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      Biological Sample Collection to Advance Research and Treatment: A Fight Osteosarcoma Through European Research and Euro Ewing Consortium Statement

      other
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 3 , 4 , 15 , 13 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 8 , 25 , 26 , 27 , 28 , 2 , 29 , 30 , 31 , 32 , 33 , 18 , 34 , 35 , 2 , 36 , 37 , 38 , 15 , 39 , 40 , 41 , 33 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , * , , 59 , 60
      Clinical Cancer Research
      American Association for Cancer Research

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          Abstract

          Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes.

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          Most cited references107

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          Gene fusion with an ETS DNA-binding domain caused by chromosome translocation in human tumours.

          Ewing's sarcoma and related subtypes of primitive neuroectodermal tumours share a recurrent and specific t(11;22) (q24;q12) chromosome translocation, the breakpoints of which have recently been cloned. Phylogenetically conserved restriction fragments in the vicinity of EWSR1 and EWSR2, the genomic regions where the breakpoints of chromosome 22 and chromosome 11 are, respectively, have allowed identification of transcribed sequences from these regions and has indicated that a hybrid transcript might be generated by the translocation. Here we use these fragments to screen human complementary DNA libraries to show that the translocation alters the open reading frame of an expressed gene on chromosome 22 gene by substituting a sequence encoding a putative RNA-binding domain for that of the DNA-binding domain of the human homologue of murine Fli-1.
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            Systematic identification of genomic markers of drug sensitivity in cancer cells

            Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers of response to targeted agents. To uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines, which represent much of the tissue-type and genetic diversity of human cancers, with 130 drugs under clinical and preclinical investigation. In aggregate, we found mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing’s sarcoma cells harboring the EWS-FLI1 gene translocation to PARP inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.
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              Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001

              Abstract Background Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. Patients and methods Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan–Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). Results KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2–30.4) and 38.6 months (95% CI, 27.2–not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8–11.1) and 16.9 months (95% CI, 9.3–35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. Conclusions This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. Clinical Trial Registry ClinicalTrials.gov, NCT01295827.
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                Author and article information

