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<p>Undifferentiated pleomorphic sarcoma (UPS) is a diagnosis of exclusion; given limited effective treatments and marked heterogeneity, there is a need to identify therapeutic targets, a task facilitated by next-generation sequencing (NGS) in clinical practice.&#xa0;We report 2 STS pts with the diagnosis of UPS, G3 - each treated in a clinical trial (NCT03651374) with <i>UNRESARC</i> protocol consisting of neoadjuvant chemotherapy (CHT), radiotherapy, and surgical resection. Biopsy samples from each patient were subjected to NGS with the TruSight™ Oncology 500 assay (Illumina) and analysed in <i>PierianDX</i> (commercial software).&#xa0;5 pathogenic alterations were identified: Case A: <i>CCNE1</i> (6 copies) and <i>MYC</i> (3 copies) amplifications; Case B: <i>CCND1</i> (3 copies), <i>EGFR</i> (3 copies) and <i>FGFR1</i> (4 copies) amplifications. Amplifications of cell-cycle associated (<i>CCNE1</i>,<i> CCND1)</i> and apoptosis-related (<i>MYC</i>) genes contribute to uncontrolled proliferation and resistance to apoptosis, while amplifications in receptor tyrosine kinases (<i>EGFR</i> and <i>FGFR1</i>) activate pathways (<i>RAS/MAPK</i> and <i>PI3K/AKT</i>), involved in tumour growth and metastasis. In both patients, a poor pathological response, early local recurrence (LRFS of 9 months in both patients) and progressive disease (PD) when treated with first-line palliative CHT (PFS of 5 months in A and 4 months in B) were noted. All tumours demonstrated a low tumour mutation burden (TMB) (1.6–3.9 mut/Mb) and no microsatellite instability (MSI), explaining no sensitivity to immune checkpoint inhibitors.&#xa0;NGS assays may enable accurate diagnosis and identify predictive biomarkers and novel therapeutic targets - of particular importance in poor-prognosis entities such as UPS. Our report is consistent with the literature classifying UPS as malignancy with a high frequency of CNAs and low TBM.</p>

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Clinicopathological and genomic profiling in undifferentiated pleomorphic sarcoma: Small series, clear message

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月19日

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  • Piotr Remiszewski,
  • Andrzej Tysarowski,
  • Katarzyna A. Seliga,
  • Klaudia Bobak,
  • Jakub Piątkowski,
  • Paweł Golik,
  • Mateusz J. Spałek,
  • Anna Szumera-Ciećkiewicz,
  • Michał Wągrodzki,
  • Piotr Rutkowski,
  • Anna M. Czarnecka

摘要

Undifferentiated pleomorphic sarcoma (UPS) is a diagnosis of exclusion; given limited effective treatments and marked heterogeneity, there is a need to identify therapeutic targets, a task facilitated by next-generation sequencing (NGS) in clinical practice. We report 2 STS pts with the diagnosis of UPS, G3 - each treated in a clinical trial (NCT03651374) with UNRESARC protocol consisting of neoadjuvant chemotherapy (CHT), radiotherapy, and surgical resection. Biopsy samples from each patient were subjected to NGS with the TruSight™ Oncology 500 assay (Illumina) and analysed in PierianDX (commercial software). 5 pathogenic alterations were identified: Case A: CCNE1 (6 copies) and MYC (3 copies) amplifications; Case B: CCND1 (3 copies), EGFR (3 copies) and FGFR1 (4 copies) amplifications. Amplifications of cell-cycle associated (CCNE1, CCND1) and apoptosis-related (MYC) genes contribute to uncontrolled proliferation and resistance to apoptosis, while amplifications in receptor tyrosine kinases (EGFR and FGFR1) activate pathways (RAS/MAPK and PI3K/AKT), involved in tumour growth and metastasis. In both patients, a poor pathological response, early local recurrence (LRFS of 9 months in both patients) and progressive disease (PD) when treated with first-line palliative CHT (PFS of 5 months in A and 4 months in B) were noted. All tumours demonstrated a low tumour mutation burden (TMB) (1.6–3.9 mut/Mb) and no microsatellite instability (MSI), explaining no sensitivity to immune checkpoint inhibitors. NGS assays may enable accurate diagnosis and identify predictive biomarkers and novel therapeutic targets - of particular importance in poor-prognosis entities such as UPS. Our report is consistent with the literature classifying UPS as malignancy with a high frequency of CNAs and low TBM.