC. Additional translational objectives include determining whether patient DTCs, CTCs, and cell-free circulating plasma tumor DNA (ptDNA) biologically reflect the primary tumor and predict response. As of 5/23/17, 58 patients have been enrolled to PENN SURMOUNT, with a DTC-positivity rate of 22.6%; CLEVER opened in 2/2017; 11 patients are currently enrolled. Contact information: angela.demichele@uphs.upenn.edu Key words: Recurrence, disseminated tumor cells, dormancy, minimal residual disease, autophagy, mTOR, Everolimus, hydroxychloroquine Citation Format: Bayne LJ, Nivar I, Goodspeed B, Wileyto P, Savage J, Shih NNC, Feldman MD, Edwards J, Clark AS, Fox KR, Matro JM, Domchek SM, Bradbury AR, Shah PD, Chislock EM, Belka GK, Wang J, Amaravadi R, Chodosh LA, DeMichele AM. Detection and targeting of minimal residual disease in breast cancer to reduce recurrence: The PENN-SURMOUNT and CLEVER trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-07-09.