Hormone therapy for prostate cancer associated with greater risk of dementia

The leading treatment for prostate cancer may, in the longer term, increase a person’s risk for dementia, a new study finds.

The retrospective study, published in JAMA Oncology Thursday, analyzed almost a decade’s worth of medical records and found that men with prostate cancer who are treated with androgen deprivation therapy (ADT) are twice as likely to develop dementia, including Alzheimer’s, within five years, compared to prostate cancer patients who do not receive testosterone-lowering therapies.

There are 1.1 million new prostate cancer diagnoses per year. In industrialized countries, 50 percent of those men will receive some level of ADT, a treatment that suppresses testosterone and helps reduce cancers or slow their growth.

But lead author Dr. Kevin Nead, a resident at the University of Pennsylvania, said that his findings shouldn’t change how prostate cancer is treated right away. Since his study looked at past data, there could be confounding factors. For example, the patients who received ADT in their data could have been older and sicker, possibly more prone to dementia anyway.

“We need to look at this prospectively, and not just retrospectively, before we would change clinical care,” he said.

The role of testosterone

Nead and Nigam Shah, a biomedical informatics researcher at Stanford, looked at medical records from the Stanford University Health System from 1994 to 2013. Of the 9,272 men they found with prostate cancer diagnoses, 1,826 were receiving ADT. The study excluded men with previous dementia diagnoses, and only included those who had records available for follow-up visits.

The results showed that men receiving ADT were almost twice as likely to develop dementia as those without ADT — in absolute terms, 7.9 percent of the former group developed the condition, compared to 3.5 percent of the latter.

The researchers’ previous work showed a correlation between ADT and Alzheimer’s; this study expands that finding to all dementias.

Testosterone is known to offer multiple protections for the brain. It regulates how much amyloid protein is produced (the buildups in the brain associated with Alzheimer’s) and helps regulate amyloid degradation and destruction. It’s useful against more general dementia as well: Testosterone decreases levels of brain inflammation, promotes growth and the ability of neurons to survive, and increases neural stem cells.

Christian Pike, an associate professor of gerontology at University of Southern California, has done studies with mice genetically altered to develop Alzheimer’s and found that if he removed their testes (decreasing testosterone by 95 percent), or gave them a common ADT drug, lupron, they had a much greater acceleration of the disease. “If you get rid of testosterone, it leads to an environment that’s really conducive to Alzheimer’s pathology,” he said.

Caution in changing treatment

A collaboration between prostate cancer and Alzheimer’s researchers could lead to benefits on both sides: Alzheimer’s researchers could learn more about the influence of low testosterone on the brain, and oncologists could learn strategies to allow them to continue ADT. Pike said that there are synthetic testosterone drugs, called selective androgen receptor modulators (SARMS), in clinical trials that could be combined with ADT. They could provide the hormone’s protective benefits to the rest of the body, while letting the ADT influence the cancer growth.

Further, it appears that not every patient has the same risk when given ADT. Brian Gonzalez, an assistant professor at the Rutgers Cancer Institute in New Jersey, compared men receiving hormonal therapy for prostate cancer to men who were not and saw that a patient’s genetic makeup partially explained why some showed a greater risk of cognitive impairment than others.

“I’m working on designing future studies that take a personalized medicine approach to identifying which patients are at greatest risk based on their DNA,” he said. “Rather than recommending an adjustment to treatment for most patients, I think this information should simply be factored into the risk-benefit conversation that oncologists and patients have before starting hormonal therapy for prostate cancer.”

All cancer treatments have side effects, Nead said, and need careful consideration before their implementation. For now, Nead doesn’t think treatment courses should be changed. Instead, what a large retrospective study like this offers is a marker of where to perform new research. “When you use ADT in appropriate selected men, they live longer,” he said. “So I think we need to have a really high bar before we start changing the way that we treat people.”