Welcome to the Science Spotlight, where we highlight the scientific advancements made possible by our consortia and data commons.
In this Science Spotlight, INSTRuCT profiles several recent consensus papers in which they offer guidelines for imaging and molecular testing that could be used to inform future clinical trial protocols for soft-tissue sarcoma.
Imaging recommendations for the management of soft tissue sarcomas
Spotlight by Dr. Reineke Schoot, on behalf of the INSTRuCT Executive Committee
The papers
Schoot RA, Shulkin BL, van Rijn RR, von Kalle T. Pediatric rhabdomyosarcoma protocols should include more detailed imaging guidelines to ensure homogeneous response assessment. J Clin Oncol. 2023 May;41(13):2337-2341. doi:10.1200/JCO.22.02613.
Schoot RA, Ferrari A, von Kalle T, Khalatbari H, McCarville MB, Morosi C, van Rijn RR, von Witzleben AA, Weiss AR, Kao SC. Imaging recommendations for the management of pediatric nonrhabdomyosarcoma soft tissue sarcoma (NRSTS): consensus statement of the International Soft Tissue Sarcoma Consortium (INSTRuCT). EJC PO. 2023 March 17. DOI: https://doi.org/10.1016/j.ejcped.2023.100008.
Schoot RA, van Ewijk R, von Witzleben AA, Kao SC, Merks JHMH, Morosi C, Pace E, Shulkin BL, Ferrari A, von Kalle T, van Rijn RR, Weiss AR, SparberSauer M, Ter Horst SAJ, McCarville MB. INternational Soft Tissue saRcoma ConsorTium (INSTRuCT) consensus statement: Imaging recommendations for the management of rhabdomyosarcoma. Eur J Radiol. 2023 Sep;166:111012. doi: 10.1016/j.ejrad.2023.111012. PMID: 37541182.
*authors contributed equally.
The research
To facilitate more uniform imaging acquisition, two imaging guidelines were published by the INSTRuCT imaging working group: one for the assessment of rhabdomyosacomas (RMS) and one for the remaining group of soft tissue sarcomas, summarized under the name of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). The RMS imaging guideline was based on literature summaries and evidence was graded by a multi-disciplinary team according to the GRADE method [EJR]. For the NRSTS imaging guideline, less literature was available, due to the heterogeneity of histotypes united under the name of NRSTS. Therefore, the group decided to provide imaging guidance, based on literature where possible, complemented by expert opinion [EJC PO]. In addition to general imaging recommendations, with many similarities to the RMS guideline, specific recommendations were made for a selection of histotypes.
Why it matters
Primary endpoints in clinical trials for patients with soft tissue sarcoma are based on imaging response definitions (either response or progression). These response assessments are subject to several confounding factors, such as differences in acquisition settings, methods of measurement, and interobserver variability. Nevertheless, very little guidance is provided in the clinical trial protocols for the acquisition of imaging for response assessment and different definitions of response have been used [JCO 2023].
Molecular testing of rhabdomyosarcoma to improve risk stratification and outcome
Spotlight by Dr. Simone Hettmer, on behalf of the INSTRuCT Executive Committee
The paper
Hettmer S, Linardic CM, Kelsey A, Rudzinski ER, Vokuhl C, Selfe J, Ruhen O, Shern JF, Khan J, Kovach AR, Lupo PJ. Molecular testing of rhabdomyosarcoma in clinical trials to improve risk stratification and outcome: A consensus view from European paediatric Soft tissue sarcoma Study Group, Children’s Oncology Group and Cooperative Weichteilsarkom Studiengruppe. Eur J Cancer. 2022 Sep 1;172:367-386. doi: 10.1016/j.ejca.2022.05.036. PMID: 35839732.
The research
The objectives of this review of rhabdomyosarcoma (RMS) biology were to inform study questions in future clinical trials, harmonize sample/ data collection across clinical trials, and stimulate integration of multi-dimensional data using machine learning and other quantitative methods. The review calls for prospective assessment of rational RMS risk stratification based on (1) canonical PAX::FOXO1 and rare alternative fusion genes, (2) somatic mutations and amplifications in RMS-relevant genes and (3) gene expression signatures. Further opportunities for innovation in newly emerging focus areas, including but not limited to germline RMS susceptibility, biomarker detection/analyses using liquid biopsies, and therapeutic targeting of actionable genetic alterations, are discussed.
Why it matters
The review reinforces the notion that tumor biology should directly inform clinical trial design. As RMS is a rare cancer with substantial clinical and pathological diversity, cooperation between national and
international cooperative working groups is advocated to secure clinical data/ biospecimens from sufficient numbers of patients and to integrate data. Robust and timely translation of preclinical findings into clinical trials and, ultimately, standard-of-care recommendations depends on effective communication between clinical and biological sciences.