Why did Carter and McCain have such different brain tumor results?

Sen. John McCain, R-Ariz., announced Friday he would seek no further treatment for an aggressive brain cancer he's been fighting since last summer.

San Diego Union-Tribune

Aug. 26, 2018 12:25 PM PT

In recent years deadly brain tumors have challenged both Jimmy Carter and John McCain, but the two political icons have had vastly different treatment results.

The Arizona senator died Saturday after a year in treatment while the former president was declared cancer-free just four months after he started therapy in 2015.

How could these two men with household names have such opposite outcomes?

The answer, said Dr. Ezra Cohen, associate director of Moores Cancer Center at UC San Diego, has to do with the specific physical and genetic characteristics involved.

Carter’s brain tumor was caused by metastatic melanoma which started in a distant part of the 39th president’s body and traveled to his brain. McCain’s tumor was a malignancy called a glioblastoma, the most common kind of malignant brain tumor.

For most of human history, both metastatic melanoma and glioblastoma had similarly dire prognoses. Most patients didn’t live more than a few years after diagnosis.

But the advent of immunotherapy drugs has dramatically changed the survival odds for melanoma.

“Metastatic melanoma, due to immunotherapy, is now on the complete other end of the spectrum from glioblastoma,” Cohen said. “We’re now seeing melanoma patients who are nearly a decade from treatment and are still showing no signs of recurrence. We’re beginning to think that these patients are cured.”

Not so for glioblastoma. Survival after diagnosis continues to range from one to two years.

Why hasn’t glioblastoma seen the same kind of progress?

Cohen said it all comes down to mutation.

Melanoma, Cohen noted, has a highly-mutated form of cancer which has made it one of the toughest forms of to treat once it spreads from its initial location. But having a high mutation rate also makes it more likely that melanoma cells will be detected and responded to by the body’s immune system. Mutation just makes it more likely that there will be all sorts of abnormal features on the outside of melanoma cells that the body’s immune system will recognize as foreign and attack.

New “checkpoint” immunotherapies such as Keytruda, the drug that produced president Carter’s miraculous recovery, rev up the response of immune systems of patients that cancer cells have tricked into semi-dormancy.

But other forms of cancer such as glioblastoma have fewer mutations, and fewer abnormal features that set off immune system alarms. Revving up the immune system, Cohen noted, doesn’t do much good if it has not adequately detected the cancer in the first place.

“Glioblastoma has 100-fold less mutation than melanoma does, and that makes it a poorer target for these drugs,” Cohen said.

Though the checkpoint inhibitors that are getting dramatic results in many forms of cancer have significantly less effect for glioblastoma, some think they may actually be capable of some change. Though initial trials have shown poor results, some researchers have speculated that what looks like continued growth after immunotherapy treatment may actually be the inflammation that indicates a strong immune response.

A large trial is currently underway to determine the exact effect of checkpoint inhibitors on glioblastoma while other smaller trials are attempting to target these tumors based on other unique characteristics they possess.

Sharp HealthCare’s Laurel Amtower Cancer Institute is one of 215 organizations worldwide enrolling patients in a trial that uses a special type of receptor that pops up on about half of glioblastoma cells to target a cancer-killing drug. Early-phase trials are also starting to show tantalizing results using cancer-killing viruses and vaccines.

Dr. Charles Redfern of the Amtower Institute said it has been difficult seeing some patients benefit while others continue to suffer. But he noted that, with melanoma, there were many years of small advances before the sudden sea change brought by the latest crop of drugs.

“I have a patient like Jimmy Carter where his disease has pretty much gone into remission. We would love to that that same kind of result in glioblastoma,” Redfern said.