title: CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment.
abstract: OBJECTIVE
  The G1-S checkpoint of the cell cycle is frequently dysregulated in breast cancer. Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a phase II, single-arm trial of palbociclib in advanced breast cancer.
  
  
  METHODS
  Eligible patients had histologically confirmed, metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1 to 21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss, and CCND1 amplification.
  
  
  RESULTS
  Thirty-seven patients were enrolled; 84% hormone-receptor (HR)(+)/Her2(-), 5% HR(+)/Her2(+), and 11% HR(-)/Her2(-), with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease ≥ 6 months for a clinical benefit rate (CBR = PR + 6moSD) of 19% overall, 21% in HR(+), and 29% in HR(+)/Her2(-) who had progressed through ≥2 prior lines of hormonal therapy. Median PFS overall was 3.7 months [95% confidence interval (CI), 1.9-5.1], but significantly longer for those with HR(+) versus HR(-) disease (P = 0.03) and those who had previously progressed through endocrine therapy for advanced disease (P = 0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). Twenty-four percent had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population.
  
  
  CONCLUSIONS
  Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, HR(+), Rb-positive breast cancer. Cytopenias were uncomplicated and easily managed with dose reduction.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania. Hematology/Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Angela.demichele@uphs.upenn.edu.
authors.forename: Angela
authors.initials: A
authors.lastname: DeMichele
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Hematology/Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Amy S
authors.initials: AS
authors.lastname: Clark
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kay See
authors.initials: KS
authors.lastname: Tan
authors.affiliation: Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Heitjan
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kristi
authors.initials: K
authors.lastname: Gramlich
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Maryann
authors.initials: M
authors.lastname: Gallagher
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Priti
authors.initials: P
authors.lastname: Lal
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Michael
authors.initials: M
authors.lastname: Feldman
authors.affiliation: Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Paul
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Christopher
authors.initials: C
authors.lastname: Colameco
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: David
authors.initials: D
authors.lastname: Lewis
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Melissa
authors.initials: M
authors.lastname: Langer
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Noah
authors.initials: N
authors.lastname: Goodman
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Hematology/Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Susan
authors.initials: S
authors.lastname: Domchek
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Hematology/Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Keerthi
authors.initials: K
authors.lastname: Gogineni
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Mark
authors.initials: M
authors.lastname: Rosen
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Hematology/Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fox
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania. Hematology/Oncology Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Dwyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016160:Retinoblastoma Protein / Q000378:metabolism; D019233:Retreatment; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D016160:Retinoblastoma Protein; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib