Activation of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin pathway and response to everolimus in endocrine receptor‑positive metastatic breast cancer – A retrospective pilot analysis and viewpoint

Jyoti Bajpai; Anant Ramaswamy; Arun Chandrasekharan; Surya Mishra; Tanuja Shet; Sudeep Gupta; R. A. Badwe

doi:10.4103/sajc.sajc_113_17

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ORIGINAL ARTICLE : Breast Cancer

06 (

); 102-105

doi:

10.4103/sajc.sajc_113_17

Activation of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin pathway and response to everolimus in endocrine receptor‑positive metastatic breast cancer – A retrospective pilot analysis and viewpoint

Jyoti Bajpai^1,, Anant Ramaswamy¹, Arun Chandrasekharan¹, Surya Mishra¹, Tanuja Shet¹, Sudeep Gupta¹, R. A. Badwe¹

1 Deparment of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra

*Corresponding author: Dr. Jyoti Bajpai. dr_jyotibajpai@yahoo.co.in

Published: 2020-12-22

MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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Abstract

Introduction: Biomarkers predictive of response to mechanistic target of rapamycin (mTOR) inhibitor, everolimus, in endocrine receptor (ER)-positive metastatic breast cancer (MBC) are a work in progress. We evaluated the feasibility of directly measuring mTOR activity and phosphatase and tensin homolog (PTEN) expression and correlating their expression with response and survival. Materials and Methods: MBC patients who received everolimus with endocrine therapy (ET) after progression on an aromatase inhibitor and had adequate tissue preservation for estimation of mTOR activity and PTEN expression were selected for analysis from a prospectively maintained database. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan–Meier method, and correlation between mTOR activity and PTEN expression with survival was done by log-rank test. Results: Thirteen ER-positive MBC patients were available for analysis. PTEN expression was lost in 11/13 (84.6%) patients and retained in 2/13 patients (15.4%). mTOR activity was absent in four patients (30.7%), weak in six patients (46.1%), and moderate in 3 patients (23.2%). Median PFS for the entire population was 2.5 months while median OS was not reached. Patients with an absent mTOR activity showed a longer PFS (5 vs. 1.5 vs. 2 months) than those with weak and moderate activity, respectively (P = 0.043). There was no correlation between loss of PTEN expression and PFS. Conclusions: Measurement of direct mTOR activity in patients with MBC receiving everolimus/ET combination appears feasible. Absent mTOR activity may predict for longer PFS with everolimus-ET combination and requires further study.

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References

Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-7.
Paplomata E, O'Regan R. New and emerging treatments for Estrogen receptor-positive breast cancer: Focus on everolimus. Ther Clin Risk Manag 2013;9:27-36.
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: Analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003;21:2101-9.
Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis. J Natl Cancer Inst 2006;98:1285-91.
Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 2013;30:870-84.
Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Overall survival results from BOLERO-2† . Ann Oncol 2014;25:2357-62.
Noh WC, Mondesire WH, Peng J, Jian W, Zhang H, Dong J, et al. Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 2004;10:1013-23.
Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res 2012;18:5816-28.
Dekter HE, Romijn FP, Temmink WP, van Pelt J, de Fijter JW, Smit NP, et al. A spectrophotometric assay for routine measurement of mammalian target of rapamycin activity in cell lysates. Anal Biochem 2010;403:79-87.
Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, Pritchard KI, et al. Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from BOLERO-2. J Clin Oncol 2016;34:419-26.
Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 2009;21:656-64.
Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004;64:252-61.
Tanaka C, O'Reilly T, Kovarik JM, Shand N, Hazell K, Judson I, et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008;26:1596-602.
O'Reilly T, McSheehy PM. Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): Processes, limitations, and further proposals. Transl Oncol 2010;3:65-79.
Lane HA, Wood JM, McSheehy PM, Allegrini PR, Boulay A, Brueggen J, et al. MTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res 2009;15:1612-22.
Jeon YJ, Kim IK, Hong SH, Nan H, Kim HJ, Lee HJ, et al. Ribosomal protein S6 is a selective mediator of TRAIL-apoptotic signaling. Oncogene 2008;27:4344-52.
Tee AR, Proud CG. DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling. Oncogene 2000;19:3021-31.
Slamon DJ, Hurvitz SA, Chen D, Andre F, Tseng LM, Jerusalem GH, et al. Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: Combined exploratory analysis from BOLERO-1 and BOLERO-3. ASCO Meet Abstr 2015;33 15 Suppl:512.
Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 2012;13:283-96.
Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc Natl Acad Sci U S A 2001;98:10320-5.
Dillon LM, Miller TW. Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets 2014;15:65-79.
Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2012;18:4173-82.
Weigelt B, Warne PH, Downward J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 2011;30:3222-33.
Treilleux I, Arnedos M, Cropet C, Wang Q, Ferrero JM, Abadie-Lacourtoisie S, et al. 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 2015;26:120-5.

