A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer

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Abstract

Purpose

Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer.

Methods

A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles.

Results

Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m ²), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD.

Conclusions

GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m ² plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC.

Electronic supplementary material

The online version of this article (doi:10.1186/s40064-016-2457-1) contains supplementary material, which is available to authorized users.

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Most cited references 19

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Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840.

Donald Berry, C Cirrincione, Andrew D Seidman … (2008)

Phase II trials suggested that weekly paclitaxel might be more effective and less toxic than every-3-weeks administration for metastatic breast cancer (MBC). Cancer and Leukemia Group B (CALGB) protocol 9840 was initiated to address this question. Subsequently trastuzumab was demonstrated to improve outcomes of paclitaxel therapy for human epidermal growth factor receptor-2 (HER-2)-positive patients, and was therefore incorporated. Because inhibition of HER-family signaling had potential efficacy even without HER-2 overexpression, we randomly assigned for trastuzumab in this population. Patients were randomly assigned to paclitaxel 175 mg/m(2) every 3 weeks or 80 mg/m(2) weekly. After the first 171 patients, all HER-2-positive patients received trastuzumab; HER-2 nonoverexpressors were randomly assigned for trastuzumab, in addition to paclitaxel schedule. A total of 577 patients were treated on 9840. An additional 158 patients were included in analyses, for combined sample of 735. The primary end point was response rate (RR); secondary end points were time to progression (TTP), overall survival, and toxicity. Primary comparisons were between weekly versus every-3-weeks paclitaxel, and trastuzumab versus no trastuzumab in HER-2 nonoverexpressors. In the combined sample, weekly paclitaxel was superior to every-3-weeks administration: RR (42% v 29%, unadjusted odds ratio [OR] = 1.75; P = .0004), TTP (median, 9 v 5 months; adjusted HR = 1.43; P < .0001), and survival (median, 24 v 12 months; adjusted HR = 1.28; P = .0092). For HER-2 nonoverexpressors, trastuzumab did not improve efficacy. Grade 3 neuropathy was more common with weekly dosing (24% v 12%; P = .0003). Weekly paclitaxel is more effective than every-3-weeks administration for MBC. Trastuzumab did not improve efficacy for HER-2 nonoverexpressors. Neurotoxicity is a treatment-limiting toxicity for weekly paclitaxel.

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Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer.

Deng Pan, Masha Kocherginsky, Suzanne D. Conzen (2011)

Estrogen receptor-negative (ER(-)) breast cancers have limited treatment options and are associated with earlier relapses. Because glucocorticoid receptor (GR) signaling initiates antiapoptotic pathways in ER(-) breast cancer cells, we hypothesized that activation of these pathways might be associated with poor prognosis in ER(-) disease. Here we report findings from a genome-wide study of GR transcriptional targets in a premalignant ER(-) cell line model of early breast cancer (MCF10A-Myc) and in primary early-stage ER(-) human tumors. Chromatin immunoprecipitation with massively parallel sequencing (ChIP-seq) coupled to time-course expression profiling led us to identify epithelial-to-mesenchymal transition (EMT) pathways as an important aspect associated with GR activation. We validated these findings by carrying out a meta-analysis of primary breast tumor gene expression from 1,378 early-stage breast cancer patients with long-term clinical follow-up, confirming that high levels of GR expression significantly correlated with shorter relapse-free survival in ER(-) patients who were treated or untreated with adjuvant chemotherapy. Notably, in ER(+) breast cancer patients, high levels of GR expression in tumors were significantly associated with better outcome relative to low levels of GR expression. Gene expression analysis revealed that ER(-) tumors expressing high GR levels exhibited differential activation of EMT, cell adhesion, and inflammation pathways. Our findings suggest a direct transcriptional role for GR in determining the outcome of poor-prognosis ER(-) breast cancers.

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Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells.

