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Clinical Trial
. 2009 Jun 1;27(16):2630-7.
doi: 10.1200/JCO.2008.18.8391. Epub 2009 Apr 20.

Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer

José Baselga  1 , Vladimir Semiglazov, Peter van Dam, Alexey Manikhas, Meritxell Bellet, José Mayordomo, Mario Campone, Ernst Kubista, Richard Greil, Giulia Bianchi, Jutta Steinseifer, Betty Molloy, Erika Tokaji, Humphrey Gardner, Penny Phillips, Michael Stumm, Heidi A Lane, J Michael Dixon, Walter Jonat, Hope S Rugo
Affiliations
Clinical Trial

"V体育平台登录" Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer

José Baselga et al. J Clin Oncol. .

Abstract

Purpose: Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models VSports手机版. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001). .

Patients and methods: Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2. 5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry. V体育安卓版.

Results: Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone (ie, placebo; 68. 1% v 59. 1%), which was statistically significant at the preplanned, one-sided, alpha = 0. 1 level (P = . 062). Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms, and dramatic downregulation of phospho-S6 occurred only in the everolimus arm. An antiproliferative response, as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15, occurred in 52 (57%) of 91 patients in the everolimus arm and in 25 (30%) of 82 patients in the placebo arm (P < . 01). The safety profile was consistent with historical results of everolimus monotherapy; grades 3 to 4 adverse events occurred in 22. 6% of patients who received everolimus and in 3. 8% of patients who received placebo V体育ios版. .

Conclusion: Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer. VSports最新版本.

Trial registration: ClinicalTrials. gov NCT00107016. V体育平台登录.

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