Brain Tumor Tests Offer Better Diagnoses and More Precise Treatments

Kelly Brown was 57 when she started complaining of frequent headaches. "It must be a sinus infection," her son, Connor Ferris, recalled her saying. But a family vacation in Italy prompted him to suspect a more sinister cause. "She wasn't her usual go-go-go self," he said of his mother, a flight attendant, former nurse and single mom to three young adults. "My mother was an intrepid traveler, but on this trip, she was constantly tired and preferred to stay at the hotel. At a restaurant, she fell asleep – that wasn't my mom."

Back home in Lake Tahoe, Nevada, Brown sought medical advice. An MRI revealed glioblastoma, the most common and deadly brain tumor, with an average survival of just 15 months. Treatment involved removing as much of the tumor as safely possible, followed by radiation and chemotherapy, with the tumor expected to recur months later.

There were closer hospitals, but Brown opted for treatment at UCSF Medical Center, ranked No. 2 in the nation for neurology and neurosurgery by U.S. News and World Report's Best Hospitals survey and the site of more than 25 state-of-the-art research laboratories dedicated to developing new treatments for brain tumors.

A new diagnosis and a clinical trial

After her initial treatment, Brown did surprisingly well. It wasn't until four years later that her tumor recurred. By then, the UCSF Brain Tumor Center had developed two new tools to provide a more precise diagnosis than the standard scans and examination of cells under a microscope. Both of these molecular tools are now available to all UCSF patients who may have a malignant brain tumor.

The first, UCSF500, is a test assessing 500 cancer-associated genes that might be mutated in the patient's tumor tissue. These include mutations that can be attacked with targeted therapies that have already been approved by the Food and Drug Administration (FDA) or are being tested in clinical trials, said Dr. David A. Solomon, a molecular neuropathologist and principal investigator at the UCSF Brain Tumor Center.

The second tool, known as DNA methylation profiling, evaluates so-called "methyl marks" on the DNA within cancer cells that regulate activity of the genes involved in cancer growth. The pattern of these methyl marks across the genome provides Solomon with critical clues about where the cancer originated, the genes that fuel growth and its potential to spread. The test also offers additional information that allows doctors to reach the most precise diagnosis and gain additional insights into personalized treatment. Research shows that this tool is the most accurate method for brain tumor classification and can change the pathologist's diagnosis in as many as 1 in 8 cases.

For Brown, these molecular tests – which used tissue extracted during surgery after her cancer recurred – revealed that the tumor was not glioblastoma after all but a different type with a better prognosis. Better yet, Brown's tumor matched with a targeted therapy being tested in a clinical trial, in which she would eventually enroll.

Eureka moments change course of therapy

"Offering patients like Kelly these two complementary precision medicine tools enables us to ensure an accurate diagnosis and tailor therapy to each patient's tumor type and unique molecular profile," said Solomon, whose work has been supported by the UCSF Glioblastoma Precision Medicine Program, Panettoni Family Foundation and other generous sources. "We can then start them on a targeted therapy as early as possible in the disease course, when it is most likely to be effective."

Solomon's molecular detective work has resulted in many eureka moments, such as a child whose adjusted diagnosis meant they were spared brain radiation, which can cause developmental delays and raise the risk of treatment-associated cancers decades later. Then there was the teen with apparent cancer of the nasal cavity that turned out to be a noncancerous issue.

Solomon's big reveals don't always mean good news. A 2022 study, in which Solomon was the senior author, identified patients whose tumors had appeared to be lower grade under a microscope but were found to be glioblastoma through genomic testing.

"While this may not have been welcome news, these patients received more appropriate treatment and survived longer," Solomon said, noting that they lived another 24 months on average, versus 16 months for those treated less aggressively.

In a 2023 study, Solomon and his colleagues identified patients with a subtype of glioblastoma who shared a mutation that triggers a response to immunotherapy. These patients lived 37 months on average, versus 16 months for those with typical glioblastoma lacking the mutation.

#Blessed and #Grateful

Back in Tahoe, Brown passed away days after her 65th birthday, outliving her initial prognosis by several years. While her illness affected her mobility and caused mild cognitive deficits, she was able to celebrate a 40-year flight attendants' reunion in New York; the birth of her first grandchild; and, months before she passed, Ferris' engagement to his girlfriend, Hailey.

If Brown was depressed and anxious, she didn't show it, her son reflected. "She was someone who liked to take care of others and truly believed she was fortunate," he said, recalling her "#blessed" and "#grateful" hashtags.

Ferris remembered accompanying his mother to the operating room before her first tumor surgery. Exiting the area, his heart heavy with the gravity of the occasion, he overheard her chatting to a clinician: "Hi sweetie, how are you doing?" she said, as if her own well-being was less critical. "That was absolutely my mom," he said. "She always wanted other people to feel comfortable."

Solomon said he feels gratified that his steady sleuthing may have prolonged Brown's life. "UCSF patients who present today are getting the most accurate and genomically tailored precision medicine available," he said. "But we are not taking a pause. We're looking ahead at new techniques that may improve both survival and quality of life for existing patients and the patients of tomorrow."

Photo courtesy of Casey Simon Photography