As many of the audience will know, everolimus is an mTOR inhibitor that in the metastatic setting demonstrated efficacy when combined with exemestane in patients with hormone receptor positive, HER2 negative tumours. There is a lot of data demonstrating that the pathway inhibited by everolimus is involved in mechanisms of endocrine therapy resistance. So, since we knew this fact and the everolimus data in the metastatic setting was positive, it was clearly of relevance to evaluate whether this drug could be effective when used in patients with early stage breast cancer.
What was the methodology of the study?
We designed a randomised phase III placebo-controlled clinical trial. This was a large trial that was done within the Cooperative Group Network led by SWOG in the United States. In this trial almost 2,000 patients were recruited, patients where all of them were high risk, hormone receptor positive, HER2 negative patients with early stage breast cancer. Different inclusion criteria but, very important, all patients received either neo- or adjuvant chemotherapy prior to registration. Patients were randomised 1-to-1 to receive either placebo or one year of everolimus in addition to adjuvant endocrine therapy that was physician’s choice.
What were the key findings?
The main objective of the study was to determine invasive disease free survival. Secondary endpoints were overall survival and safety, some of the main ones. What we observed with almost five years of follow-up is that the addition of adjuvant everolimus did not improve invasive disease free survival or overall survival in the entire population. We did, however, do some exploratory analysis evaluating whether there is a differential effect according to different risk factors and observed that amongst premenopausal patients, this is among about 571 premenopausal patients enrolled in the study, in this group of patients there was a statistically significant improvement in both invasive disease free survival and overall survival with the addition of adjuvant everolimus. This is a very interesting and thought-provoking observation but it is hypothesis generating so we’re going to be looking more into the data.
We also observed that everolimus was associated with a higher discontinuation rate. Our study had a high discontinuation rate and most patients discontinued therapy because of adverse events. So we need to take that into consideration in terms of the tolerance of the drug.
What do you think could be the clinical impact of these results on the future treatment of breast cancer?
Since this is a negative trial, at this point we cannot state that these results are going to impact the treatment of our patients. There are, however, secondary endpoints and translational studies that will hopefully inform about the biology of patients with high risk tumours, about mechanisms of endocrine therapy resistance, that can be of help for our patients.
It is possible that in the future our observation suggesting benefit in premenopausal patients could lead to development in this specific patient population of additional drugs – new generation mTOR inhibitors, new generation AKT inhibitors. I, however, do not think that next week in clinic this result will impact the way that we treat our patients.