Wei Wu, Shamita Chaudhuri, Deanna R Brickley … (2004)

Activation of the glucocorticoid receptor (GR) results in diverse physiological effects depending on cell type. For example, glucocorticoids (GC) cause apoptosis in lymphocytes but can rescue mammary epithelial cells from growth factor withdrawal-induced death. However, the molecular mechanisms of GR-mediated survival remain poorly understood. In this study, a large-scale oligonucleotide screen of GR-regulated genes was performed. Several of the genes that were found to be induced 30 min after GR activation encode proteins that function in cell survival signaling pathways. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced apoptosis in a GR-dependent manner and is associated with the transcriptional induction of at least two genes identified in our screen, serum and GC-inducible protein kinase-1 (SGK-1) and mitogen-activated protein kinase phosphatase-1 (MKP-1). Furthermore, GC treatment alone or GC treatment followed by chemotherapy increases both SGK-1 and MKP-1 steady-state protein levels. In the absence of GC treatment, ectopic expression of SGK-1 or MKP-1 inhibits chemotherapy-induced apoptosis, suggesting a possible role for these proteins in GR-mediated survival. Moreover, specific inhibition of SGK-1 or MKP-1 induction by the introduction of SGK-1- or MKP-1-small interfering RNA reversed the anti-apoptotic effects of GC treatment. Taken together, these data suggest that GR activation in breast cancer cells regulates survival signaling through direct transactivation of genes that encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding GR-induced survival mechanisms is essential for achieving optimal therapeutic responses.

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Author and article information

Contributors

Rita Nanda:

ORCID: http://orcid.org/0000-0001-5248-0876

773-834-2756 , rnanda@medicine.bsd.uchicago.edu

Erica M. Stringer-Reasor: esreasor@uabmc.edu

Poornima Saha: psaha@medicine.bsd.uchicago.edu

Masha Kocherginsky: mkocherg@northwestern.edu

Jean Gibson: jeangibson1002@gmail.com

Bernadette Libao: blibao@medicine.bsd.uchicago.edu

Philip C. Hoffman: phoffman@medicine.bsd.uchicago.edu

Elias Obeid: Elias.Obeid@fccc.edu

Douglas E. Merkel: dmerkel@northshore.org

Galina Khramtsova: gkhramts@medicine.bsd.uchicago.edu

Maxwell Skor: maxwellskor@gmail.com

Thomas Krausz: thomas.krausz@uchospitals.edu

Ronald N. Cohen: roncohen@medicine.bsd.uchicago.edu

Mark J. Ratain: mratain@medicine.bsd.uchicago.edu

Gini F. Fleming: gfleming@medicine.bsd.uchicago.edu

Suzanne D. Conzen: sconzen@medicine.bsd.uchicago.edu

Journal

Journal ID (nlm-ta): Springerplus

Journal ID (iso-abbrev): Springerplus

Title: SpringerPlus

Publisher: Springer International Publishing (Cham )

ISSN (Electronic): 2193-1801

Publication date (Electronic): 30 June 2016

Publication date PMC-release: 30 June 2016

Publication date Collection: 2016

Volume: 5

Issue: 1

Electronic Location Identifier: 947

Affiliations

[ ]Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC 2115, Chicago, IL 60637 USA

[ ]Department of Health Studies, The University of Chicago, 5841 S. Maryland Ave., MC 2000, Chicago, IL 60637 USA

[ ]Northshore University Health Systems, 2650 Ridge Ave # 4805, Evanston, IL 60201 USA

[ ]Department of Pathology, The University of Chicago, 5841 S Maryland Ave., MC 6101, Chicago, IL USA

[ ]Section of Endocrinology, Department of Medicine, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637 USA

[ ]5841 S. Maryland Ave., MC 2115, Chicago, IL 60637-1470 USA

Author information

Rita Nanda http://orcid.org/0000-0001-5248-0876

Article

Publisher ID: 2457

DOI: 10.1186/s40064-016-2457-1

PMC ID: 4929099

PubMed ID: 27386391

SO-VID: ff58436a-a5fa-4d9a-bcfb-f2853767f996

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 18 May 2016

Date accepted : 27 May 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: CA14599

Award Recipient : Rita Nanda

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: CA089208

Award Recipient : Suzanne D. Conzen

Funded by: FundRef http://dx.doi.org/10.13039/100000869, Susan G. Komen for the Cure;

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A randomized phase I trial of nanoparticle albumin-bound paclitaxel with or without mifepristone for advanced breast cancer

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Abstract

Purpose

Methods

Results

Conclusions

Electronic supplementary material

Related collections

Cancer Metabolism

Most cited references 19

Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840.

Activation of the glucocorticoid receptor is associated with poor prognosis in estrogen receptor-negative breast cancer.

Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells.

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