A trial of everolimus, letrozole and exemestane for advanced HER2 negative breast cancer (BOLERO 4)

Cancer type:

Breast cancer
Secondary cancers




Phase 2
This trial looked at adding everolimus to letrozole and exemestane for breast cancer. 
It was for post menopausal Open a glossary item women whose breast cancer had grown into the surrounding tissue or had spread elsewhere in the body. And whose breast cancer cells had:
  • receptors for oestrogen or progesterone (is hormone receptor positive)
  • low or no amounts of HER2 (HER2 Open a glossary item negative cancer)

More about this trial

Breast cancer can sometimes grow outside the breast or spread to another part of the body. This is advanced breast cancer.
Doctors often treat this type of breast cancer with hormone therapy. 2 hormone drugs they can use are: 
  • letrozole
  • exemestane 
But sometimes hormone therapy stops working. So, doctors want to find ways to improve treatment. In this trial, they looked at adding a drug called everolimus. 
Everolimus stops a protein called mTOR from working properly. Cells usually divide and grow in an orderly way. But in cancer cells, proteins such as mTOR can behave abnormally and the cells grow out of control. Blocking mTOR may stop or slow the growth of the cancer.
In this trial, women had everolimus alongside letrozole to begin with. And some started taking everolimus and exemestane if their cancer got worse.
The main aims of this trial were to find out:
  • how well everolimus and letrozole worked for advanced breast cancer
  • how well everolimus and exemestane worked as the second treatment 
  • more about the side effects

Summary of results

The trial team found that everolimus and letrozole helped some women with HER2 negative breast cancer that had spread. And most of the side effects were manageable. 

They analysed the results in December 2016. They published them in 2018. 

202 women took part. Everyone had everolimus and letrozole to begin with. 50 women went on to have everolimus and exemestane when their cancer got worse. 

Results for everolimus and letrozole
The trial team followed everyone up for an average of 30 months. They looked at the average length of time before the cancer started to grow again. This was 22 months. 
Results for everolimus and exemestane
50 women had everolimus and exemestane. The researchers looked at the average length of time before their cancer started to grow again. This was 3.7 months.
Side effects
The most common side effects of everolimus and letrozole were:
  • a swollen mouth and lips (stomatitis)
  • weight loss
  • diarrhoea 
51 women had to stop treatment early because of side effects. 
The most common side effects of everolimus and exemestane were:
  • a swollen mouth and lips
  • weight loss
 A total of 9 women died because of a serious side effect. The main causes were a serious:
  • chest infection (pneumonia)
  • complication of an infection (septic shock)
The researchers suggested that everolimus and letrozole helped control the cancer in this group of women. 
But everolimus and exemestane didn’t work as well as they had hoped. This is because these women had a number of areas of cancer spread and they had already had everolimus. So, the researchers say that care should be taken when considering the results of this group. 
This trial has increased knowledge about what works and what doesn’t for advanced breast cancer.
We have based this summary on information from the research team. The information they sent us has been reviewed by independent specialists (peer reviewed Open a glossary item) and published in a medical journal. The figures we quote above were provided by the trial team who did the research. We have not analysed the data ourselves.

Recruitment start:

Recruitment end:

How to join a clinical trial

Please note: In order to join a trial you will need to discuss it with your doctor, unless otherwise specified.

Please note - unless we state otherwise in the summary, you need to talk to your doctor about joining a trial.

Chief Investigator

Dr Mark Beresford

Supported by


If you have questions about the trial please contact our cancer information nurses

Freephone 0808 800 4040

Last review date

CRUK internal database number:


Please note - unless we state otherwise in the summary, you need to talk to your doctor about joining a trial.

Last reviewed:

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