Genetic testing at UPMC pinpoints mutations to match patients, therapies |

Genetic testing at UPMC pinpoints mutations to match patients, therapies

Wesley Venteicher
Stephanie Strasburg | Tribune-Review
Dr. Marina Nikiforova has developed a test that identifies several of the gene mutations that cause brain cancer. She sits for a portrait with a DNA model in her Oakland office at UPMC's Clinical Laboratory Building on Thursday, Feb. 4, 2016.
James Knox | Tribune-Review
Chris Keim (far left) talks with his oncologist Dr. Jan Drappatz (right) and neurosurgeon Dr. Nduka Amankulor (center) Friday Feb. 5, 2016 at the Hillman Cancer Center in Shady Side. Keim, 51 is a Fox Chapel resident, who was diagnosed with a dangerous brain cancer a year ago. His treatment has been aided by a new genetic sequencing tool developed at UPMC that targets molecular mutations that are at the root of cancer.
James Knox | Tribune-Review
Chris Keim gets good news from his brain scans with his oncologist Dr. Jan Drappatz (right) Friday Feb. 5, 2016 at the Hillman Cancer Center in Shady Side. Keim, 51 is a Fox Chapel resident, who was diagnosed with a dangerous brain cancer a year ago. His treatment has been aided by a new genetic sequencing tool developed at UPMC that targets molecular mutations that are at the root of cancer.
Stephanie Strasburg | Tribune-Review
Dr. Marina Nikiforova, left, watches Melissa Melan, 57, of Ross, work prepping samples for next generation sequencing at UPMC's Clinical Laboratory Building on Thursday, Feb. 4, 2016 in Oakland. Dr. Nikiforova developed a test to identify different gene mutations that cause brain cancer, allowing for doctors to use different treatments that are more likely to work better for different gene mutations.
Stephanie Strasburg | Tribune-Review
Wayne Ernst of Ross prepares DNA and RNA samples for sequencing at UPMC's Clinical Laboratory Building on Thursday, Feb. 4, 2016 in Oakland. Ernst is part of Dr. Marina Nikiforova's team working on testing gene mutations that cause brain cancer.

Chris Keim's words seemed to bounce off the walls of his Fox Chapel home when he stepped inside 13 months ago. His ears amplified and distorted household sounds as he called out to his wife. He feared he might be having a stroke.

“I didn't know what it was, but I just knew that something was wrong,” said Keim, 51.

His wife called 911.

An MRI later that day revealed a nickel-sized tumor in supportive brain tissue above Keim's right ear. A UPMC Presbyterian surgeon removed the growth, a cancerous tumor known as a glioblastoma.

Doctors sent tissue from the tumor to a UPMC lab, where a new test called GlioSeq fingerprinted the genetic mutations driving the tumor's growth. The test found an aggressive mutation, but delivered some hope: A vaccine had been developed to help fight that mutation.

Doctors say GlioSeq, developed by UPMC pathologist Dr. Marina Nikiforova, is helping advance treatment by tailoring it to individual tumors, which take more than 100 forms and most often are fatal.

Before Keim's tumor appeared, he was a vice president at the Bank of New York Mellon in the technology sector. He has a daughter and stepdaughter in college and a son who is a high school senior. His wife, Melissa Murphy, describes him as constantly busy, always engaged in some task.

The MRI found the tumor on Christmas Eve of 2014. His parents and three brothers traveled Christmas Day to be with him, and the surgery took place early in the morning the day after Christmas. The tumor had grown in a part of his brain that is associated with seizures, and after the surgery, his body shook in increasingly frequent convulsions.

On Jan. 7, doctors induced a coma and removed part of his brain to stop the seizures. He remained unconscious for nearly two weeks before his body began to awaken. He could wiggle his fingers and stick out his tongue. With a little instruction he could kiss visitors, said his wife. But he could not lift his head.

An athletic man who had run 11 marathons, played hockey and coached his son's hockey team, Keim learned to stand, then to balance on one foot, then to walk and speak.

“I still don't have my strength back,” he said this month. “I at least can walk without any assistance, and I can jog.”

Benefits of tumor typing

GlioSeq discovered in Keim's tumor a mutation known as EGFRvIII, which is present in about 30 percent of glioblastoma patients. His neuro-oncologist, Dr. Jan Drappatz, prescribed the standard regimen of chemotherapy and radiation along with a vaccine called rindopepimut, which in early clinical trials appears to have increased survival in some people with the EGFRvIII mutation.

Drappatz, of UPMC CancerCenter, is cautious when discussing Keim's recovery. Although rindopepimut might help Keim's immune system fight the EGFRvIII mutation, other genes in his brain have mutated in other ways, and glioblastomas tend to adapt.

It is not possible to say conclusively that Keim recovered better with the monthly vaccine than he would have with just the biweekly chemotherapy and radiation, Drappatz said.

“We're hopeful that it benefited him, but we don't know,” he said.

Median survival for glioblastoma patients — the point at which an equal number of patients live longer and an equal number live for less time — is 16 to 19 months with treatment. About 10 percent of glioblastoma patients live more than five years, and research shows survival rates vary widely according to the underlying genetic profile.

Targeted therapies show promise, but few are yet available, said Dr. Keith Ligon, an executive committee member of the Society for Neuro-Oncology.

“It's been much more challenging than people would have thought,” Ligon said. “Things that have worked in other cancers have not worked in gliomas.”

