First results of the GAIN/iCAT2 Consortium trial show the importance of molecular profiling of solid tumors in young patients.

Next generation sequencing (NGS) assays are now a standard part of clinical care for many adult solid cancers. The significance of molecular tumor profiling for the care of children with cancer is not well understood. To determine the clinical impact of identifying genomic alterations by NGS for young patients with relapsed, refractory, or high-risk extracranial solid tumors, the GAIN/iCAT2 Consortium study (NCT02520713) was started. Dr Allana Church (Boston Children’s Hospital, MA, USA) reported on the first 389 participants (of estimated 825 patients) in this prospective cohort study enrolling patients at 12 institutions in the USA with extracranial solid tumors diagnosed at age 30 years or less. Targeted DNA NGS was performed on 1 tumor samples from each patient. Selected patients also had tumors subjected to RNA sequencing. Test results were returned to the treating oncologist and follow-up treatment and response data were collected. Genomic alterations were classified according to evidence of impact on diagnosis, prognosis, or response to targeted therapy matched to an identified alteration (matched targeted therapy, MTT) using established guidelines. Response to MTT was determined and reported as a response if either there was radiographic response according to RECIST or the duration of therapy was over 4 months. Molecular tumor profiling (MTP) was successful in 345 (89%) patients (mean age 11 years at diagnosis; 65% with sarcoma).

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Of these, 299 (87%) had one or more alterations of clinical significance. Genomic alterations with diagnostic, prognostic, or therapeutic significance were present in 208 (60%), 51 (15%), and 240 (70%) patients, respectively. Of the 240 patients with tumors harboring genomic alterations designated as having therapeutic impact, 23 (11%) had Tier 1 molecular findings (clinical evidence same/similar alteration, same disease). In total, 205 patients were eligible to receive MTT based on having a molecular alteration with therapeutic significance and sufficient follow-up; 31 of these patients (15%) received MTT. Seven patients (23%) receiving MTT responded, 6 of these were kinase fusions (TCF12-NOTCH1 fusion, KHDRBS2-BRAF fusion, RBPMS-NTRK2 fusion, SEPT17-BRAF fusion, CCDC6-ALK fusion, MYH10-RET fusion).

All of the responders received targeted therapy matched to a fusion (respectively: crenigacestat, trametinib, larotrectinib, trametinib, crizotinib, and vendetinib) and 78% of diagnostically significant alterations were fusions. Bases on these first results, Dr Church concluded that molecular tumor profiling has a significant impact on diagnosis and treatment recommendations for young patients with extracranial solid tumors. “These results emphasise the importance of fusion detection for patients with sarcomas and rare tumors.”

  1. Church AJ, et al. Clinical impact of molecular tumor profiling in pediatric, adolescent, and young adult patients with extra-cranial solid malignancies: An interim report from the GAIN/iCat2 study. ASCO 2021 Virtual Meeting, abstract 10005.