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

Andrea Napolitano, David S Moura, Nadia Hindi, José L Mondaza-Hernandez, José A Merino-Garcia, Rafael Ramos, Gian Paolo Dagrada, Silvia Stacchiotti, Francesco Graziano, Bruno Vincenzi, Javier Martin-Broto, Andrea Napolitano, David S Moura, Nadia Hindi, José L Mondaza-Hernandez, José A Merino-Garcia, Rafael Ramos, Gian Paolo Dagrada, Silvia Stacchiotti, Francesco Graziano, Bruno Vincenzi, Javier Martin-Broto

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.

Keywords: TP53; biomarkers; pazopanib; sarcoma; solitary fibrous tumours.

Conflict of interest statement

Competing Interests: AN: reports non-financial and travel support from PharmaMar, Eisai and Lilly DSM: reports institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis outside the submitted work; travel support from PharmaMar, Eisai, Celgene, Bayer and Pfizer NH: reports grants, personal fees and non-financial support from PharmaMar, personal fees from Lilly, grants from Eisai, and Novartis, outside the submitted work and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daichii-Sankyo JLMH: reports institutional research grants from PharmaMar, Eisai, Immix BioPharma and Novartis outside the submitted work SS: reports grants and personal fees from Bayer, Lilly and PharmaMar, grants from GlaxoSmithKline, Novartis and Pfizer outside the submitted work BV: reports personal fees from Eisai, Eli Lilly, Novartis, PharmaMar and Abbott; paid testimony for Abbott; and institutional research funding from Eli Lilly, Novartis and PharmaMar, all outside the submitted work JM-B: reports research grants from PharmaMar, Eisai, Immix BioPharma and Novartis outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar, Eli Lilly and Company, Bayer and Eisai; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, BMS, Pfizer, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daichii-Sankyo RR, JAMG, GPD and FG: declare that they have no competing interests

© The Author(s), 2022.

Figures

Figure 1.
Figure 1.
PFS in the different SFT groups. PFS, progression-free survival; SFT, solitary fibrous tumours.
Figure 2.
Figure 2.
IHC p53 analysis. Representative IHC of a negative, 1+ and 2+ sample (a); distribution of p53 IHC expression levels among groups (b); PFS in the different SFT groups based on p53 IHC expression (c). IHC, immunohistochemistry; PFS, progression-free survival; SFT, solitary fibrous tumours.
Figure 3.
Figure 3.
Normalized expression levels of TP53 in the different SFT subgroups, with group-specific cut-offs (a); PFS based onTP53 expression levels in SFTLOW (b); PFS based on TP53 expression levels in SFTHIGH (c). PFS, progression-free survival; SFT, solitary fibrous tumours.

References

    1. WHO Classification of Tumours Editorial Board. Soft tissue and bone tumours. International Agency for Research on Cancer, Lyon, France, 2020.
    1. Martin-Broto J, Mondaza-Hernandez JL, Moura DS, et al.. A comprehensive review on solitary fibrous tumor: new insights for new horizons. Cancers (Basel). 2021; 13: 2913.
    1. Stacchiotti S, Libertini M, Negri T, et al.. Response to chemotherapy of solitary fibrous tumour: a retrospective study. Eur J Cancer 2013; 49: 2376–2383.
    1. Stacchiotti S, Negri T, Libertini M, et al.. Sunitinib malate in solitary fibrous tumor (SFT). Ann Oncol 2012; 23: 3171–3179.
    1. Park MS, Patel SR, Ludwig JA, et al.. Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor. Cancer 2011; 117: 4939–4947.
    1. Park MS, Ravi V, Conley A, et al.. The role of chemotherapy in advanced solitary fibrous tumors: a retrospective analysis. Clin Sarcoma Res 2013; 3: 7.
    1. Martin-Broto J, Cruz J, Penel N, et al.. Pazopanib for treatment of typical solitary fibrous tumours: a multicentre, single-arm, phase 2 trial. Lancet Oncol 2020; 21: 456–466.
    1. Martin-Broto J, Stacchiotti S, Lopez-Pousa A, et al.. Pazopanib for treatment of advanced malignant and dedifferentiated solitary fibrous tumour: a multicentre, single-arm, phase 2 trial. Lancet Oncol 2019; 20: 134–144.
    1. Teodoro JG, Evans SK, Green MR. Inhibition of tumor angiogenesis by p53: a new role for the guardian of the genome. J Mol Med (Berl) 2007; 85: 1175–1186.
    1. Koehler K, Liebner D, Chen JL. TP53 mutational status is predictive of pazopanib response in advanced sarcomas. Ann Oncol 2016; 27: 539–543.
    1. Park HK, Yu DB, Sung M, et al.. Molecular changes in solitary fibrous tumor progression. J Mol Med (Berl) 2019; 97: 1413–1425.
    1. Machado I, Morales GN, Cruz J, et al.. Solitary fibrous tumor: a case series identifying pathological adverse factors-implications for risk stratification and classification. Virchows Arch 2020; 476: 597–607.
    1. Dagrada GP, Spagnuolo RD, Mauro V, et al.. Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation. Mod Pathol 2015; 28: 1074–1083.
    1. Ogluszka M, Orzechowska M, Jedroszka D, et al.. Evaluate cutpoints: adaptable continuous data distribution system for determining survival in Kaplan-Meier estimator. Comput Methods Programs Biomed 2019; 177: 133–139.
    1. Choi H, Charnsangavej C, Faria SC, et al.. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007; 25: 1753–1759.
    1. Haronikova L, Olivares-Illana V, Wang L, et al.. The p53 mRNA: an integral part of the cellular stress response. Nucleic Acids Res 2019; 47: 3257–3571.
    1. Hemann MT, Lowe SW. The p53-Bcl-2 connection. Cell Death Differ 2006; 13: 1256–1259.
    1. Park JH, Yang SW, Park JM, et al.. Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification. Nat Commun 2016; 7: 12513.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner