TY - JOUR
T1 - Genomic profiling of NETs
T2 - A comprehensive analysis of the RADIANT trials
AU - Yao, James
AU - Garg, Abhishek
AU - Chen, David
AU - Capdevila, Jaume
AU - Engstrom, Paul
AU - Pommier, Rodney
AU - Van Cutsem, Eric
AU - Singh, Simron
AU - Fazio, Nicola
AU - He, Wei
AU - Riester, Markus
AU - Patel, Parul
AU - Voi, Maurizio
AU - Morrissey, Michael
AU - Pavel, Marianne
AU - Helmut Kulke, Matthew
N1 - Funding Information:
The study was sponsored by Novartis Pharmaceuticals Corporation.
Funding Information:
J Yao is a consultant and received personal fees from Novartis and Ipsen outside the submitted work. S Singh has received research grants from Novartis and 阀psen, and received personal fees and nonfinancial support from Novartis, 阀psen and Pfizer outside the submitted work. E Van Cutsem has received research grants from Amgen, Bayer, Boehringer, Celgene, 阀psen, Lilly, Merck, Merck KgA, Novartis, Roche, Sanofi and Servier outside the submitted work. R Pommier is a consultant to Novartis and Ipsen, speaker for Novartis, and has received travel and accommodations from both. M Pavel has received personal fees from Novartis, Ipsen, Lexicon and Pfizer; research grants from Novartis and 阀psen outside the submitted work. M H Kulke has received personal fees from Lexicon, Novartis and Ipsen. J Capdevila has received grants and personal fees from Novartis, 阀psen and Pfizer outside the submitted work. N Fazio has received grants and personal fees from Novartis and personal fees from 阀psen and Pfizer outside the submitted work. P Engstrom has no financial disclosures. D Chen (during the time of this research) and M Voi are employees of Novartis and holders of Novartis stocks. A Garg (during the time of this research), M Morrissey, M Riester, P Patel and W He are employees of Novartis.
Publisher Copyright:
© 2019 The authors
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2018
Y1 - 2018
N2 - Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.
AB - Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.
KW - Chromosomal instability
KW - Clinical biomarkers
KW - Everolimus
KW - Neuroendocrine tumors
UR - http://www.scopus.com/inward/record.url?scp=85062810607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062810607&partnerID=8YFLogxK
U2 - 10.1530/ERC-18-0332
DO - 10.1530/ERC-18-0332
M3 - Article
C2 - 30667365
AN - SCOPUS:85062810607
VL - 26
SP - 391
EP - 403
JO - Endocrine-Related Cancer
JF - Endocrine-Related Cancer
SN - 1351-0088
IS - 4
ER -