Genomic profiling of NETs

A comprehensive analysis of the RADIANT trials

James Yao, Abhishek Garg, David Chen, Jaume Capdevila, Paul Engstrom, Rodney Pommier, Eric Van Cutsem, Simron Singh, Nicola Fazio, Wei He, Markus Riester, Parul Patel, Maurizio Voi, Michael Morrissey, Marianne Pavel, Matthew Helmut Kulke

    Research output: Contribution to journalArticle

    3 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish (US)
    Pages (from-to)391-403
    Number of pages13
    JournalEndocrine-Related Cancer
    Volume26
    Issue number4
    DOIs
    StatePublished - Jan 1 2018

    Fingerprint

    Neuroendocrine Tumors
    Chromosomal Instability
    Clinical Trials
    Exome
    Chromogranin A
    Phase III Clinical Trials
    Survival
    Phosphopyruvate Hydratase
    Neoplasms
    Multivariate Analysis
    Biomarkers

    Keywords

    • Chromosomal instability
    • Clinical biomarkers
    • Everolimus
    • Neuroendocrine tumors

    ASJC Scopus subject areas

    • Endocrinology, Diabetes and Metabolism
    • Oncology
    • Endocrinology
    • Cancer Research

    Cite this

    Yao, J., Garg, A., Chen, D., Capdevila, J., Engstrom, P., Pommier, R., ... Helmut Kulke, M. (2018). Genomic profiling of NETs: A comprehensive analysis of the RADIANT trials. Endocrine-Related Cancer, 26(4), 391-403. https://doi.org/10.1530/ERC-18-0332

    Genomic profiling of NETs : A comprehensive analysis of the RADIANT trials. / Yao, James; Garg, Abhishek; Chen, David; Capdevila, Jaume; Engstrom, Paul; Pommier, Rodney; Van Cutsem, Eric; Singh, Simron; Fazio, Nicola; He, Wei; Riester, Markus; Patel, Parul; Voi, Maurizio; Morrissey, Michael; Pavel, Marianne; Helmut Kulke, Matthew.

    In: Endocrine-Related Cancer, Vol. 26, No. 4, 01.01.2018, p. 391-403.

    Research output: Contribution to journalArticle

    Yao, J, Garg, A, Chen, D, Capdevila, J, Engstrom, P, Pommier, R, Van Cutsem, E, Singh, S, Fazio, N, He, W, Riester, M, Patel, P, Voi, M, Morrissey, M, Pavel, M & Helmut Kulke, M 2018, 'Genomic profiling of NETs: A comprehensive analysis of the RADIANT trials', Endocrine-Related Cancer, vol. 26, no. 4, pp. 391-403. https://doi.org/10.1530/ERC-18-0332
    Yao, James ; Garg, Abhishek ; Chen, David ; Capdevila, Jaume ; Engstrom, Paul ; Pommier, Rodney ; Van Cutsem, Eric ; Singh, Simron ; Fazio, Nicola ; He, Wei ; Riester, Markus ; Patel, Parul ; Voi, Maurizio ; Morrissey, Michael ; Pavel, Marianne ; Helmut Kulke, Matthew. / Genomic profiling of NETs : A comprehensive analysis of the RADIANT trials. In: Endocrine-Related Cancer. 2018 ; Vol. 26, No. 4. pp. 391-403.
    @article{ddd5753cee4d4d2083f5e6059e06ba80,
    title = "Genomic profiling of NETs: A comprehensive analysis of the RADIANT trials",
    abstract = "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.",
    keywords = "Chromosomal instability, Clinical biomarkers, Everolimus, Neuroendocrine tumors",
    author = "James Yao and Abhishek Garg and David Chen and Jaume Capdevila and Paul Engstrom and Rodney Pommier and {Van Cutsem}, Eric and Simron Singh and Nicola Fazio and Wei He and Markus Riester and Parul Patel and Maurizio Voi and Michael Morrissey and Marianne Pavel and {Helmut Kulke}, Matthew",
    year = "2018",
    month = "1",
    day = "1",
    doi = "10.1530/ERC-18-0332",
    language = "English (US)",
    volume = "26",
    pages = "391--403",
    journal = "Endocrine-Related Cancer",
    issn = "1351-0088",
    publisher = "Society for Endocrinology",
    number = "4",

    }

    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

    PY - 2018/1/1

    Y1 - 2018/1/1

    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

    VL - 26

    SP - 391

    EP - 403

    JO - Endocrine-Related Cancer

    JF - Endocrine-Related Cancer

    SN - 1351-0088

    IS - 4

    ER -