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Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study.
- Source :
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Breast (Edinburgh, Scotland) [Breast] 2016 Aug; Vol. 28, pp. 191-8. Date of Electronic Publication: 2016 Jun 20. - Publication Year :
- 2016
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Abstract
- 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.<br />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.<br />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.<br />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).<br /> (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Subjects :
- Aged
Aminopyridines administration & dosage
Aminopyridines adverse effects
Aminopyridines pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols adverse effects
Antineoplastic Combined Chemotherapy Protocols pharmacokinetics
Breast Neoplasms chemistry
Breast Neoplasms genetics
Breast Neoplasms surgery
Cyclin D2 genetics
Cyclin D3 genetics
Cyclin E genetics
Cyclin-Dependent Kinase 4 genetics
Cyclin-Dependent Kinase 6 genetics
Female
Humans
Letrozole
Middle Aged
Neoadjuvant Therapy
Nitriles administration & dosage
Nitriles adverse effects
Nitriles pharmacokinetics
Oncogene Proteins genetics
Purines administration & dosage
Purines adverse effects
Purines pharmacokinetics
Receptor, ErbB-2 analysis
Receptors, Estrogen analysis
Receptors, Progesterone analysis
Retinoblastoma Protein genetics
Signal Transduction genetics
Triazoles administration & dosage
Triazoles adverse effects
Triazoles pharmacokinetics
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Breast Neoplasms drug therapy
DNA, Neoplasm blood
Gene Expression drug effects
Ki-67 Antigen analysis
Subjects
Details
- Language :
- English
- ISSN :
- 1532-3080
- Volume :
- 28
- Database :
- MEDLINE
- Journal :
- Breast (Edinburgh, Scotland)
- Publication Type :
- Academic Journal
- Accession number :
- 27336726
- Full Text :
- https://doi.org/10.1016/j.breast.2016.06.008