Mental ‘fogginess’ with tamoxifen use should be taken seriously

Tamoxifen use among some women with breast cancer has been reported to cause mental “fogginess” while on the medication, and researchers have demonstrated that the side effect is real, according to an online study published Sept. 17 in the Journal of Neuroscience.

Tamoxifen, one of the most widely used anti-cancer agents, is toxic to certain cells of the brain and the central nervous system, which may explain the phenomenon of mental fogginess that occurs in some women who take it. Tamoxifen is a selective estrogen-receptor modifier (SERM), which binds to estrogen receptors. In the cells of some tissues (such as breast tissue), this blocks the action of estrogen, so that cells (like some cancer cells) that need estrogen to divide stop growing and die. 

For some patients the effects wear off over time, but others experience symptoms that can lead to job loss, depression, and other debilitating events, according to study author Mark Noble, PhD, professor of genetics, neurology, neurobiology and anatomy, and director, University of Rochester Stem Cell and Regenerative Medicine Institute, University of Rochester Medical Center. 

“Patients aren't always taken seriously when they report these mental side effects, but now we can say this is an organic syndrome to which we have to pay attention. It’s critical to find safe treatments that can rescue the brain from impairment, because despite increasing awareness and research in this area, some people continue to endure short-term memory loss, mental cloudiness, and trouble concentrating,” said Noble. “The answer is these problems is either to develop ways to protect nervous system cells but not cancer cells or to develop cancer treatments that are more targeted and safer to the cells of the body. We are working on both approaches, but our latest findings have come from the first strategy-protecting normal cells. 

“Thus, while tamoxifen is widely used and relatively benign, it can produce troubling side effects among a subsection of the large group of women who use it,” Nobel continued. “We also discovered a drug compound that helps to save brain cells from such adverse effects of tamoxifen and has the very desirable property of not rescuing cancer cells.”

Noble and colleagues first isolated the cells in the brain and nervous system that might be harmed by tamoxifen therapy and studied them. They found one type of cell that was particularly vulnerable to the drug. 

After just 2 days of exposure to tamoxifen at levels similar to those someone in treatment would receive, 75% of these cells died. 

“The next step was to try to find a medication that could protect these cells from tamoxifen while still allowing the drug to keep its cancer-fighting ability,” Noble said. “In this search, we only studied drugs that are already approved or in clinical trials. Due to the urgency of these problems, [we] don’t have time for 10 to 15 years of drug discovery, so repurposing drugs and finding new uses for them is tremendously important.”

“Our work demonstrates that damage caused by tamoxifen is a real problem,” Noble said. “For the women who take tamoxifen and have these effects-which is probably a minority of women, but exact numbers are not available-they are not imagining things.

“Our work also demonstrates, for the first time, that it is possible to discover agents that protect normal cells but do not protect cancer cells from a particular treatment,” he said. “The agent (AZD6244) we studied [in brain cells of mice] is particularly interesting because it seems to enhance sensitivity of cancer cells to treatment. As far as we know, no one else has discovered an agent that singles out and protects brain and central nervous system cells while also not protecting cancer cells.”

Noble hopes this study inspires more researchers to enter this field, “by demonstrating that discovery of agents with these very attractive properties is actually possible,” he concluded.