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

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

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. 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, 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.

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

Trial registration: ClinicalTrials.gov NCT00107016.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibiotics, Antineoplastic / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Aromatase Inhibitors / administration & dosage
  • Biomarkers, Tumor / metabolism*
  • Biopsy
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Chemotherapy, Adjuvant
  • Class I Phosphatidylinositol 3-Kinases
  • Cyclin D1 / metabolism
  • Double-Blind Method
  • Europe
  • Everolimus
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Ki-67 Antigen / metabolism
  • Letrozole
  • Middle Aged
  • Mutation
  • Neoadjuvant Therapy
  • Nitriles / administration & dosage
  • Palpation
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphorylation
  • Postmenopause
  • Receptors, Estrogen / metabolism*
  • Receptors, Progesterone / metabolism
  • Ribosomal Protein S6 Kinases / metabolism
  • Sirolimus / administration & dosage
  • Sirolimus / analogs & derivatives
  • Time Factors
  • Treatment Outcome
  • Triazoles / administration & dosage
  • United States

Substances

  • Antibiotics, Antineoplastic
  • Aromatase Inhibitors
  • Biomarkers, Tumor
  • CCND1 protein, human
  • Ki-67 Antigen
  • Nitriles
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Triazoles
  • Cyclin D1
  • Letrozole
  • Everolimus
  • Phosphatidylinositol 3-Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • Ribosomal Protein S6 Kinases
  • Sirolimus

Associated data

  • ClinicalTrials.gov/NCT00107016