Molecular and Pathological Profiling of Corresponding Treatment-Naïve and Neoadjuvant Pazopanib-Treated High-Risk Soft Tissue Sarcoma Samples of the GISG-04/NOPASS Study.

Timo Gaiser,Christian Sauer,Jens Jakob,Bernd Kasper,Ulrich Ronellenfitsch,Alexander Marx,Peter Hohenberger,Daniela Hirsch

doi:10.3390/biology10070639

Abstract

Simple SummaryPatients with malignant soft tissue tumors, called soft tissue sarcoma (STS), show alterations in their deoxyribonucleic acid (DNA). Pathologists use these alterations for classification of STS and as drug-related biomarkers. Some drugs show better effectiveness in association with certain genetic alterations. In this study, we examined STS tumor tissue from a specific sarcoma study (GISG-04/NOPASS) with massively parallel DNA sequencing in order to find genetic biomarkers for pazopanib, a multi-target tyrosine kinase inhibitor approved for the treatment of advanced STS. While we could not clearly identify a specific genetic target, we were able to improve diagnostic accuracy and could detect mutations that are potentially useful for individualized therapy.In the framework of the German Interdisciplinary Sarcoma Group GISG-04/NOPASS trial, we evaluated soft tissue sarcoma samples taken before and after neoadjuvant pazopanib therapy using histopathology and next generation sequencing (NGS) to find potential predictive biomarkers. We also aimed to improve the genetically based sarcoma classification and to elucidate additional potentially druggable mutations. In total, 30 tumor samples from 18 patients consisting of 12 pre-therapeutic biopsies and 18 resection specimens following neoadjuvant pazopanib therapy were available for analyses. NGS was performed with the Oncomine Focus Assay (Ion Torrent) covering 0.03 Mb of DNA and enabled the detection of genetic variants in 52 cancer-relevant genes. Pathological analysis showed significant regression (≥50%) after pazopanib treatment in only one undifferentiated (pleomorphic) sarcoma. NGS analyses revealed a very high frequency of CDK4 amplification (88%; 7/8) in the group of dedifferentiated liposarcoma. In addition, two potentially druggable mutations, a MAP2K1 missense mutation (E203K) and a BRAF missense mutation (V600E), were traceable in two undifferentiated (pleomorphic) sarcoma patients (11%; 2/18). Our findings demonstrate that NGS testing is a powerful technology helping to improve diagnostic accuracy and offering some patients the chance for personalized medicine even in a “mutation unlikely” cohort like STS.

Highlights

Sarcomas are a heterogeneous group of malignancies descending from a mesenchymal cell of origin and are often associated with a poor prognosis
Out of the 21 patients enrolled in the GISG-04/NOPASS trial, tissue for histopathological analyses was available from 18 patients (9 females, 9 males) (Table S1)
In our study, CDK4 amplification was not detectable in one out of four pre-therapeutic dedifferentiated liposarcomas (DDLS) biopsies, it is independent of pazopanib treatment and treatment response

Summary

Introduction

Sarcomas are a heterogeneous group of malignancies descending from a mesenchymal cell of origin and are often associated with a poor prognosis. Pre-operative treatment strategies with the aim of tumor reduction and devascularization are of great benefit. Following this rationale, we carried out a phase II window-of-opportunity trial under the auspices of the German Interdisciplinary Sarcoma. Group (GISG-04/NOPASS trial) to assess the effect of pre-operative pazopanib therapy for unselected high-risk STS patients [2]. Pazopanib is a multi-target tyrosine kinase inhibitor with activity against vascular endothelial growth factors 1, 2, and 3, and platelet-derived growth factors. It is approved in the treatment of metastatic or non-resectable STS. The trial was carried out from 2013 to 2016 and met neither its primary nor its secondary endpoint [7]

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