Analysis Suggests Need to Revise Low-Grade Glioma Classification, Treatment
A comprehensive genomic and molecular analysis has shown that some low-grade gliomas have the molecular hallmarks of glioblastoma multiforme, the deadliest of brain tumors.
“The immediate clinical implication is that a group of patients with tumors previously categorized as low-grade should actually be treated as glioblastoma patients and receive that standard of care—temozolomide chemotherapy and radiation,” said Roeland Verhaak, Ph.D., an assistant professor in the Department of Bioinformatics and Computational Biology at The University of Texas MD Anderson Cancer Center and the lead author of the study’s report.
Using advanced platforms from The Cancer Genome Atlas, the researchers first analyzed 293 low-grade gliomas to group them by their gene expression, protein expression, microRNA expression, DNA methylation, and gene copy profiles. They then performed a second analysis to identify superclusters of tumors with similar combined profiles.
“The results overwhelmingly point to a natural grouping of low-grade gliomas into three superclusters based on the mutational status of the IDH1 and IDH2 genes and co-deletion of chromosome arms 1p and 19q,” Dr. Verhaak said.
The researchers defined the three groups as tumors with 1) wild-type IDH1 and IDH2 (a glioblastoma-like phenotype), 2) IDH1 or IDH2 mutations and intact 1p and 19q chromosome arms, or 3) IDH1 or IDH2 mutations and codeletion of chromosome arms 1p and 19q. The median patient survival durations for the groups were 18 months, 7 years, and 8 years, respectively.
“Classifying low-grade tumors in these three molecular clusters more accurately characterizes them than current methods used to group and grade tumors,” Dr. Verhaak said.
Because the molecular markers that define the three tumor clusters are already assessed as part of patients’ workup, the new categories can be implemented relatively quickly.
The researchers reported their findings at the American Association for Cancer Research Annual Meeting in April.
Combination of Antiangiogenic Drugs Shows Activity Against Solid Tumors
The combination of two antiangiogenic agents, bevacizumab and cediranib, has demonstrated activity against several types of solid tumors.
Bevacizumab, which targets vascular endothelial growth factor (VEGF), is active against several types of cancer but typically does not produce lasting responses because drug resistance develops. Combinations of drugs that target the VEGF pathway in different places might produce more robust or more durable responses.
The combination of bevacizumab and cediranib, an investigational VEGF receptor tyrosine kinase inhibitor, was tested in a phase I clinical trial led by David Hong, M.D., an associate professor in the Department of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.
The study enrolled patients who had advanced-stage solid tumors that were refractory to treatment or had no standard treatment. The patients received intravenous bevacizumab on days 1 and 15 and oral cediranib on days 1–21 of each 28-day cycle. The bevacizumab doses escalated from 3 mg/kg to 5 mg/kg and 10 mg/kg as more patients entered the trial; the cediranib doses escalated from 15 mg to 20 mg, 30 mg, and 45 mg.
The goals of the study were to determine the safety of the drug combination and to determine the doses that should be used in future studies. Treatment response was also evaluated.
Fifty-one patients were enrolled in the study: 17 with soft tissue sarcomas, 7 with renal cell cancers, 6 with colorectal cancers, and 21 with other cancers.
Nineteen patients, including 9 with soft tissue sarcoma, had stable disease and were still receiving therapy at 16 weeks. In addition, tumor regression exceeding 30% occurred in 4 patients (1 each with triple-negative breast cancer, basal cell carcinoma, alveolar soft part sarcoma, and synovial sarcoma), and tumor regression between 20% and 30% was seen in 4 patients (2 with renal cell cancer and 1 each with prostate cancer and alveolar soft part sarcoma).
The dose-limiting toxic effects (adverse events of grade 3 or higher) observed were chest pain in 1 patient, fatigue in 1 patient, thrombocytopenia in 2 patients, hypertension in 3 patients (including 1 with intracranial hemorrhage), and hemoptysis in 1 patient.
The recommended doses for future studies were 20 mg of cediranib daily and 5 mg/kg of bevacizumab; only one dose-limiting toxic effect occurred at this dose level.
The study’s report was published in April (online ahead of print) in the journal Cancer. Dr. Hong and his coauthors recommended that future studies of the drug combination focus on patients with sarcoma.
Computed Tomography Predicts Chemotherapy Response in Pancreatic Cancer
Routine computed tomography (CT) scans of pancreatic tumors may not only guide treatment but also predict how well chemotherapy will penetrate the tumor.
The first clinical study to investigate the penetration of chemotherapy into pancreatic tumors was recently conducted at The University of Texas MD Anderson Cancer Center. Pancreatic tumors contain disorganized or nonfunctional blood vessels, high proportions of fibrotic tissue, and molecular variations that impede the transport of chemotherapy drugs from the blood vessels into tumor cells.
“We found that the distribution of intravenous dye used in CT scans is a surrogate for chemotherapy delivery in the tumor,” said Jason Fleming, M.D., a professor in the Department of Surgical Oncology and the corresponding author of the study’s report.
The researchers first enrolled 12 patients with primary pancreatic cancer who would undergo a surgical resection. During surgery, each patient received an infusion of the chemotherapy drug gemcitabine. After surgery, DNA from throughout the tumor was analyzed for gemcitabine incorporation.
Dr. Fleming and his colleagues found that gemcitabine penetrated the tumors to varying degrees and that tumors whose DNA had higher levels of gemcitabine incorporation also had higher levels of human equilibrative nucleoside transporter (hENT1) and lower levels of collagen. High hENT1 levels and low collagen levels both are known to correlate with good outcomes from gemcitabine treatment in patients with pancreatic cancer.
Dr. Fleming and his colleagues also noticed differences in the absorption of the CT contrast agent among the tumors and hypothesized that the uptake of contrast material could predict the path and absorption of gemcitabine. To test this hypothesis, the researchers analyzed pretreatment CT scans from 11 patients in the clinical study, 110 pancreatic cancer patients who had received gemcitabine before surgical resection, and 55 patients who had not received chemotherapy before their pancreatic tumors were resected. By employing mathematical models to measure transport factors in resected tumors, the researchers found that the pattern of CT contrast agent uptake was associated with gemcitabine incorporation, tumor response to therapy, and overall survival.
“The implication is that molecular information from a biopsy of the tumor can be combined with data from a standard CT study to place patients into categories that predict the way an individual tumor will respond to therapy,” Dr. Fleming said.
The study’s report was published in the Journal of Clinical Investigation in April. Dr. Fleming said future studies will focus on the application of this new knowledge to patient care and improving the delivery of chemotherapy to pancreatic tumors.
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Other articles in OncoLog, May 2014 issue: