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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 3/2011

01-08-2011 | Clinical trial

The mammalian target of rapamycin inhibitor everolimus (RAD001) in early breast cancer: results of a pre-operative study

Authors: E. J. Macaskill, J. M. S. Bartlett, V. S. Sabine, D. Faratian, L. Renshaw, S. White, F. M. Campbell, O. Young, L. Williams, J. S. Thomas, M. D. Barber, J. M. Dixon

Published in: Breast Cancer Research and Treatment | Issue 3/2011

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Abstract

mTOR plays a key role in tumor cell cycle control, proliferation, and survival. RAD001 (everolimus) is a novel macrolide that inhibits mTOR and thus downstream signaling pathways. 31 post-menopausal women with early breast cancer were given 5 mg RAD001 once daily for 14 days prior to surgery. Biopsies were taken at diagnosis and at surgery (post 14 days of treatment) and assessed for immunohistochemical changes in proliferation (Ki67), apoptosis (active caspase-3), p-AKT (s473), p-S6 (s235/236 and s240/244), p-mTOR (s2448), ER, and PR. Five patients did not complete the 2-week treatment period due to adverse events. All adverse events were grade 1 or 2 (NCIC-CTC scale). RAD001 treatment significantly decreased proliferation (geometric mean reduction 74% from baseline (p = 0.019)), particularly in HER-2 positive tumors. High Ki67 pre-treatment correlated with reduction in Ki67, an increase in apoptosis, a reduction in p-AKT (cytoplasmic) and reduction in p-mTOR following treatment. Nuclear expression of p-AKT was significantly reduced with treatment. Tumors that had a reduction in Ki67 with treatment exhibited a significant reduction in cytoplasmic p-AKT. p-S6 staining was significantly reduced independently of Ki67 (p < 0.001 for two sites of phosphorylation). RAD001 5 mg/daily is safe and tolerable in postmenopausal early breast cancer patients and inhibits the mTOR pathway and its downstream effectors, significantly reducing tumor cell proliferation. Tumors with high Ki67, high p-AKT, and HER-2 positivity may be more responsive to mTOR inhibition with RAD001. This is the first study to report results of RAD001 5 mg as a single agent in early breast cancer.
Footnotes
1
See Ref. [28].
 
