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Why are men more likely to die of glioblastoma? This study helps explain

Brain tumors are different in males and females at a basic cellular level, the researchers found.

Men are more likely to die of brain cancer than women and a new study helps explain why. Glioblastoma tumors are fundamentally different in men and women, the researchers found.

Different processes drive glioblastoma tumors in men and women, and they respond differently to treatment, Dr. Josh Rubin of Washington University in St. Louis and colleagues showed. They believe the same may be true for other tumors, too, and say cancer researchers may need to go back to the drawing board when evaluating treatments for men versus women.

Dr. Josh Rubin, a neuro-oncologist at Washington University in St. Louis.
Dr. Josh Rubin, a neuro-oncologist at Washington University in St. Louis.Washington University

“We found that standard therapy is more effective in female compared with male patients with glioblastoma,” they wrote in their report, published in Science Translational Medicine.

Even more surprising: hormones have little to do with these differences.

Glioblastomas are a rare subtype of brain tumor. According to the American Cancer Society, just under 24,000 people were diagnosed with any kind of malignant brain tumor in 2018, including close to 14,000 men and 10,000 women. The survival rate for glioblastoma is low: 19 percent of adults aged up to 44 will live five years or more after a glioblastoma diagnosis, and only 5 percent for those over 55 will live that long.

While the outlook is poor for both men and women with glioblastoma, women live a little longer after treatment, which usually involves surgery, radiation and then chemotherapy, usually with a drug called temozolomide.

Rubin has been interested in sex differences in cancer rates and in how people are helped by cancer therapy. In previous research, Rubin’s team has shown it’s easier to transform a male cell into a tumor cell.

“It’s been recognized for many years that, overall, males tend to die more frequently and faster of their cancer than females do,” Rubin told NBC News. According to the American Cancer Society’s 2018 estimates, 856,000 men and 879,000 women were diagnosed with cancer and 323,000 men died of cancer, versus 286,000 women.

Rubin took a closer look at glioblastoma patients, using magnetic resonance imaging (MRI) scans and data from a large cancer database. They homed in on 63 patients getting standard care for glioblastoma and found that women were helped more by standard treatment than men were.

"The males did not respond as well, and we wanted to understand why, so we looked at the underlying genetics of patients' tumors," Rubin said. They used the Cancer Genome Atlas, where details of the genetics of various tumors are stored for research.

"We observed tremendous genetic sex differences in the tumors of glioblastoma patients that correlated with survival," said Jingqin "Rosy" Luo, who worked on the study.

They found 10 different glioblastoma groups — five in men, and five in women. One subtype for each sex, different for men and women, tended to be easier to treat. Females with that subtype lived an average of three years, compared to just over a year for those with the other four types. For men, those with the “good” subtype lived about 18 months, compared to about a year for the others.

This is an argument for what’s called personalized therapy, which involved DNA tests of a patient’s tumor to determine the best course of treatment. But the findings also show that sex is an important and separate consideration, Rubin said.

In the women, the genes that were important involved the spread of cancer cells, while in men, it was about the proliferation of tumor cells, Rubin’s team found.

Males and females are different from the moment of conception. Male blastocysts — the balls of cells that start growing after sperm meets egg — grow more quickly, Rubin said. Genetics affect this: men have an X and Y chromosome while females have two X chromosomes. There’s a process called imprinting in which certain genes are silenced depending on whether they come from the father or mother, and a woman’s hormones affect the activity of a baby’s genes in the womb.

After a person is born, their own circulating hormones such as testosterone and estrogen affect many areas of health. But that does not appear to matter in glioblastoma, Rubin said. That’s because the sex differences are there despite age — and circulating hormones vary greatly depending on age.

Rubin said his team will have to demonstrate the same findings with other cancer types, but he believes the effect will be common. “The work that we have been doing would suggest that molecular mechanisms are just fundamentally different in males and females,” he said.

“Personalized cancer treatment approaches have to take into account whether a patient is male versus female, in the same way personalized medicine has to take into account the age of a patient,” he added.