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Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling
BACKGROUND: One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated t...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005625/ https://www.ncbi.nlm.nih.gov/pubmed/31867841 http://dx.doi.org/10.1002/mgg3.1079 |
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author | Chen, Zhanhong Sun, Tian Yang, Ziyan Zheng, Yabing Yu, Ruoying Wu, Xue Yan, Junrong Shao, Yang W Shao, Xiying Cao, Wenming Wang, Xiaojia |
author_facet | Chen, Zhanhong Sun, Tian Yang, Ziyan Zheng, Yabing Yu, Ruoying Wu, Xue Yan, Junrong Shao, Yang W Shao, Xiying Cao, Wenming Wang, Xiaojia |
author_sort | Chen, Zhanhong |
collection | PubMed |
description | BACKGROUND: One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. METHODS: Targeted next‐generation sequencing (NGS) of 416 cancer‐relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2‐ BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. RESULTS: In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2‐targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2‐ BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. CONCLUSIONS: In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2‐ BC patients, respectively. |
format | Online Article Text |
id | pubmed-7005625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-70056252020-02-13 Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling Chen, Zhanhong Sun, Tian Yang, Ziyan Zheng, Yabing Yu, Ruoying Wu, Xue Yan, Junrong Shao, Yang W Shao, Xiying Cao, Wenming Wang, Xiaojia Mol Genet Genomic Med Original Articles BACKGROUND: One of the major challenges in managing invasive breast cancer (BC) is the lack of reliable biomarkers to track response. Circulating tumor DNA (ctDNA) from liquid biopsy, as a candidate biomarker, provides a valuable assessment of BC patients. In this retrospective study, we evaluated the utility of ctDNA to reflect the efficacy of treatment and to monitor resistance mechanisms. METHODS: Targeted next‐generation sequencing (NGS) of 416 cancer‐relevant genes was performed on 41 plasma biopsy samples of 19 HER2+ and 12 HER2‐ BC patients. Longitudinal ctDNA samples were analyzed in three BC patients over the treatment course for detecting acquired mutations. RESULTS: In HER2+ BC patients, ERBB2 somatic copy numbers in ctDNA samples were significantly higher in patients progressed on HER2‐targeted therapy than those who were still responding to the treatment. Recurrent acquired mutations were detected in genes including ERBB2, TP53, EGFR, NF1, and SETD2, which may contribute to trastuzumab resistance. In longitudinal analyses, the observed mutation allele frequencies were tracked closely in concordance with treatment responses. A novel ERBB2 p.(Leu869Arg) mutation was acquired in one patient upon resistant to trastuzumab therapy, which was further validated as an oncogenic mutation in vitro and contributed to resistance. In HER2‐ BC patients with chemotherapy resistance, genetic alterations on TP53, PIK3CA, and DNA damage repair genes were frequently observed. CONCLUSIONS: In summary, ctDNA monitoring, particularly longitudinal analyses, provides valuable insights into the assessment of targeted therapy efficacy and gene alterations underlying trastuzumab resistance and chemotherapy resistance in HER2+ and HER2‐ BC patients, respectively. John Wiley and Sons Inc. 2019-12-23 /pmc/articles/PMC7005625/ /pubmed/31867841 http://dx.doi.org/10.1002/mgg3.1079 Text en © 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Chen, Zhanhong Sun, Tian Yang, Ziyan Zheng, Yabing Yu, Ruoying Wu, Xue Yan, Junrong Shao, Yang W Shao, Xiying Cao, Wenming Wang, Xiaojia Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling |
title | Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling |
title_full | Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling |
title_fullStr | Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling |
title_full_unstemmed | Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling |
title_short | Monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor DNA genomic profiling |
title_sort | monitoring treatment efficacy and resistance in breast cancer patients via circulating tumor dna genomic profiling |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005625/ https://www.ncbi.nlm.nih.gov/pubmed/31867841 http://dx.doi.org/10.1002/mgg3.1079 |
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