Background: Breast cancer (BC) patients (pts) with low/intermediate Oncotype Dx recurrence scores (RS) ≤ 25 represent a large fraction of BC cases, and a substantial number of distant recurrences occur in this group despite their low to moderate risk and high sensitivity to endocrine therapy. These pts are also the least likely to be sensitive to or benefit from adjuvant chemotherapy. Anatomical risk factors (nodal status, tumor size) continue to define a higher risk group among these endocrine sensitive and molecularly low risk BC pts. The goal of this study is to assess tumor response to a combination of the mTOR inhibitor everolimus and an aromatase inhibitor (AI) in this patient population, utilizing the preoperative endocrine prognostic index (PEPI). Our hypothesis is that everolimus will improve the efficacy of AI in this setting. 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/intermediate risk RS ( ≤ 25). Patient enrollment initiated in November 2014 at the Yale Cancer Center/Smilow Cancer Hospital and Care Centers. The study will enroll up to 66 pts. Key inclusion criteria are ECOG 0-2, adequate organ function, a fasting cholesterol ≤ 300 mg/dl and triglycerides ≤ 2.5 x IULN. Pts who had prior surgical resection of their BC, uncontrolled diabetes mellitus (HbA1c > 7%), and a prior exposure to mTOR inhibitors are excluded. Eligible pts will receive daily AI therapy (anastrozole 1 mg, letrozole 2.5 mg or exemestane 25 mg) and everolimus 10 mg daily for a total of 26 weeks. The primary objective of the study is to determine the percent of postmenopausal pts with clinical stage II-III HR+ 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 pathologic response (PEPI 0) to neoadjuvant AI and everolimus in this patient population. Clinical trial information: NCT02236572