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

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

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.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Anastrozole
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • Biomarkers, Tumor
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / 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*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • Sequence Analysis, DNA
  • Signal Transduction / drug effects
  • Treatment Outcome
  • Triazoles / administration & dosage

Substances

  • 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