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Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer
Receptor-activator of nuclear-factor –κB-ligand (RANKL) and its receptor RANK have been recently identified as key players in breast cancer bone metastases. Since Circulating Tumor Cells (CTCs) are considered a crucial step of metastatic process, we explored RANK expression on CTCs in metastatic bre...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987166/ https://www.ncbi.nlm.nih.gov/pubmed/31992773 http://dx.doi.org/10.1038/s41598-020-58339-2 |
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author | Pantano, Francesco Rossi, Elisabetta Iuliani, Michele Facchinetti, Antonella Simonetti, Sonia Ribelli, Giulia Zoccoli, Alice Vincenzi, Bruno Tonini, Giuseppe Zamarchi, Rita Santini, Daniele |
author_facet | Pantano, Francesco Rossi, Elisabetta Iuliani, Michele Facchinetti, Antonella Simonetti, Sonia Ribelli, Giulia Zoccoli, Alice Vincenzi, Bruno Tonini, Giuseppe Zamarchi, Rita Santini, Daniele |
author_sort | Pantano, Francesco |
collection | PubMed |
description | Receptor-activator of nuclear-factor –κB-ligand (RANKL) and its receptor RANK have been recently identified as key players in breast cancer bone metastases. Since Circulating Tumor Cells (CTCs) are considered a crucial step of metastatic process, we explored RANK expression on CTCs in metastatic breast cancer (MBC), and the predictive value of RANK-positive CTCs in monitoring patients during treatment with denosumab (anti-RANKL antibody). To this purpose, we developed a novel CTC assay to quantify RANK-positive CTCs in forty-two bone MBC patients, candidates to denosumab treatment. Companion algorithms ΔAUC and Slope were developed, and correlated with time to first skeletal-related-events (SRE), time to bone metastasis progression and time to visceral metastasis progression. Twenty-seven patients had at least one CTC at baseline and, among these, nineteen (70%) had one or more RANK–positive CTCs. Notably, the baseline total CTCs, but not the RANK-positive, were associated with Time-to-first-SRE, Time-to-Bone-Metastasis-Progression and Time-to-Visceral-Metastasis-Progression. Conversely, during treatment monitoring, positive ΔAUC value, expression of RANK-positive CTCs persistence, correlated with longer Time-to-first-SRE (p = 0.0002) and Time-to-Bone-Metastasis-Progression (p = 0.0012). Furthermore, the early increase at second day, in RANK-positive CTCs (Positive-Slope) was associated with delay in time-to-first-SRE (p = 0.0038) and Time-to-Bone-Metastasis-Progression (p = 0.0024). We demonstrate, for the first time, the expression of RANK on CTCs in MBC patients and that the persistence of RANK expression determines denosumab effectiveness. |
format | Online Article Text |
id | pubmed-6987166 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69871662020-02-03 Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer Pantano, Francesco Rossi, Elisabetta Iuliani, Michele Facchinetti, Antonella Simonetti, Sonia Ribelli, Giulia Zoccoli, Alice Vincenzi, Bruno Tonini, Giuseppe Zamarchi, Rita Santini, Daniele Sci Rep Article Receptor-activator of nuclear-factor –κB-ligand (RANKL) and its receptor RANK have been recently identified as key players in breast cancer bone metastases. Since Circulating Tumor Cells (CTCs) are considered a crucial step of metastatic process, we explored RANK expression on CTCs in metastatic breast cancer (MBC), and the predictive value of RANK-positive CTCs in monitoring patients during treatment with denosumab (anti-RANKL antibody). To this purpose, we developed a novel CTC assay to quantify RANK-positive CTCs in forty-two bone MBC patients, candidates to denosumab treatment. Companion algorithms ΔAUC and Slope were developed, and correlated with time to first skeletal-related-events (SRE), time to bone metastasis progression and time to visceral metastasis progression. Twenty-seven patients had at least one CTC at baseline and, among these, nineteen (70%) had one or more RANK–positive CTCs. Notably, the baseline total CTCs, but not the RANK-positive, were associated with Time-to-first-SRE, Time-to-Bone-Metastasis-Progression and Time-to-Visceral-Metastasis-Progression. Conversely, during treatment monitoring, positive ΔAUC value, expression of RANK-positive CTCs persistence, correlated with longer Time-to-first-SRE (p = 0.0002) and Time-to-Bone-Metastasis-Progression (p = 0.0012). Furthermore, the early increase at second day, in RANK-positive CTCs (Positive-Slope) was associated with delay in time-to-first-SRE (p = 0.0038) and Time-to-Bone-Metastasis-Progression (p = 0.0024). We demonstrate, for the first time, the expression of RANK on CTCs in MBC patients and that the persistence of RANK expression determines denosumab effectiveness. Nature Publishing Group UK 2020-01-28 /pmc/articles/PMC6987166/ /pubmed/31992773 http://dx.doi.org/10.1038/s41598-020-58339-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Pantano, Francesco Rossi, Elisabetta Iuliani, Michele Facchinetti, Antonella Simonetti, Sonia Ribelli, Giulia Zoccoli, Alice Vincenzi, Bruno Tonini, Giuseppe Zamarchi, Rita Santini, Daniele Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer |
title | Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer |
title_full | Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer |
title_fullStr | Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer |
title_full_unstemmed | Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer |
title_short | Dynamic changes of Receptor activator of nuclear factor-κB expression in Circulating Tumor Cells during Denosumab predict treatment effectiveness in Metastatic Breast Cancer |
title_sort | dynamic changes of receptor activator of nuclear factor-κb expression in circulating tumor cells during denosumab predict treatment effectiveness in metastatic breast cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987166/ https://www.ncbi.nlm.nih.gov/pubmed/31992773 http://dx.doi.org/10.1038/s41598-020-58339-2 |
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