@article{71efd31e62284e9daf9b94acbaacf919,
title = "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",
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. ",
author = "Ma, {Cynthia X.} and Vera Suman and Goetz, {Matthew P.} and Donald Northfelt and Burkard, {Mark E.} and Foluso Ademuyiwa and Michael Naughton and Julie Margenthaler and Rebecca Aft and Richard Gray and Amye Tevaarwerk and Lee Wilke and Tufia Haddad and Timothy Moynihan and Charles Loprinzi and Tina Hieken and Barnell, {Erica K.} and Skidmore, {Zachary L.} and Feng, {Yan Yang} and Kilannin Krysiak and Jeremy Hoog and Zhanfang Guo and Leslie Nehring and Wisinski, {Kari B.} and Elaine Mardis and Hagemann, {Ian S.} and Kiran Vij and Souzan Sanati and Hussam Al-Kateb and Griffith, {Obi L.} and Malachi Griffith and Laurence Doyle and Charles Erlichman and Ellis, {Matthew J.}",
note = "Funding Information: This study was funded in part by the Siteman Cancer Center, Fashion Footwear Association of New York, the Mayo PIIC (N01-CM-2011-00099), UWCCC CCSG (P30 CA014520), Saint Louis Men's Group Against Cancer, and Cancer Clinical Investigator Team Leadership Award awarded by the NCI through a supplement to P30CA091842 (to C. Ma). A Komen Promise Grant PG12220321 to M.J. Ellis also supported the study and the McNair Medical Institute and the Cancer Prevention Institute of Texas also support M.J. Ellis. Funding Information: C.X. Ma reports receiving commercial research grants from Merck, Novartis, and Pfizer and is a consultant/advisory board member for AstraZeneca, Eli Lilly, Merck, Novartis, and Pfizer. M.P. Goetz reports receiving commercial research grants from Eli Lilly and Pfizer and is a consultant/advisory board member for Biotheranostics, Eli Lilly, Myriad, and RNA diagnostics. M.E. Burkard reports receiving other commercial research support from Abbvie, Bristol-Myers Squibb, and Genentech and is a consultant/advisory board member for Point-care Genomics. M.J. Naughton reports receiving speakers bureau honoraria from Amgen, Astra Zeneca, Biotheranostics, Celgene, Genentech, Novartis, and Pfizer. S. Sanati is a consultant/advisory board member for Genentech. M.J. Ellis reports receiving other commercial research support from Bioclassifier/Pro-signa/Nanostring, holds ownership interest (including patents) in Bioclassifier/ Prosigna, and is a consultant/advisory board member for AstraZenica, Nano-string, Novartis, and Pfizer. No potential conflicts of interest were disclosed by the other authors. Funding Information: This study was approved by the Institutional Review Board at all participating institutions; all patients provided signed informed consent. This trial is sponsored by the NCI (NCI Protocol #: 9170) and was conducted through the Mayo Phase 2 Consortium. The trial was registered at ClinicalTrials.gov (NCT01776008). Publisher Copyright: {\textcopyright}2017 AACR.",
year = "2017",
month = nov,
day = "15",
doi = "10.1158/1078-0432.CCR-17-1260",
language = "English (US)",
volume = "23",
pages = "6823--6832",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "22",
}