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Recurrent Brain Cancers Follow Distinctive Genetic Paths

UCSF Team Shows Commonly Used Brain Tumor Chemotherapy Agent May Propel Recurrent Tumors to Malignancy

By Pete Farley    |   UCSF.edu | December 17, 2013

Recurrent Brain Cancers Follow Distinctive Genetic Paths

Barry S. Taylor, PhD

Brain tumors known as low-grade gliomas can be treated with surgery, sometimes in combination with chemotherapy and/or radiation therapy, with some patients living for decades after treatment. But because these tumors infiltrate normal brain tissue, it is difficult to remove them completely, and more often than not, gliomas recur at the same site in the brain, in some cases many years after surgery.

Now, a team led by scientists from UC San Francisco has discovered that recurrent gliomas may have genetic profiles that are markedly different from those of the initial tumors that spawned them, and has shown that these differences are vastly amplified when a commonly used chemotherapy drug is employed to treat the initial tumors.

The new work, published online in Science Express on Dec. 12, may prompt a rethinking of targeted approaches to glioma treatment based on genetic profiling of tumors, and also argues for the judicious use of temozolomide (TMZ), the chemotherapy agent most often used in glioma cases, the team said. The findings on TMZ have prompted the launch of a clinical trial, expected to open at UCSF in early 2014, which will explore the use of a targeted drug to block TMZ’s deleterious effects.

In developing a plan for cancer therapy, the genetic characteristics of a patient’s tumor are increasingly used to customize treatment, but “if the tumor recurrence has a genetic pattern that differs in some way from the initial tumor, using only the initial tumor as a guide might be missing the mark,” said Joseph F. Costello, PhD, professor and Karen Osney Brownstein Endowed Chair of neurological surgery and co-senior author of the new research with Barry S. Taylor, PhD, assistant professor of epidemiology and biostatistics.

Joseph F. Costello, PhD

Genetic disparities in recurrent tumors may be of particular concern when glioma patients have been treated with TMZ, Costello said. In more than half of the TMZ-treated cases studied by the research team, the recurrence had taken an “alternative evolutionary path,” transforming from low-grade glioma to highly malignant glioblastoma. Some patients with a low-grade glioma can live for decades after treatment, but glioblastoma is almost always fatal, with a median survival of 12 to 15 months.

“The natural history of low-grade gliomas is that they will progress, and over enough time will progress to a higher grade,” said Susan Chang, MD, professor and Lai Wan Kan Endowed Chair of neurological surgery and director of UCSF’s Division of Neuro-oncology. “It’s a challenge dealing with these patients because it’s the nature of these tumors that they will recur.”

To better understand what genetic changes cause low-grade gliomas to undergo malignant transformation to glioblastoma, the team joined with colleagues at The University of Tokyo to collect paired tissue samples from initial and recurrent gliomas in 23 patients who had undergone a second surgery for the recurrent disease. Led by graduate students and co-first authors Brett E. Johnson and Tali Mazor, the group then performed genomic sequencing on each sample.

Previous research has shown that tumors continually evolve, accumulating additional mutations to adapt and thrive in changing physiological conditions. Normally this evolution is “clonal”: even if tumors metastasize and take up residence in another part of the body, they carry much of the genetic signature of the initial tumor.

But in the new study, the authors were surprised to find that, although the recurrent gliomas could be confidently related to the initial tumor with genetic tools, the newer tumors only shared about half of their mutations with the original glioma. “This is quite different than metastasis,” stressed Costello. “It is a local recurrence, typically within 2 centimeters of the site of the original tumor.”

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