Gene expression-based prediction of pazopanib efficacy in sarcoma (HIPO, H021)

The multi-receptor tyrosine kinase (RTK) inhibitor pazopanib is approved for the treatment of advanced non-adipocytic 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 date to select patients who are most likely to benefit from this drug. We analyzed the molecular profiles and clinical outcomes of pazopanib-treated sarcoma patients enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing (WGS/WES) and transcriptome sequencing to inform the care of adults with advanced cancer across histologies who are younger than 51 and patients with rare tumors, including rare subtypes of more common entities, regardless of age. Among a total of 109 patients with available WGS/WES data, there was no correlation between clinical parameters, specific genetic alterations, or mutational signatures and clinical outcome. In contrast, 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 RTK genes, i.e., the features NTRK3-high, IGF1R-low, and KDR-high, we developed a pazopanib efficacy predictor (PEP) that stratified patients into three groups with significantly different PFS (p<0.0001). Application of the PEP to an independent cohort of pazopanib-treated sarcoma patients 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 sarcoma patients from DKTK MASTER (n=77) or The Cancer Genome Atlas sarcoma cohort (n=256) who were not treated with pazopanib. A score based on the combined expression of NTRK3, IGF1R, and KDR allows identification of sarcoma patients with good, intermediate, and poor outcome following pazopanib therapy and warrants investigation as a predictive tool in prospective studies to optimize the use of this drug in the clinic.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

5 Datasets 1 Publication

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001010257	Sequencing data of 77 sarcoma tumor and control runs, which were uploaded to EGAS00001004813. The sequencing was always paired.	HiSeq X Ten	1
EGAD00001010258	Sequencing data of 144 sarcoma tumor and control runs, which were uploaded to EGAS00001004813. The sequencing was always paired.	Illumina HiSeq 2000 Illumina HiSeq 2500 Illumina HiSeq 4000	1
EGAD00001010276	Sequencing data of 410 sarcoma tumor runs, which were uploaded to EGAS00001004813. The sequencing was always paired.	HiSeq X Ten Illumina HiSeq 2000 Illumina HiSeq 2500 Illumina HiSeq 4000	1
EGAD00001010277	Paired WGS samples (tumor and control) of one Sarcoma case. The paired sequencing was done on Hiseq X Ten with Illlumina TruSeq Nano DNA.	HiSeq X Ten	2
EGAD00001010278	Paired Exome sequencing of Sarcoma tumor and control of 10 samples (5 tumor/control pairs). The sequencing was done on Illumina Hiseq 4000 and Agilent Sureselect V5+UTRs kit.	Illumina HiSeq 4000	10

Publications	Citations
Gene expression-based prediction of pazopanib efficacy in sarcoma. Heilig CE, Laßmann A, Mughal SS, Mock A, Pirmann S, Teleanu V, Renner M, Andresen C, Köhler BC, Aybey B, Bauer S, Siveke JT, Hamacher R, Folprecht G, Richter S, Schröck E, Brandts CH, Ahrens M, Hohenberger P, Egerer G, Kindler T, Boerries M, Illert AL, von Bubnoff N, Apostolidis L, Jost PJ, Westphalen CB, Weichert W, Keilholz U, Klauschen F, Beck K, Winter U, Richter D, Möhrmann L, Bitzer M, Schulze-Osthoff K, Brors B, Mechtersheimer G, Kreutzfeldt S, Heining C, Lipka DB, Stenzinger A, Schlenk RF, Horak P, Glimm H, Hübschmann D, Fröhling S. Eur J Cancer 172: 2022 107-118	2

Publications

Citations

Gene expression-based prediction of pazopanib efficacy in sarcoma.
Heilig CE, Laßmann A, Mughal SS, Mock A, Pirmann S, Teleanu V, Renner M, Andresen C, Köhler BC, Aybey B, Bauer S, Siveke JT, Hamacher R, Folprecht G, Richter S, Schröck E, Brandts CH, Ahrens M, Hohenberger P, Egerer G, Kindler T, Boerries M, Illert AL, von Bubnoff N, Apostolidis L, Jost PJ, Westphalen CB, Weichert W, Keilholz U, Klauschen F, Beck K, Winter U, Richter D, Möhrmann L, Bitzer M, Schulze-Osthoff K, Brors B, Mechtersheimer G, Kreutzfeldt S, Heining C, Lipka DB, Stenzinger A, Schlenk RF, Horak P, Glimm H, Hübschmann D, Fröhling S. Eur J Cancer 172: 2022 107-118