A new comprehensive genomic profiling test may help lead to more individualized treatment for pediatric malignancies; it may be an important new tool for improving morbidity and mortality related to pediatric cancers, according to new data presented at the American Association for Cancer Research (AACR) Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery Into Improved Outcomes, held in early November. Researchers from Foundation Medicine in Cambridge, MA, reported that they could identify genomic alterations that indicate the potential for a targeted treatment option in 56% of pediatric patient samples by using a new genomic profile product called FoundationOne™.
FoundationOne is a next-generation sequencing-based genomic profiling test that provides comprehensive analysis of more than 200 genes known to be altered in human cancers. Researchers used the test to analyze 193 tumors from patients up to 21 years of age. The patients had a wide variety of tumor types, including sarcomas, solid tumors, and hematologic malignancies. The test detected 361 genomic alterations among the patient samples and 75% of the patients had at least one genomic alteration, with an average of 2.5 alterations per patient.
“We found that almost half the tumors were actionable and had genomic problems that could be treated,” said study investigator Matthew Hawryluk, PhD, who is with Foundation Medicine.
Dr. Hawryluk said that over the last 5 years there have been several new therapies approved for adult patients that target specific genomic alterations. However, he added, there is a significant lack of targeted therapies for pediatric cancers. “The pediatric malignancies are a small population, so it is taking longer for them to get attention,” Hawryluk told ChemotherapyAdvisor.com. “We don’t know how similar they are to solid tumors in adults. The colon and bone and some of the leukemias have a higher rate of genomic alterations than what we see in adults. In [the] liver, kidney and lung, there are less genomic alterations (in pediatric malignancies).”
Hawryluk and his colleagues presented new data on how well this new genomic profiling test performed in 17 patients with advanced high-risk neuroblastoma: they found actionable genomic alterations in 94% of cases.1 Their study suggests that it may be worthwhile to re-biopsy tumors from patients with progressive or recurrent high-risk neuroblastomas to identify avenues for treatment with targeted therapies.
Helping Predict Aggressive Cancers with a New Biomarker?
In children with central nervous system (CNS) cancers, the presence of a specific genetic modification (ie, hypermethylation of the telomerase reverse transcriptase [TERT] promoter) may help predict tumor progression and patient survival, according to a new Canadian study. TERT, a component of the enzyme telomerase, is a protein found at elevated levels in the majority of cancers. Even though this makes telomerase and its components potential biomarkers for cancer, there are currently no sensitive and specific methods of measuring levels of TERT or its components.
Study investigator Uri Tabori, MD, and his team at The Hospital for Sick Children in Toronto, Ontario, Canada, have found that a region of the DNA near the TERT gene was hypermethylated in malignant pediatric cancer tissues expressing TERT.2 Dr. Tabori and his team conducted whole-genome methylation arrays on 280 pediatric brain tumor tissue samples. The researchers included six normal brain tissue samples and used 219 tissue samples from multiple types of pediatric CNS cancers, including pediatric gliomas, ependymomas, choroid plexus tumors, medulloblastomas, and atypical teratoid-rhabdoid tumors, to help validate their findings.
The study results revealed that a specific region of the TERT gene was hypermethylated in 100% of the malignant tumor tissue samples expressing TERT. In addition, hypermethylation of this region of DNA, which the researchers termed the TERT hypermethylated oncological region (THOR), was able to distinguish malignant tumor tissue samples from normal tissue and low-grade tumor tissue samples with a sensitivity of 95%. In addition, THOR was hypermethylated in tumors that progressed from low grade to high grade.
“This biomarker will correlate with tumor aggressiveness. Currently, we are grading tumors, and the issue is that tumor grade is pathology-based and it is not [sufficient to determine how aggressive the disease is],” said Dr. Tabori in an interview with ChemotherapyAdvisor.com. “This new assay is easy to do in any clinical lab.”
Dr. Tabori indicated his team now hopes to test the new assay in common adult cancers such as gliomas, prostate cancers, and colon cancers. Among these tumor types, in particular, this assay may be highly beneficial in detecting which patients may need the most aggressive therapies.
Identifying Patients with Pediatric Osteosarcoma at Risk for Metastasis with a Genetic Variant
Another study presented at the AACR Special Conference on Pediatric Cancer suggested a new avenue for predicting aggressiveness in pediatric osteosarcoma. A genome-wide association study (GWAS) found that two specific variations of the nuclear factor I/B (NFIB) gene may be associated with a high risk for metastasis in children and adolescents with osteosarcoma. Researchers from the National Cancer Institute (NCI) presented new data identifying a novel locus associated with metastasis in this patient population.3
“We showed that osteosarcoma patients of European ancestry with specific inherited genetic variants in the nuclear factor I/B gene were 2.5 times more likely to have metastases at diagnosis,” said study investigator Lisa Mirabello, PhD, in an interview with ChemotherapyAdvisor.com. “Osteosarcoma is the most common malignant bone tumor in children and adolescents, and the vast majority of patient deaths occur as a result of metastasis. If these results are validated in other populations, such genetic markers may one day serve as a tool to help clinicians identify patients with metastasis or possibly those at risk of metastasis.”
Dr. Mirabello, who is with the Division of Cancer Epidemiology and Genetics at the National Cancer Institute in Bethesda, MD, said the identification of a genetic prognostic marker could potentially improve patient management. In addition, a better understanding of the mechanism through which NFIB confers risk of metastasis, Dr. Mirabello described, could lead to the development of specific treatment strategies for these patients.
Mirabello and her colleagues conducted a clinical-outcome GWAS analysis of 550 patients of European ancestry out of the 1,128 patients from whom the researchers obtained DNA. The researchers had complete clinical outcome data on all the patients and 23.3% had metastatic disease at the time of diagnosis. Mirabello said NFIB is known to be an important regulator in both lung and brain development, but it also appears to be involved in the development and progression of several tumor types. In this current study, two linked intronic single nucleotide polymorphisms in the NFIB were significantly associated with an increased risk of metastasis (odds ratio [OR], 2.52; 95% CI: 1.76-3.60; P = 7.6×10-7 and OR, 2.54; 95% CI: 1.75-3.69; P = 1.84×10-6).3
Although the field of oncology is now in a new genomics era, Mirabello said, in terms of pediatric malignancies, it is just the beginning of individualized targeted therapy.
Dr. Tabori expects significant improvements in the management of pediatric cancers in the not too distant future, but he cautioned that we are not there yet. “We have acquired a great deal of knowledge in the last 5 years and it is a very exciting time for doctors and patients,” said Dr. Tabori. “We are in a new era, but we also still have a long way to go.”
Ali SM, Hawryluk MJ, Wang K, et al. Clinical next generation sequencing (NGS) reveals genomic alterations (GAs) to guide targeted therapy in advanced neuroblastoma patients. Presented at the American Association for Cancer Research (AACR) Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery Into Improved Outcomes; November 3-6, 2013; San Diego, CA. Abstract A23.
Castelo-Branco P, Choufani S, Mack S, et al. hTERT promoter hypermethylation is a cancer signature which predicts survival and response to targeted therapy in pediatric nervous system tumors. Presented at the American Association for Cancer Research (AACR) special conference on Pediatric Cancer at the Crossroads: Translating Discovery Into Improved Outcomes; November 3-6, 2013; San Diego, CA. Abstract A20.
Mirabello L, Wang Z, Gastier-Foster JM, et al. A genome-wide scan identifies a novel locus associated with metastasis in osteosarcoma patients. Presented at the American Association for Cancer Research (AACR) Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery Into Improved Outcomes; November 3-6, 2013; San Diego, CA. Abstract A7.