Confronting the side effects of a common anti-cancer treatment

December 26, 2018

AMHERST, Mass. - Results of a new study by neuroscientists at the University of Massachusetts Amherst and the University of Toronto suggest that a new treatment approach is needed - and how this may be possible - to address adverse effects of aromatase inhibitors, drugs commonly prescribed to both men and women to prevent recurrence of estrogen-positive breast cancer.

The current drug therapy is linked to such complaints as hot flashes, memory lapses, anxiety and depression, side effects so bothersome that some patients discontinue the life-saving treatment, the researchers point out. Their study found that aromatase inhibitors do indeed suppress estrogen synthesis in body tissues, but their unexpected findings in the brain could explain some of the negative effects and provide insight into more effective, less disruptive future therapies.

Neuroscientists Agnès Lacreuse, Luke Remage-Healey and their graduate students at UMass Amherst, collaborator Jessica Mong at the University of Maryland and first author Nicole Gervais worked together on this research. Gervais, who conducted the experiments as a postdoctoral researcher at UMass Amherst, is now at the University of Toronto. The authors studied a small group of aged male and female marmosets, non-human primates whose brains are much like humans' and which exhibit "complex behavior," senior author Lacreuse explains.

She adds, "This drug is given to prevent recurrent breast cancer in humans and it does save lives, but a lot of times, patients are not compliant because of unpleasant side effects that affect quality of life." Their study, showing changes in the animals consistent with some of the human complaints, allowed the researchers to assess cognitive behavior, thermal regulation and neuronal changes in drug-treated vs. control groups. Their findings appear this week in the Journal of Neuroscience.

As Gervais explains, studies in humans are hampered by confounders. "The patients have had cancer, so it's hard to disentangle the stress of their disease and treatment from the drug effects." She adds, "We wanted to know if the symptoms while using the aromatase inhibitors can be reproduced in an animal model, and further explore the mechanisms to understand how they work and find alternative treatments."

In this work supported by the NIH's National Institute on Aging and National Institute of Neurological Disorders and Stroke, the researchers administered the estrogen-inhibiting drug orally "the way it's given to humans and at a similar dose," Gervais explains, for one month, and observed that it did indeed suppress estrogen production in the body. They then compared changes in behavior, memory, electrophysiology, and thermoregulation in the treated and control groups

Gervais says, "Sure enough, we found deficits in some aspects of memory and we also saw the most striking results in thermal regulation, a deficit in the ability to regulate body temperature when the ambient temperature increases, but only in females. It doesn't match hot flashes exactly but it's consistent with what we know about the regulation of hot flashes by estrogens in women. Females on the drug could not regulate their temperature as well as control females."

It was in the investigation of neurons that the researchers saw something quite surprising, says Remage-Healey. "In the hippocampus, which is thought to be critical for learning and memory functions, instead of reduced estrogen levels we found that the drug caused a paradoxical increase in estrogen levels."

Gervais adds, "We believe that the hippocampus may have synthesized its own estrogens to compensate for low levels it senses in peripheral tissues. According to our results, the mechanism for an adverse effect on memory may be due to an increase of estrogen synthesis in the hippocampus. Perhaps, future treatments could find a way to block this increased synthesis, and maybe prevent some of the negative side effects."

Remage-Healey points out that "We were also able to follow the excitability of hippocampal neurons, which was compromised in the treatment but not control group. This is consistent with the occasional memory problems reported by patients. It seems the hippocampus is particularly sensitive to estrogens and their blockade. But we have a lot of work to do to understand the precise mechanism underlying these effects."

The authors state, "These findings suggest adverse effects of aromatase inhibitors on the primate brain and call for new therapies that effectively prevent breast cancer recurrence while minimizing side effects that further compromise quality of life."

University of Massachusetts at Amherst

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to