000			03351 am a22003373u 4500
042			_adc
100	1	0	_aXia, Youli _eauthor _91280
700	1	0	_aHe, Xiaping _eauthor _91281
700	1	0	_aRenshaw, Lorna _eauthor _91282
700	1	0	_aMartinez-Perez, Carlos _eauthor _91283
700	1	0	_aKay, Charlene _eauthor _91284
700	1	0	_aGray, Mark _eauthor _91285
700	1	0	_aMeehan, James _eauthor _91286
700	1	0	_aParker, Joel S. _eauthor _91287
700	1	0	_aPerou, Charles M. _eauthor _91288
700	1	0	_aCarey, Lisa A. _eauthor _91289
700	1	0	_aDixon, J. Michael _eauthor _91290
700	1	0	_aTurnbull, Arran _eauthor _91291
245	0	0	_aIntegrated DNA and RNA Sequencing Reveals Drivers of Endocrine Resistance in Estrogen Receptor-Positive Breast Cancer
260			_bAmerican Association for Cancer Research, _c2022-08-15.
500			_a/pmc/articles/PMC7613305/
500			_a/pubmed/35653148
520			_aPURPOSE: 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.
540			_a©2022 The Authors; Published by the American Association for Cancer Research
540			_ahttps://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
546			_aen
690			_aTranslational Cancer Mechanisms and Therapy _91292
655	7		_aText _2local
786	0		_nClin Cancer Res
856	4	1	_uhttp://dx.doi.org/10.1158/1078-0432.CCR-21-3189 _zConnect to this object online.
999			_c1886 _d1886