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Overcoming Endocrine Resistance in Advanced Breast Cancer by Inhibiting the mTOR Pathway

09 Jan 2012
Breast cancer
Valentina Guarneri

Hormone receptor positive tumours are largely dependent on hormones and endocrine manipulation is the cornerstone of therapy. However, several hormone receptor positive patients are not responsive to hormonal therapy. Moreover, resistance to treatment can occur also in initially responsive patients.  Several studies have been conducted aiming to identify the molecular mechanisms of endocrine resistance and to identify potential drugable targets.

The phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway  is emerging as one of the most attractive targets since aberrant activation of this pathway has been associated with ligand-independent oestrogen receptor activation.

In a phase II neoadjuvant trial in patients with HR positive tumours, the mTOR inhibitor everolimus significantly increased letrozole activity (Baselga J et al, J Clin Oncol 2009). In the metastatic setting, the most interesting results derive from the TamRAD phase II study, where patients with prior exposure to aromatase inhibitors (AIs) were randomly assigned to receive tamoxifen versus tamoxifen plus everolimus (Bachelot, SABCS 2010). In this study, patients were stratified as having primary (recurrence while on AIs or progression within 6 months of AIs for metastatic disease) or secondary endocrine resistance. The primary endpoint of the study was met, resulting in a significant improvement in the clinical benefit rate with the combination. Moreover, a significant improvement in time to disease progression and overall survival was observed in patients receiving everolimus plus tamoxifen. The higher benefit in terms of time to progression was observed in patients with secondary resistance, possibly as a consequence of an enrichment of tumours dependent on the PI3K/AKT/mTOR pathway.

In the December issue of the New England Journal of Medicine, the results of the BOLERO-2 randomized, double blind, Phase III study were published. In this study, 724 metastatic breast cancer patients with hormone receptor positive, HER2 negative disease were randomized in a 2:1 ratio to everolimus and examestane versus placebo and examestane. Patients were eligible if they had recurrence or progression while on hormonal therapy with a non-steroidal AI in adjuvant or metastatic setting. The majority (84%) of patients was classified as having previous endocrine sensitive disease, as defined as at least 24 months of endocrine therapy before recurrence in the adjuvant setting, or a response/disease stabilization for at least 24 weeks of hormonal therapy therapy for  advanced disease.

The study met its primary end point since the progression free survival was significantly prolonged for patients receiving exemestane-everolimus as compared to patients receiving exemestane-placebo (median PFS: 6.9 months versus 2.8 months, HR 0.43, p<0.001).  Response rates were 9.5% and 0.5%, respectively (p<0.001). The results according to the central assessment were consistent for both PFS and RR.  With a total of 83 deaths, OS results are immature. As expected on the basis of everolimus and other rapamycin analogues safety profile, the combination of exemestane-everolimus was associated with a higher incidence of adverse events, including stomatitis, rash, fatigue, diarrhoea, hyperglycaemia, and pneumonitis. The rate of serious adverse events as well as the rate of treatment discontinuation was higher in the exemestane-everolimus arm. Thus, the inhibition of the mTOR pathway with everolimus in addition to exemestane significantly prolongs progression free survival in hormone receptor positive advanced breast cancer. However, the basis of the observed toxicity, careful monitoring of patients and adequate physician training are necessary, as also acknowledged by the authors.

Last update: 09 Jan 2012

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