Molecular tumor profiling beneficial in pediatric solid cancers
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Molecular profiling of solid tumors in children and young adults has a significant impact on diagnosis and treatment recommendations, according to results of an interim analysis presented during the virtual ASCO Annual Meeting.
“Molecular tumor profiling has made significant strides during the past decade and is now standard of care for many adult solid tumors. Although we are learning more each day about the pediatric cancer genome and targeted therapies, the significance of molecular tumor profiling for children with cancer is not well-understood,” Alanna J. Church, MD, associate director of the Laboratory for Molecular Pediatric Pathology and staff pathologist in the department of pathology at Boston Children’s Hospital, said during her presentation.
The prospective cohort GAIN/iCat2 consortium study evaluated the use of genomic profiling of solid tumors among 345 children and young adults (mean age at diagnosis, 11 years; 56% male; 71% white) with high-risk refractory or relapsed solid non-brain tumors (65% sarcoma) receiving treatment across 12 U.S. pediatric cancer centers.
Researchers performed targeted DNA next-generation sequencing on one or more tumor samples from each patient, with some samples subjected to RNA sequencing. They then used established guidelines to classify all identified genomic alterations according to impact on diagnosis, prognosis or response to targeted therapy matched to an identified alteration.
The study’s primary aim was to describe OS according to whether patients received matched targeted therapy identified by tumor profiling. Secondary and exploratory objectives included description of the frequency and range of molecular alterations and in-depth evaluation of extraordinary response to matched targeted therapy.
Results of the interim analysis showed 87% of patients had at least one genomic alteration of clinical significance. Among them, 60% had genomic alterations of diagnostic significance, 15% had alterations of prognostic significance and 70% had alterations of therapeutic significance; 11% of the latter group had Tier 1 molecular findings. Researchers noted that 78% of alterations deemed diagnostically significant were fusions.
In addition, 31 (15%) of the 205 patients deemed eligible to receive matched targeted therapy received such therapy. Among them, six had extraordinary responses to treatment, and all these responders had treatment matched to a gene fusion.
“These results emphasize the importance of fusion detection for patients with sarcomas and rare tumors,” Church said.
Perspective
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Lu Wang, MD, PhD
Targeted therapies hold great promise in treating cancers, but there is still a lot to learn for pediatric cancers, because much of the evaluation of targeted therapy has been in adult patients. In this study, Church and colleagues demonstrated the clinical significance of identifying genomic alterations by next-generation sequencing-based tests for young patients with extracranial solid tumors; in particular, their results emphasize the importance of fusion detection for patients with sarcomas and rare tumors.
The identification and successful targeting of oncogenic gene fusions is one of the most important breakthroughs in medical oncology during the past decade. For instance, advances in molecular technologies, especially the application of next-generation sequencing-based methods, have improved diagnosis and refined classification of pediatric soft tissue tumors based on characteristic gene fusions. Importantly, some tumor entities are characterized by recurrent gene fusions involving either growth factors, such as PDGFB, or protein kinases, such as ALK, ROS, NTRK and BRAF, which have paved the way for targeted treatments.
Results of this study by Church and colleagues highlighted the importance of comprehensive molecular tumor profiling, especially screening for oncogenic gene fusions, in extracranial solid tumors of young patients for molecular diagnosis and selection of both FDA-approved treatments and clinical trial participation with targeted therapeutics. Of note, RNA-based next-generation sequencing strategies are superior to traditional techniques and targeted DNA next-generation sequencing for the detection of complex and/or cryptic fusions or of those with unknown partners. Therefore, a reasonable approach in clinic may involve establishing rapid and comprehensive RNA-based next-generation sequencing testing to detect gene fusions associated with tumors.
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Church AJ, et al. Abstract 10005. Presented at: Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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