                Journal
                Clin Cancer Res
                Clin Cancer Res
                Clinical Cancer Research
                American Association for Cancer Research
                1078-0432
                1557-3265
                15 August 2024
                13 June 2024
                : 30
                : 16
                : 3395-3406
                Affiliations
                [1 ] Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich, United Kingdom.
                [2 ] Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
                [3 ] Pediatric Oncology, Regina Margherita Children’s Hospital, Turin, Italy.
                [4 ] Department of Public Health and Pediatrics, University of Turin, Turin, Italy.
                [5 ] Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria.
                [6 ] Pediatric Oncology Unit, Karolinska University Hospital, Stockholm, Sweden.
                [7 ] Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland.
                [8 ] Center for Pediatric, Adolescent and Women’s Medicine, Klinikum Stuttgart—Olgahospital, Stuttgart Cancer Centre, Stuttgart, Germany.
                [9 ] Department of Musculoskeletal Radiology, Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham, United Kingdom.
                [10 ] Department of Oncology, Oslo University Hospital, Oslo, Norway.
                [11 ] Paediatric Oncology, Royal Manchester Children’s Hospital, Central Manchester University Hospital NHS Foundation Trust, Manchester, United Kingdom.
                [12 ] Haematology/Oncology, Children’s Health Ireland at Crumlin, Dublin, Ireland.
                [13 ] Department of Pathology, UCL Cancer Institute, University College London, London, United Kingdom.
                [14 ] Pediatrics III, West German Cancer Center, University Hospital Essen, German Cancer Consortium (DKTK) Site Essen, Cancer Research Center (NCT) Cologne-Essen, University of Duisburg-Essen, Essen, Germany.
                [15 ] Patient and Parent Advocacy Group, FOSTER, Washington, District of Columbia.
                [16 ] Histopathology, The Royal National Orthopaedic Hospital NHS Trust, Stanmore, United Kingdom.
                [17 ] Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
                [18 ] Department of Oncology for Child and Adolescent, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
                [19 ] U1015, Université Paris-Saclay, Villejuif, France.
                [20 ] Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
                [21 ] Orthopaedic Oncology, The Royal National Orthopaedic Hospital NHS Trust, Stanmore, United Kingdom.
                [22 ] Department of Pathology, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France.
                [23 ] EQ ONCOSARC, CRCT Inserm/UT3, ERL CNRS, Toulouse, France.
                [24 ] Tumour Orthopaedics, University Hospital Essen, German Cancer Consortium (DKTK) Site Essen, Cancer Research Center (NCT) Cologne-Essen, University of Duisburg-Essen, Essen, Germany.
                [25 ] Paediatric Haematology and Oncology, University Hospital Motol, Prague, Czech Republic.
                [26 ] Pediatrics, St Anna Children’s Hospital, Medical University Vienna, Vienna, Austria.
                [27 ] St Anna Children’s Cancer Research Institute, Vienna, Austria.
                [28 ] Hematology-Oncology and Stem Cell Transplantation, HUS Helsinki University Hospital, New Children’s Hospital, Helsinki, Finland.
                [29 ] Computational Biology and Systems Medicine Group, Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway.
                [30 ] Pathology, Leiden University Medical Center, Leiden, the Netherlands.
                [31 ] Leiden Center for Computational Oncology, Leiden University Medical Center, Leiden, the Netherlands.
                [32 ] Department of Medical Oncology, Institut Curie, Paris, France.
                [33 ] Department of Pediatrics and AYA Oncology, Centre Oscar Lambret, Lille, France.
                [34 ] Institute of Hematology and Pediatric Oncology, Léon Bérard Center, Lyon, France.
                [35 ] Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal.
                [36 ] Division of Imaging and Oncology, University Medical Center Utrecht, Utrecht, the Netherlands.
                [37 ] School of Medicine, Nantes Université, Nantes, France.
                [38 ] Bone and Soft Tissue Sarcomas and Innovative Therapies Unit, IRCCS Istituto Orthopedico Rizzoli, Bologna, Italy.
                [39 ] Anticancer Fund, Meise, Belgium.
                [40 ] The George Pantziarka TP53 Trust, London, United Kingdom.
                [41 ] Pediatric Hematology-Oncology, Ippokratio General Hospital of Thessaloniki, Thessaloniki, Greece.
                [42 ] Oncology and Surgical Oncology for Children and Youth, Institute of Mother and Child, Warsaw, Poland.
                [43 ] Children’s Cancer Research Group, Leeds Institute of Medical Research, University of Leeds, Leeds, United Kingdom.
                [44 ] Center for Pediatric Oncology and Hematology, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.
                [45 ] The Danish Centre for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark.
                [46 ] Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
                [47 ] Orthopaedics and Trauma, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
                [48 ] Department of Oncology, University College London Hospitals NHS Foundation Trust, UCL Cancer Institute, London, United Kingdom.
                [49 ] Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland.
                [50 ] Department of Orthopaedic Surgery and Traumatology, Ghent University Hospital, Belgium.
                [51 ] Department of Hematology and Oncology, A. Trousseau Hospital, Sorbonne University, APHP, Paris, France.
                [52 ] Department of Medical Oncology, Institut Bergonié, Bordeaux, France.
                [53 ] Medical Oncology, Vall d’Hebron University Hospital, Barcelona, Spain.
                [54 ] Orthopaedic Oncology, Leiden University Medical Centre, Leiden, the Netherlands.
                [55 ] Musculoskeletal Radiology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
                [56 ] Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
                [57 ] Division of Cancer Sciences, School of Medical Sciences, The University of Manchester, Manchester, United Kingdom.
                [58 ] The Christie NHS Foundation Trust, Manchester, United Kingdom.
                [59 ] Children’s Cancer Research Center, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
                [60 ] Pediatric Oncology, Klinikum Kassel, Kassel, Germany.
                Author notes
                [* ] Corresponding Author: Martin G. McCabe, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester M20 4BX, United Kingdom. E-mail: martin.mccabe@ 123456manchester.ac.uk

                Clin Cancer Res 2024;30:3395–406

                D. Green, R. van Ewijk, and E. Tirtei are joint first authors to this article.

                Q. Campbell-Hewson, M.G. McCabe, and M. Nathrath are joint senior authors to this article.

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                https://orcid.org/0000-0002-0217-3322
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                https://orcid.org/0000-0003-1333-2912
                https://orcid.org/0000-0002-2137-7507
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                https://orcid.org/0000-0002-5552-6283
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                https://orcid.org/0000-0002-1872-6630
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                https://orcid.org/0000-0002-4676-7835
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                https://orcid.org/0000-0001-9915-2810
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                https://orcid.org/0000-0002-9486-8454
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                https://orcid.org/0000-0003-1509-6925
                https://orcid.org/0000-0002-5138-0707
                https://orcid.org/0000-0002-1584-1115
                Article
                CCR-24-0101
                10.1158/1078-0432.CCR-24-0101
                11334773
                38869831
                55c5b7b9-4ec6-4f13-8906-2e22c02a2c96
                ©2024 The Authors; Published by the American Association for Cancer Research

                This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.

                History
                : 09 January 2024
                : 27 March 2024
                : 11 June 2024
                Funding
                Funded by: Bone Cancer Research Trust (BCRT), DOI http://dx.doi.org/10.13039/100011719;
                Award ID: BCRT/8422 and BCRT/7721
                Award Recipient : Award Recipient :
                Funded by: Foerderkreis Krebskranke Kinder eV Stuttgart, DOI http://dx.doi.org/10.13039/;
                Award Recipient :
                Funded by: German Child Cancer Foundation, DOI http://dx.doi.org/10.13039/;
                Award ID: DKS 2021.13
                Award Recipient :
                Categories
                Liquid Biopsy
                Pediatric Cancers
                Sarcomas
                Osteosarcoma
                Translational Research
                Tumor Heterogeneity
                Perspectives

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