Journal article
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
Clinical cancer research, Vol.23(22), pp.6823-6832
11/15/2017
DOI: 10.1158/1078-0432.CCR-17-1260
PMCID: PMC6392430
PMID: 28874413
Abstract
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
-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
mutant ER
breast cancer.
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
sequencing. Patients positive for
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.
Fifty-one patients preregistered and 16 of 22 with
-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (
= 2) and toxicity (
= 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
mutation at surgery.
MK-2206 is unlikely to add to the efficacy of anastrozole alone in
-mutant ER
breast cancer and should not be studied further in the target patient population.
.
Details
- Title: Subtitle
- 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
- Creators
- Cynthia X Ma - Department of Medicine, Washington University School of Medicine, St. Louis, MissouriVera Suman - Mayo ClinicMatthew P Goetz - Mayo ClinicDonald Northfelt - Mayo ClinicMark E Burkard - University of Wisconsin School of Medicine and Public HealthFoluso Ademuyiwa - Department of Medicine, Washington University School of Medicine, St. Louis, MissouriMichael Naughton - Department of Medicine, Washington University School of Medicine, St. Louis, MissouriJulie Margenthaler - Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MissouriRebecca Aft - Section of Endocrine and Oncologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MissouriRichard Gray - Mayo ClinicAmye Tevaarwerk - University of Wisconsin School of Medicine and Public HealthLee Wilke - University of Wisconsin School of Medicine and Public HealthTufia Haddad - Mayo ClinicTimothy Moynihan - Mayo ClinicCharles Loprinzi - Mayo ClinicTina Hieken - Mayo ClinicErica K Barnell - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MissouriZachary L Skidmore - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MissouriYan-Yang Feng - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MissouriKilannin Krysiak - McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MissouriJeremy Hoog - Department of Medicine, Washington University School of Medicine, St. Louis, MissouriZhanfang Guo - Department of Medicine, Washington University School of Medicine, St. Louis, MissouriLeslie Nehring - Department of Medicine, Washington University School of Medicine, St. Louis, MissouriKari B Wisinski - University of Wisconsin School of Medicine and Public HealthElaine Mardis - Department of Genetics, Washington University School of Medicine, St. Louis, MissouriIan S Hagemann - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MissouriKiran Vij - Department of Medicine, Washington University School of Medicine, St. Louis, MissouriSouzan Sanati - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MissouriHussam Al-Kateb - Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MissouriObi L Griffith - Department of Genetics, Washington University School of Medicine, St. Louis, MissouriMalachi Griffith - Department of Genetics, Washington University School of Medicine, St. Louis, MissouriLaurence Doyle - Cancer Therapy Evaluation Program, NCI, Bethesda, MarylandCharles Erlichman - Mayo ClinicMatthew J Ellis - Baylor College of Medicine
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.23(22), pp.6823-6832
- DOI
- 10.1158/1078-0432.CCR-17-1260
- PMID
- 28874413
- PMCID
- PMC6392430
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- UM1 CA186686 / NCI NIH HHS P30 CA091842 / NCI NIH HHS K22 CA188163 / NCI NIH HHS R01 CA214893 / NCI NIH HHS P30 CA014520 / NCI NIH HHS
- Language
- English
- Date published
- 11/15/2017
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984700654402771
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