Everolimus improved PFS in advanced hormone receptor positive breast cancer

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Published: 16 Dec 2011
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Dr Gabriel Hortobagyi - MD Anderson Cancer Center, Houston, Texas, USA

The BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2) trial evaluated the use of everolimus in the treatment of postmenopausal women with advanced oestrogen receptor-positive breast cancer. This study established that adding the mTOR inhibitor everolimus to second line hormone therapy with exemestane significantly improved progression-free survival (PFS). Among 724 patients, median PFS with everolimus was 7.4 months, compared with 3.2 months for exemestane alone. Dr Gabriel Hortobagyi discusses the results of this study, outlines the associated side effects and explains the work being done to develop biomarkers for response or resistance to everolimus.

2011 SABCS, San Antonio Breast Cancer Symposium, 6-10 December, San Antonio, USA


Everolimus improved PFS in advanced hormone receptor positive breast cancer


Dr Gabriel Hortobagyi – MD Anderson Cancer Center, Houston, Texas, USA


The BOLERO trial was a prospective randomised trial for postmenopausal women with hormone receptor positive breast cancer who had progressed on prior treatment with anastrozole or letrozole. It was designed to determine whether the addition of everolimus, an mTOR inhibitor, to second line hormone therapy would reverse a mechanism of resistance. We recruited 724 patients from about 34 countries around the world; it was a 2-2-1 randomisation to either exemestane plus placebo or exemestane plus everolimus. After a median follow-up of 12.5 months the median progression free survival, which was the primary efficacy variable for this trial, was prolonged by about 4 months in the combination group as compared to the exemestane plus placebo group. This was a 54% reduction in progression events, or a hazard ratio of 0.44 and a very highly significant p-value.


In addition, there was a significant improvement in clinical benefit rate, it was double in the combination arm or about 50% compared to about 25% in the exemestane-placebo arm. While there were some increased side effects in the combination arm, such as mucositis and fatigue and rash and hyperglycaemia, these side effects were mostly of low grade and did not affect the quality of life of patients during the study. The study is still immature for an overall survival analysis, we will need another year or year and a half of follow-up for that to occur.


At this meeting we presented results with five additional months of follow-up and that increased observation period allowed us to narrow the confidence intervals in the observations and to really reaffirm the marked therapeutic benefit with the combination. It also gave us five additional months of exposure to the combination and gave us reassuring information about the safety profile and the maintenance of quality of life of patients who received the combination therapy. So this was an important update because of that and we will continue to watch the two groups as additional follow-up occurs to make sure that we really provide totally mature data to the community.


When we designed the BOLERO-2 trial, we incorporated in the design a number of correlative science projects, the major purpose of which is to identify biomarkers of response or of resistance to everolimus. We know that there’s no drug in the oncology world that benefits 100% of patients, in fact there’s no drug in the oncology world that benefits even 100% of the patients of one subtype of breast cancer. So we know that we need to narrow this down to a population that will truly benefit and for that we need biomarkers, one or several biomarkers that will help us identify that population. We don’t want to expose patients who will not benefit to the side effects and the cost and inconvenience of the drug. This is a costly agent like most newer targeted therapies so the more we can target the population, so to speak, the more we will have accomplished our goals.


Is there a timespan for coming up with the biomarker?


We collected tumour samples and blood samples from all patients who participated in the trial. The samples are currently being analysed in several laboratories of collaborating investigators. I would expect that by the middle of 2012 or, at the very latest, by this time next year we will have completed all of those analyses and assays and we will have some information to provide to our colleagues.