Respone to Škudar

1.

We thank Stjepan Škudar for his interest in our article which describes lack of response to RET inhibition in a patient with a CNS embryonal tumour with PLAGL2 amplification [1]. The rationale for the use of a RET inhibitor was clearly described and is because ChIP‐seq analysis has shown that the receptor tyrosine kinase RET is a direct target of PLAGL1 and PLAGL2 and that RET is overexpressed in PLAGL1/2‐amplified tumours [2]. It has therefore been surmised that amplification of PLAGL2 leads to RET pathway overactivation and potential sensitivity to RET inhibition. Given the lack of clinical response to a RET inhibitor, we performed further analysis of the patient's tumour to show lower RET expression than in other PLAGL amplified tumours and also lower levels of RET and RET phosphorylation which may help to explain the lack of clinical response. Our case report justifies the use of a RET inhibitor in this patient and provides further insight into possible reasons for treatment failure.

Škudar does raise a broader point about the use of off‐label or compassionate use medicines for paediatric patients with relapsed or progressive malignancies when there is only limited preclinical evidence to support their use. In contrast to his suggestions, we do not feel comprehensive target validation pretreatment is currently feasible. Target validation for individual patients would typically be performed by whole genome sequencing [3], ideally in combination with RNA sequencing, and potentially supplemented with the results of ex vivo drug screening [4]. Even with such an approach, there is no guarantee of a clinical response with only 36% of patients responding to molecularly guided treatments in a recent cohort [5]. More importantly, these techniques are also expensive, time‐consuming and frequently inaccessible to most centres outside a clinical trial.

Children with rare relapsed or progressive CNS malignancies generally have a poor prognosis with few treatment options. Patients and their families are therefore willing to trial off‐label or compassionate use medicines based on limited data as long as they will be well tolerated. Such an approach is well‐established in rare paediatric cancers and has led to the identification of effective treatments such as trastuzumab for desmoplastic small round cell tumours [6]. What we feel is important is that tolerability and efficacy data are recorded for these medications which often does not happen systematically. This is one of the reasons we were keen to publish this case report despite the negative results. The recently opened SACHA study [7] is a prospective observational study that monitors the use of off‐label or compassionate use anticancer therapies in children, adolescents and young adults. We would encourage clinicians in paediatric oncology to open this study if possible and contribute real‐world data to help inform the use of novel medications for rare paediatric cancers in the future.

Author Contributions

All authors wrote and reviewed the final draft.

Funding

The authors have nothing to report.

Ethics Statement

Consent for publication of the referenced case was obtained from the patient's family.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.