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.