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Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial.

ABSTRACT: Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-? (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population.This is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson ?(2) test) in the same molecular subgroups.Of the 1124 sunitinib-treated patients in the treatment-use study, 230 (20%) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39-0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment.This large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status.NCT01459757.

SUBMITTER: Reichardt P

PROVIDER: S-EPMC4714485 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial.

Reichardt Peter P Demetri George D GD Gelderblom Hans H Rutkowski Piotr P Im Seock-Ah SA Gupta Sudeep S Kang Yoon-Koo YK Schöffski Patrick P Schuette Jochen J Soulières Denis D Blay Jean-Yves JY Goldstein David D Fly Kolette K Huang Xin X Corsaro Massimo M Lechuga Maria Jose MJ Martini Jean-Francois JF Heinrich Michael C MC

BMC cancer 20160115

<h4>Background</h4>Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population.<h4>Methods</h4>This ...[more]

PMID: 26772734

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Project description:The aim of the present study was to investigate mutation status of the c-Kit gene (KIT) and PDGFRA in patients with a gastrointestinal stromal tumor (GIST). In total, 93 patients with a GIST were included in the study, in which polymerase chain reaction amplification and gene sequencing were used to detect the sequences of exons 9, 11, 13 and 17 in KIT and exons 12 and 18 in PDGFRA. KIT mutations were detected in 64 cases (68.82%), of which exon 11 mutations were detected in 56 cases (60.22%), exon 13 mutations were detected in three cases (3.23%) and one case (1.08%) was shown to have a mutation in exon 17. The most common mutation in exon 11 was a deletion, which accounted for 55.36% (31/56) of the cases, followed by a point mutation observed in 26.79% (15/56) of the cases, while an insertion (tandem repeats) was identified in 14.29% (8/56) of the cases, and 3.57% (2/56) of the exon 11 mutations were deletions associated with a point mutation. The majority of the mutations were heterozygous, with only a few homozygous mutations. Mutational analysis revealed the mutations to be more concentrated in the classic hot zone at the 5'-end, followed by the tandem repeat frame at the 3'-end. In four cases, a mutation was detected in exon 18 of PDGFRA, of which one was associated with a mutation in KIT. The remaining three cases (10.34%, 3/29) were not associated with mutations in KIT and accounted for 37.5% (3/8) of the CD117-negative GIST cases. Therefore, the majority of the GIST cases were characterized by mutations in KIT or PDGFRA, which were directly associated with the disease. Pairs of different mutations in the same exon of KIT, or KIT mutations coupled with pairs of mutations in PDGFRA, were detected in a small number of patients. Imatinib is a small molecule tyrosine kinase inhibitor and is the first line targeted treatment for GIST, resulting in markedly improved survival rates. Thus, gene mutation genotyping may provide inspiration and guidance for imatinib-based targeted cancer therapy.

Dataset Information

Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial.

Publications

Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial.

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