title: Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Istituto Europeo di Oncologia, via Ripamonti 435, 20141, Milan, Italy. Electronic address: giuseppe.curigliano@ieo.it.
authors.forename: G
authors.initials: G
authors.lastname: Curigliano
authors.affiliation: Servicio Oncologia Médica, Vall d'Hebron University Hospital, Vall d'Hebron 119-129, 08035, Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Gómez Pardo
authors.affiliation: The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Houston, TX, 77030, USA.
authors.forename: F
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Istituto Oncologico Veneto, Via Gattamelata 64, 35128, Padua, Italy; University of Padova, Via Giustiniani 22, 35121, Padua, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Conte
authors.affiliation: University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands; Erasmus Medical Center Cancer Institute, Erasmus Medical Center, s-Gravendijkwal 230, 3015 CE, Rotterdam, The Netherlands.
authors.forename: M P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Highlands Oncology Group, 3232 N North Hills Blvd, Fayetteville, AR, 72703, USA.
authors.forename: J T
authors.initials: JT
authors.lastname: Beck
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
authors.forename: A
authors.initials: A
authors.lastname: Bardia
authors.affiliation: Oncología Médica, Hospital del Mar, Passeig Marítim 25-29, 08003, Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Martínez García
authors.affiliation: Centre Jean Perrin, Unicancer and EA 4677 Université d'Auvergne, 58 rue Montalembert, 63011, Clermont-Ferrand, France.
authors.forename: F
authors.initials: F
authors.lastname: Penault-Llorca
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dhuria
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Tang
authors.affiliation: Novartis Institutes for BioMedical Research, 230 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: N
authors.initials: N
authors.lastname: Solovieff
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ, 07936-1080, USA.
authors.forename: M
authors.initials: M
authors.lastname: Miller
authors.affiliation: Novartis Institutes for BioMedical Research, 230 Massachusetts Avenue, Cambridge, MA, 02139, USA.
authors.forename: E
authors.initials: E
authors.lastname: Di Tomaso
authors.affiliation: University of California, Los Angeles, 2825 Santa Monica Blvd, Suite 211, Santa Monica, CA, 90404, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Hurvitz
mesh_terms: D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000601:surgery; D056742:Cyclin D2 / Q000235:genetics; D056743:Cyclin D3 / Q000235:genetics; D019927:Cyclin E / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis*; D000077289:Letrozole; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015513:Oncogene Proteins / Q000235:genetics; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D016160:Retinoblastoma Protein / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000631:Aminopyridines; D056742:Cyclin D2; D056743:Cyclin D3; D019927:Cyclin E; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D000077289:Letrozole; D009570:Nitriles; D015513:Oncogene Proteins; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016160:Retinoblastoma Protein; D014230:Triazoles; C080336:CCND2 protein, human; C534696:CCND3 protein, human; C475820:CCNE1 protein, human; C508053:ERBB2 protein, human; C495911:CDK6 protein, human; C000589651:ribociclib
keywords: Breast cancer; CDK4/6; Letrozole; Ribociclib