Elsevier

European Journal of Cancer

Volume 52, January 2016, Pages 173-180
European Journal of Cancer

Original Research
Long-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group

https://doi.org/10.1016/j.ejca.2015.10.069Get rights and content

Highlights

  • KIT exon 11 mutation is an independent prognostic factor for PFS and OS in GIST patients.

  • Clinico-biological factors (gender, PS, tumour size, lymphocyte & neutrophil count) are also significant.

  • Subsets of exon 11 mutations have significantly different response patterns and PFS in GIST patients.

Abstract

Background

The added value of tumoural genomic profiles to conventional clinico-biological factors to predict progression-free survival (PFS) and overall survival (OS) was prospectively investigated in patients with advanced gastrointestinal stromal tumours (GIST) treated in the BFR14 study.

Methods

Of the 434 included patients, mutational analysis was performed in 322 patients. Survival analysis was performed in patients with validated mutational status.

Results

Mutational status was validated in 228 patients. We identified 196 patients with tumours harbouring 200 KIT alterations (exon 11: 173 patients, exon 9: 22 patients, exon 17: 3 patients, exon 13: 2 patients; 4 patients had double KIT mutations), 6 patients with PDGFRA mutations and 26 patients with wild-type (WT) GIST genotype. On a median follow-up of 73 months, median PFS/OS were 12.3/54.9 months for WT GIST, 12.6/55 months for KIT exon 9, and 39.4 months/not reached (69.1% at 5 years) for KIT exon 11. Tumour size, female gender, KIT exon 11 mutations and CD34 positivity were independent prognostic factors for a higher PFS. A higher OS was predicted by performance status (PS) <2, low neutrophil and normal lymphocyte counts, KIT exon 11 mutations, non-advanced tumour and female gender. KIT exon 11 mutations at codons 557–558 showed better tumour response (p=0.028) but shorter PFS (p=0.0176).

Conclusions

In GIST patients, presence of a KIT exon 11 mutation is an independent prognostic factor for PFS and OS, along with gender, PS, tumour size, lymphocyte and neutrophil counts. Subsets of exon 11 mutations are associated with significantly different response patterns and PFS.

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.

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