Background: Breast cancer (BC) patients (pts) with Oncotype Dx recurrence scores (RS) ≤ 25 represent a large fraction of BC cases. The TAILORx study demonstrated that these pts did not receive significant benefit from adjuvant chemotherapy. Despite their low to moderate risk and sensitivity to endocrine therapy, a number of BC pts may benefit from neoadjuvant therapy. The goal of this study is to assess tumor response, utilizing the preoperative endocrine prognostic index (PEPI), to a combination of the mTOR inhibitor everolimus and an aromatase inhibitor (AI) in this pt population. Methods: This is a phase II study evaluating the efficacy and safety of neoadjuvant AI and everolimus in postmenopausal pts with hormone receptor positive (HR+)/HER2 negative clinical stage II-III BC with low risk RS (≤ 25). Patient enrollment initiated in November 2014 at the Yale Cancer Center/Smilow Cancer Hospital and Care Centers. Key inclusion criteria are ECOG 0-2, adequate organ function, a fasting cholesterol ≤ 300 mg/dl and triglycerides ≤ 2.5 x IULN. Eligible pts received daily AI therapy (anastrozole 1 mg, letrozole 2.5 mg, or exemestane 25 mg) and everolimus 10 mg daily for up to a total of 26 weeks. The primary objective of the study was to determine the percent of postmenopausal pts with clinical stage II-III HR+/HER2- BC and a RS ≤ 25 who achieve a PEPI score of 0 following neoadjuvant AI and everolimus. The secondary objectives are to assess the tolerability and side effect profile, and to identify biologic markers predictive of a PEPI 0. Simon’s optimal two-stage design was utilized with a planned sample size of 27 eligible pts. First, 15 pts will be enrolled, if 5 or more of 15 eligible patients achieve a PEPI 0, the plan is to enroll another 12 pts. If 10 or more of the 27 eligible patients achieve a PEPI 0, we will conclude that the regimen warrants further study. This design has a power of 80% and a one-sided significance level of 0.1. Results: Of the 17 pts initially enrolled, 15 were evaluable for response; 4 of 15 (26%) had a PEPI scores of 0 which did not meet the primary endpoint; 4 (26%) had a path CR and 6 (40%) had PR. Grade 3 toxicities determined to be possibly/probably study related included anemia, anorexia, hypertension, maculopapular rash and hyperglycemia. One pt developed grade 3 atrial flutter and grade 4 QT prolongation which required a dose delay. One pt required hospitalization for pneumonia. Gene expression analysis by RNA seq was performed on 9 baseline (6 pts with CR/PR vs 3 non-responders); 13 post treatment (8 pts with CR/PR vs 5 non-responders) samples with 8 matched pairs (5 pts with CR/PR vs 3 non-responders). Baseline samples from pts who had CR/PR have significantly lower expression of MYC targets and oxidative phosphorylation genes, and significantly higher expression of genes associated with epithelial mesenchymal transition and interferon signaling, in comparison to non-responders. The expression of CYP19A1 gene, that codes aromatase, is significantly increased after therapy in samples from pts with CR/PR (logFC=1.33), but not in other pts. Expression of mTORC1 signaling pathway genes is increased after therapy only in samples from pts with CR/PR. Conclusion: Although this trial did not meet the set primary endpoint, 26% of pts achieved a PEPI 0. The combination of an AI and everolimus was overall well tolerated. Our study suggested that baseline expression levels of key pathways were associated with response to neoadjuvant AI plus everolimus. Citation Format: Maysa M Abu-Khalaf, Kimberly Aderhold, Michal Marczyk, Gina Chung, Erin Hofstatter, Tara Sanft, Andrea Silber, Michael DiGiovanna, Daniel Zelterman, Lajos Puzstai, Christos Hatzis. Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-13-02.