Gene expression-based prediction of pazopanib efficacy in sarcoma

Copyright © 2022 Elsevier Ltd. All rights reserved..

BACKGROUND: The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.

PATIENTS AND METHODS: We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers.

RESULTS: Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib.

CONCLUSION: A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:172

Enthalten in:

European journal of cancer (Oxford, England : 1990) - 172(2022) vom: 05. Sept., Seite 107-118

Sprache:

Englisch

Beteiligte Personen:

Heilig, Christoph E [VerfasserIn]
Laßmann, Andreas [VerfasserIn]
Mughal, Sadaf S [VerfasserIn]
Mock, Andreas [VerfasserIn]
Pirmann, Sebastian [VerfasserIn]
Teleanu, Veronica [VerfasserIn]
Renner, Marcus [VerfasserIn]
Andresen, Carolin [VerfasserIn]
Köhler, Bruno C [VerfasserIn]
Aybey, Bogac [VerfasserIn]
Bauer, Sebastian [VerfasserIn]
Siveke, Jens T [VerfasserIn]
Hamacher, Rainer [VerfasserIn]
Folprecht, Gunnar [VerfasserIn]
Richter, Stephan [VerfasserIn]
Schröck, Evelin [VerfasserIn]
Brandts, Christian H [VerfasserIn]
Ahrens, Marit [VerfasserIn]
Hohenberger, Peter [VerfasserIn]
Egerer, Gerlinde [VerfasserIn]
Kindler, Thomas [VerfasserIn]
Boerries, Melanie [VerfasserIn]
Illert, Anna L [VerfasserIn]
von Bubnoff, Nikolas [VerfasserIn]
Apostolidis, Leonidas [VerfasserIn]
Jost, Philipp J [VerfasserIn]
Westphalen, C Benedikt [VerfasserIn]
Weichert, Wilko [VerfasserIn]
Keilholz, Ulrich [VerfasserIn]
Klauschen, Frederick [VerfasserIn]
Beck, Katja [VerfasserIn]
Winter, Ulrike [VerfasserIn]
Richter, Daniela [VerfasserIn]
Möhrmann, Lino [VerfasserIn]
Bitzer, Michael [VerfasserIn]
Schulze-Osthoff, Klaus [VerfasserIn]
Brors, Benedikt [VerfasserIn]
Mechtersheimer, Gunhild [VerfasserIn]
Kreutzfeldt, Simon [VerfasserIn]
Heining, Christoph [VerfasserIn]
Lipka, Daniel B [VerfasserIn]
Stenzinger, Albrecht [VerfasserIn]
Schlenk, Richard F [VerfasserIn]
Horak, Peter [VerfasserIn]
Glimm, Hanno [VerfasserIn]
Hübschmann, Daniel [VerfasserIn]
Fröhling, Stefan [VerfasserIn]

Links:

Volltext

Themen:

7RN5DR86CK
Indazoles
Journal Article
Multi-omics
Observational Study
Pazopanib
Precision oncology
Predictor
Pyrimidines
Research Support, Non-U.S. Gov't
Sarcoma
Sulfonamides

Anmerkungen:

Date Completed 16.08.2022

Date Revised 08.11.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.ejca.2022.05.025

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM342847945