Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor–Positive Breast Cancer

Abstract

Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

“…Activation of AKT and overexpression of EGF and ERBB receptors are consistent with previous observations in MCF7-LTED cells and related breast cancer conditions (Masamura et al, 1995;Jeng et al, 1998;Shim et al, 2000;McClelland et al, 2001;Knowlden et al, 2003;Osborne et al, 2005;Yue et al, 2005;Song et al, 2006;Beeram et al, 2007;LewisWambi et al, 2008;Santen et al, 2008;Ghayad et al, 2009). Notably, ERBB2 amplification was associated with resistance to endocrine therapies (Ellis et al, 2006), and treatment with the mTOR inhibitor RAD001 increased letrozole efficacy in a neoadjuvant setting of ERa-positive breast cancer (Baselga et al, 2009).…”

“…However, these approaches have shown limited efficacy; in fact, fulvestrant only elicits a response in approximately 7% of ERa-positive tumors that regrow under AI therapy, although its clinical use is justified based on a clinical benefit rate of 32% (Chia et al, 2008). On the other hand, trials with combinations of AIs and growth factor signal inhibitors have not improved outcomes in most cases , except for recent results on novel combinations that are still under research (Baselga et al, 2009;Johnston et al, 2009). In this scenario, the dynamic profiles of our model coincide with previous findings concerning the relevance of growth factor signaling but, importantly, our data also support a different explanation of the role of ERa: firstly, the switch from pS118-to pS167-ERa, an isoform known to be related to MAPK/AKT signaling (Campbell et al, 2001), may indicate that sustained ERa expression is more a consequence of the activation of other pro-growth signals than a reflection of the importance of canonical ERa function; secondly, the fact that both over-and underexpressed gene sets during MCF7-LTED adaptation showed infra representation of ERa-responsive elements and were not enriched in 17bE2-mediated regulation from original MCF7 data (Carroll et al, 2006), suggests a molecular landscape in which ERa, despite sustained expression, is no longer a highly active transcription modulator.…”

Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

“…In phase III BOLERO-2 study, the addition of everolimus to exemestane can significantly improve the response rate and survival compared with women treated with exemestane alone in patient with metastatic breast cancer refractory to previous antiestrogen therapies (11). In neoadjuvant setting, combination of everolimus and letrozole had a better response rate and greater Ki67 expression inhibition compared with letrozole alone (12). Furthermore, everolimus also enhanced the treatment efficacy of tamoxifen in patients with ER-positive metastatic breast cancer (TAMRAD study; ref.…”

“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

“…Even the overall clinical response rate was significantly greater than letrozole alone treatment in this subset of patients [3].…”

“…Temsirolimus and everolims are currently selected for clinical trials. In the case of everolimus, on breast cancer, the Phase I trial identified the dose of 10 mg/day as optimal for further clinical development [3,11]. In the phase II, double-blind, randomized study of everolimus in combination with letrozole versus placebo and letrozole in the neoadjuvant setting [13], the combination arm proved to be superior over letrozole and placebo with a higher significant response rate (68% vs. 59%) [13].…”