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. Clin Cancer Res; 23(22); 6823-32. ©2017 AACR.

• Authors: Cynthia X Ma, Vera Suman, Matthew P Goetz, Donald Northfelt, Mark E Burkard, Foluso Ademuyiwa, Michael Naughton, Julie Margenthaler, Rebecca Aft, Richard Gray, Amye Tevaarwerk, Lee Wilke, Tufia Haddad, Timothy Moynihan, Charles Loprinzi, Tina Hieken, Erica K Barnell, Zachary L Skidmore, Yan-Yang Feng, Kilannin Krysiak, Jeremy Hoog, Zhanfang Guo, Leslie Nehring, Kari B Wisinski, Elaine Mardis, Ian S Hagemann, Kiran Vij, Souzan Sanati, Hussam Al-Kateb, Obi L Griffith, Malachi Griffith, Laurence Doyle, Charles Erlichman, Matthew J Ellis
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 22 Pg. 6823-6832 (Nov 15 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28874413 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Nitriles
• Receptors, Estrogen
• Triazoles
• Anastrozole
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Receptor, ErbB-2
• Proto-Oncogene Proteins c-akt

Topics

• Anastrozole
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Apoptosis (drug effects)
• Biomarkers, Tumor
• Breast Neoplasms (diagnosis, drug therapy, genetics, metabolism)
• Cell Proliferation (drug effects)
• Centrifugation, Density Gradient
• Class I Phosphatidylinositol 3-Kinases (genetics)
• Combined Modality Therapy
• Female
• Heterocyclic Compounds, 3-Ring (administration & dosage)
• Humans
• Mutation
• Neoplasm Staging
• Nitriles (administration & dosage)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Receptor, ErbB-2 (metabolism)
• Receptors, Estrogen (metabolism)
• Sequence Analysis, DNA
• Signal Transduction (drug effects)
• Treatment Outcome
• Triazoles (administration & dosage)