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

BackgroundSeveral 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.MethodsThis 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 χ2 test) in the same molecular subgroups.ResultsOf 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.ConclusionsThis 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.Trial registrationNCT01459757.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2051-5) contains supplementary material, which is available to authorized users.

PDGFRA mRNA overexpression is associated with regional metastasis and reduced survival in oral squamous cell carcinoma

“…Heterodimerization of PDGFRA allows its transactivation with other signaling components, along with its ability to work independently and entering a vicious cycle via autocrine or paracrine stimulation. The implication of PDGFRA in various cancers is evident, yet there is no research on the role of PDGFRA in head and neck squamous cell carcinoma. Hence, the aim of this study was to quantify the expression of PDGFRA in oral SCC and find its relationship with tumor features and patient cancer outcomes…”

“…The role of EGFR and VGFR in oncogenesis and neovascularization is established but that of PDGFRA is unclear. The role of the PDGFRA signaling pathway is evident in various cancers . The authors believe that a research directed toward the common events in tumorigenesis and progression among heterogeneous tumors could provide a potential target for therapy in majority of the cases.…”

“…Platelet-derived growth factor alpha (PDGFRA) is a mitogen for cells of mesenchymal origin and mutation within this gene is implicated in leukemia, gastrointestinal tract, testicular, cervical, and thyroid cancers. [14][15][16] Physiologically, the PDGFRA gene encodes cell surface tyrosine kinase receptor for the PDGFs and plays a role in organ development and wound healing. 14 Pathological, PDGFRA activation causes kinase phosphorylation and subsequently induces the tumor cell growth and invasion.…”

Phase IV Study of Sunitinib in Chinese Patients with Imatinib-Resistant or Imatinib-Intolerant Gastrointestinal Stromal Tumors

“…Patients with exon 9 mutations require an escalated dose of imatinib [25], whereas certain patients, especially those with exon 11 mutations, show no benefit from imatinib dose escalation [26]. More recent studies [27,28] showed improved efficacy in sunitinib-treated patients with primary mutations in KIT exon 9 compared with exon 11. A limitation of the current study is that correlation between mutational status and sunitinib efficacy and safety were not examined.…”

Nationwide trends in the incidence and outcome of patients with gastrointestinal stromal tumour in the imatinib era

“…It has become increasingly important to genotype GISTs, as not all genotypes respond equally to TKIs. These advances in the diagnosis and treatment of GIST have changed rapidly and dramatically over the past decade.…”