Results from a molecular tumor profiling study in young patients revealed a high degree of genetic alterations potentially impacting clinical care, including clarifying diagnoses and treatment with matched, accurate cancer drugs.
Researchers at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center reported in Nature Medicine that molecular profiling of solid tumors found 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 the tumor’s DNA, could be used to choose a targeted, precision therapy to match those changes. Of these patients, 200 were eligible for matched drug therapy.
Targeted therapies were used to treat 29 patients, and 24% of patients responded to the targeted drugs or experienced sustained clinical benefit. In addition, the molecular profiling – done by a process called next-generation sequencing – clarified the diagnostic classification in 17 patients.
“By making a more accurate diagnosis or identifying a 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 the GAIN/iCat2, is being conducted at 12 centers in the United States to evaluate the clinical impact of genomic sequencing of solid pediatric tumors, which is performed much less frequently than in adult patients with solid tumors. In adults, tumor profiling is recommended in national practice guidelines as an aid to diagnosis and treatment. But there are no such guidelines or insurance coverage decisions for the use of tumor profiling in pediatric solid malignancies and few clinical studies of tumor profiling include young people with cancer.
Solid tumors in children are much rarer than in adults, and large studies of genetic changes are difficult to conduct. In fact, there were 59 different tumor types that affected the patients in this study, and some cancers are so rare that they affected only one patient. Pediatric tumors also have fewer gene mutations than those in adults, so there are fewer drug targets 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 instead of precision medication.
The current study is a prospective observational cohort study led by Janeway and Alanna J. Church, MD, associate director for Molecular Pediatric Pathology at Boston Children’s Hospital. Janeway has worked to provide personalized, molecularly targeted treatments for children with cancer. The results of Janeway’s first study, called Individualized Cancer Therapy (iCat), were published in 2016 and showed the feasibility of bringing clinical genomic sequencing into pediatric oncology practice. Janeway and colleagues are now conducting a follow-up study, the Genomic Assessment Improves Novel Therapy (GAIN) Consortium, iCat2 study.
The study participants were patients with relapsed/refractory or high-risk non-brain tumors aged 30 years or younger; the mean age at diagnosis was 12 years. Researchers performed next-generation targeted DNA sequencing with OncoPanel testing on one or more tumor samples from each patient, with some samples also subjected to RNA sequencing. Based on the analysis, a comprehensive report is made and sent to the referring physician. This allows the physician to develop a patient plan that takes into account the genetic changes detected in their tumors and associated with matched drugs that have shown success in the lab or in the clinic in treating patients with such tumors. The study follows each patient to determine the impact of the treatment plan on patient outcome. The primary aim of the study is to observe whether tumor profiling and matched targeted drug therapy affect overall survival.
Molecular Targeted Therapy (MTT) recommendations based on data from the previous iCat study were sent back to 240 of 345 patients whose tumors had at least one gene variant. Of these, 200 patients were eligible for assessment of reception and response to MTT, are alive and have full follow-up data. 96 of the patients would not have been expected to consider targeted therapy because they were receiving first-line therapy, had not received cancer-targeted systemic therapy during the follow-up period, or no matched targeted drugs were available.
Seven patients who received matched targeted therapy had measurably significant responses to the therapy. In six of those tumors, the therapies were linked to a gene fusion. Fusion genes are formed in a cell when a piece of one chromosome breaks off and attaches to another chromosome, causing broken segments of DNA to fuse together to form an entirely new gene. Some of these genes produce fusion proteins that can cause cells to grow uncontrollably and form tumors.
“Gene fusions are very important in pediatric tumors,” Church says. “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 solid tumors in children, covered by insurance – just as it is for adults.
“We know there are patients who are not allowed access to these tests because they are not consistently reimbursed,” Church says. “We want to broaden access to molecular profiling for any child with a solid tumor.”
This study was funded by: Precision For Kids Pan Mass Challenge Team; 4C’s Fund; Lam Family Fund; C&S Wholesalers and C&S Charities; and Alexandra Simpson Pediatric Research Fund.
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