ESMO 2011 Report – Bolero-2 Trial: Paradigm shift in the management of breast cancer

by Dr Sunil Upadhyay – Breast cancer is one of the commonest malignancies among women all over the world. Though the incidence of diagnosed breast cancer continues to rise, mortality rate has continued to improve due to early diagnosis, improved understanding of its biology and better multimodality treatment. Breast cancer is a heterogeneous disease with a variable and unpredictable natural history. Nearly 85% of the tumours are endocrine receptor positive and the majority of these are endocrine treatment sensitive. However, some tumours are resistant to endocrine therapy de novo or acquire resistance after initial benefit. Significant progress has been made in the understanding of the development of resistance to oestrogen deprivation with aromatase inhibitors. One of the mechanisms of the development of resistance is the presence of cross talk between the oestrogen receptor and EGFR1 and activation of alternate signalling pathways within the cancer cell. Hyperactivation of the PI3K/mTOR pathway is observed in endocrine-resistant breast cancer cells. Therefore, mTOR is a rational target to enhance the efficacy of hormone therapy and overcome resistance.

Some of the Phase I/II studies have shown that mTOR inhibitors like everolimus improve the efficacy of aromatase inhibitors and possibly reverse resistance to these agents. The results of the Phase III BOLERO-2 trial were presented by Jose Baselga from Boston on the use of everolimus in combination with exemestane for post-menopausal women with advanced breast cancer who were refractory to letrozole or anastrozole.

In this study, post-menopausal, ER positive, HER2 negative patients resistant to non-steroidal aromatase inhibitors were randomised to receive everolimus 10 mg/day plus exemestane 25mg daily (n=485) or placebo plus exemestane 25mg daily (n=239) until disease progression or unacceptable toxicity. The primary end point was PFS and the secondary end points were overall survival, response rate and safety. No cross over was permitted

The results presented showed that the baseline characteristics were well balanced between the two arms of the study. The median age was 62 years and 56% had visceral involvement including liver or lung metastases. At the pre-planned interim analysis, the PFS assessed by local investigators was 6.9 vs 2.8 months in favour of everolimus (HR=0.43; p ≤0.0001) and the results were consistent across the various subgroups. The PFS based on central assessment was also in favour of the combination treatment group.

Both analyses crossed the pre-specified thresholds for significance. The overall response rates were 9.5% vs 0.4% and clinical benefit 33.4% vs 18.0% in favour of the combination arm (p<0.0001). The most common grade 3/4 toxicities were stomatitis (8% vs 1%), anaemia (5% vs <1%), dyspnoea (4% vs 1%), hyperglycaemia (4% vs <1%), fatigue (3% vs 1%) and pneumonitis (3% vs 0%) for the everolimus + exemestane and exemestane groups respectively.

Development of hormone resistance and its management remains a critical unmet need in post-menopausal ER positive, HER 2 negative breast cancer patients particularly women who are either unsuitable for cytotoxic systemic therapy or do not want to take that route. Everolimus is the first drug to show significant efficacy when combined with hormone therapy in a Phase III randomised trial. The magnitude of benefit seen is encouraging. These data are robust and clinically meaningful. It is the most important advancement in the management of breast cancer and can be a paradigm shift in the management of these patients. (Abstract 9LBA)