Molecular profiling identifies potential treatment targets in many hard-to-treat pediatric cancers

By Will Boggs MD

NEW YORK (Reuters Health) - 7/5/2019

Molecular profiling enables the identification of potentially treatable alterations in many hard-to-treat childhood and adolescent cancers, according to results from the TRICEPS study.

"The cure rate of childhood and adolescent cancer reached a plateau at approximately 80% in the mid-1990s," Dr. Daniel Sinnett from Centre Hospitalier Universitaire Sainte-Justine, in Montreal, Canada, told Reuters Health by email. "We need to find new strategies to treat these hard-to-treat cancer patients."

Comprehensive molecular profiling, including next-generation sequencing (NGS), offers the potential to improve patient care and outcomes in children and adolescents with cancer, particularly those with hard-to-treat cancers.

Dr. Sinnett and colleagues assessed the feasibility of identifying potentially actionable mutations using NGS-based assays in a clinically relevant timeframe in their study of 84 children and adolescents with relapsed or refractory or hard-to-treat cancer.

Three-quarters of the patients had tissues suitable for molecular profiling. Of these 62 patients, 47 (76%) had drug-targetable alterations, 13 (21%) had alterations that modified the diagnosis or risk stratification, and 23 (37%) had alterations with a potential for disease monitoring.

Comprehensive genomic analysis detected at least one potentially actionable alteration in 54 patients (87%), including 47 patients with at least one mutation that could be targeted by a U.S. Food and Drug Administration-approved drug or a drug in clinical trial, and actions were taken for 22 of these patients.

The remaining patients were classified as being on treatment or in remission or having stable disease (18/54) or having no action taken for a variety of reasons (14/54).

About 10% of patients (6/59) had a tumor mutation burden higher than 5, which may gauge a response to immunotherapy agents, the researchers write in JAMA Network Open, online April 26.

The median time from NGS to data annotation was 24 calendar days (range, 4-41 days).

"A molecular strategy such as the one described in our paper is one of the ways to offer therapeutic options based on molecular anomalies," Dr. Sinnett said. "I think that in the near future, clinical trials will be based on molecular profiles rather than simply relying on the diagnostic (i.e., leukemia, sarcoma, etc.)."

"The application of precision medicine in the management of childhood and adolescent cancers is not a fiction; it is actually happening now," he said.

Dr. Carl Koschmann from Michigan Medicine, in Ann Arbor, who recently reviewed molecular profiling and targeted therapy in pediatric gliomas, told Reuters Health by email, "By incorporating whole-exome sequencing (WES) and RNA-seq, the authors present some of the highest rates of potentially actionable results (87%) and action taken (41%) in response to sequencing results."

"This article builds on recent pediatric sequencing studies which make an excellent case that clinically integrated sequencing should become standard of care for children with high-risk cancers," he said.

Dr. Jennifer A. Byrne from Children's Cancer Research Unit and The University of Sydney, in Westmead, Australia, who has also researched molecular profiling of childhood cancer, said, "Although potentially actionable mutations can be identified in many hard-to-treat pediatric cancer patients, not all patients are currently benefiting from molecular testing. Real-world issues, such as lack of access to drugs, lack of available clinical trials, and obtaining molecular results too late in the patient's clinical course, can get in the way of translating personalized medicine to pediatric cancer patients. Some of these issues could be overcome through broader implementation of molecular testing, which could also involve testing patients earlier."

"The article makes the point that the field needs information about what happens to patients whose treatments change in response to molecular profiling," she told Reuters Health by email. "Molecular profiling studies typically describe how many patients' therapies changed (or could have changed), but it is arguably more important to know what happens afterwards - i.e., do patients achieve lasting benefits, how often does this happen, and can these benefits be better predicted for individual patients."

"The study also calls for better agreed definitions of terms such as actionable variants, so that the results from different molecular profiling platforms can be meaningfully compared," Dr. Byrne said. "Given the cost and complexity of personalized cancer medicine, we need to find the best way to deliver this care, which can only happen if we can compare the results from different profiling approaches, in both the short and longer term."


JAMA Netw Open 2019.

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