Genetic profiling ‘feasible’ for paediatric cancer patients

Feb 2 2016

By Lynda Williams, Senior medwireNews Reporter

Research published in JAMA Oncology demonstrates that tumour and germline molecular profiling is feasible in paediatric cancer patients and can have actionable findings.

In the first of two studies, 81% of 150 children, aged an average of 7.4 years, had solid tumour samples suitable for whole-exome sequencing (WES), and 39% of these 121 patients had potentially clinically significant or actionable somatic or germline mutations.

Analysis of somatic mutations revealed that 3% had category I mutations, known to be diagnostic, prognostic or predictive for treatment for their tumour type, and 24% had category II mutations in targetable pathways, gene families or functional groups with potential clinical utility across a range of tumour types. The most commonly detected mutations affected CTNNB1, BRAF, KRAS and KIT.

And category III mutations, occurring in consensus cancer genes such as TP53, were identified in 20% of the patients, say D Williams Parsons (Baylor College of Medicine in Houston, Texas, USA) and co-authors.

In addition, pathogenic or likely pathogenic germline mutations were found in 10% of 150 patients, including 13 patients with dominant variants associated with childhood cancer, such as TP53. One patient with hepatocellular carcinoma and severe liver disease, and another with unexplained proteinuria were found to have recessive mutations associated with their phenotype.

“The further integration of methods to detect copy number abnormalities and fusion genes will increase the diagnostic yield of these tests, particularly for tumor types that are known to harbor few mutations detectable by WES”, write Parsons et al.

“Strategies to effectively and responsibly use these diverse results are required to incorporate WES and other genomic tests into childhood cancer care and clinical trials.”

In the second report, the Individualized Cancer Therapy (iCat) Study investigators successfully used tumour profiling techniques on clinical specimens from 89 of 100 patients, all of whom were aged less than 30 years old, with high-risk, recurrent or refractory extracranial tumours.

Overall, 43% of study participants had a potentially clinically significant finding, report Katherine Janeway (Dana-Farber Institute, Boston, Massachusetts, USA) and co-authors.

This included 31 patients who were given an iCat recommendation for treatment based on the presence of an actionable mutation, exceeding the 14 recommendations that were required for the study to “conclude feasibility”, the researchers say.

One patient had a tier 1 and two patients a tier 2 recommendation for treatment, based on the strongest evidence from clinical studies, while the remainder had tier 3 or 4 recommendations based on preclinical research.

Actionable alterations included focal copy number alterations in 20 patients and known or suspected pathogenic mutations in 10 patients, with a further six patients having mutations of unknown significance, two having alterations to an expressed target and a third having a translocation.

The use of CDK4/6 inhibitors were implicated in 11 patients and BET bromodomain inhibitors in six patients, with other potential targets including BRAF/MEK/ERK, ALK and PARP.

“The actionable alterations identified in this study highlight the drug classes in which there is a high priority to develop early phase clinical trials with integrated genomic characterization for children with recurrent or refractory solid tumors”, the researchers say, emphasising this is “an important study outcome given the limited number of these children available to enroll in early-phase clinical trials, and the large number of novel targeted therapies not yet studied in children.”

Just three patients were given treatment based on their recommendations, including a child with recurrent retinoblastoma who had a tier 1 iCat recommendation and was given the ALK inhibitor, crizotinib. None of the three patients achieved an objective response to the recommended treatment.

Barriers to receipt of matched targeted therapies included the lack of an available clinical trial or inability to enter such a trial, and also patient clinical status, having stable disease or being too poorly for the treatment.

“This result suggests that profiling tumors earlier in the disease course may increase the number of patients treated with matched targeted therapy”, the team comments.

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