The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study.

BACKGROUND: Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure. METHODS: We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes. RESULTS: One year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs. 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively). CONCLUSIONS: We confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.

Regeneration of comparative genomic hybridization oligonucleotide microarrays with dimethylurea.

Reuse of materials in DNA hybridization-based methods has been known since the advent of Southern membranes. Array-based comparative genomic hybridization is essentially Southern hybridization with multiple probes immobilized on a solid surface. We show that comparative genomic hybridization microarrays fabricated with maskless array synthesizer technology can be used up to four times with the application of 1,3-dimethylurea as an array-stripping agent. We reproducibly detected chromosomal aberrations (0.6-22.4Mb in size) in four hybridization rounds using regenerated microarray slides. We also demonstrated that regenerated arrays can detect smaller alterations (16-200kbp), such as common copy number variants, as well as complex aberration profiles in tumor DNA.

EGFR, PIK3CA and PTEN gene status and their protein product expression in neuroblastic tumours.

PI3K/AKT/mTOR pathway signalling is often upregulated in cancer, usually by the constitutional activation of growth factor receptors, amplification or mutation of PIK3CA and loss of tumour suppressor PTEN function. The way of PI3K/AKT/mTOR pathway activation in neuroblastoma (NB) is not well established. The study was performed on paraffin-embedded tissue sections from 106 patients with NB. The aim of the study was to analyse the mutational status of EGFR (exons 18-21), PIK3CA (exons 5, 6, 10 and 21) and PTEN (all exons) genes, as well as to assess expression of their protein products by immunohistochemistry. A novel mutation in exon 5 of PIK3CA, c.931 A>G (p.I311V), in two infantile tumours (2.7%) was identified. In addition some polymorphisms were found in all examined genes, including a novel one, c.285 A>T in PTEN. Polymorphism PIK3CA c.1060-17 C>A was significantly more frequent in extra-adrenal tumours. Polymorphism PIK3CA c.1145+54 A>G showed a tendency to be more frequent in children older than 18 months and in extra-adrenal tumours. Expression of EGFR was present in 95% of cases, PI3Kp110 in 92% of tumours and PTEN in all tumours (low in 39%) and did not correlate with the genetic alterations. EGFR and PTEN expression showed an association with tumour differentiation. Mutations in the EGFR, PIK3CA and PTEN genes are infrequent in neuroblastoma. Both newly detected mutations in exon 5 of PIK3CA occurred in very low risk neuroblastic tumours in infants. EGFR, PI3Kp110 and PTEN expression is a common feature of NB.