PMID- 19380449
OWN - NLM
STAT- MEDLINE
DCOM- 20090611
LR  - 20220330
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Linking)
VI  - 27
IP  - 16
DP  - 2009 Jun 1
TI  - Phase II randomized study of neoadjuvant everolimus plus letrozole compared with 
      placebo plus letrozole in patients with estrogen receptor-positive breast cancer.
PG  - 2630-7
LID - 10.1200/JCO.2008.18.8391 [doi]
AB  - 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.
FAU - Baselga, Jose
AU  - Baselga J
AD  - Medical Oncology Department, Vall d'Hebron University Hospital, P Vall d'Hebron, 
      Barcelona, Spain. jbaselga@vhebron.net
FAU - Semiglazov, Vladimir
AU  - Semiglazov V
FAU - van Dam, Peter
AU  - van Dam P
FAU - Manikhas, Alexey
AU  - Manikhas A
FAU - Bellet, Meritxell
AU  - Bellet M
FAU - Mayordomo, Jose
AU  - Mayordomo J
FAU - Campone, Mario
AU  - Campone M
FAU - Kubista, Ernst
AU  - Kubista E
FAU - Greil, Richard
AU  - Greil R
FAU - Bianchi, Giulia
AU  - Bianchi G
FAU - Steinseifer, Jutta
AU  - Steinseifer J
FAU - Molloy, Betty
AU  - Molloy B
FAU - Tokaji, Erika
AU  - Tokaji E
FAU - Gardner, Humphrey
AU  - Gardner H
FAU - Phillips, Penny
AU  - Phillips P
FAU - Stumm, Michael
AU  - Stumm M
FAU - Lane, Heidi A
AU  - Lane HA
FAU - Dixon, J Michael
AU  - Dixon JM
FAU - Jonat, Walter
AU  - Jonat W
FAU - Rugo, Hope S
AU  - Rugo HS
LA  - eng
SI  - ClinicalTrials.gov/NCT00107016
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20090420
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Aromatase Inhibitors)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (CCND1 protein, human)
RN  - 0 (Ki-67 Antigen)
RN  - 0 (Nitriles)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Receptors, Progesterone)
RN  - 0 (Triazoles)
RN  - 136601-57-5 (Cyclin D1)
RN  - 7LKK855W8I (Letrozole)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
CIN - J Clin Oncol. 2009 Jun 1;27(16):2580-2. PMID: 19380439
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibiotics, Antineoplastic/administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use
MH  - Aromatase Inhibitors/administration & dosage
MH  - Biomarkers, Tumor/*metabolism
MH  - Biopsy
MH  - Breast Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Cell Proliferation/drug effects
MH  - Chemotherapy, Adjuvant
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Cyclin D1/metabolism
MH  - Double-Blind Method
MH  - Europe
MH  - Everolimus
MH  - Female
MH  - Gene Expression Regulation, Enzymologic
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Ki-67 Antigen/metabolism
MH  - Letrozole
MH  - Middle Aged
MH  - Mutation
MH  - Neoadjuvant Therapy
MH  - Nitriles/administration & dosage
MH  - Palpation
MH  - Phosphatidylinositol 3-Kinases/genetics
MH  - Phosphorylation
MH  - Postmenopause
MH  - Receptors, Estrogen/*metabolism
MH  - Receptors, Progesterone/metabolism
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - Sirolimus/administration & dosage/analogs & derivatives
MH  - Time Factors
MH  - Treatment Outcome
MH  - Triazoles/administration & dosage
MH  - United States
EDAT- 2009/04/22 09:00
MHDA- 2009/06/12 09:00
CRDT- 2009/04/22 09:00
PHST- 2009/04/22 09:00 [entrez]
PHST- 2009/04/22 09:00 [pubmed]
PHST- 2009/06/12 09:00 [medline]
AID - JCO.2008.18.8391 [pii]
AID - 10.1200/JCO.2008.18.8391 [doi]
PST - ppublish
SO  - J Clin Oncol. 2009 Jun 1;27(16):2630-7. doi: 10.1200/JCO.2008.18.8391. Epub 2009 
      Apr 20.