Dataset Information

Expression of p53 as a biomarker of pazopanib efficacy in solitary fibrous tumours: translational analysis of a phase II trial.

ABSTRACT:

Background

Solitary fibrous tumours (SFT) are soft tissue sarcomas molecularly defined by the presence of the NAB2::STAT6 intrachromosomal fusion gene. Recently, a prospective phase II trial evaluating the role of the antiangiogenic tyrosine kinase inhibitor pazopanib in SFT has been conducted (NCT02066285).

Methods

Here, we analysed the mRNA and protein expression levels of the tumour suppressor and angiogenesis regulator p53 (TP53) in pre-treatment tumour samples from 22 patients with low aggressive (or typical) SFT and 28 patients with high aggressive (26 malignant and 2 dedifferentiated) SFT enrolled in the aforementioned pazopanib phase II trial. These results were correlated with radiological progression-free survival (PFS) and objective response. Univariate and multivariate Cox regression analyses were also performed, including known clinic-pathological prognostic factors.

Results

Diffuse immunohistochemistry (IHC) expression of p53 was only found in patients with aggressive SFT and was associated with significantly shorter PFS [hazard ratio (HR): 4.39, 95% confidence interval (CI): 1.19-16.14). TP53 mRNA levels were significantly higher in the low aggressive SFT group. Only in the high aggressive SFT group, relatively higher levels of TP53 were significantly associated with shorter PFS (HR: 4.16, 95% CI: 1.46-11.89) as well as to a lower rate of disease control following treatment with pazopanib. In the multivariate analysis, the only independent prognostic factor in the whole cohort was mitotic count.

Conclusion

Diffuse p53 IHC expression and higher TP53 mRNA levels are associated with worse prognosis in the subset of aggressive SFT patients treated with pazopanib.

SUBMITTER: Napolitano A

PROVIDER: S-EPMC9364178 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Expression of p53 as a biomarker of pazopanib efficacy in solitary fibrous tumours: translational analysis of a phase II trial.

Napolitano Andrea A Moura David S DS Hindi Nadia N Mondaza-Hernandez José L JL Merino-Garcia José A JA Ramos Rafael R Dagrada Gian Paolo GP Stacchiotti Silvia S Graziano Francesco F Vincenzi Bruno B Martin-Broto Javier J

Therapeutic advances in medical oncology 20220806

<h4>Background</h4>Solitary fibrous tumours (SFT) are soft tissue sarcomas molecularly defined by the presence of the NAB2::STAT6 intrachromosomal fusion gene. Recently, a prospective phase II trial evaluating the role of the antiangiogenic tyrosine kinase inhibitor pazopanib in SFT has been conducted (NCT02066285).<h4>Methods</h4>Here, we analysed the mRNA and protein expression levels of the tumour suppressor and angiogenesis regulator p53 (<i>TP53</i>) in pre-treatment tumour samples from 22 ...[more]

PMID: 35965642

Similar Datasets

Project description:BackgroundPatients with advanced gastrointestinal stromal tumours (GISTs) resistant to the tyrosine kinase inhibitors imatinib and sunitinib may be treated with regorafenib, which resulted in a median progression-free survival (PFS) of 4.8 months in the GRID trial. Also, pazopanib, another tyrosine kinase inhibitor, has been studied in a randomized, placebo-controlled trial (PAZOGIST) in the third line, which showed a PFS of 45.2% 4 months after study entry, but patients intolerant to sunitinib were also included. We designed another trial evaluating pazopanib, enrolling only patients with progression on both imatinib and sunitinib.Patients and methodsSince all eligible patients had progressive disease, we preferred a non-randomized, phase II multicentre trial so that all patients could receive a potentially active drug. Patients had a progressive metastatic or locally advanced GIST and were ≥18 years of age, with a performance status of 0-2, and sufficient organ functions. The primary endpoint was disease control rate (defined as complete remission + partial remission + stable disease) at 12 weeks on pazopanib. A Simon's two-stage analysis was used with an interim analysis 12 weeks after enrollment of the first 22 patients, and if passed, there was a full enrolment of 72 patients. GIST mutational analysis was done, and most patients had pazopanib plasma concentration measured after 12 weeks.ResultsSeventy-two patients were enrolled. The disease control rate after 12 weeks was 44%, and the median PFS was 19.6 weeks (95% confidence interval 12.6-23.4 weeks). Pazopanib-related toxicity was moderate and manageable. No statistically significant differences were found related to mutations. Plasma concentrations of pazopanib had a formal but weak correlation with outcome.ConclusionPazopanib given in the third line to patients with GIST progressing on both imatinib and sunitinib was beneficial for about half of the patients. The PAGIST trial confirms the results from the PAZOGIST trial, and the median PFS achieved seems comparable to the PFS achieved with regorafenib in the third-line setting.

Dataset Information

Expression of p53 as a biomarker of pazopanib efficacy in solitary fibrous tumours: translational analysis of a phase II trial.

Background

Methods

Results

Conclusion

Publications

Expression of p53 as a biomarker of pazopanib efficacy in solitary fibrous tumours: translational analysis of a phase II trial.

Similar Datasets

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