Eagerly anticipated results of gene panel sequencing from the first cohort of patients with advanced colorectal cancer participating in a large European molecular screening platform were reported at the ESMO 2016 Congress in Copenhagen, Denmark on 10 October. New, potentially actionable genetic alterations were identified in these patients, many of whom were now elegible to enter a clinical trial of targeted therapies.
Findings from the first cohort of screened patients reported
Gunnar Folprecht, University Hospital Carl Gustav Carus in Dresden, Germany, presented findings on behalf of EORTC investigators from the first cohort screened in conjunction with the Screening Platform for Efficient Clinical Trial Access in advanced colorectal cancer (SPECTAcolor). The SPECTAcolor was initiated by the European Organisation for Research and Treatment of Cancer (EORTC) as the first prospective, fully annotated tumour sample biobank and biomarker analysis platform for genetic profiling of patients with advanced colorectal cancer. The aim is to facilitate patient-access to a clinical trial for treatment with a targeted agent. Since the inception in 2013, this bio-bank has enrolled more than 900 patients from 32 clinical centres in 11 European countries and anticipates enrolling at least this many patients yearly in the upcoming years.
Dr. Folprecht reported findings from a cohort of 389 patients with colorectal cancer who underwent screening using a large next generation sequencing (NGS) panel comprising 328 cancer genes. All analyses were performed according to Good Clinical Laboratory Practice Standards: Limited gene fusions were assessed in a subset of samples and genetic events were detected by an ISO 13485-accredited analysis pipeline.
The prevalence of gene mutations differed between patients with microsatellite stable and instable tumours
Using immunohistochemistry or fragment length analysis, the investigators determined that 370 of the 389 (95.2%) patients overall were microsatellite stable (MSS) and 19 (4.8%) patients were highly microsatellite instable (MSI-H). Both MSS and MSI-H tumours were found to contain a median of 3 (Range: 0 to 16) driver mutations and a median of 8 (range: 3 to 16) potential driver mutations.
Among patients with MSS colorectal cancer, 77.8% had mutations in APC, 72.2% in TP53, and 47.8% of patients showed KRAS mutation. Mutated PIK3CA, FBXW7, and BRAF were present in 17.6%, 11.1% and 10.5% of patients. Mutations in the SOX9, SMAD4, ARD1A, and NRAS were present in less than 10% of patients.
More patients with MSI-H tumours showed TP53 mutations (52.6%), PIK3CA (47.4%), and 42.1% had KRAS mutation. FBXW7 and BRAF mutations were each present in 36.8% of patients and APC and SOX9 were each mutated in 21.1% of patients. No mutations in SMAD4, ARD1A, and NRAS were detected in MSI-H patients.
Tumour localisation of APC and TP53 was more often on the left versus right side, 80.8% versus 73.6%, and 76.5% versus 62.3%, respectively, whereas KRAS and PIK3CA occurred more often on the right; KRAS location was 45.5% versus 53.8%, and PIK3CA was 14.1% versus 25.5%, left versus right, respectively. The prevalence of BRAF mutated tumours was predominately right side: 5.1% left versus 22.6% right (p < 0.0001).
Additionally, the investigators detected BRCA2 mutation in 1.6% of patients, located left at 0.8% versus 3.8% right, and in 5.3% of MSI-H tumours. A total of 1.9% of patients showed ERBB2 mutation, that was found twice as often in left sided tumours; left 2.0% versus 1.0% right. Other potentially actionable targets included ERBB2 amplification in 2.5% of patients, FGFR1/2/3 amplification in 3.5%, and TSC1 mutation in 16% of patients with MSI-H tumours. Single ALK and ROS fusions were also observed.
SPECTAcolor is an effective platform for molecular screening in patients with colorectal cancer to identify rare but potentially actionable genomic targets, and to allow patient access to clinical trials of targeted therapies. The authors stated that they were able to detect new therapeutic targets by gene panel sequencing in approximately 10% of patients with advanced colorectal cancer who participated in SPECTAcolor.
Frequency of potentially actionable genetic alterations in EORTC SPECTAcolor
G. Folprecht, P. Beer, R. Salazar, A. Roth, D. Aust, R. Salgado, P. Laurent-Puig, J. Tabernero, D. Arnold, A. Stein, V. Golfinopoulos, A. Atasoy, E. Szepessy, M.P. Ducreux, T. Gorlia, S. Tejpar
This study was funded by an EORTC charitable trust.