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Molecular tumour profiling impacts the diagnosis and treatment of solid tumours

Presented by
Dr Alanna Church , Boston Children’s Hospital, MA, USA
ASCO 2021
The first results of the GAIN/iCAT2 Consortium trial showed the importance of molecular profiling of solid tumours 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 tumour 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 tumours, the GAIN/iCAT2 Consortium study (NCT02520713) was started. Dr Alanna 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 tumours diagnosed at age 30 years or less [1].

Targeted DNA NGS was performed on ≥1 tumour samples from each patient. Selected patients also had tumours 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 a radiographic response according to RECIST or the duration of therapy was over 4 months. Molecular tumour profiling was successful in 345 (89%) patients (mean age 11 years at diagnosis; 65% with sarcoma). Of these, 299 (87%) had 1 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 tumours harbouring 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 (i.e 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). Furthermore, 78% of diagnostically significant alterations were fusions.

  1. Church AJ, et al. Clinical impact of molecular tumour profiling in pediatric, adolescent, and young adult patients with extra-cranial solid malignancies: An interim report from the GAIN/iCat2 study. Abstract 10005, ASCO 2021 Virtual Meeting, 4–8 June.

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