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Frequency of potentially actionable genetic alterations in EORTC SPECTAcolor

Date

10 Oct 2016

Session

Gastrointestinal tumours, colorectal 2

Presenters

Gunnar Folprecht

Citation

Annals of Oncology (2016) 27 (6): 149-206. 10.1093/annonc/mdw370

Authors

G. Folprecht1, P. Beer2, R. Salazar3, A. Roth4, D. Aust5, R. Salgado6, P. Laurent-Puig7, J. Tabernero8, D. Arnold9, A. Stein10, V. Golfinopoulos11, A. Atasoy11, E. Szepessy11, M.P. Ducreux12, T. Gorlia13, S. Tejpar14

Author affiliations

  • 1 Medical Department I, University Hospital Carl Gustav Carus, 01307 - Dresden/DE
  • 2 Sanger Institute, Wellcome Trust, Cambridge/GB
  • 3 Medical Oncology, Catalan Institute of Oncology, 08907 - L´Hospitalet/ES
  • 4 Department Of Medical Oncology, Hôpitaux Universitaires de Genève - HUG, 1211 - Geneva/CH
  • 5 Institute Of Pathology, University Hospital of the Technical University Dresden, 1307 - Dresden/DE
  • 6 Department Of Pathology, Breast Cancer Translational Research Laboratory (bctl), Institut Jules Bordet, Antwerp/BE
  • 7 Université Paris Descarte-bases Moléculaires De La Réponse Aux Xénobiotiques, Paris Descartes University, 75006 - Paris/FR
  • 8 Medical Oncology Department, Vall d’Hebron University Hospital and Institute of Oncology (VHIO), 08035 - Barcelona/ES
  • 9 Medical Oncology, Oncologia CUF, CUF Hospitals Cancer Centre, Lisboa/PT
  • 10 Medical Dpt, UKE Universitätsklinikum Hamburg-Eppendorf KMTZ, 20246 - Hamburg/DE
  • 11 Department Of Medical Oncology, European Organisation for Research and Treatment of Cancer (EORTC AISBL), 1200 - Brussels/BE
  • 12 Medical Dpt, Institut de Cancérologie Gustave Roussy, 94805 - Villejuif/FR
  • 13 Department Of Biostastics, European Organisation for Research and Treatment of Cancer (EORTC AISBL), 1200 - Brussels/BE
  • 14 Medical Dpt, University Hospital Gasthuisberg, 3000 - Leuven/BE
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Resources

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Background

The EORTC Screening Platform for Efficient Clinical Trial Access in advanced colorectal cancer (SPECTAcolor) is a prospective, Europe-wide screening program for molecular characterization of tumours to facilitate participation in clinical studies with targeted agents and enrolled more than 900 patients (pts). Here, we report on the first cohort screened with a large next generation sequencing (NGS) panel.

Methods

328 cancer genes were analysed in 389 colorectal cancer pts with NGS according to GCLP standards; limited gene fusions were assessed in a subset of samples. Genetic events were detected by an ISO 13485-accredited analysis pipeline. Driver events were annotated by curation of published literature.

Results

Out of the 389 pts, 370 pts were microsatellite stable (MSS) and 19 pts (4.8%) were highly microsatellite instable (MSI-H) by either immunohistochemistry or fragment length analysis. MSS and MSI-H tumors harboured a median of 3 (range 0- 16) and 8 potential “driver” mutations (range 3-16) respectively. Prevalence of mutations according to MSI status and tumor localization (left colon/rectum, L, or right colon, R) are listed in table 1. In addition to BRAF and MSI-H, we detected 1.6% of patients with BRCA2 mutation (L 0.8%, R 3.8%, MSI-H 5.3%), 1.9% with ERBB2 mutation (L 2.0%, R 1.0%), 2.5% with ERBB2 amplification, 3.5% with FGFR1/2/3 amplification, and in 16% of MSI-H patients TSC1 mutation as potentially actionable alterations. In addition, we observed single ALK and ROS fusions.

Most frequent mutations according to location and MSI-H (%)

MSS (n = 370) MSI-H (n = 19)
total left right total
APC 77.8 80.8 73.6 21.1
TP53 72.2 76.5 62.3 52.6
KRAS 47.8 45.5 53.8 42.1
PIK3CA 17.6 14.1 25.5 47.4
FBXW7 11.1 12.2 8.5 36.8
BRAF 10.5 5.1$ 22.6 36.8
SOX9 8.1 6.2 13.2 21.1
SMAD4 7.6 7.1 9.4 0
ARD1A 5.1 5.5 3.8 0
NRAS 5.1 4.3 7.5 0

$ L vs R: p 

Conclusions

Gene panel sequencing identified new potential therapeutic targets in an approximated total of 10% of patients with colorectal cancer. The SPECTA programme provides an effective platform for identifying rare, potentially actionable genomic targets.

Clinical trial identification

NCT01723969

Legal entity responsible for the study

EORTC

Funding

EORTC charity trust

Disclosure

P. Beer: Former employee of 14MG Genomics Ltd. J. Tabernero: Consultant/Advisory role: Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai, Lilly, MSD, Merck Serono, Novartis, Roche, Sanofi, Symphogen, Takeda and Taiho. All other authors have declared no conflicts of interest.

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