Advertisement

Clinical and Translational Oncology

, Volume 20, Issue 11, pp 1474–1483 | Cite as

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

  • K. Kalinsky
  • J. A. Sparano
  • X. Zhong
  • E. Andreopoulou
  • B. Taback
  • L. Wiechmann
  • S. M. Feldman
  • P. Ananthakrishnan
  • A. Ahmad
  • S. Cremers
  • A. N. Sireci
  • J. R. Cross
  • D. K. Marks
  • P. Mundi
  • E. Connolly
  • K. D. Crew
  • M. A. Maurer
  • H. Hibshoosh
  • S. Lee
  • D. L. Hershman
Research Article
  • 130 Downloads

Abstract

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.

Keywords

Phase 0 Pre-surgical MK-2206 AKT inhibitor Breast cancer 

Notes

Funding

Women at Risk funded this research. This work is also supported by contract N01-CM-62,204 to the New York Cancer Consortium (PI: Joseph A. Sparano) from the National Institutes of Health. In addition, this publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number KL2 TR000081. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Compliance with ethical standards

Conflicts of interest

The authors would like to report the following conflicts of interest: KK (Advisory: Biotheranostics, Lilly, Pfizer, Amgen, Novartis, Eisai) and MM (Stock and Employment: Bristol-Myers Squibb).

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12094_2018_1888_MOESM1_ESM.doc (38 kb)
Supplementary material 1 (DOC 38 kb)
12094_2018_1888_MOESM2_ESM.docx (7.2 mb)
Supplementary material 2 (DOCX 7411 kb)

