title: Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer.
abstract: OBJECTIVE
  Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients.
  
  
  METHODS
  This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor-positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events).
  
  
  RESULTS
  Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003).
  
  
  CONCLUSIONS
  Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation.
authors.affiliation: Johns Hopkins Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. awolff@jhmi.edu
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.forename: Ann A
authors.initials: AA
authors.lastname: Lazar
authors.forename: Igor
authors.initials: I
authors.lastname: Bondarenko
authors.forename: August M
authors.initials: AM
authors.lastname: Garin
authors.forename: Stephen
authors.initials: S
authors.lastname: Brincat
authors.forename: Louis
authors.initials: L
authors.lastname: Chow
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Zora
authors.initials: Z
authors.lastname: Neskovic-Konstantinovic
authors.forename: Rodrigo C
authors.initials: RC
authors.lastname: Guimaraes
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: Arlene
authors.initials: A
authors.lastname: Chan
authors.forename: Soulef
authors.initials: S
authors.lastname: Hachemi
authors.forename: Andrew
authors.initials: A
authors.lastname: Strahs
authors.forename: Maria
authors.initials: M
authors.lastname: Cincotta
authors.forename: Anna
authors.initials: A
authors.lastname: Berkenblit
authors.forename: Mizue
authors.initials: M
authors.lastname: Krygowski
authors.forename: Lih Lisa
authors.initials: LL
authors.lastname: Kang
authors.forename: Laurence
authors.initials: L
authors.lastname: Moore
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects; D010919:Placebos; D017698:Postmenopause; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D009570:Nitriles; D010919:Placebos; D014230:Triazoles; C401859:temsirolimus; D000077289:Letrozole; D020123:Sirolimus