Presurgical evaluation of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer.

Abstract

TPS147 Background: To serve as a bridge between preclinical and early clinical testing, pre-surgical studies are being designed to expose patients to a limited duration of an anti-cancer agent before launching a lengthy clinical trial program. In this model, modulation of predictive tissue and serum biomarkers are assessed. At Columbia, we have completed 2 pre-surgical studies, with a third ongoing. The PI3K/Akt signaling pathway is an important signaling pathway in breast cancer (BC). The first allosteric Akt inhibitor to enter clinical development, MK-2206 is well-tolerated and has demonstrated anti-cancer properties in preclinical and early phase clinical studies. The purpose of this study (NCI P8740) is to determine the effects of MK-2206 on women with newly diagnosed BC between breast biopsy and surgery. Methods: The main eligibility criteria for this open-label pre-surgical trial include operable, clinical stage I (at least T1c) to IIIC invasive BC. Patients not considered for neoadjuvant chemotherapy are eligible. Patients (n=30) will receive 2 doses of weekly MK-2206 (200 mg): first dose at day -9 and second at day -2 from surgery. This drug administration consistency will decrease the potential for noise in detecting true biomarker response. This time period was selected based upon the PK profile of weekly MK-2206. Our hypothesis is that MK-2206 will decrease phospho-AktSer473 in tumor tissue after 2 weekly doses. To maintain sample quality and ensure that phospho-Akt evaluated on FFPE tissue is comparable across samples (given the 20 minute half life of AKT), all samples will be processed rapidly by a standardized protocol. Secondary objectives include the following in FFPE tissue: modulation of downstream PI3K/Akt pathway signaling [IHC and reverse phase-protein microarray analysis (RPPA)]; change in tumor proliferation (Ki-67 staining); and exploration of whether PI3K/Akt signaling change depends upon tumor genetics (PIK3CA mutation or PTEN loss) or expression (HR/HER2 status). Pre- and post-MK-2206 blood will be collected for phospho-expression analysis in PBMCs (RPPA and western blotting). Patients will be enrolled and treated at affiliated institutions in the New York Cancer Consortium.