Clinical utility of circulating tumor DNA sequencing with a large panel in patients with advanced soft‐tissue sarcomas

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Abstract

To the editor Soft-tissue sarcomas (STS) represent a very heterogeneous group of rare tumors including more than 100 different subtypes [1]. Surgery and neo/adjuvant radiation therapy represent the cornerstone of treatment for STS. However, despite an optimal resection of the tumor, up to 40% of patients will develop metastatic relapse and will die from the disease [1]. Doxorubicin represents the first-line standard of care for patients with advanced disease since the 1970s, despite several attempts to identify better regimens. The median overall survival (OS) of patients with metastatic disease is 16 MB). The MTB recommended treatment with an immune checkpoint inhibitor (ICI) for 4 patients (4.1%); 2 patients refused the recommended treatment. Two patients (2.1%) received an ICI. The best response was progressive disease in both. The two other patients did not receive ICI as per the physician's decision. Forty patients also underwent NGS of tissue samples besides ctDNA profiling. Tissue profiling was unsuccessful for 7 (17.5%) patients. No actionable alteration was found in both ctDNA and tissue profiles for 17 (42.5%) patients. The numbers of actionable aberrations in tissue and ctDNA profiles were similar in 5 (12.5%) patients. The number of actionable alterations was higher in tissue than in ctDNA for 10 (25.0%) patients. The 15 actionable alterations observed in tissue but not in ctDNA are listed in Supplementary Table S3: 10 of them (66.7%) were copy number variants (CNVs). The number of actionable aberrations was higher in ctDNA than in tissue for 1 (2.5%) patient. Tissue profiling allowed the identification of an ESCAT I, IIIA and IV aberration not presented in ctDNA for 1, 4 and 7 patients, respectively, whereas ctDNA profiling allowed the identification of an actionable aberration (ESCAT IIIA) not presented in tissue for 1 patient. Thus far, data on ctDNA in STS have been very limited. In patients with localized Ewing sarcoma and osteosarcoma, the amount of ctDNA at diagnosis correlates with survival [7]. Monitoring ctDNA can also have clinical implications particularly to evaluate response to treatment and disease progression [8]. In patients with gastrointestinal stromal tumor, ctDNA and tissue sequencing results were similar, suggesting that liquid biopsy represents a robust approach for tumor genotyping and treatment tailoring [8]. In the present study, we found that 66.7% of ctDNA findings were also identified in tissue profiles. We also found more alterations in tissue than in ctDNA profiling, with the majority (66.7%) being CNVs. This result is in line with a previous study showing lower sensitivity of ctDNA profiling in identifying CNVs [10]. Five patients also had a single nucleotide variant in tissue which was not found through ctDNA profiling. Among them, 3 patients had no detectable ctDNA. ctDNA profiling represents an alternative tool for detecting actionable alterations in STS but is less sensitive than tissue sequencing to detect CNVs (losses or amplifications). We have previously shown that NGS of tissue allowed the identification of actionable alterations in up to 41% of patients with advanced STS [5]. We demonstrated the capacity of ctDNA profiling to detect actionable aberrations in up to 38% of patients with STS. Future technological development would increase the sensitivity of this approach for CNVs even more. Conceptualization, Antoine Italiano; methodology, Julie Blanchi, Sofiane Taleb, Arnaud Bayle, Melissa Alame, Yechan Laizet, Paul Dubos; investigation, BV, EK, MT, MS, AI; resources, Antoine Italiano; writing—original draft preparation, Julie Blanchi, Antoine Italiano; writing—review and editing, Julie Blanchi, Sofiane Taleb, Antoine Italiano; supervision, Antoine Italiano; project administration, Antoine Italiano. All authors have read and agreed to the published version of the manuscript. The authors have nothing to report. AI received research grant and honoraria from ROCHE, BAYER, MSD, ASTRAZENECA, MERCK, PHARMAMAR, BMS, PARTHENON, CHUGAI, NOVARTIS. The other authors have no competing interests. FONDATION MSDAVENIR (HEART grant). The study was approved by the Institutional Review Board of Institut Bergonié (IRB 2-323Z). All patients signed informed consent. Not applicable. Source data are available on request to the corresponding author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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