Discussion
In this pilot study, we investigated the clinical utility of CGP for pediatric and AYA patients with solid tumors. A previous study reported that pediatric cancer patients have fewer point mutations than adult patients (1). Profiling data of adult cancer patients are gradually accumulating, but there are few data sets of pediatric cancer patients. If genomic profiling data of pediatric cancer patients are accumulated in the future, biomarker-matched therapy such as entrectinib for neurotrophic receptor tyrosine kinase (NTRK) solid tumors will increase. Currently, the most common therapeutic method for pediatric cancer patients is multiple combination chemotherapy and radiation therapy, and side effects such as hair loss and nausea reduce quality of life. Further studies of the molecular biology of pediatric cancer patients will contribute to improved prognosis and quality of life.
Unfortunately, no patients were able to receive biomarker-matched therapy according to their genomic alterations. Seven patients (53.8%) were unable to receive biomarker-matched therapy despite having candidates for treatment. The reasons were as follows: two (15.4%) patients had worsening general conditions, and five (38.5%) patients were prioritized for standard chemotherapy.
One of the reasons is that fewer clinical trials in pediatric cancer were available in Japan compared with the USA. (four trials in Japan vs 145 trials in the USA, as searched in clinicaltrials.gov on July 14, 2021 using the following search criteria: condition or disease = pediatric cancer; recruitment status = recruiting and not yet recruiting studies; and country = Japan or United States.). Thus, clinical trials in pediatric patients may need to be conducted at the same time as clinical trials in adult patients. Better access to investigational drugs or liberal off-label use might improve the clinical outcome in Japan after CGP. A previous study reported that potentially actionable finding for 23 of the 58 patients (40%) were detected by genomic profiling and six of the 23 patients (26%) received matched targeted therapy (9).
ATM missense mutations were detected as VUS in the genetic report of one patient. However, it was revealed by the Molecular Tumor Board that this mutation was an inactivating mutation on the basis of a previously published in vitro experiment (10). We noted that if single nucleotide polymorphism information of the corresponding ethnicity is not used in the evaluation of genetic variants, there is an increased possibility of false-positive or false-negative results. Therefore, we need to be careful when interpreting the results of genomic profiling and the Molecular Tumor Board is considered to have an extremely important role.
It is important to determine whether the pediatric patient has a hereditary tumor. In this study, germline aberrations were suspected in four patients (30.8%). FoundationOne® CDx and OncoGuide® NCC oncopanels for CGP were widely adopted after coverage by national healthcare insurance was provided from June 2019 in Japan. One of the differences between the two CGP panels is whether CGP is conducted on blood cells. OncoGuide®NCC oncopanel can identify germline variants by interrogating DNA from white blood cells. However, FoundationOne® CDx interrogates tumor tissue only, and hereditary tumors are “suspected” by identifying somatic variants, combined with family history and allele frequency. If the patients were children, we consulted their parents regarding genetic counseling and confirmation testing. The findings of hereditary tumors in pediatric and AYA cancer patients are especially important, and these patients often receive radiation therapy. However, radiation therapy should be carefully discussed with patients withTP53 germline mutations (Li-Fraumeni syndrome) to minimize secondary tumors.
This study had a small sample size, and the clinical utility of CGP in pediatric cancer patients need to be validated in a larger study, ideally combined with prospective randomized therapeutic clinical trials.
In conclusion, this pilot study indicated CGP could identify actionable alterations in pediatric and AYA patients with solid tumors in the Japanese population. Further studies of the clinical utility of precision cancer medicine in pediatric and AYA patients are warranted to improve clinical outcomes and quality of life.