Precision medicine advances pediatric brain tumor diagnosis and treatment
January 19, 2017
Note: This study was covered by Forbes,
MIT
Technology Review, Harvard
Gazette, Harvard
Medical School and United
Press International.
Largest study to date finds genomic sequencing and copy number analysis can provide vital information
(News release)
BOSTON – Precision medicine – in which diagnosis and treatments are keyed to the genetic
susceptibilities of individual cancers – has advanced to the point where it can
now impact the care of a majority of children with brain tumors, a new study by
investigators at Dana-Farber/Boston
Children’s Cancer and Blood Disorders Center suggests.
In the largest clinical study
to date of genetic abnormalities in pediatric
brain tumors, researchers performed clinical testing on more than 200 tumor
samples and found that a majority had genetic irregularities that could
influence how the disease was diagnosed and/or treated with approved drugs or
agents being evaluated in clinical trials. The findings, reported online today
by the journal Neuro-Oncology,
demonstrate that testing pediatric brain tumor tissue for genetic abnormalities
is clinically feasible and that in many cases the results can guide patients’
treatment.
The need for new approaches to
treating brain cancer in children is urgent, the study authors say. “Although
there has been a great deal of progress over the past 30 years in improving
survival rates for children with cancer, advances in pediatric brain cancer
haven’t been as dramatic,” says co-lead author Pratiti
Bandopadhayay, MBBS, PhD, of Dana-Farber/Boston Children’s. “In a recent
study, brain tumors accounted for 25 percent of all pediatric deaths attributed
to cancer. In addition, many of the current therapies can result in long-term
difficulties in cognitive or physical functioning.”
Since emerging from research
labs more than a decade ago, targeted therapies for cancer have significantly
improved the treatment of certain types of leukemia, digestive system tumors,
and breast cancer, among other malignancies. The new study is unique in that it
reports on the largest collection of pediatric brain tumors to be genetically
profiled as patients came to clinic. Pathologists and cytogeneticists performed
the testing in a federally approved clinical laboratory—certified under
Clinical Laboratory Improvement Amendments (CLIA) as the only type of labs in
the United States whose findings can guide patient treatment.
Dana-Farber/Boston Children’s, the researchers noted, is one of the few centers
in the country to regularly analyze the genetics of patients’ pediatric brain
tumors.
The researchers plumbed the
genomes of 203 pediatric brain tumor samples, representing all major subtypes
of the disease. They analyzed 117 of the samples with OncoPanel testing, a
technology that sequences the exomes – the sections of DNA that hold the
blueprints for making specific cell proteins --- for irregularities in
300 cancer-related genes. They also studied 146 samples tested with OncoCopy,
which examines how many copies of genes are missing or overabundant within the
tumor cells. Sixty samples underwent both forms of testing ,which allowed
researchers to explore whether combining the two tests was more powerful
than each alone.
Of the samples tested by
OncoPanel, 56 percent harbored genetic abnormalities that were clinically
relevant – that could impact a patient’s diagnosis or be targeted by drugs
already in clinical use or under study in clinical trials. (Many of these drugs
cross the blood-brain barrier, the dense web of cells that can prevent
medicines from exiting the bloodstream to reach the brain.) Among the findings:
- Alterations
were found in the gene BRAF,
one of the most commonly mutated genes in pediatric brain tumors, and one
for which several targeted drugs are being tested.
- The
two-pronged testing approach revealed clinically relevant abnormalities in
89 percent of medulloblastomas,
which account for nearly a fifth of all brain tumors in children.
Combining the two tests was found to be particularly useful for these
patients.
“The importance of genomic
profiling in the diagnosis and treatment of pediatric brain cancers is
reflected in the World Health Organization’s recent decision to classify such
tumors by the genetic alterations within them, rather than by broad tumor type”
says study co-senior author Susan
Chi, MD, of Dana-Farber/Boston Children’s. “Targeted therapies are likely
to be most effective when they’re matched to specific abnormalities within
tumor cells. Our findings show that precision medicine for pediatric brain
tumors can now be a reality.”
The co-lead authors, with
Bandopadhayay, of the study are: Shakti Ramkissoon of Dana-Farber Cancer
Institute and Brigham and Women’s Hospital, Jaeho Hwang, of Harvard Medical
School, and Lori Ramkissoon, PhD, of Dana-Farber. Co-senior authors, with Chi,
are Rameen Beroukhim, MD, PhD, of Dana-Farber, Brigham and Women’s, and the
Broad Institute of MIT and Harvard, and Keith Ligon, MD, PhD, of
Dana-Farber/Boston Children’s, Brigham and Women’s and the Broad Institute.
The co-authors are Hayley
Malkin, Mariella Filbin, MD, PhD, Ashley Plant, MD, Michael Chang, MD, MS,
Edward Yang, Karen Wright, MD, Peter Manley, MD, Sanda Alexandrescu, MD, Alanna
Church, Katherine Janeway, MD, Marian Harris, MD, and Mark Kieran, MD, PhD, of
Dana-Farber/Children’s; Liliana Goumnerova, MD, of Boston Children’s Hospital;
Noah Greenwald, Ryan O'Rourke, Nathan Pinches, Claire Sinai, Matthew Ducar, and
Charles Stiles, PhD, of Dana-Farber; Steven Schumacher, MS, of Dana-Farber and
the Broad Institute; Wenya Bi, MD, Laura MacConaill, PhD, Rebecca Folkerth,
Azra Ligon, PhD, and Sandro Santagata, MD, PhD, of Dana-Farber and Brigham and
Women’s; Hart Lidov, MD, Ivana Delalle, MD, PhD, Neal Lindeman, MD, and Adrian
Dubuc, PhD, of Brigham and Women’s.
Funding for the study was provided by: The PLGA
Foundation; A Kids’ Brain Tumor Cure Foundation: Stop and Shop Pediatric Brain
Tumor Program; the Path to Cure Foundation; St Baldrick’s Foundation; Team Jack
Foundation; the Pediatric Brain Tumor Foundation; the Andrysiak Fund for LGG;
Jared Branfman Sunflowers For Life Fund For Pediatric Brain And Spinal Cancer
Research; the Sontag Foundation ; the National Institutes of Health (grant
numbers P50CA165962, R01 CA188228, P01 CA142536, CA165962, and K08NS087118-03),
Ian’s Friends Foundation, Alex’s Lemonade Stand Foundation, the Gilmore Fund,
Cure ATRT Now, the Hamilton Low-Grade Glioma Fund, the Joe Andruzzi Fund, the
Itzkovitz Low-Grade Glioma Fund, the Olivia Caldwell Foundation, and Lauren’s
First and Goal Foundation.