Study shows genomic profiling of pediatric tumors can improve clinical care

Results of a molecular profiling study of tumors in young patients revealed a high rate of genetic alterations that may impact clinical care, including clarifying diagnoses and treating with precision cancer drugs adapted.

Reporting in Nature Medicine, researchers from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center said molecular profiling of solid tumors revealed clinically significant genetic variations in 298, or 86% of 345 pediatric patients. In 240 patients, the genetic “fingerprint” or pattern of cancer-related changes in tumor DNA could be used to choose a targeted precision therapy tailored to these alterations. Of these patients, 200 were eligible for appropriate pharmacotherapy.

Targeted therapies were used to treat 29 patients, and 24% of patients responded to targeted drugs or experienced lasting clinical benefit. Additionally, molecular profiling – performed by a process called next-generation sequencing – clarified the diagnostic classification in 17 patients.

“By providing a more accurate diagnosis or identifying targeted therapy, molecular tumor profiling has a significant impact on the care we provide. The result is a cancer treatment that is more effective and, in some cases, has fewer side effects,” said Katherine A. Janeway, MD, MMSc, ​​senior physician, Dana-Farber/Boston Children’s Cancer and Blood. Disorders; Center Director, Clinical Genomics, Dana-Farber Cancer Institute and Associate Professor of Pediatrics, Harvard Medical School.

The ongoing study, known as GAIN/iCat2, is being conducted at 12 centers in the United States to assess the clinical impact of genomic sequencing of pediatric solid tumors, which is performed far less than in adult patients with solid tumors. In adults, tumor profiling is recommended in national practice guidelines as an aid in diagnosis and treatment. But there are no such guidelines or insurance coverage rulings for the use of tumor profiling in pediatric solid malignancies, and few tumor profiling clinical trials include young people with cancer.

Pediatric solid tumors are much rarer than in adults, and large studies of genetic alterations are difficult to perform. In fact, there were 59 different types of tumors affecting the patients in this study and some of the cancers are so rare that they only affected one patient. Pediatric tumors also tend to have fewer genetic mutations than those in adults, so there are fewer targets for drugs to attack — and fewer drugs available to target them. The net result is that most solid tumors in children are treated with standard chemotherapy or radiation therapy rather than precision drug agents.

The current study is a prospective observational cohort study led by Janeway and Alanna J. Church, MD, associate director of pediatric molecular pathology at Boston Children’s Hospital. Janeway has worked to bring personalized, molecularly targeted treatments to children with cancer. The results of Janeway’s first study, Individualized Cancer Therapy (iCat), were published in 2016 and showed that it was possible to integrate clinical genomic sequencing into pediatric oncology practice. Janeway and her colleagues are currently conducting a follow-up study, the Genomic Evaluation Consortium Improves Novel Therapy (GAIN), iCat2 study.

Study participants were patients with relapsed/refractory or high-risk non-brain tumors at age 30 or younger; the mean age at diagnosis was 12 years. Researchers performed targeted next-generation DNA sequencing with OncoPanel assays on one or more tumor samples from each patient, with some samples also undergoing RNA sequencing. Based on the analysis, a comprehensive report is created and sent to the attending physician. This allows the doctor to develop a plan for the patient that takes into account the genetic changes detected in their tumors that are associated with matched drugs that have shown laboratory or clinical success in treating patients with such tumors. The study follows each patient to determine the impact of the treatment plan on patient outcomes. The main objective of the study is to observe whether tumor profiling and corresponding targeted drug therapy affect overall survival.

Recommendations for molecular targeted therapy (MTT) based on data from the previous iCat study were returned to 240 of 345 patients whose tumors had at least one genetic variant. Of these, 200 patients were eligible for assessment of MTT receipt and response, being alive and having complete follow-up data. Ninety-six of the patients should not have considered targeted therapy because they were receiving first-line therapy, had not received systemic cancer therapy during the follow-up period, or no matching targeted drug was not available.

Seven patients who received matched targeted therapy had significant measurable responses to therapy. In six of these tumours, the therapies corresponded to a gene fusion. Fusion genes form in a cell when a piece of a chromosome breaks off and attaches to another chromosome, causing broken DNA segments to fuse together to form an entirely new gene. Some of these genes produce fusion proteins that can lead to uncontrollable cell growth and tumor formation.

“Gene fusions are very important in pediatric tumors,” says Church. “It’s an exciting time because there are so many new drugs that can target these fusions and we have new tests that can reliably detect them.”

Church and Janeway hope their work will help make genomic profiling the standard of care for new or recurrent, insurance-reimbursable pediatric solid tumors — just as it does for adults.

“We know there are patients who don’t have access to these tests because they’re not being reimbursed consistently,” Church says. “We want to expand access to molecular profiling for every child with a solid tumor.”

This study was funded by: Precision For Kids Pan Mass Challenge Team; 4C Fund; Lamb Family Fund; C&S Wholesale Grocers and C&S Charities; and Alexandra Simpson Pediatric Research Fund.

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