title: Phase II randomized study of neoadjuvant everolimus plus letrozole compared with placebo plus letrozole in patients with estrogen receptor-positive breast cancer.
abstract: OBJECTIVE
  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).
  
  
  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.
  
  
  CONCLUSIONS
  Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.
authors.affiliation: Medical Oncology Department, Vall d'Hebron University Hospital, P Vall d'Hebron, Barcelona, Spain. jbaselga@vhebron.net
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Vladimir
authors.initials: V
authors.lastname: Semiglazov
authors.forename: Peter
authors.initials: P
authors.lastname: van Dam
authors.forename: Alexey
authors.initials: A
authors.lastname: Manikhas
authors.forename: Meritxell
authors.initials: M
authors.lastname: Bellet
authors.forename: José
authors.initials: J
authors.lastname: Mayordomo
authors.forename: Mario
authors.initials: M
authors.lastname: Campone
authors.forename: Ernst
authors.initials: E
authors.lastname: Kubista
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Giulia
authors.initials: G
authors.lastname: Bianchi
authors.forename: Jutta
authors.initials: J
authors.lastname: Steinseifer
authors.forename: Betty
authors.initials: B
authors.lastname: Molloy
authors.forename: Erika
authors.initials: E
authors.lastname: Tokaji
authors.forename: Humphrey
authors.initials: H
authors.lastname: Gardner
authors.forename: Penny
authors.initials: P
authors.lastname: Phillips
authors.forename: Michael
authors.initials: M
authors.lastname: Stumm
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Lane
authors.forename: J Michael
authors.initials: JM
authors.lastname: Dixon
authors.forename: Walter
authors.initials: W
authors.lastname: Jonat
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D017024:Chemotherapy, Adjuvant; D058534:Class I Phosphatidylinositol 3-Kinases; D019938:Cyclin D1 / Q000378:metabolism; D004311:Double-Blind Method; D005060:Europe; D000068338:Everolimus; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D000077289:Letrozole; D008875:Middle Aged; D009154:Mutation; D020360:Neoadjuvant Therapy; D009570:Nitriles / Q000008:administration & dosage; D010173:Palpation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage; D014481:United States
chemical_list: D000903:Antibiotics, Antineoplastic; D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; C530104:CCND1 protein, human; D019394:Ki-67 Antigen; D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D019938:Cyclin D1; D000077289:Letrozole; D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus