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Mechanism of action biomarkers predicting response to AKT inhibition in the I-SPY 2 breast cancer trial.

  • Author(s): Wolf, Denise M;
  • Yau, Christina;
  • Wulfkuhle, Julia;
  • Brown-Swigart, Lamorna;
  • Gallagher, Rosa I;
  • Magbanua, Mark Jesus M;
  • O'Grady, Nick;
  • Hirst, Gillian;
  • I-SPY 2 TRIAL Investigators;
  • Asare, Smita;
  • Tripathy, Debu;
  • Berry, Don;
  • Esserman, Laura;
  • Chien, A Jo;
  • Petricoin, Emanuel F;
  • van 't Veer, Laura
  • et al.
Abstract

The AKT inhibitor MK2206 (M) was evaluated in I-SPY 2 and graduated in the HER2+, HR-, and HR- HER2+ signatures. We hypothesized that AKT signaling axis proteins/genes may specifically predict response to M and tested 26 phospho-proteins and 10 genes involved in AKT-mTOR-HER signaling; in addition, we tested 9 genes from a previous study in the metastatic setting. One hundred and fifty patients had gene expression data from pretreatment biopsies available for analysis (M: 94, control: 56) and 138 had protein data (M: 87, control: 51). Logistic modeling was used to assess biomarker performance in pre-specified analysis. In general, phospho-protein biomarkers of activity in the AKT-mTOR-HER pathway appeared more predictive of response to M than gene expression or total protein biomarkers in the same pathway; however, the nature of the predictive biomarkers differed in the HER2+ and TN groups. In the HER2+ subset, patients achieving a pCR in M had higher levels of multiple AKT kinase substrate phospho-proteins (e.g., pmTOR, pTSC2). In contrast, in the TN subset responding patients had lower levels of AKT pathway phospho-proteins, such as pAKT, pmTOR, and pTSC2. Pathway mutations did not appear to account for these associations. Additional exploratory whole-transcriptome analysis revealed immune signaling as strongly associated with response to M in the HER2+ subset. While our sample size is small, these results suggest that the measurement of particular AKT kinase substrate phospho-proteins could be predictive of MK2206 efficacy in both HER2+ and TN tumors and that immune signaling may play a role in response in HER2+ patients.

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