Unaligned DNA sequences viewed on LCD screen
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In a study published in Nature Medicine, researchers used clinical data from a large patient cohort to show that children with high-risk cancers had better response rates and survival outcomes when treated with sequencing-guided treatment that used comprehensive molecular profiling.

The PRISM trial in Australia used whole-genome, transcriptomic, and DNA methylation sequencing to find molecular targets in high-risk pediatric cancers. It was part of the ZERO Childhood Cancer Precision Medicine Program. When sequencing-guided treatment recommendations were used instead of standard cytotoxic treatments (26% vs. 12%) or unguided targeted agents (26% vs. 5.2%), the objective response rate and two-year progression-free survival rates were higher.

This study supports the finding that biomarkers are crucial and that precision medicine should be a part of routine treatment for pediatric patients. This further supports the idea that, to the extent feasible, biomarkers should drive clinical trials of novel targeted therapies.

Non-ZERO sum game

The ZERO Childhood Cancer Precision Medicine Program’s PRISM trial collected sequential data from 384 patients with high-risk pediatric cancer, defined as a disease with a projected cure rate below 30%. Each patient was monitored for at least 18 months.

While the study showed that sequencing-guided treatment substantially improves progression-free survival compared to other treatments, the impact on overall survival is still unclear. The two-year overall survival rate in sequencing-guided treatment, which was 38%, did not show a statistically significant difference when compared to the two-year overall survival rates of non-sequencing guided treatment (24%), unguided treatment (20%), and standard of care (23%). Patients who underwent multiple lines of therapy and various salvage therapies may have impacted their overall survival. A more thorough evaluation of the impact on overall survival may necessitate additional research.

Over 90% of cases had genomic drivers, which may encourage pharmaceutical companies to develop new treatments targeting pediatric tumor drivers. Future research is necessary to enhance results for children who do not have identifiable findings that can be targeted or only have targets with limited supporting evidence. Additional indicators such as toxicity metrics, quality of life, and patient-reported outcomes must be considered in order to evaluate the therapeutic benefits of sequencing-guided treatment. Results like these highlight the urgent need for targeted, precision treatment for patients with known genetic mutations, ideally before symptoms worsen.

The extensive collaborative effort was supervised by senior authors Glenn M. Marshall, MD, who holds the position of head of translational research at the Children’s Cancer Institute and serves as the clinical lead of the Zero Childhood Cancer Program, and David S. Ziegler, MD, PhD, who leads the Brain Tumours Group at the Children’s Cancer Institute and is responsible for overseeing the clinical trials for the Zero Childhood Cancer Program.

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