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      The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies

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          Abstract

          Pediatric, adolescent, and young adult patients underwent molecular profiling of their recurrent or refractory tumors as part of the MAPPYACTS trial, which identified actionable alterations and suggested a role for circulating tumor DNA for their identification within the blood.

          Abstract

          Abstract

          MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA).

          Significance:

          MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity.

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          New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

          E A Eisenhauer, P Therasse, J. Bogaerts … (2009)
          Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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            Hallmarks of Cancer: New Dimensions

            Douglas Hanahan (2022)
            The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
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              Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.

              Patrick Wen, David R. Macdonald, David A. Reardon … (2010)
              Currently, the most widely used criteria for assessing response to therapy in high-grade gliomas are based on two-dimensional tumor measurements on computed tomography (CT) or magnetic resonance imaging (MRI), in conjunction with clinical assessment and corticosteroid dose (the Macdonald Criteria). It is increasingly apparent that there are significant limitations to these criteria, which only address the contrast-enhancing component of the tumor. For example, chemoradiotherapy for newly diagnosed glioblastomas results in transient increase in tumor enhancement (pseudoprogression) in 20% to 30% of patients, which is difficult to differentiate from true tumor progression. Antiangiogenic agents produce high radiographic response rates, as defined by a rapid decrease in contrast enhancement on CT/MRI that occurs within days of initiation of treatment and that is partly a result of reduced vascular permeability to contrast agents rather than a true antitumor effect. In addition, a subset of patients treated with antiangiogenic agents develop tumor recurrence characterized by an increase in the nonenhancing component depicted on T2-weighted/fluid-attenuated inversion recovery sequences. The recognition that contrast enhancement is nonspecific and may not always be a true surrogate of tumor response and the need to account for the nonenhancing component of the tumor mandate that new criteria be developed and validated to permit accurate assessment of the efficacy of novel therapies. The Response Assessment in Neuro-Oncology Working Group is an international effort to develop new standardized response criteria for clinical trials in brain tumors. In this proposal, we present the recommendations for updated response criteria for high-grade gliomas.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancer Discov
                Journal ID (iso-abbrev): Cancer Discov
                Title: Cancer Discovery
                Publisher: American Association for Cancer Research
                ISSN (Print): 2159-8274
                ISSN (Electronic): 2159-8290
                Publication date (Print): 02 May 2022
                Publication date (Electronic): 16 March 2022
                Volume: 12
                Issue: 5
                Pages: 1266-1281
                Affiliations
                [1 ]Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
                [2 ]Unité de Génétique Somatique, Service de Génétique, Hospital Group, Institut Curie, Paris, France.
                [3 ]Department of Pathology and Laboratory Medicine, Translational Research Laboratory and Biobank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
                [4 ]INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Research Center, PSL Research University, Institut Curie, Paris, France.
                [5 ]Clinical Research Direction, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
                [6 ]INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.
                [7 ]Equipe SiRIC RTOP Recherche Translationelle en Oncologie Pédiatrique, Institut Curie, Paris, France.
                [8 ]Biostatistics and Epidemiology Unit, Gustave Roussy Cancer Campus, INSERM U1018, CESP, Université Paris-Saclay, Villejuif, France.
                [9 ]Laboratory of Translational Research in Child and Adolescent Cancer, Vall d'Hebron Research Institute (VHIR)-UAB, Barcelona, Spain.
                [10 ]Institut Curie Genomics of Excellence (ICGex) Platform, Research Center, Institut Curie, Paris, France.
                [11 ]Department of Pathology, PSL Research University, Institut Curie, Paris, France.
                [12 ]Department of Pediatric Oncology, Institut d'Hematologie et d'Oncologie Pédiatrique/Centre Léon Bérard, Lyon, France.
                [13 ]Department of Pediatric Hematology and Oncology, Hôpital de La Timone, AP-HM, Marseille, France.
                [14 ]UMR Inserm 1068, CNRS UMR 7258, Aix Marseille Université U105, Marseille Cancer Research Center (CRCM), Marseille, France.
                [15 ]SIREDO Oncology Center (Care, Innovation and Research for Children and AYA with Cancer), Institut Curie, PSL Research University, Paris, France.
                [16 ]Department of Pediatric Oncology, Centre Hospitalier Universitaire, Nantes, France.
                [17 ]Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy.
                [18 ]Paediatric Haematology/Oncology, Children's Health Ireland, Crumlin, Dublin, Republic of Ireland.
                [19 ]Division of Paediatric Haematology and Oncology, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
                Author notes
                [#]

                P. Berlanga, G. Pierron, and L. Lacroix are co–first authors.

                [##]

                G. Schleiermacher and B. Geoerger are co–last authors.

                Prior presentation: This work was presented in part at the AACR Annual Meeting 2017 in Washington, DC; the AACR Annual Meeting 2019 in Atlanta, GA; the 2019 ASCO Annual Meeting in Chicago, IL; and the 51st Congress of the International Society for Paediatric Oncology (SIOP 2019) in Lyon, France.

                [* ] Corresponding Author: Birgit Geoerger, Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, 114 Rue Eduard Vaillant, 94805 Villejuif, France. Phone: 33-1-42-11-46-61; Fax: 33-1-42-11-52-75; E-mail: birgit.geoerger@ 123456gustaveroussy.fr
                Author information
                https://orcid.org/0000-0002-2536-7680
                https://orcid.org/0000-0003-2535-1010
                https://orcid.org/0000-0002-7022-0725
                https://orcid.org/0000-0003-1604-6823
                https://orcid.org/0000-0003-3096-6204
                https://orcid.org/0000-0002-7159-8869
                https://orcid.org/0000-0002-6786-4968
                https://orcid.org/0000-0001-6559-3239
                https://orcid.org/0000-0003-4361-3643
                Article
                Publisher ID: CD-21-1136
                DOI: 10.1158/2159-8290.CD-21-1136
                PMC ID: 9394403
                PubMed ID: 35292802
                SO-VID: c4f23081-bc17-435a-aa83-e4b19186b675
                Copyright © ©2022 The Authors; Published by the American Association for Cancer Research
                License:

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

                History
                Date received : 20 August 2021
                Date revision received : 03 November 2021
                Date accepted : 07 February 2022
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                Page count
                Pages: 16
                Categories
                Subject: Research Articles

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