Monday June 6 2016
Aromatase inhibitors are usually offered to postmenopausal women
"Taking hormonal drugs for up to 15 years reduces the risk of breast cancers coming back," BBC News reports.
A new study looked at 1,918 postmenopausal women with what is known as oestrogen receptor-positive (or ER+) breast cancers – where cancer growth is stimulated by the hormone oestrogen.
A class of drugs known as aromatase inhibitors are often used in such cases, as they are able to reduce the production of oestrogen.
The women had previously responded well to a five-year course of hormone treatments.
They were randomised into two groups: either they took an aromatase inhibitor called letrozole for another five years, or they were given a dummy treatment (placebo).
Disease-free survival after five years was 95% in the treatment group and 91% in the placebo group.
Extended aromatase inhibitor treatment cut the risk of recurrent or new breast cancer development by about a third.
Osteoporosis was the most significant side effect from extended treatment with letrozole.
However, there was no effect on overall survival, and no effect on disease-free survival when taking into account baseline differences between the participants.
It is hoped further evidence will be forthcoming to identify which women – in terms of characteristics, stage of breast cancer and prior treatment – may be most suited to this treatment, and for whom the benefits of prolonged treatment would outweigh the side effects.
Where did the story come from?
The study was carried out by researchers from the Avon International Breast Cancer Research Program at Massachusetts General Hospital Cancer Center and other institutions in the US.
Funding was provided by the Canadian Cancer Society Research Institute, the National Cancer Institute, the Canadian Cancer Trials Group, the ECOG-ACRIN Cancer Research Group, and Novartis Pharmaceuticals.
Several researchers declared conflicts of interest for serving on advisory boards for various pharmaceutical companies.
The study was published in the peer-reviewed journal, The New England Journal of Medicine, on an open access basis, so you can read it for free online.
The UK media reported on the study accurately, but many of the headlines included the phrase "women should stay on hormonal drugs for 10 years", or variations on it.
The researchers actually went out of their way to make the point that this study should not be taken as some sort of blanket recommendation for all women with ER+ breast cancer.
There was also apparent headline confusion on the BBC website over whether women should continue treatment for 10 or 15 years. This seems to come from the fact that most women had taken 5 years of tamoxifen prior to 10 years of an aromatase inhibitor.
What kind of research was this?
This was a placebo-controlled randomised controlled trial that aimed to investigate the effects of extended treatment with an aromatase inhibitor (letrozole) in women with ER+ breast cancer.
ER+ means that the breast cancer cells have oestrogen receptors and the body's natural hormone is stimulating the cancer to grow. These cancers can be treated by hormone treatments, which can block this.
There are two types of hormone treatment – aromatase inhibitors, which are only given to postmenopausal women, and tamoxifen, which is most often used in premenopausal women, but can also be used in the treatment of postmenopausal women.
The problem is that even after treatment, there is always a risk the cancer will relapse or recur.
Hormone therapy regimens vary, depending on what treatment the person is having alongside it.
They can involve giving just an aromatase inhibitor for five years, or a combination of tamoxifen for five years and then an aromatase inhibitor for five years.
This placebo-controlled trial specifically aimed to look at the effect of giving an aromatase inhibitor for 10 years rather than 5, after any duration of previous treatment with tamoxifen.
What did the research involve?
The trial involved postmenopausal women with ER+ breast cancer who had received 4.5 to 6 years of treatment with an aromatase inhibitor.
In most women (two-thirds) this had been preceded by about five years of tamoxifen treatment.
A total of 1,918 women who were still disease-free after using aromatase inhibitor treatment were randomised to then receive the aromatase inhibitor letrozole or placebo for a further five years. Treatment started within six months of stopping their previous treatment.
Participants received yearly clinical assessments, including blood tests, mammography, bone scans, and assessment of drug side effects and quality of life.
The main outcome of interest was disease-free survival, defined as time from randomisation to breast cancer recurrence.
Other outcomes included overall survival, cancer development in the other breast, quality of life and long-term safety.
After five years, as the number of recurrence events in the placebo group was less than expected, the trial design was amended to look at the time that events occurred, rather than just looking at the number of events over continued follow-up time.
The duration of the study was five years, and the average follow-up period was 6.3 years.
What were the basic results?
The rate of cancer recurrence or new cancer development in the opposite breast was lower in the letrozole group, at 7%, compared with 10.2% of the placebo group.
The rate of disease recurrence specifically was 5.7% in the letrozole group versus 7.1% in the placebo group. Each year, around 0.21% of the letrozole group and 0.49% of the placebo group developed a new cancer in the other breast.
Five-year disease-free survival was higher in the letrozole group, at 95%, compared with 91% in the placebo group.
Letrozole reduced the risk of recurrence or development of cancer in the other breast by a third (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.48 to 0.91).
There was no statistically significant difference when looking at overall survival, which was 90% in the letrozole group and 88% in the placebo group. Deaths were due to breast cancer, other primary cancers and cardiovascular disease.
Loss of bone density was a significantly more common side effect in the letrozole group, though few people in either group stopped treatment because of side effects. There was no difference between groups in terms of quality of life.
There was no significant difference between groups when adjusting for baseline characteristics and duration of prior aromatase inhibitor treatment.
How did the researchers interpret the results?
The researchers concluded that, "Extension of treatment with an aromatase inhibitor to 10 years resulted in significantly higher rates of disease-free survival and a lower incidence of [opposite] breast cancer than those with placebo, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo."
This trial suggests that extending the duration of aromatase inhibitor treatment for postmenopausal women to 10 years, rather than five, may reduce the risk of the cancer recurring or new cancer developing in the other breast.
The trial has many strengths, including:
- a double-blind design, with neither participants nor the research team aware of allocation to treatment or placebo groups – this is regarded as the gold standard of assessing the effect of an intervention; adherence rates to five years were equivalent in both groups (62% in each), suggesting that participants were unaware of treatment
- stratified randomisation – this ensured baseline characteristics were balanced between the groups
- a large sample size and prior power calculation – this ensured the researchers enrolled a sufficient number of people to detect a difference in survival between the groups
However, there are points to bear in mind. There was no difference between groups when including the outcome of overall survival – this was seen only when comparing new or recurrent breast cancer rates.
There was also no significant difference between groups when taking into account baseline characteristics.
This suggests some women may be better suited to, or would gain more benefit from, prolonged aromatase inhibitor treatment than others.
The trial has only looked at disease-free survival up to five years. Though this was better in the treatment group, this is comparing women who had just stopped 10 years of treatment with an aromatase inhibitor with women who took an aromatase inhibitor for five years, and stopped five years ago.
We don't know the outcomes for the extended treatment group another 5 or 10 years down the line.
Extended treatment with an aromatase inhibitor may prolong disease-free survival, but this doesn't necessarily mean it would definitely prevent breast cancer ever coming back.
These were also a select group of postmenopausal women with ER+ breast cancer, the majority of whom had received about five years of tamoxifen before taking an aromatase inhibitor.
The results cannot be applied to all women with breast cancer, who may have different characteristics, types and stages of breast cancer, as well as different treatment regimens.
Overall, the results of this large and well-designed randomised controlled trial suggest that extended treatment with an aromatase inhibitor to 10 years may be suitable for some women.
However, the potential side effects should be balanced with the quality of life that could be had from this treatment.
The manufacturers of letrozole report menopausal-like side effects, such as hot flushes, increased sweating and fatigue, are very common, affecting more than 1 in 10 women.
It needs to be determined which women would be most suited to this regimen, and for whom the benefits would outweigh the side effects. Such information would allow women to make an informed choice about their treatment.