Sequencing panels like GlioSeq help match patients with targeted drugs in clinical trials. Patients can get drugs through off-label uses or, in Keim's case, under the FDA's “compassionate use” program, which makes new drugs available to patients who don't qualify for clinical trials.

Doctors increasingly are finding mutations in the brain that are associated with cancer in other organs. Nikiforova recently tested a brain tumor that had mutations associated with bladder cancer, opening up the possibility of off-label treatment with a bladder cancer drug.

In addition to pairing patients with targeted therapies, doctors said genetic tests help make decisions about when and how aggressively to apply chemotherapy and radiation. Tumor diagnosis starts with pathologists examining tissue samples under microscopes, assessing the number and character of cells to classify them and estimate how quickly they will grow. But sometimes tumors that look the same in the early stages develop in unexpected ways — which is problematic if what appears to be a low-grade tumor develops more quickly than expected.

Using genetic testing, doctors have pinpointed mutations that more accurately predict a tumor's development.

“Before, we were treating patients blindly. … Now it's like an eye-opener,” Nikiforova said. “We understand this tumor will not respond to this drug; it may respond to another.”

Nikiforova's panel tests for 30 brain tumor mutations by bundling individual tests. She said it is cheaper, more efficient and requires smaller tissue samples than the individual tests. She published a paper in December in the journal Neuro-Oncology showing the panel is just as accurate as the individual tests.

UPMC sequences the genes of every brain tumor patient, returning results in about two weeks, she said.

Work at other centers

Since the paper's publication, Nikiforova said she has been getting calls from doctors interested in using the panel at other medical centers.

The panel caught the attention of pathologists at Cleveland Clinic because of its efficiency and accuracy, said Dr. Jeremy Rich, chairman of the Department of Stem Cell Biology and Regenerative Medicine at the Clinic's Lerner Research Institute.

Cleveland Clinic runs genetic tests for most brain cancer patients and is moving toward broader use, Rich said.

The Dana-Farber Cancer Institute in Boston uses a similar panel that scans for about 300 mutations known to be associated with cancer, said Ligon, who is a pathologist there. Doctors at Farber use an even broader test that scans the whole genome for abnormalities, which he said could be referenced later in patients who develop problems doctors don't yet know about.

Doctors still face challenges of what to do with the information obtained in laboratories, especially if there are no treatments for the mutations the tests find, Rich said.

“The frustrating thing is that we can recognize the train's out of control, there's a runaway train, and we don't have many tools to stop it,” he said.

Nonetheless, he believes the genetic tests are driving treatment forward.

“The goal is to understand the natural history of this tumor, to give the patient the best shot, and eventually when there are targeted therapies for some of these, we'll know exactly which patients to use it on,” he said.

Staying positive

Keim's tumor has regrown since the first surgery, requiring more surgery and radiation to shrink it.

He can't read and can barely type a text without extreme head pain, he said. Even watching TV for more than a few minutes hurts, he said. He likes to cook, eat at restaurants and visit friends, said Murphy, his wife. Family members, friends, former co-workers and members of his hockey team visit constantly, she said.

“You have to maintain a positive attitude,” Keim said. “And I say that so easily. But there have been so many nights when Melissa and I have been together, or my father, or just to be alone, fighting to stay positive.”

He launched a nonprofit foundation, the United Initiative to Cure Brain Cancer, to raise money for research and to create something positive from what has happened to him. The idea came after his friends, family and acquaintances pledged $40,000 for brain cancer research in a May walk, Murphy said.

In the days leading up to a Feb. 5 doctor's appointment where he would view the latest MRI of his brain, Keim said he experienced once again what he has come to call “scan anxiety.”

He gathered with his wife; his father, Peter; and his medical team in front of the black-and-white MRI screen in a room at Hillman Cancer Center.

“The MRI looked great,” Drappatz said. “There's been substantial shrinkage.”

Chemotherapy was scheduled for the rest of the day. He'll continue chemo and bimonthly MRIs.

“I have brain cancer, and unfortunately, it's not in remission,” Keim said. “I'll be fighting it for the rest of my life.”

Wes Venteicher is a Tribune-Review staff writer. Reach him at 412-380-5676 or [email protected].

TribLIVE commenting policy

You are solely responsible for your comments and by using you agree to our Terms of Service.

We moderate comments. Our goal is to provide substantive commentary for a general readership. By screening submissions, we provide a space where readers can share intelligent and informed commentary that enhances the quality of our news and information.

While most comments will be posted if they are on-topic and not abusive, moderating decisions are subjective. We will make them as carefully and consistently as we can. Because of the volume of reader comments, we cannot review individual moderation decisions with readers.

We value thoughtful comments representing a range of views that make their point quickly and politely. We make an effort to protect discussions from repeated comments either by the same reader or different readers

We follow the same standards for taste as the daily newspaper. A few things we won't tolerate: personal attacks, obscenity, vulgarity, profanity (including expletives and letters followed by dashes), commercial promotion, impersonations, incoherence, proselytizing and SHOUTING. Don't include URLs to Web sites.

We do not edit comments. They are either approved or deleted. We reserve the right to edit a comment that is quoted or excerpted in an article. In this case, we may fix spelling and punctuation.

We welcome strong opinions and criticism of our work, but we don't want comments to become bogged down with discussions of our policies and we will moderate accordingly.

We appreciate it when readers and people quoted in articles or blog posts point out errors of fact or emphasis and will investigate all assertions. But these suggestions should be sent via e-mail. To avoid distracting other readers, we won't publish comments that suggest a correction. Instead, corrections will be made in a blog post or in an article.