Background: The PI3K/AKT/mTOR pathway is frequently activated in BC, with mutations in PIK3CA particularly common in hormone receptor-positive (HR+) tumors. In preclinical studies of HR+ BC, BYL719 (an α-specific PI3K inhibitor) and buparlisib (a pan-PI3K inhibitor) have shown synergistic effects in vitro and near-complete tumor regression in vivo, respectively, when used in combination with hormone therapy. Methods: This is a Phase II, randomized, double-blind, placebo-controlled trial of BYL719 (300 mg QD) or buparlisib (100 mg QD) combined with letrozole (2.5 mg QD) for the neoadjuvant treatment of postmenopausal women with HR+/HER2– BC (NCT01923168). Key inclusion criteria are stage T1c–T3, any N, M0, operable BC; measurable disease; HR+, HER2– BC; known PIK3CA status (mutant or wild type) and Ki-67 level, determined centrally; Eastern Cooperative Oncology Group performance status ≤1; and adequate bone marrow and organ function. Key exclusion criteria are locally recurrent/metastatic disease and prior systemic therapy or radiotherapy for current BC. Patients will be assigned to 1 of 2 cohorts (PIK3CA mutant or wild type) and randomized to 1 of 3 arms (letrozole + BYL719, buparlisib, or placebo), stratified by Ki-67 level (<14% vs ≥14%) and lymph node status (+ve or –ve). Patients will be treated for 24 weeks, until surgery. The primary endpoint is pathologic complete response (pCR; defined as ypT0/Tis, ypN0) after 24 weeks’ treatment. The secondary endpoints are objective response rate (complete + partial, per RECIST 1.1), safety, rate of breast-conserving surgery, correlation between pCR and Ki-67 changes from baseline to Day 15 and to surgery, response (defined as central preoperative endocrine prognostic index score of 0), and pharmacokinetic profiles of all drugs used in the combination treatments. For each cohort, pCR rates will be summarized by treatment arm. The activity signal with either combination will be established if pre-defined proof-of-concept criteria are met. Approximately 360 patients will be randomized. Global recruitment is ongoing. Clinical trial information: NCT01923168.