Molecular Profiling with Targeted Panel Tests that Includes Fusion Detection Has a Substantial Clinical Impact for Young Patients with Solid Tumours

The multicentre observational prospective Genomic Assessment Informs Novel Therapy Consortium (GAIN)/iCat2 Study follows a patient cohort, performs targeted next-generation sequencing (NGS) from formalin-fixed paraffin-embedded (FFPE) tumour samples and collects clinical data to address the impact of molecular tumour profiling on patient outcomes. An interim report from the study shows that molecular profiling of paediatric solid tumours clarifies diagnostic classifications and provides opportunities for matched targeted therapy. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61%, 16% and 65% of patients, respectively. Of the diagnostic variants identified, 77% were gene fusions. The findings are published by Alanna J. Church, Assistant Professor at Boston Children’s Hospital in Boston, MA, USA and colleagues on 23 June 2022 in the Nature Medicine.

The authors wrote in the background that the US Food and Drug Administration (FDA) has fully approved 5 targeted NGS tests for advanced solid malignancies and approved the development of several additional targeted molecular tumour profiling assays. These FDA-approved and preapproved molecular tumour profiling tests for solid malignancies use FFPE samples to sequence DNA and, in some cases RNA, and issue reports on several hundred cancer-related gene mutations and copy number alterations and a more limited number of gene fusions. In addition, some academic laboratories have developed similar in-house targeted molecular tumour profiling assays generally referred to as laboratory-developed tests.

Recommendations for use of these targeted NGS tests are included in the US practice guidelines and US insurance coverage decisions for adult cancers. However, clinical studies supporting biomarker validation and subsequent targeted NGS testing and new therapeutic FDA approvals have not included children with solid malignancies, with the exception of the diagnosis- and age-agnostic study that led to larotrectinib approval. Thus, in US there are no national coverage determinations or practice guidelines regarding molecular tumour profiling for paediatric solid malignancies.

However, some paediatric patients with solid malignancies have targeted molecular tumour profiling performed. Patients with paediatric cancer treated at academic institutions are undergoing targeted molecular tumour profiling, as evidenced that targeted sequencing data for over 2,000 patients aged 18 or younger with extracranial solid tumours have been deposited into the American Association of Cancer Research project Genomics Evidence Neoplasia Information Exchange repository from 7 institutions. Paediatric oncologists also utilise commercial targeted molecular tumour profiling, with Foundation Medicine reporting on 711 paediatric solid malignancies sequenced in 2017. But molecular tumour profiling of paediatric solid tumours is not universal; only one-third of National Cancer Institute – Children’s Oncology Group paediatric Molecular Analysis for Therapy Choice (MATCH) screening protocol participants had definitive evidence of molecular tumour profiling before enroling on this basket study and one-third had definitive evidence of not having had molecular tumour profiling before enrolment. There is absence of a national standard of care for molecular tumour profiling and uneven access to modern molecular analyses in paediatric patients with cancer represents important health equity.

Several recently published studies demonstrated that comprehensive sequencing, including whole-genome, whole-exome and whole-transcriptome of paediatric cancers can identify clinically relevant alterations in a substantial fraction of childhood patients with cancer and that some patients with actionable tumour alterations will receive and respond to matched targeted therapy. Fresh-frozen tumour samples have been used for these studies. In the US, where targeted NGS tests are commonly performed on FFPE samples, these studies do not reflect typical clinical practice.

Patients with extracranial solid tumours are enroled in GAIN/iCat2 to facilitate data-driven insurance coverage decisions and testing guideline development in the US and inform molecular testing practices in clinical settings where resource limitations prohibit acquisition, storage and transport of fresh-frozen tissue and comprehensive sequencing data generation, analysis and storage.

The GAIN/iCat2 is a prospective observational cohort study conducted at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range, 0–27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61%, 16% and 65% of patients, respectively.

After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with a molecular tumour profiling result that could be used to select molecularly targeted therapy matched to identified alterations. Of the 29 patients who received molecularly targeted therapy matched to identified alterations, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions.

The authors commented that their results inform molecular testing approaches in this patient population and priorities for future paediatric oncology research efforts. The GAIN/iCat2 study is ongoing, with continued patient accrual. Further data collection will allow for additional analyses, such as frequency of rare genomic variants, and outcomes, such as event-free and overall survival.


Church AJ, Corson LB, Kao P-C, et al. Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer. Nature Medicine; Published online 23 June 2022.