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[1] Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-7.

[2] Paplomata E, O'Regan R. New and emerging treatments for Estrogen receptor-positive breast cancer: Focus on everolimus. Ther Clin Risk Manag 2013;9:27-36.

[3] Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: Analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 2003;21:2101-9.

[4] Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: Meta-analysis. J Natl Cancer Inst 2006;98:1285-91.

[5] Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther 2013;30:870-84.

[6] Piccart M, Hortobagyi GN, Campone M, Pritchard KI, Lebrun F, Ito Y, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Overall survival results from BOLERO-2† . Ann Oncol 2014;25:2357-62.

[7] Noh WC, Mondesire WH, Peng J, Jian W, Zhang H, Dong J, et al. Determinants of rapamycin sensitivity in breast cancer cells. Clin Cancer Res 2004;10:1013-23.

[8] Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res 2012;18:5816-28.

[9] Dekter HE, Romijn FP, Temmink WP, van Pelt J, de Fijter JW, Smit NP, et al. A spectrophotometric assay for routine measurement of mammalian target of rapamycin activity in cell lysates. Anal Biochem 2010;403:79-87.

[10] Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, Pritchard KI, et al. Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: Results from BOLERO-2. J Clin Oncol 2016;34:419-26.

[11] Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 2009;21:656-64.

[12] Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 2004;64:252-61.

[13] Tanaka C, O'Reilly T, Kovarik JM, Shand N, Hazell K, Judson I, et al. Identifying optimal biologic doses of everolimus (RAD001) in patients with cancer based on the modeling of preclinical and clinical pharmacokinetic and pharmacodynamic data. J Clin Oncol 2008;26:1596-602.

[14] O'Reilly T, McSheehy PM. Biomarker development for the clinical activity of the mTOR inhibitor everolimus (RAD001): Processes, limitations, and further proposals. Transl Oncol 2010;3:65-79.

[15] Lane HA, Wood JM, McSheehy PM, Allegrini PR, Boulay A, Brueggen J, et al. MTOR inhibitor RAD001 (everolimus) has antiangiogenic/vascular properties distinct from a VEGFR tyrosine kinase inhibitor. Clin Cancer Res 2009;15:1612-22.

[16] Jeon YJ, Kim IK, Hong SH, Nan H, Kim HJ, Lee HJ, et al. Ribosomal protein S6 is a selective mediator of TRAIL-apoptotic signaling. Oncogene 2008;27:4344-52.

[17] Tee AR, Proud CG. DNA-damaging agents cause inactivation of translational regulators linked to mTOR signalling. Oncogene 2000;19:3021-31.

[18] Slamon DJ, Hurvitz SA, Chen D, Andre F, Tseng LM, Jerusalem GH, et al. Predictive biomarkers of everolimus efficacy in HER2+ advanced breast cancer: Combined exploratory analysis from BOLERO-1 and BOLERO-3. ASCO Meet Abstr 2015;33 15 Suppl:512.

[19] Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol 2012;13:283-96.

[20] Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice. Proc Natl Acad Sci U S A 2001;98:10320-5.

[21] Dillon LM, Miller TW. Therapeutic targeting of cancers with loss of PTEN function. Curr Drug Targets 2014;15:65-79.

[22] Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2012;18:4173-82.

[23] Weigelt B, Warne PH, Downward J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 2011;30:3222-33.

[24] Treilleux I, Arnedos M, Cropet C, Wang Q, Ferrero JM, Abadie-Lacourtoisie S, et al. 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 2015;26:120-5.

Activation of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin pathway and response to everolimus in endocrine receptor‑positive metastatic breast cancer – A retrospective pilot analysis and viewpoint

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Abstract

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