Longitudinal heterogeneity in glioblastoma: moving targets in recurrent versus primary tumors.
Adult
Aged
Antineoplastic Agents
/ therapeutic use
Antineoplastic Agents, Immunological
/ therapeutic use
Biomarkers, Tumor
/ genetics
Brain Neoplasms
/ diagnosis
Disease Progression
Epigenesis, Genetic
/ drug effects
Female
Genetic Heterogeneity
Glioblastoma
/ diagnosis
Humans
Longitudinal Studies
Male
Middle Aged
Molecular Targeted Therapy
/ methods
Neoplasm Recurrence, Local
/ genetics
Patient Care Planning
Retrospective Studies
Young Adult
EGFR
Glioblastoma
Heterogeneity
MLPA
Targeted therapy
Journal
Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741
Informations de publication
Date de publication:
20 03 2019
20 03 2019
Historique:
received:
10
10
2018
accepted:
12
03
2019
entrez:
22
3
2019
pubmed:
22
3
2019
medline:
6
5
2020
Statut:
epublish
Résumé
Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored common drug targets in paired primary vs. recurrent GBM tissue samples. Paired surgical tissue samples were derived from a homogeneously treated cohort of 34 GBM patients. All patients received radiotherapy and temozolomide chemotherapy. Verification of common drug targets included immunohistological analysis of PDGFR-β, FGFR-2, FGFR-3, and mTOR-pathway component (phospho-mTOR Paired tumor tissue exhibited significant changes of expression in 9 of the 10 investigated druggable targets (90%). Only one target (FGFR1) was found "unchanged", since dissimilar expression was observed in only one of the 34 paired tumor tissue samples. All other targets were variably expressed with an 18-56% discordance rate between primary and recurrent tissue. The high incidence of dissimilar target expression status in clinical samples from primary vs. recurrent GBM suggests clinically relevant heterogeneity along the course of disease. Molecular target expression, as determined at primary diagnosis, may not necessarily present rational treatment clues for the clinical care of recurrent GBM. Further studies need to analyze the therapeutic impact of longitudinal heterogeneity in GBM.
Sections du résumé
BACKGROUND
Molecularly targeted therapies using receptor inhibitors, small molecules or monoclonal antibodies are routinely applied in oncology. Verification of target expression should be mandatory prior to initiation of therapy, yet, determining the expression status is most challenging in recurrent glioblastoma (GBM) where most patients are not eligible for second-line surgery. Because very little is known on the consistency of expression along the clinical course we here explored common drug targets in paired primary vs. recurrent GBM tissue samples.
METHODS
Paired surgical tissue samples were derived from a homogeneously treated cohort of 34 GBM patients. All patients received radiotherapy and temozolomide chemotherapy. Verification of common drug targets included immunohistological analysis of PDGFR-β, FGFR-2, FGFR-3, and mTOR-pathway component (phospho-mTOR
RESULTS
Paired tumor tissue exhibited significant changes of expression in 9 of the 10 investigated druggable targets (90%). Only one target (FGFR1) was found "unchanged", since dissimilar expression was observed in only one of the 34 paired tumor tissue samples. All other targets were variably expressed with an 18-56% discordance rate between primary and recurrent tissue.
CONCLUSIONS
The high incidence of dissimilar target expression status in clinical samples from primary vs. recurrent GBM suggests clinically relevant heterogeneity along the course of disease. Molecular target expression, as determined at primary diagnosis, may not necessarily present rational treatment clues for the clinical care of recurrent GBM. Further studies need to analyze the therapeutic impact of longitudinal heterogeneity in GBM.
Identifiants
pubmed: 30894200
doi: 10.1186/s12967-019-1846-y
pii: 10.1186/s12967-019-1846-y
pmc: PMC6425567
doi:
Substances chimiques
Antineoplastic Agents
0
Antineoplastic Agents, Immunological
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
96Références
Cancer Cell. 2011 Dec 13;20(6):810-7
pubmed: 22137795
N Engl J Med. 2013 Aug 22;369(8):722-31
pubmed: 23964934
Nat Rev Clin Oncol. 2017 Jul;14(7):434-452
pubmed: 28031556
Brain Pathol. 2015 Jul;25(4):409-17
pubmed: 25231549
Ann Neurol. 2015 Dec;78(6):929-38
pubmed: 26381530
Cancer Cell. 2015 Sep 14;28(3):318-28
pubmed: 26373279
Int J Cancer. 2011 Aug 1;129(3):659-70
pubmed: 21425258
J Clin Oncol. 2013 Sep 10;31(26):3212-8
pubmed: 23940216
Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):3041-6
pubmed: 22323597
N Engl J Med. 2015 Jun 25;372(26):2499-508
pubmed: 26061753
Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4009-14
pubmed: 23412337
N Engl J Med. 2014 Feb 20;370(8):699-708
pubmed: 24552317
Ann Oncol. 2013 Oct;24 Suppl 6:vi99-105
pubmed: 23813929
J Clin Oncol. 2015 Aug 20;33(24):2695-704
pubmed: 26195705
Lancet Oncol. 2014 Sep;15(10):1100-8
pubmed: 25163906
Lancet Oncol. 2014 Aug;15(9):e395-403
pubmed: 25079102
Acta Neuropathol. 2016 Jun;131(6):803-20
pubmed: 27157931
Cancer Discov. 2015 Nov;5(11):1164-1177
pubmed: 26410082
J Clin Oncol. 2010 Mar 1;28(7):1168-74
pubmed: 20124186
Breast Cancer Res Treat. 2012 Apr;132(3):1049-62
pubmed: 22198468
Clin Cancer Res. 2016 Oct 1;22(19):4797-4806
pubmed: 27143690
Diagn Mol Pathol. 2012 Dec;21(4):189-206
pubmed: 23111197
Cancer Cell. 2010 Jan 19;17(1):98-110
pubmed: 20129251
Cancer Cell. 2010 May 18;17(5):510-22
pubmed: 20399149
Oncotarget. 2016 Aug 23;7(34):55026-55042
pubmed: 27391150
Cell. 2013 Oct 10;155(2):462-77
pubmed: 24120142
Cancer Cell. 2015 Sep 14;28(3):307-317
pubmed: 26373278
Nature. 2008 Oct 23;455(7216):1061-8
pubmed: 18772890
Neuro Oncol. 2015 Jul;17(7):992-8
pubmed: 25758746
Ann Oncol. 2014 Sep;25(9):1681-90
pubmed: 24718890
N Engl J Med. 2010 Oct 28;363(18):1693-703
pubmed: 20979469
Lancet. 2012 Jul 28;380(9839):358-65
pubmed: 22735384
N Engl J Med. 2015 Jun 25;372(26):2481-98
pubmed: 26061751
Clin Cancer Res. 2017 Jan 15;23(2):562-574
pubmed: 27521447
N Engl J Med. 2011 Oct 6;365(14):1273-83
pubmed: 21991949
Neuro Oncol. 2014 Apr;16(4):567-78
pubmed: 24470557
J Oncol. 2015;2015:809835
pubmed: 25699082
Science. 2014 Jan 10;343(6167):189-193
pubmed: 24336570
Ann Neurol. 2010 Aug;68(2):264-9
pubmed: 20695020
N Engl J Med. 2014 Feb 20;370(8):709-22
pubmed: 24552318