title: NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer.
abstract: Purpose:Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor-positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies.Experimental Design:Eligible patients with clinical stage II/III ER+/HER2-breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%).Results:Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%,P< 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) andPIK3CAstatus with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression.Conclusions:Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect.Clin Cancer Res; 23(15); 4055-65. ©2017 AACR.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. cynthiaxma@wustl.edu mjellis@bcm.edu.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.affiliation: Division of Public Health Science, Siteman Cancer Center Biostatistics Core, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Division of Public Health Science, Siteman Cancer Center Biostatistics Core, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jingqin
authors.initials: J
authors.lastname: Luo
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, Arizona.
authors.forename: Donald W
authors.initials: DW
authors.lastname: Northfelt
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Matthew
authors.initials: M
authors.lastname: Goetz
authors.affiliation: Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hoog
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Michael
authors.initials: M
authors.lastname: Naughton
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Foluso
authors.initials: F
authors.lastname: Ademuyiwa
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Rama
authors.initials: R
authors.lastname: Suresh
authors.affiliation: Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, Arizona.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
authors.affiliation: Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Julie
authors.initials: J
authors.lastname: Margenthaler
authors.affiliation: Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Aft
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hobday
authors.affiliation: Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Timothy
authors.initials: T
authors.lastname: Moynihan
authors.affiliation: Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: William
authors.initials: W
authors.lastname: Gillanders
authors.affiliation: Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Amy
authors.initials: A
authors.lastname: Cyr
authors.affiliation: Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Eberlein
authors.affiliation: Department of Surgery, Mayo Clinic, Rochester, Minnesota.
authors.forename: Tina
authors.initials: T
authors.lastname: Hieken
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Helen
authors.initials: H
authors.lastname: Krontiras
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Zhanfang
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Michelle V
authors.initials: MV
authors.lastname: Lee
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Spies
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Skidmore
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.|McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.|Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Obi L
authors.initials: OL
authors.lastname: Griffith
authors.affiliation: McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.|Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Shana
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bumb
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Kiran
authors.initials: K
authors.lastname: Vij
authors.affiliation: Pfizer Pharmaceuticals, New York, New York.
authors.forename: Cynthia Huang
authors.initials: CH
authors.lastname: Bartlett
authors.affiliation: Pfizer Pharmaceuticals, New York, New York.
authors.forename: Maria
authors.initials: M
authors.lastname: Koehler
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Hussam
authors.initials: H
authors.lastname: Al-Kateb
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Souzan
authors.initials: S
authors.lastname: Sanati
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. cynthiaxma@wustl.edu mjellis@bcm.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ellis
mesh_terms: D000328:Adult; D000368:Aged; D000077384:Anastrozole; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D018572:Disease-Free Survival; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage*; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D000077384:Anastrozole; D058534:Class I Phosphatidylinositol 3-Kinases; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D047628:Estrogen Receptor alpha; D009570:Nitriles; D010879:Piperazines; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014230:Triazoles; C506487:ESR1 protein, human; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C495911:CDK6 protein, human; C500026:palbociclib