Comprehensive characterization of pre- and post-treatment samples of breast cancer reveal potential mechanisms of chemotherapy resistance.
Journal
NPJ breast cancer
ISSN: 2374-4677
Titre abrégé: NPJ Breast Cancer
Pays: United States
ID NLM: 101674891
Informations de publication
Date de publication:
06 May 2022
06 May 2022
Historique:
received:
06
09
2021
accepted:
12
04
2022
entrez:
6
5
2022
pubmed:
7
5
2022
medline:
7
5
2022
Statut:
epublish
Résumé
When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome, and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identify biomarkers of response and resistance mechanisms. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response, and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p = 0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; p = 0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatment sample (CDKN1B) or in the post-treatment sample (TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.
Identifiants
pubmed: 35523804
doi: 10.1038/s41523-022-00428-8
pii: 10.1038/s41523-022-00428-8
pmc: PMC9076915
doi:
Types de publication
Journal Article
Langues
eng
Pagination
60Subventions
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : 2014-6007
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : 2014-6007
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : 2014-6007
Organisme : KWF Kankerbestrijding (Dutch Cancer Society)
ID : 2014-6007
Informations de copyright
© 2022. The Author(s).
Références
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Cancer Discov. 2015 Nov;5(11):1164-1177
pubmed: 26410082
Cell Biol Int. 2008 Sep;32(9):1031-43
pubmed: 18550395
Nat Methods. 2015 May;12(5):453-7
pubmed: 25822800
PLoS Comput Biol. 2016 Apr 21;12(4):e1004873
pubmed: 27100738
Mod Pathol. 2011 Feb;24(2):209-31
pubmed: 21076461
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Database (Oxford). 2017 Jan 1;2017(1):
pubmed: 28365736
Nat Genet. 2015 May;47(5):505-511
pubmed: 25822088
J Cell Biochem. 1994 Apr;54(4):440-52
pubmed: 8014193
Bioinformatics. 2012 Jul 15;28(14):1811-7
pubmed: 22581179
Bioinformatics. 2012 Mar 15;28(6):882-3
pubmed: 22257669
Breast Cancer Res Treat. 2015 Aug;153(1):145-52
pubmed: 26210520
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Br J Cancer. 2014 Oct 14;111(8):1532-41
pubmed: 25101563
Breast Cancer Res. 2008;10(5):R81
pubmed: 18823530
Nucleic Acids Res. 2014 Dec 16;42(22):e168
pubmed: 25300484
Nat Commun. 2020 Dec 2;11(1):6175
pubmed: 33268821
Cell Rep. 2016 Jun 28;16(1):263-277
pubmed: 27320919
Nat Rev Cancer. 2018 Nov;18(11):696-705
pubmed: 30293088
J Clin Oncol. 2010 Jan 1;28(1):105-13
pubmed: 19917869
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cell. 2015 Jan 15;160(1-2):48-61
pubmed: 25594174
Ann Oncol. 2010 Mar;21(3):481-487
pubmed: 19717533
Nature. 2012 Oct 4;490(7418):61-70
pubmed: 23000897
Oncol Lett. 2018 Jan;15(1):610-617
pubmed: 29387236
Lancet Oncol. 2015 Jan;16(1):25-35
pubmed: 25524798
Nature. 2016 May 02;534(7605):47-54
pubmed: 27135926
Pigment Cell Melanoma Res. 2015 May;28(3):318-23
pubmed: 25515853
Drug Resist Updat. 2012 Feb-Apr;15(1-2):123-31
pubmed: 22365330
Breast Cancer Res Treat. 2013 Jan;137(1):213-23
pubmed: 23203637
Ann Surg. 2015 Sep;262(3):434-9; discussion 438-9
pubmed: 26222764
Int J Cancer. 2010 Jul 15;127(2):355-60
pubmed: 19904758
Nucleic Acids Res. 2016 Jan 4;44(D1):D481-7
pubmed: 26656494
Front Genet. 2012 Mar 15;3:35
pubmed: 22435069
Nature. 2015 Feb 12;518(7538):240-4
pubmed: 25409150
Cell. 2018 May 3;173(4):879-893.e13
pubmed: 29681456
Genome Res. 2003 Nov;13(11):2498-504
pubmed: 14597658
Bioinformatics. 2011 Nov 1;27(21):2987-93
pubmed: 21903627
Oncogene. 2007 Oct 25;26(49):6997-7005
pubmed: 17486065
Fly (Austin). 2012 Apr-Jun;6(2):80-92
pubmed: 22728672
J Clin Oncol. 2007 Oct 1;25(28):4414-22
pubmed: 17785706
Nat Methods. 2014 Aug;11(8):783-784
pubmed: 25075903
Clin Cancer Res. 2013 Aug 15;19(16):4521-31
pubmed: 23812670
Nature. 2012 Jul 18;487(7407):330-7
pubmed: 22810696
Nat Genet. 2000 Jun;25(2):217-22
pubmed: 10835641
Nat Med. 2012 Jul;18(7):1052-9
pubmed: 22683778
Genome Biol. 2013 Apr 25;14(4):R36
pubmed: 23618408
Cell. 2018 Apr 5;173(2):291-304.e6
pubmed: 29625048
Clin Cancer Res. 2020 Jun 15;26(12):2838-2848
pubmed: 32046998
Lancet. 2014 Jul 12;384(9938):164-72
pubmed: 24529560
J Natl Cancer Inst. 2016 Jul 05;108(11):
pubmed: 27381626
Stat Methods Med Res. 2013 Oct;22(5):519-36
pubmed: 22127579
Cancer Discov. 2014 Feb;4(2):232-45
pubmed: 24356096
Genes Dev. 2016 Jun 15;30(12):1470-80
pubmed: 27340177
Breast Cancer Res Treat. 2011 Jun;127(2):363-73
pubmed: 20585850
Nature. 2013 May 2;497(7447):67-73
pubmed: 23636398
Clin Cancer Res. 2016 Dec 15;22(24):6039-6050
pubmed: 27330058
Breast Cancer Res. 2015 May 29;17:73
pubmed: 26021444
Oncol Res Treat. 2014;37(10):563-8
pubmed: 25486071
Breast Cancer Res Treat. 2014 Dec;148(3):525-34
pubmed: 25395319
Sci Rep. 2015 Jul 23;5:12465
pubmed: 26202299
Cell. 2016 Jul 28;166(3):740-754
pubmed: 27397505