From OncoLog, May 2014, Vol. 59,
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.
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
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
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
“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.
information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.
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