References

  1. 1.
    Mundi PS, Sachdev J, McCourt C, et al. AKT in cancer: new molecular insights and advances in drug development. Br J Clin Pharmacol. 2016;82:943–56.CrossRefGoogle Scholar
  2. 2.
    Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9.CrossRefGoogle Scholar
  3. 3.
    Kalinsky K, Jacks LM, Heguy A, et al. PIK3CA mutation associates with improved outcome in breast cancer. Clin Cancer Res. 2009;15:5049–59.CrossRefGoogle Scholar
  4. 4.
    Sangai T, Akcakanat A, Chen H, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res. 2012;18:5816–28.CrossRefGoogle Scholar
  5. 5.
    Ma CX, Sanchez C, Gao F, et al. A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016;22:2650–8.CrossRefGoogle Scholar
  6. 6.
    Gonzalez-Angulo AM, Krop I, Akcakanat A, et al. SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer. J Natl Cancer Inst. 2015;107:dju493.CrossRefGoogle Scholar
  7. 7.
    Chien AJ, Cockerill A, Fancourt C, et al. A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2−amplified solid tumor malignancies. Breast Cancer Res Treat. 2016;155:521–30.CrossRefGoogle Scholar
  8. 8.
    Hudis C, Swanton C, Janjigian YY, et al. A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2−positive solid tumors. Breast Cancer Res. 2013;15:R110.CrossRefGoogle Scholar
  9. 9.
    Wisinski KB, Tevaarwerk AJ, Burkard ME, et al. Phase I study of an AKT inhibitor (MK-2206) combined with lapatinib in adult solid tumors followed by dose expansion in advanced HER2+ breast cancer. Clin Cancer Res. 2016;22:2659–67.CrossRefGoogle Scholar
  10. 10.
    Kalinsky K, Zheng T, Hibshoosh H, et al. Proteomic modulation in breast tumors after metformin exposure: results from a “window of opportunity” trial. Clin Transl Oncol. 2016;19:180–8.CrossRefGoogle Scholar
  11. 11.
    Baker AF, Dragovich T, Ihle NT, et al. Stability of phosphoprotein as a biological marker of tumor signaling. Clin Cancer Res. 2005;11:4338–40.CrossRefGoogle Scholar
  12. 12.
    Hammond ME, Hayes DF, Wolff AC. Clinical notice for American Society of Clinical Oncology–College of American Pathologists guideline recommendations on ER/PgR and HER2 testing in breast cancer. J Clin Oncol. 2011;29:e458.CrossRefGoogle Scholar
  13. 13.
    Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013.CrossRefGoogle Scholar
  14. 14.
    Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554–9.CrossRefGoogle Scholar
  15. 15.
    Saal LH, Johansson P, Holm K, et al. Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA. 2007;104:7564–9.CrossRefGoogle Scholar
  16. 16.
    Dowsett M, Nielsen TO, A’Hern R, et al. Assessment of Ki67 in breast cancer: recommendations from the international Ki67 in breast cancer working group. J Natl Cancer Inst. 2011;103:1656–64.CrossRefGoogle Scholar
  17. 17.
    Kalinsky K, Crew KD, Refice S, et al. Presurgical trial of metformin in overweight and obese patients with newly diagnosed breast cancer. Cancer Invest. 2014;32:150–7.CrossRefGoogle Scholar
  18. 18.
    Piovan E, Yu J, Tosello V, et al. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell. 2013;24:766–76.CrossRefGoogle Scholar
  19. 19.
    Guix M, Granja Nde M, Meszoely I, et al. Short preoperative treatment with erlotinib inhibits tumor cell proliferation in hormone receptor-positive breast cancers. J Clin Oncol. 2008;26:897–906.CrossRefGoogle Scholar
  20. 20.
    Yap TA, Yan L, Patnaik A, et al. First-in-man clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol. 2011;29:4688–95.CrossRefGoogle Scholar
  21. 21.
    Yap TA, Yan L, Patnaik A, et al. Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers. Clin Cancer Res. 2014;20:5672–85.CrossRefGoogle Scholar
  22. 22.
    Schmid P, Pinder SE, Wheatley D, et al. Phase II randomized preoperative window-of-opportunity study of the PI3K inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2016;34:1987–94.CrossRefGoogle Scholar
  23. 23.
    Dowsett M, Smith IE, Ebbs SR, et al. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99:167–70.CrossRefGoogle Scholar
  24. 24.
    Baselga J, Semiglazov V, van Dam P, et al. Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer. J Clin Oncol. 2009;27:2630–7.CrossRefGoogle Scholar
  25. 25.
    Kalinsky K, Hershman DL. Cracking open window of opportunity trials. J Clin Oncol. 2012;30:2573–5.CrossRefGoogle Scholar
  26. 26.
    Ma CX, Suman V, Goetz MP, et al. 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;23:6823–32.CrossRefGoogle Scholar
  27. 27.
    Krop IE, Mayer IA, Ganju V, et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17:811–21.CrossRefGoogle Scholar
  28. 28.
    Pinhel IF, Macneill FA, Hills MJ, et al. Extreme loss of immunoreactive p-Akt and p-Erk1/2 during routine fixation of primary breast cancer. Breast Cancer Res. 2010;12:R76.CrossRefGoogle Scholar
  29. 29.
    Meric-Bernstam F, Akcakanat A, Chen H, et al. Influence of biospecimen variables on proteomic biomarkers in breast cancer. Clin Cancer Res. 2014;20:3870–83.CrossRefGoogle Scholar
  30. 30.
    Hyman DM, Smyth LM, Donoghue MTA, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35:2251–9.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  • K. Kalinsky
    • 1
    • 2
  • J. A. Sparano
    • 3
  • X. Zhong
    • 4
  • E. Andreopoulou
    • 5
  • B. Taback
    • 2
    • 6
  • L. Wiechmann
    • 6
  • S. M. Feldman
    • 7
  • P. Ananthakrishnan
    • 8
  • A. Ahmad
    • 9
  • S. Cremers
    • 9
  • A. N. Sireci
    • 9
  • J. R. Cross
    • 10
  • D. K. Marks
    • 1
  • P. Mundi
    • 1
    • 2
  • E. Connolly
    • 2
    • 11
  • K. D. Crew
    • 1
    • 2
    • 4
  • M. A. Maurer
    • 1
    • 2
  • H. Hibshoosh
    • 2
    • 9
  • S. Lee
    • 2
    • 4
  • D. L. Hershman
    • 1
    • 2
    • 4
  1. 1.Department of Medicine, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  2. 2.Herbert Irving Comprehensive Cancer CenterColumbia University Medical CenterNew YorkUSA
  3. 3.Department of Medicine, Albert Einstein College of MedicineMontefiore Medical CenterNew YorkUSA
  4. 4.Department of Biostatistics, Mailman School of Public HealthColumbia UniversityNew YorkUSA
  5. 5.Weill Cornell MedicineNew YorkUSA
  6. 6.Department of Surgery, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  7. 7.Department of Surgery, Albert Einstein College of MedicineMontefiore Medical CenterNew YorkUSA
  8. 8.Department of SurgeryWhite Plains HospitalNew YorkUSA
  9. 9.Department of Pathology and Cell Biology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA
  10. 10.Donald B. and Catherine C. Marron Cancer Metabolism CenterMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  11. 11.Department of Radiation Oncology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA

Personalised recommendations