OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of 
CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone 
receptor-positive (HR+) breast cancer (BC). This study assessed the biological 
activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with 
single-agent letrozole in the presurgical setting.
MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human 
epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 
1:1:1 to receive 2.5 mg/day letrozole alone (Arm 1), or with 400 or 600 mg/day 
ribociclib (Arm 2 or 3). Circulating tumor DNA and tumor biopsies were collected 
at baseline and, following 14 days of treatment, prior to or during surgery. The 
primary objective was to assess antiproliferative response per Ki67 levels in 
Arms 2 and 3 compared with Arm 1. Additional assessments included safety, 
pharmacokinetics, and genetic profiling.
RESULTS: Mean decreases in the Ki67-positive cell fraction from baseline were: 
Arm 1 69% (range 38-100%; n = 2), Arm 2 96% (range 78-100%; n = 6), Arm 3 92% 
(range 75-100%; n = 3). Decreased phosphorylated Rb levels and CDK4, CDK6, 
CCND2, CCND3, and CCNE1 gene expression were observed following ribociclib 
treatment. Ribociclib and letrozole pharmacokinetic parameters were consistent 
with single-agent data. The ribociclib plus letrozole combination was well 
tolerated, with no Grade 3/4 adverse events over the treatment.
CONCLUSION: The results suggest absence of a drug-drug interaction between 
ribociclib and letrozole and indicate ribociclib plus letrozole may reduce Ki67 
expression in HR+, HER2- BC (NCT01919229).