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Clin Cancer Res. 2017 Aug 1;23(15):4055-4065. doi: 10.1158/1078-0432.CCR-16-3206. Epub 2017 Mar 7.

NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer.

Author information

1
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri. cynthiaxma@wustl.edu mjellis@bcm.edu.
2
Division of Public Health Science, Siteman Cancer Center Biostatistics Core, Washington University School of Medicine, St. Louis, Missouri.
3
Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, Arizona.
4
Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.
5
Department of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
6
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
7
Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
8
Department of Surgery, Mayo Clinic, Rochester, Minnesota.
9
Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama.
10
Department of Radiology, Washington University School of Medicine, St. Louis, Missouri.
11
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
12
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
13
Pfizer Pharmaceuticals, New York, New York.
14
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
15
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. cynthiaxma@wustl.edu mjellis@bcm.edu.

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) and PIK3CA status 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.

PMID:
28270497
PMCID:
PMC5555232
DOI:
10.1158/1078-0432.CCR-16-3206
[Indexed for MEDLINE]
Free PMC Article

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