MAPPYACTS (NCT02613962) is an international prospective precision medicine study recruiting children and adolescents with recurrent/refractory malignancies.

Design: Patients < 18 years at diagnosis underwent on-purpose tumor biopsy/surgery of recurrent/refractory malignancies for molecular characterization by WES and whole RNA sequencing. Results were reviewed in a dedicated weekly molecular tumor board (MTB), followed by discussion with the treating physician in a clinical MTB (CMTB). Whenever possible, patients were enrolled subsequently in clinical trials based on CMTB recommendations. In parallel, plasma was collected for cell free DNA (cfDNA) analysis by WES (100x) and capture sequencing (> 2000x) targeting alterations identified by tumor WES.

Results: From February 2016 to October 2018, 500 patients have been included in 17 centers in France, Italy and Ireland. Median age at inclusion was 13 years (range, 1-33). 38% had sarcomas, 28% brain tumors, 22% other solid tumors, 12% hematological malignancies with a median of one prior relapse/progression. Eleven patients were excluded (10 screening failures, 1 consent withdrawal). 489 patients underwent 525 interventions: biopsy (57%), surgery (34%), blood/bone marrow (9%), in 55% done to metastatic sites. Molecular profiling was performed in 433 patients (88%) and was contributive for 390 patients. Known pathogenic germline variants were identified in 33 patients (8%). For 271/390 patients (70%), there were at least one genetic alteration that could represent a potential therapeutic target. A total of 548 ”actionable” alterations were identified (311 SNV, 208 focal CNA, 29 gene fusions). Overall 448 treatment recommendations were given, 1 to 5 per patient (median 2) and 8% had alterations considered as “ready for use” for treatment at relapse. Recommendations involved mainly cell cycle checkpoint (n=97), PI3K/AKT/mTOR (n=83) and RAF/MAPK (n=68), cell cycle (n=67), growth factor receptor signaling (n=62) and DNA damage repair (n=33). Follow-up information is available for 197 patients discussed in the CMTB before January 2018. Fifty-six patients (28%) were treated with a matched targeted agent, 48 of them in a clinical trial, mostly in our proof-of-concept AcSé-ESMART trial. CfDNA WES of the first 40 samples revealed at least 1 tumor specific SNV in all cases, with a mean of 38% of SNVs seen in the tumor also displayed in cfDNA (range, 2-89%) and correlation between cfDNA quantity and percentage of tumor SNVs in the cfDNA (p=0.02).

Conclusion: MAPPYACTS underlines the role of precision medicine approaches to identify actionable molecular alterations in recurrent pediatric cancer enabling access to innovative treatment through early clinical trials. The impact of surrogate approach based on cfDNA testing to identify targetable genetic alterations is currently under evaluation.

Citation Format: Pablo Berlanga, Gudrun Schleiermacher, Ludovic Lacroix, Gaelle Pierron, Tiphaine Adam de Beaumais, Mathieu Chicard, Yasmine Iddir, Jean Yves Scoazec, Paul Freneaux, Mohamed Amine Bayar, Sophie Cotteret, Samuel Abbou, Michela Casanova, Cormac Owens, Stefan Michiels, Olivier Delattre, Gilles Vassal, Birgit Geoerger. Pediatric precision medicine program in recurrent tumors: Results of the first 500 patients included in the European MAPPYACTS molecular profiling trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT081.