Integrated DNA and RNA Sequencing Reveals Drivers of Endocrine Resistance in Estrogen Receptor-Positive Breast Cancer.

Autor:	Xia Y; Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., He X; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Renshaw L; Edinburgh Breast Unit Western General Hospital, Edinburgh, United Kingdom., Martinez-Perez C; Edinburgh Cancer Research Center, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom., Kay C; Edinburgh Cancer Research Center, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom., Gray M; Edinburgh Cancer Research Center, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom., Meehan J; Edinburgh Cancer Research Center, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom., Parker JS; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Perou CM; Curriculum in Bioinformatics and Computational Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Carey LA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Dixon JM; Edinburgh Breast Unit Western General Hospital, Edinburgh, United Kingdom.; Edinburgh Cancer Research Center, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom., Turnbull A; Edinburgh Cancer Research Center, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Aug 15; Vol. 28 (16), pp. 3618-3629.
DOI:	10.1158/1078-0432.CCR-21-3189
Abstrakt:	Purpose: Endocrine therapy resistance (ETR) remains the greatest challenge in treating patients with hormone receptor-positive breast cancer. We set out to identify molecular mechanisms underlying ETR through in-depth genomic analysis of breast tumors. Experimental Design: We collected pre-treatment and sequential on-treatment tumor samples from 35 patients with estrogen receptor-positive breast cancer treated with neoadjuvant then adjuvant endocrine therapy; 3 had intrinsic resistance, 19 acquired resistance, and 13 remained sensitive. Response was determined by changes in tumor volume neoadjuvantly and by monitoring for adjuvant recurrence. Twelve patients received two or more lines of endocrine therapy, with subsequent treatment lines being initiated at the time of development of resistance to the previous endocrine therapy. DNA whole-exome sequencing and RNA sequencing were performed on all samples, totalling 169 unique specimens. DNA mutations, copy-number alterations, and gene expression data were analyzed through unsupervised and supervised analyses to identify molecular features related to ETR. Results: Mutations enriched in ETR included ESR1 and GATA3. The known ESR1 D538G variant conferring ETR was identified, as was a rarer E380Q variant that confers endocrine hypersensitivity. Resistant tumors which acquired resistance had distinct gene expression profiles compared with paired sensitive tumors, showing elevated pathways including ER, HER2, GATA3, AKT, RAS, and p63 signaling. Integrated analysis in individual patients highlighted the diversity of ETR mechanisms. Conclusions: The mechanisms underlying ETR are multiple and characterized by diverse changes in both somatic genetic and transcriptomic profiles; to overcome resistance will require an individualized approach utilizing genomic and genetic biomarkers and drugs tailored to each patient. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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