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Clin Cancer Res. 2017 Nov 15;23(22):6823-6832. doi: 10.1158/1078-0432.CCR-17-1260. Epub 2017 Sep 5.

A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III PIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer.

Author information

1
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. cynthiaxma@wustl.edu mjellis@bcm.edu.
2
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
3
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
4
Department of Oncology, Mayo Clinic, Rochester, Minnesota.
5
Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, Arizona.
6
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
7
Division of Oncology, Washington University School of Medicine, St. Louis, Missouri.
8
Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
9
Department of General Surgery, Mayo Clinic, Phoenix, Arizona.
10
Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.
11
Department of General Surgery, Mayo Clinic, Rochester, Minnesota.
12
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, Missouri.
13
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri.
14
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
15
Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
16
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas. cynthiaxma@wustl.edu mjellis@bcm.edu.

Abstract

Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor-positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer.Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17.Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery.Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population. Clin Cancer Res; 23(22); 6823-32. ©2017 AACR.

PMID:
28874413
DOI:
10.1158/1078-0432.CCR-17-1260
[Indexed for MEDLINE]

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