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Source: University Of Toronto  Dec 26, 2018  5 years ago
Breast Cancer Drug; Letrozole found to impair brain function. Countries like India have already banned the usage of the drug.
Breast Cancer Drug; Letrozole found to impair brain function. Countries like India have already banned the usage of the drug.
Source: University Of Toronto  Dec 26, 2018  5 years ago
  • Letrozole was found to damage normal function in the hippocampus of monkeys
  • The animals also showed anxiety and hot flashes after four weeks of treatment
  • Side effects like fatigue are experienced by up to 30% of women on the drug
A drug commonly given out  to breast-cancer patients may affect their brain function and memory, research suggests.Letrozole is primarily used to treat breast cancer and was prescribed more than 20 million times last year globally.
Although Cancer Research UK and also the National Cancer Institute in the US report up to 45 per cent of patients experiencing  side effects like hot flushes and fatigue, new research suggests the medication's complications may be far more serious. 

When given to monkeys, the drug reduced the function of their brain cells in a region known as the hippocampus, and worsened their performance on memory tests, after just four weeks. 

The study was carried out by the University of Toronto and led by research associate Dr Nicole Gervais.

Some breast cancers are stimulated by the hormone oestrogen, which may get converted from testosterone via the enzyme aromatase. Letrozole - which is given as a tablet - is an aromatase inhibitor (AI).

Letrozole only works in women with this form of breast cancer who have been through the menopause. This is due to them no longer producing oestrogen via their ovaries, with the hormone therefore only coming about via aromatase. 

The drug is linked to joint pain and raised cholesterol levels in one in ten people, as well as loss of appetite, hair thinning and vaginal dryness in one per cent of cases. It is often given after surgery or chemo to prevent cancer returning or spreading. 

Letrozole may bring about depression, forgetfulness and insomnia due to aromatase being expressed in the hippocampus, which is the brain region that controls emotion, memory and thought processing. 

Four weeks of an oral AI has adverse effects on multiple behavioral, neuronal and physiological outcomes in marmosets,' the authors wrote in The Journal of Neuroscience.

In the first study of its kind, three male and five female marmoset monkeys were fed letrozole - also known by its brand name Femara - hidden in pudding. The amount given was calculated 'based on the recommended dose for women'. 

These monkeys were compared against six males and two females who were just fed the pudding.  

Marmosets were chosen due to the 'organisation of the brain being comparable to a human's', the authors wrote. The monkeys also 'share many similarities with humans in sleep, cognitive ability and anxiety profiles'. 

Urine samples from the animals were analysed to determine levels of the stress hormone cortisol. Signs of anxiety were also monitored in the animals' behaviour, such as their 'hair standing on end' or any agitated movements. 

When the experiment ended, the monkeys were put down so changes to their brain structure could be analysed.
Results suggest the animals given letrozole had reduced brain cell activity in the hippocampus and performed worse on memory tests. 

The letrozole group demonstrated a drop in performance of five to seven per cent, however it is difficult for the authors to interpret how meaningful this change would be. 

They also spent more time acting agitated and had higher facial temperatures - a sign of hot flushes. 
While the link between these symptoms, including effects to the brain, and the use of aromatase inhibitors has been made before, it's the first time a clear direct link has been made.  

Dr Gervais said 'Women have also been treated with chemotherapy, radiation therapy and other anti-estrogen medications with known effects on the brain, and so it has been a challenge to tease apart the unique contributions of aromatase inhibitors to the reported side effects.'

Although the findings can't be applied to women in general, Dr Gervais said: 'They can inform women considering taking this medication about what some of the effects might be. 

'These findings might also help normalize some of the experiences women currently taking the medication are having.'

Although concerning, the researchers stress further studies are required and letrozole has been shown to boost survival among breast-cancer patients.

Five-year disease-free survival was higher in a group treated with letrozole - at 95 per cent - compared with 91 per cent among a placebo group, researchers at the Avon International Breast Cancer Research Program at Massachusetts General Hospital Cancer Center found.  

Reference:  Adverse effects of aromatase inhibition on the brain and behavior in a nonhuman primate, JNeurosci (2018). … EUROSCI.0353-18.2018 

Editors Note: As of 18th December 2018, India has banned the use of the drug letrozole and many other countries are also following suit. Patients taking letrozole are advised to contact their existing physicians or any other reputable qualified and licensed medical specialists.


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