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Does gender determine how fast you will die from brain cancer?

A group of black and white men and women stand together and smile. Drs. Nitesh Patel and John Boockvar explain gender's role in why men die faster than women with glioblastoma multiforme.

Studies continue to show the role that age, gender and genetics play in certain types of brain cancer, including glioblastoma multiforme (GBM)

It’s remarkable how the two words — “brain cancer” — can change the decades-long trajectory of any patient’s life. Every memory, decision and experience suddenly is reframed. Those words carry an incredible amount of weight.

Cancer is the driving force behind the work of millions of scientists worldwide. And despite the technological, imaging and other advancements that have improved outcomes and our understanding of the disease, brain cancer continues to be the most evasive of human cancers.

Glioblastoma multiforme (GBM), for example, was recently in the news after a study led by Washington University St. Louis’ Josh Rubin, MD, determined that glioblastomas are fundamentally different in men than women. An expert oncologist and scientist, Dr. Rubin explored the role of gender in the prognosis of GBM, building on decades of observations that have shown males and females have different survival statistics for brain cancers.

Dr. Rubin and his colleagues identified 10 different genetic groups — five male and five female — in which one male and one female group responded better to treatment and lived longer. The study proposed that more studies should look at creating ways to better personalize GBM treatment.

Gender’s role in GBM prognosis

The role of gender for the prognosis of GBM is being widely studied. In fact, for every female diagnosed with GBM, 1.6 males receive the same diagnosis.

Many studies have shown that females, overall, not only live longer but also respond better to standard therapy.

Dr. Rubin and colleagues cited that this phenomenon is rooted in the way our bodies are designed; male and female genes lead to different responses in the context of cancer.

Scientists from Italy previously observed that females with a specific mutation in a DNA repair gene responded better to the chemotherapy temodar than males with the same mutation.

A group of Cornell scientists noted that the amount of tumor removed during surgery also shared the same trend; larger amounts of tumor removal in females led to better survival than in males.

Gliosarcoma is an aggressive and challenging form of GBM. Researchers from Utah showed that females with a gliosarcoma diagnosis had a significantly better prognosis. However, these observations are not uniform — a 2016 study led by MD Anderson classified GBM as a cancer type with a weak sex-effect.

The mechanisms are not entirely clear, but the message is simple: clinicians need to consider gender as a major factor. Gender is the most basic demographic that remains static — it can change phenotypically (appearance) but not genotypically (our inherent genes).

How does age factor?

Age is another factor for GBM survival. A joint study between UCLA and the Barrow Neurological Institute examined the molecular signatures of GBMs across different age groups. The molecular signature of a tumor is based on the types of proteins and cell machinery it produces — it can vary greatly even among the same tumor type.

Glioblastoma is more common in adults. And their study wanted to determine why younger patients survive longer, finding that GBM cells in younger patients had a different molecular signature, which play a large role in how a tumor cell grows and responds to chemotherapy and radiation.

This echoed the need to further drive research into defining different GBM subtypes.

At the moment, GBM is not considered a genetic disease, despite all of the studies examining genes and their products. It is likely that GBM is more of an umbrella that needs more evaluation. Future studies should have the goal of determining not only if gender affects survival from GBM but also what specific molecular markers determine treatment response.

Understanding glioblastoma and brain tumors

Brain tumors can be split into two broad categories: primary and secondary. Primary brain tumors are those arising from cells within the brain. Secondary tumors are those that have metastasized to the brain — from some other cancer-stricken area of the body. However, the term tumor can be misleading as not all tumors are cancerous. Even with primary brain tumors, not all are cancerous.

Brain tumors that are relatively more common, such as meningiomas or pituitary adenomas, are usually not cancer. Other brain tumors such as gliomas have more cancerous potential.

Gliomas are typically graded on a scale from 1-4. Glioblastoma multiforme (GBM) is considered a grade 4 lesion and persists as a very challenging entity to treat with no known cure.

The only way to determine if a glioma is GBM is to examine the tumor’s tissue under a microscope and perform a series of genetic and molecular laboratory tests. Cancerous tumors tend to be more aggressive — their cells duplicate more rapidly, they cause new blood vessels to grow toward them and they compress normal tissue around them. Higher grade gliomas carry some of these features and GBM carries all of them. However, not each GBM is the same. Although the cells can be seen with a microscope, the cell’s machinery, proteins and DNA changes require advanced laboratory studies. The presence or absence of these features impacts not only the patient’s response to treatment but also how long he/she is expected to survive.

Glioblastoma treatment

The current standard of care for GBM is maximal safe surgical resection followed by chemotherapy and radiation. The choice of chemotherapy is most commonly temozolomide (Temodar), which damages DNA while it’s being made.

Tumor cells divide faster than normal cells and therefore make DNA more frequently. Temozolomide (TMZ) damages the rapidly made DNA and thus tumor cells cannot duplicate as quickly. But the chemotherapy does not work as well in all GBMs: some possess repair mechanisms that can reverse the damage caused by TMZ.

John Boockvar, MD, is vice chair of the Department of Neurosurgery and director of the Brain Tumor and Pituitary/ Neuroendocrine Center at Lenox Hill Hospital. He is also an investigator in the Laboratory for Brain Tumor Biology at the Feinstein Institute for Medical Research and a professor of neurosurgery and otolaryngology/head and neck surgery at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.

Nitesh Patel, MD, is a clinical fellow at Lenox Hill Hospital.

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