Prospective genome and transcriptome sequencing in advanced-stage neuroendocrine neoplasms

Date 22 October 2018
Event ESMO 2018 Congress
Session Poster Discussion session - NETs and endocrine tumours
Topics Neuroendocrine Tumours
Translational Research
Presenter Leonidas Apostolidis
Citation Annals of Oncology (2018) 29 (suppl_8): viii467-viii478. 10.1093/annonc/mdy293
Authors L. Apostolidis1, S. Kreutzfeldt2, M. Oles2, L. Gieldon3, C. Heining4, P. Horak2, B. Hutter5, M. Fröhlich5, B. Klink3, M. Lamping6, S. Uhrig5, A. Stenzinger7, E.C. Winkler1, B. Wiedenmann8, D. Jäger1, E. Schröck3, U. Keilholz6, M.E. Pavel9, H. Glimm4, S. Fröhling2
  • 1Department Of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 - Heidelberg/DE
  • 2Department Of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120 - Heidelberg/DE
  • 3Institute For Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Dresden/DE
  • 4National Center For Tumor Diseases (nct) Dresden, University Hospital Carl Gustav Carus, Dresden/DE
  • 5Division Applied Bioinformatics, Dkfz And Nct, German Cancer Consortium (DKTK), Heidelberg/DE
  • 6Charité Comprehensive Cancer Center, Charité University Medicine, Berlin/DE
  • 7Institute Of Pathology, University Hospital Heidelberg, 69120 - Heidelberg/DE
  • 8Department Of Gastroenterology And Hepatology, Charité University Medicine, 13353 - Berlin/DE
  • 9Department Of Medicine, Division Of Endocrinology, Friedrich Alexander University Erlangen-Nürnberg, 91054 - Erlangen/DE

Abstract

Background

Therapeutic options for neuroendocrine neoplasms (NEN) are limited. Within the NCT/DKTK-MASTER precision oncology trial, we apply prospective whole-genome (WGS), whole-exome (WES), and transcriptome sequencing (TS) in a wide range of solid tumors to evaluate the feasibility of optimizing treatment by deep analysis of genomic alterations. Here we report the first clinical results of the NEN cohort within this study.

Methods

Between 2012 and 2017, we included 84 NEN patients. All patients had advanced disease and had received at least one line of prior standard therapy. We performed WES (n = 60) or WGS (n = 24) and TS (n = 69). Molecular findings (somatic/germline small nucleotide variants, insertions, deletions, copy number variations, mutational burden and signatures, homologous recombination deficiency scores, gene expression patterns, etc.) were discussed in a molecular tumor board, and recommendations were sent to the treating physician.

Results

Based on WES/WGS/TS, we recommended genomics-guided treatment in 74 patients (88%). Treatment recommendations were grouped as follows: PARP inhibition (n = 31), immunotherapy (n = 22), mTOR inhibition (n = 22), multi-kinase inhibition (n = 13), CDK4/6 inhibition (n = 12), tyrosine or serine/threonine kinase inhibition (ALK, n = 1; ERBB, n = 5; FGFR, n = 5; MET, n = 2; RET, n = 7; VEGFR, n = 3), MEK inhibition (n = 6), chemotherapy (n = 3) or other (n = 34). 17 patients received recommended therapies. Among those, 11 were evaluable for response with 4 partial responses (PR), 2 stable (SD) and 5 progressive diseases (PD). 25 patients died before therapy could be started, 9 patients are currently receiving other successful regimens, for 12 patients follow-up data are still pending.Table: 1310PD

HistologyPrimary sitesGenomics-guided treatments
HNThGILv/PcUGothsuccess (PR or SD)not evaluableno success (PD)
NET G1123MKI1
NET G21551411Cx2, METInh3, PARPInh4, CI5MKI10
NET G314PARPInh4, CI5, MKI7ALKInh11
NEC G32512654mTORInh6FGFRInh8, METInh92x PARPInh4
MANEC1713CI5CI5

HN = head & neck, Th = thorax, GI = gastrointestinal, Lv/Pc = liver & pancreas, UG = urogenital, oth = other

1sunitinib, 2EWSR-FLI-fusion lead to ewing-sarcoma chemotherapy treatment, 3cabozantinib, 4olaparib, 5checkpoint-inhibitor, 6everolimus, 7pazopanib, 8ponatinib, 9crizotinib, 10vandetanib, 11alectinib

Conclusions

Extensive genomic and transcriptomic characterization offers valuable insight into pathogenic mechanisms in NEN and facilitates optimized treatment for certain patients. Genomic landscape data and predictive biomarker analysis are currently in preparation.

Clinical trial identification

This trial has been approved by the institutional research ethics committee (approval S-206/2011).

Legal entity responsible for the study

National Center for Tumor Diseases (NCT) Heidelberg.

Funding

Grant H021 from DKFZ-HIPO (Heidelberg Center for Personalized Oncology), Joint Funding Project grant from DKTK (German Cancer Consortium).

Editorial Acknowledgement

Disclosure

All authors have declared no conflicts of interest.