Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

• K. Kalinsky ^[1] ; J. A. Sparano ^[2] ; X. Zhong ^[1] ; E. Andreopoulou ^[6] ; B. Taback ^[3] ; L. Wiechmann ^[1] ; S. M. Feldman ^[2] ; P. Ananthakrishnan ^[4] ; A. Ahmad ^[1] ; S. Cremers ^[1] ; A. N. Sireci ^[1] ; J. R. Cross ^[5] ; D. K. Marks ^[1] ; P. Mundi ^[1] ; E. Connolly ^[3] ; K. D. Crew ^[1] ; M. A. Maurer ^[1] ; H. Hibshoosh ^[3] ; S. Lee ^[3] ; D. L. Hershman ^[1]
  1. [1] Columbia University

     Columbia University

     Estados Unidos

     
  2. [2] Albert Einstein College of Medicine

     Albert Einstein College of Medicine

     Estados Unidos

     
  3. [3] Columbia University Medical Center

     Columbia University Medical Center

     Estados Unidos

     
  4. [4] White Plains Hospital

     White Plains Hospital

     City of White Plains, Estados Unidos

     
  5. [5] Memorial Sloan Kettering Cancer Center

     Memorial Sloan Kettering Cancer Center

     Estados Unidos

     
  6. [6] Weill Cornell Medicine, Estados Unidos

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• Localización: Clinical & translational oncology, ISSN 1699-048X, Vol. 20, Nº. 11 (November 2018), 2018, págs. 1474-1483
• Idioma: inglés
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• Resumen

  • Introduction The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC.

    Materials and methods Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls.

    Results Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06).

    Conclusion While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.