Literature
1.
Kunz J, Henriquez R, Schneider U et al (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73(3):585–596PubMedCrossRef
2.
Brown EJ, Albers MW, Shin TB et al (1994) A mammalian protein targeted by G1-arresting rapamycin–receptor complex. Nature 369:756–758PubMedCrossRef
3.
Chiu MI, Katz H, Berlin V (1994) RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA 91:12574–12578PubMedCrossRef
4.
Sabatini DM, Erdjument-Bromage H, Lui M, Tempst P, Snyder SH (1994) RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78:35–43PubMedCrossRef
5.
Sabers CJ, Martin MM, Brunn GJ et al (1995) Isolation of a protein target of the FKBP12–rapamycin complex in mammalian cells. J Biol Chem 270(2):815–822PubMedCrossRef
6.
Chan S (2004) Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer 91:1420–1424PubMedCrossRef
7.
Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501PubMedCrossRef
8.
Inoki K, Corradetti MN, Guan KL (2005) Dysregulation of the TSC–mTOR pathway in human disease. Nat Genet 37:19–24PubMedCrossRef
9.
Sansal I, Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22:2954–2963PubMedCrossRef
10.
Vignot S, Faivre S, Aguirre D, Raymond E (2005) mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol 16:525–537PubMedCrossRef
11.
12.
Loewith R, Jacinto E, Wullschleger S et al (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol Cell 10:457–468PubMedCrossRef
13.
Kim DH, Sarbassov DD, Ali SM et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110:163–175PubMedCrossRef
14.
Sarbassov DD, Ali SM, Kim DH et al (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14:1296–1302PubMedCrossRef
15.
Wullschleger S, Loewith R, Oppliger W, Hall MN (2005) Molecular organization of target of rapamycin complex 2. J Clin Biol 280(35):30697–30704
16.
Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307:1098–1101PubMedCrossRef
17.
Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM (1998) RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci USA 95:1432–1437PubMedCrossRef
18.
Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484PubMedCrossRef
19.
Sarbassov DD, Ali SM, Sabatini DM (2005) Growing roles for the mTOR pathway. Curr Opin Cell Biol 17:596–603PubMedCrossRef
20.
Sarbassov DD, Ali SM, Sengupta S et al (2006) Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159–168PubMedCrossRef
21.
Motzer RJ, Escudier B, Oudard S et al (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372:449–456PubMedCrossRef
22.
Yee KWL, Zeng Z, Konopleva M et al (2006) Phase I/II study of the mammalian target of rapamycin inhibitor everolimus (RAD001) in patients with relapsed or refractory hematologic malignancies. Clin Cancer Res 12(17):5165–5173PubMedCrossRef
23.
Baselga J, Semiglazov V, van Dam P et al (2009) 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 27(16):2630–2637PubMedCrossRef
24.
Kris MG, Riely GJ, Azzoli CG et al (2007) Combined inhibition of mTOR and EGFR with everolimus (RAD001) and gefitinib in patients with non-small cell lung cancer who have smoked cigarettes: A phase II trial. J Clin Oncol 25(18s):7575
25.
Kirkegaard T, Naresh A, Sabine VS et al (2008) Expression of tumor necrosis factor alpha converting enzyme in endocrine cancers. Am J Pathol 129(5):735–743CrossRef
26.
McCarty KS, Szabo E, Flowers JL et al (1986) Use of a monoclonal anti-estrogen receptor antibody in the immunohistochemical evaluation of human tumors. Cancer Res 46:4244s–4248sPubMed
27.
28.
29.
Kirkegaard T, Edwards J, Tovey S, McGlynn LM, Krishna SN, Mukherjee R et al (2006) Observer variation in immunohistochemical analysis of protein expression, time for a change? Histopathology 48(7):787–794PubMedCrossRef
30.
Tabernero J, Rojo F, Calvo E et al (2008) Dose- and Schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26:1603–1610PubMedCrossRef
31.
O’Donnell A, Faivre S, Burris HA et al (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595PubMedCrossRef
32.
Galea MH, Blamey RW, Elston CE, Ellis IO (1992) The Nottingham Prognostic Index in primary breast cancer. Breast Cancer Res Treat 22:207–219PubMedCrossRef
33.
Dowsett M, Smith I, Ebbs SR, on behalf of the IMPACT Trialists (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–958sPubMed
34.
Viale G, Giobbie-Hurder A, Regan MM et al (2008) Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1–98 comparing adjuvant tamoxifen with letrozole. J Clin Oncol 28:5569–5575CrossRef
35.
Murray J, Young OE, Renshaw L et al (2009) A randomised study of the effects of letrozole and anastrozole on oestrogen receptor positive breast cancers in postmenopausal women. Breast Cancer Res Treat 114(3):495–501PubMedCrossRef
36.
Young O, Renshaw L, Macaskill EJ et al (2008) Effects of fulvestrant 750 mg in premenopausal women with oestrogen-receptor-positive primary breast cancer. Eur J Cancer 44:391–399PubMedCrossRef
37.
Knuefermann C, Lu Y, Liu B et al (2003) HER2/PI3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene 22:3205–3212PubMedCrossRef
38.
Tokanuga E, Kataoka A, Kimura Y et al (2006) The association between Akt activation and resistance to hormone therapy in metastatic breast cancer. Eur J Cancer 42:629–635CrossRef
39.
Clark AS, West K, Streicher S, Dennis PA (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1:707–717PubMed
40.
Kirkegaard T, Witton CJ, McGlynn LM et al (2005) Akt activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207:139–146PubMedCrossRef
41.
Zhou X, Tan M, Hawthorne VS et al (2004) Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers. Clin Cancer Res 10:6779–6788PubMedCrossRef
42.
Beeram M, Tan QT, Tekmal RR et al (2007) Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Ann Oncol 18(8):1323–1328PubMedCrossRef
43.
Iwenofu OH, Lackman RD, Staddon AP et al (2008) Phospho-S6 ribosomal protein: a potential new predictive marker for targeted mTOR therapy. Mod Pathol 21:231–237PubMedCrossRef
44.
Rosner M, Siegel N, Valli A, Fuchs C, Hengstschlager (2010) mTOR phosphorylated at s2448 binds to raptor and rictor. Amino Acids 38(1):223–228PubMedCrossRef
45.
Generali D, Fox SB, Brizzi MP et al (2008) Down-regulation of phosphatidylinositol 3-kinase/AKT/molecular target of rapamycin metabolic pathway by primary letrozole-based therapy in human breast cancer. Clin Cancer Res 14(9):2673–2680PubMedCrossRef
46.
Sabine VS, Ferguson J, Thelwell N et al (2009) Mutation of PI3KCA in post-menopausal with breast cancer and response to RAD001 treatment. Cancer Res 69(Suppl 2):4063sCrossRef
47.
Burge CN, Chang HR, Apple SK (2006) Do the histologic features and results of breast cancer biomarker studies differ between core biopsy and surgical excision specimens. Breast 15:167–172PubMedCrossRef
48.
Iqbal S, Anderson TJ, Marson LP et al (2002) MIB-1 assessments in breast cancers. Breast 11:252–256PubMedCrossRef
49.
Bhat-Nakshatri P, Wang G, Appaiah H et al (2008) AKT alters genome-side estrogen receptor alpha binding and impacts estrogen signaling in breast cancer. Mol Cell Biol 28(24):7487–7503PubMedCrossRef
50.
Chan S, Scheulen ME, Johnston S et al (2005) Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol 23:5314–5322PubMedCrossRef
51.
Sorlie T, Perou CM, Tibshirani R et al (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 98:10869–10874PubMedCrossRef
Metadata
Title
The mammalian target of rapamycin inhibitor everolimus (RAD001) in early breast cancer: results of a pre-operative study
Authors
E. J. Macaskill
J. M. S. Bartlett
V. S. Sabine
D. Faratian
L. Renshaw
S. White
F. M. Campbell
O. Young
L. Williams
J. S. Thomas
M. D. Barber
J. M. Dixon
Publication date
01-08-2011
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 3/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-010-0967-z

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