Precision cancer treatment improving paediatric outcomes

Childhood cancers

By Siobhan Calafiore

16 Sep 2023

A precision oncology program has changed the model of care for children with high-risk cancer in Australia, with many participants achieving remission and stabilisation of disease, delegates at VCCC Alliance’s research conference have heard.

Professor Michelle Haber said the Zero Childhood Cancer Program was established as a pilot study in 2015 because of a clinical need, with childhood cancer still the most common cause of death from disease in children nationally.

Three Australian children died from cancer every week, she told delegates.

She said at any one time in Australia, there were about 2000 children and young adolescents who were being treated for cancer or who were at risk of relapse.

Of the 1000 children newly diagnosed with cancer each year, about 200 had refractory cancer or relapse and most of these patients died of their disease.

“For those children who do survive, their journey is far from over,” said Professor Haber, who is executive director of the Children’s Cancer Institute, Sydney.

“Up to two-thirds of childhood cancer survivors will have serious life-altering and in many cases, life-threatening health conditions due to the nonspecific cytotoxicity of the intensive combination chemotherapy, radiotherapy, surgery, and, increasingly, immunotherapy they receive, and despite that they still die.”

“So there is a critical need for not only more effective therapies but safer therapies.”

Speaking in Melbourne on 12 September, Professor Haber said the Zero Childhood Cancer Program launched with a focus on high-risk patients with less than 30% chance of survival.

Rather than following the traditional model of care, where every child with the same cancer receives the same treatment, researchers use comprehensive molecular profiling – including whole-genome sequencing and methylation profiling – to match drugs to molecular targets.

Professor Haber said results from an analysis conducted on the program’s first 247 patients showed a reportable finding in 94% of patients and the researchers were able to make a personalised treatment recommendation in over two-thirds of patients.

Further, there was a change of diagnosis based on profiling in over 5% of cases.

“And because we were profiling not only the tumour, but also the germline DNA of these patients, we found that in one in six of these high-risk cancer patients, there was evidence for an inherited genetic predisposition,” Professor Haber said.

“That was twice the level that had been identified in any other previous studies.

“Most importantly, although these were children with less than 30% chance of survival, in over two-thirds of these patients, there was either a complete remission, a partial remission or a stabilisation of the disease,” she said.

A unique aspect of the program was the use of preclinical drug testing, which occurred whenever cancer centres provided sufficient fresh tumour samples, to empirically determine to which drug or drug combinations the cells would respond.

This occurred through in vitro high-throughput drug screening against a library of over 100 conventional and targeted drugs, but, where possible, researchers also established patient-derived xenografts in mice to test potential novel therapeutics.

Professor Haber said two of their recent studies showed preclinical drug testing broadened the therapeutic options available to these high-risk cancer patients, particularly in the one-third of patients who had no molecular target identified.

“Importantly, high-throughput screening provided orthogonal proof or validation of drug efficacy that was suggested by molecular analyses, but in addition, it identified many new drug responses in patients without a molecular target.”

A few weeks ago, the program passed a milestone of 1000 children enrolled.

The cases involved all types of children’s cancers, but the majority of children enrolled had brain cancer (33%), sarcoma (27%), blood cancer (16%), neuroblastoma (7%) and a variety of other rare childhood cancers (17%).

By the end of the year the program will be rolled out to every child with cancer in Australia, irrespective of their cancer type, where they lived or their level of risk.

“On the original Zero national clinical trial, many of the patients had to wait to relapse before they were eligible to be enrolled, now every patient in the country will be eligible for enrollment at the time of diagnosis,” Professor Haber said.

Researchers are also looking into immunoprofiling to better identify tumours that might be targetable with checkpoint inhibitors or other immunotherapies since biomarkers of “hot” or inflamed tumours aren’t necessarily predictive in children.

These include high tumour mutation burden, high neoantigen load, high PD-L1 expression and tumour immune microenvironment: TIL Signature.

They’ve come up with a paediatric specific immune inflammation signature to assist in the identification of a new subset of patients with immune inflamed tumours, independent of tumor mutation burden or neoantigen predictions.

A liquid biopsy program will also be introduced with the hope of improving monitoring of treatment response and minimal residual disease detection without the need for repeat biopsies, which were neither practical or ethical in children.

“We have the evidence that we’re going to be able to quantitate disease burden, that we can identify the emergence of de novo mutations,” Professor Haber said.

“And we’re very excited that this is creating the opportunity to potentially intervene with novel therapies prior to the emergence of clinical resistance.”

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