Original ResearchLong-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group
Introduction
Imatinib mesylate (IM) has dramatically improved the outcome of patients with advanced gastrointestinal stromal tumours (GIST), from a 5-year overall survival (OS) rate of 10% before the imatinib era to around 50% since its introduction 1, 2, 3, 4, 5. The BFR14 trial, performed within the French Sarcoma Group, addressed the question of optimal imatinib treatment duration by randomising patients after 1, 3, and 5 years to treatment interruption or maintenance 4, 5, 6. Imatinib interruption results in rapid progression in the vast majority of patients with advanced disease, whatever the pattern of response achieved. The study results also strongly suggest that patients in complete response (CR) under imatinib still have residual disseminated, persistent active tumour cells and show that it is not safe to interrupt imatinib on the basis of a CR by standard morphological criteria, even after long treatment 7, 8. The quality of tumour status at IM interruption influenced time to re-progression since patients in CR re-progressed more slowly following IM interruption [7]. Nevertheless, imatinib rechallenge in progressing patients in the interruption arms of the three randomisation time points resulted in a tumour control rate of 96% [7].
The type of KIT/PDGFRA gene alteration largely influences the outcome of advanced GIST patients treated with imatinib 2, 9, 10, 11. The mutational analysis was a pre-planned analysis within the prospective randomised BRF14 study design. The objective of this article is to explore the prognostic and predictive value of driver gene alterations in addition to clinical prognostic factors.
Section snippets
BFR14 population and study procedures
The BFR14 trial is an open-label, multicentre, randomised phase III trial allocating treatment interruption versus maintenance in non-progressing patients with advanced GIST who received a daily dose of 400 mg of imatinib. The original study design assessed the effect of imatinib interruption in patients with controlled disease according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria [12] after 1 year of treatment [4]. Two subsequent amendments allowed randomisation after 3
Mutational analysis
Four hundred thirty-four patients were included in the trial from June 2002 to July 2009. Mutational analysis was performed in 322 patients. Analysis was non-informative due to insufficient material in 55 patients (12.5%), incomplete in another 39 patients (9%) and successfully completed in 228 patients (78.5%). Tumoural DNA mutations were identified in 202 patients (88.6%). KIT mutations were found in 86% of analysed GISTs (196 of 228 patients), whilst PDGRFA mutations were found in 2.6% (6 of
Discussion
This study provides a description of the impact of the genomic profile of GIST patients treated with standard daily dose of IM with a long-term follow-up beyond the initial reports, providing a more representative picture. Further to confirming the greatest prevalence of KIT mutations in advanced GIST 15, 16, it also confirms the frequency of exon 11 mutations in KIT-mutated GISTs, even higher (88%) than previously reported 15, 16, 17. We demonstrate that GIST patients harbouring a KIT exon 11
Conclusion
This analysis shows that the nature and topography of KIT exon 11 mutations, along with specific clinico-biological factors, are prognostic and predictive of PFS and OS for advanced GIST patients treated with standard-dose IM. Despite a favourable sensitivity to imatinib, GIST patients harbouring a codon 557–558 alteration develop secondary resistance more rapidly. These results have implications for the design of clinical trials of TKI (tyrosine kinase inhibitors) treatment in the first-line
Funding
Financial support for the BRF14 study (NCT00367861) was provided by the 2003 Emergence Fund of the French Institut National du Cancer through the Canceropole CLARA, an unrestricted grant of the Comité de l'Ain de la Ligue Contre Le Cancer, a grant from the Comité du Rhône de la Ligue Contre Le Cancer, the CONTICANET Network of Excellence of the Sixth Framework Programme of the European Commission. No specific funding existed for the substudy reported in this paper. There was no role of the
Conflict of interest statement
None declared.
References (27)
- et al.
Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial
Lancet
(2004) - et al.
Discontinuation of imatinib in patients with advanced gastrointestinal stromal tumours after 3 years of treatment: an open-label multicentre randomised phase 3 trial
Lancet Oncol
(2010) - et al.
Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomize phase III trial
Ann Oncol
(2013) - et al.
Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group
Eur J Cancer
(2004) - et al.
KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours
Eur J Cancer
(2006) - et al.
Prognostic time dependence of deletions affecting codons 557 and/or 558 of KIT gene for relapse-free survival (RFS) in localized GIST: a Spanish Group for Sarcoma Research (GEIS)
Study Ann Oncol
(2010) - et al.
Effects of endoplasmic reticulum stressors on maturation and signaling of hemizygous and heterozygous wild type and mutants forms of KIT
Mol Oncol
(2013) - et al.
Phase III randomised, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumours expressing the kit receptor tyrosine kinase: S0033
J Clin Oncol
(2008) - et al.
Long-term results from a randomised phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT
J Clin Oncol
(2008) - et al.
Prospective multicentric randomised phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group
J Clin Oncol
(2007)
Risk of relapse with imatinib (IM) discontinuation at 5 years in advanced GIST patients: results of the prospective BRF14 randomised phase III study comparing interruption versus continuation of IM at 5 years of treatment: a French Sarcoma Group Study
J Clin Oncol
Key messages from the BRF14 trial
Follow-up results after 9 years (yrs) of the ongoing, phase II B2222 trial of imatinib mesylate (IM) in patients (pts) with metastatic or unresectable KIT+ gastrointestinal stromal tumors (GIST)
J Clin Oncol
Cited by (66)
Treatment of molecular resistance and rare GIST subtypes in 2023
2023, Bulletin de l'Academie Nationale de MedecineMolecular pathology of gastrointestinal stromal tumors
2023, Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing, Second EditionPrognostic and predictive values of the KIT11-mutated grading system in patients with gastrointestinal stromal tumors: a retrospective study
2021, Human PathologyCitation Excerpt :Several studies have focused on KIT11 mutations at codon 557–558. It was reported that KIT exon 11 mutations at codon 557–558 showed a favorable response to IM [37] but poor progression-free survival [38,39]. Ramaswamy et al. [40] divided patients into mutations upstream to 557, mutations involving codon 557–558, and mutations downstream to codon 558.
Expression and prognostic significance of PDGF ligands and receptors across soft tissue sarcomas
2021, ESMO OpenCitation Excerpt :Genomic alterations of PDGFB and PDGFRA genes are therefore well documented in dermatofibrosarcoma protuberans (DFSP) and subsets of gastrointestinal stromal tumors (GISTs), with translocation and nonsynonymous mutations as key oncogenic events. Not only the discovery of these genetic alterations has been helpful to identify targeted treatments (imatinib), but it is also useful as prognostic and predictive parameters (in particular for GIST).11 Besides DFSP and PDGFRA-mutated GIST, the role of PDGFR and the according ligands in the biology of sarcomas remains unclear.