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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...

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Autores principales: Chen, Zhanhong, Sun, Tian, Yang, Ziyan, Zheng, Yabing, Yu, Ruoying, Wu, Xue, Yan, Junrong, Shao, Yang W, Shao, Xiying, Cao, Wenming, Wang, Xiaojia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
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.
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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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