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Published online: 26 March 2013
© Springer International Publishing Switzerland 2013
Abstract Oral everolimus (Aftnitor') in combination with exemestane is indicated for the treatment of hormone receptor-positive, human epidermal growth factor receptor (HER) 2-negative advanced breast cancer in postmenopausal women after failure of treatment with letrozole or anastrozole (in the USA) or after recurrence of progression following a nonsteroidal aromatase inhibitor (AI) in women without symptomatic visceral disease (in the EU). Everolimus, a selective inhibitor of mammalian target of rapamycin (mTOR), inhibits the downstream signalling events of the mTOR pathway. This review summarizes the pharmacology of everolimus and reviews its efficacy and tolerability when administered in combination with exemestane in postmenopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer refractory to nonsteroidal Als. In the well-designed BOLERO-2 study, the addition of everolimus to exemestane was shown to significantly prolong progression-free survival in this patient population. However, treatment-emergent adverse events and treatment discontinuations occurred more frequently with combination therapy than with exemestane alone, suggesting a need for careful benefit/risk assessment prior to initiating therapy. Matine survival data from this study are awaited and additional studies would help to further demonstrate the benefit of combination therapy. Nevertheless, current evidence suggests that everolimus plus exemestane combination therapy may be a useful treatment option in patients with postmenopausal hormone receptor-positive, HER2-negative, advanced breast cancer refractory to nonsteroidal Als.
Keywords: Everolimus, advanced breast cancer, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
1 Introduction
Breast cancer is the most common cancer in women worldwide, accounting for an estimated 519,000 deaths in 2004 [1]. The use of therapies targeting the oestrogen receptor (ER) and human epidermal growth factor receptor (HER) 2 pathways (major drivers of 85 % of all tumours) in patients with early-stage breast cancer has resulted in marked reductions in tumour recurrence and death 12-41. However, some tumours are resistant to these therapies and others develop resistance to treatment after an initial response to hormone therapy (often due to the activation of alternative survival pathways), resulting in disease progression [2, 5, 6], It has been suggested that blocking the alternative or 'escape' pathways in addition to the main driver pathway may improve treatment outcome.
One such potential mechanism of treatment resistance is the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway...