Abstract
Introduction
Neoadjuvant endocrine therapy is often utilized to downstage Estrogen Receptor-positive (ER+) breast cancer prior to surgery. However, this approach is sometimes met with endocrine resistance mechanisms within the tumor. This trial examines the safety and efficacy of tamoxifen in combination with an mTORC1/2 inhibitor, TAK-228, in the neoadjuvant treatment of ER+ breast cancer.
Methods
In this single-arm, open-label trial, pre- and post-menopausal women were enrolled to receive neoadjuvant tamoxifen (20 mg daily) with TAK-228 (30 mg weekly) for 16 weeks prior to surgery. Patient had tissue sampling at baseline, week 6, and week 16. The primary endpoint was change in Ki-67 from baseline to 6 weeks. The toxicity, change in tumor size, pathologic complete response rate, PEPI score, and baseline Oncotype Dx score were also assessed.
Results
Twenty-eight women were enrolled on the trial, and 25 completed the entire study course. The combination of tamoxifen and TAK-228 resulted in a significant reduction in Ki-67 from 18.3 to 15.2% (p = 0.0023). The drug was also found to be safe and tolerable. While nausea and hyperglycemia were common side effects, these were manageable. The tumor size also significantly decreased with the treatment, with a median decrease of 0.75 cm (p < 0.0001). There were no pathologic complete responses.
Conclusion
Tamoxifen and TAK-228 was safe and well tolerated neoadjuvant treatment for ER+ breast cancer, preliminary evidence of activity with significant reduction in both Ki-67 and tumor size, warranting further evaluation in a larger study.
Similar content being viewed by others
References
Osborne CK, Zhao H, Fuqua SAW (2000) Selective estrogen receptor modulators: structure, function, and clinical use. J ClinOncol. https://doi.org/10.1200/JCO.2000.18.17.3172
Osborne CK, Schiff R (2011) Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. https://doi.org/10.1146/annurev-med-070909-182917
Beaver JA, Park BH (2012) The BOLERO-2 trial: the addition of everolimus to exemestane in the treatment of postmenopausal hormone receptor-positive advanced breast cancer. Future Oncol. https://doi.org/10.2217/fon.12.49
Bachelot T, Bourgier C, Cropet C et al (2012) Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study. J ClinOncol. https://doi.org/10.1200/JCO.2011.39.0708
Sabatini DM (2006) mTOR and cancer: insights into a complex relationship. Nat Rev Cancer. https://doi.org/10.1038/nrc1974
Chiang GG, Abraham RT (2007) Targeting the mTOR signaling network in cancer. Trends Mol Med. https://doi.org/10.1016/j.molmed.2007.08.001
Ghobrial IM, Siegel DS, Vij R et al (2016) TAK-228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: a phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non-Hodgkin lymphoma, or Waldenström’smacroglobulinemia. Am J Hematol. https://doi.org/10.1002/ajh.24300
Moore KN, Bauer TM, Falchook GS et al (2018) Phase I study of the investigational oral mTORC1/2 inhibitor sapanisertib (TAK-228): Tolerability and food effects of a milled formulation in patients with advanced solid tumours. ESMO Open. https://doi.org/10.1136/esmoopen-2017-000291
Burris HA, Kurkjian CD, Hart L et al (2017) TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. Cancer ChemotherPharmacol. https://doi.org/10.1007/s00280-017-3343-4
Dowsett M, Ebbs SR, Dixon JM et al (2005) Biomarker changes during neoadjuvantanastrozole, tamoxifen, or the combination: Influence of hormonal status and HER-2 in breast cancer—a study from the IMPACT trialists. J ClinOncol. https://doi.org/10.1200/JCO.2005.07.559
Treilleux I, Arnedos M, Cropet C, Wang Q, Ferrero JM, Abadie-Lacourtoisie S, Levy C, Legouffe E, Lortholary A, Pujade-Lauraine E, Bourcier AV, Eymard JC, Spaeth D, Bachelot T (2015) Translational studies within the TAMRAD randomized GINECO trial: evidence for mTORC1 activation marker as a predictive factor for everolimus efficacy in advanced breast cancer. Ann Oncol 26(1):120–125. https://doi.org/10.1093/annonc/mdu497
Dowsett M, Smith IE, Ebbs SR et al (2005) Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res 11:951s–958s
Smith IE, Dowsett M, Ebbs SR et al (2005) Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the immediate preoperative anastrozole, tamoxifen, or combined with tamoxifen (IMPACT) multicenter double-blind randomized trial. J ClinOncol. https://doi.org/10.1200/JCO.2005.04.005
Funding
This Study was funded by Takeda Pharmaceuticals U.S.A.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict interest
The authors declare that they have no conflict of interests.
Consent for publication
With selection for publication, the authors grant permission for reproduction of the manuscript as well as all associated tables and figures.
Ethical approval
Trial monitoring occurred through the institutional Data Safety and Monitoring Board (DSMB).
Informed consent
Informed consent was obtained from all individual participants included in the study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Koca, E., Niravath, P.A., Ensor, J. et al. ANETT: PhAse II trial of NEoadjuvant TAK-228 plus Tamoxifen in patients with hormone receptor-positive breast cancer. Breast Cancer Res Treat 188, 433–439 (2021). https://doi.org/10.1007/s10549-021-06214-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-021-06214-7