Originally published as JCO Early Release 10.1200/JCO.2008.18.8391 on April 20 2009

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

From the Vall d'Hebron University Hospital, Barcelona; Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain; NN Petrov Research Institute of Oncology; and City Oncological Dispensary, St Petersburg, Russian Federation; Onc Centrum St Augustinus, Wilrijk, Belgium; Centre Rene Gauducheau, Nantes, France; Department of Special Gynecology, Medical University of Vienna/Austria; University Hospital, Salzburg, Austria; Istituto Nazionale Tumori, Milan, Italy; Novartis Pharma AG, Basel, Switzerland; Novartis Institutes for Biomedical Research, Cambridge, MA; Novartis Pharmaceuticals, East Hanover, NJ; Western General Hospital, Edinburgh, United Kingdom; Univ-Frauenklinik, Kiel, Germany; and University of California, San Francisco, CA.

Corresponding author: José Baselga, MD, Medical Oncology Department, Vall d'Hebron University Hospital, P Vall d'Hebron, 119-129, 08035 Barcelona, Spain; e-mail: jbaselga{at}vhebron.net.

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. 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.

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, = 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.

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

Supported by Novartis Pharma AG, Basel, Switzerland.

Presented in part at the 30th Annual San Antonio Breast Cancer Symposium, December 13-16, 2007, San Antonio, TX, and at the 44th Annual Meeting of the American Society for Clinical Oncology, May 31-June 3, 2008, Chicago IL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical trial information can be found for the following: NCT00107016.

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