title: Effect of everolimus on bone marker levels and progressive disease in bone in BOLERO-2.
abstract: BACKGROUND
  Breast Cancer Trials of Oral Everolimus 2 (BOLERO-2), a phase III study in postmenopausal women with estrogen receptor-positive breast cancer progressing despite nonsteroidal aromatase inhibitor therapy, showed statistically significant benefits with adding everolimus to exemestane. Moreover, in preclinical studies, mammalian target of rapamycin inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of everolimus on bone marker levels and progressive disease in bone.
  
  
  METHODS
  Patients were treated with exemestane (25mg/day) and randomized (2:1) to everolimus (10mg/day; combination) or placebo (exemestane only). Exploratory endpoints included changes in bone turnover marker levels vs baseline and progressive disease in bone, defined as unequivocal progression of a preexisting bone lesion or the appearance of a new bone lesion.
  
  
  RESULTS
  Baseline disease characteristics were well balanced between arms (N = 724); baseline bisphosphonate use was not (43.9% combination vs 54.0% exemestane only). At a median of 18 months of follow-up, median progression-free survival (primary endpoint) was statistically significantly longer with the combination vs exemestane only (Cox proportional hazard ratio = 0.45, 95% confidence interval = 0.38 to 0.54; log-rank, 1-sided P < .0001). Bone marker levels at 6 and 12 weeks increased with exemestane only, as expected, but decreased with the combination. The cumulative incidence rate of progressive disease in bone was lower in the combination arm. Bone-related adverse events occurred with similar frequency in both arms (3.3% combination vs 4.2% exemestane only).
  
  
  CONCLUSIONS
  These exploratory analyses suggest that everolimus has beneficial effects on bone turnover and progressive disease in bone in patients receiving exemestane for hormone receptor-positive breast cancer progressing during/after nonsteroidal aromatase inhibitor therapy.
authors: Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. michael.gnant@meduniwien.ac.at
authors: Michael
authors: M
authors: Gnant
authors: Jose
authors: J
authors: Baselga
authors: Hope S
authors: HS
authors: Rugo
authors: Shinzaburo
authors: S
authors: Noguchi
authors: Howard A
authors: HA
authors: Burris
authors: Martine
authors: M
authors: Piccart
authors: Gabriel N
authors: GN
authors: Hortobagyi
authors: Janice
authors: J
authors: Eakle
authors: Hirofumi
authors: H
authors: Mukai
authors: Hiroji
authors: H
authors: Iwata
authors: Matthias
authors: M
authors: Geberth
authors: Lowell L
authors: LL
authors: Hart
authors: Peyman
authors: P
authors: Hadji
authors: Mona
authors: M
authors: El-Hashimy
authors: Shantha
authors: S
authors: Rao
authors: Tetiana
authors: T
authors: Taran
authors: Tarek
authors: T
authors: Sahmoud
authors: David
authors: D
authors: Lebwohl
authors: Mario
authors: M
authors: Campone
authors: Kathleen I
authors: KI
authors: Pritchard
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood; D000730:Androstadienes / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000097:blood* / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D016723:Bone Remodeling / Q000187:drug effects*; D001862:Bone Resorption / Q000188:drug therapy / Q000517:prevention & control; D001943:Breast Neoplasms / Q000097:blood / Q000737:chemistry / Q000473:pathology*; D024042:Collagen Type I / Q000378:metabolism; D015986:Confounding Factors, Epidemiologic; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D005598:Fractures, Spontaneous / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D010012:Osteogenesis / Q000187:drug effects; D017698:Postmenopause; D011347:Procollagen / Q000097:blood; D016016:Proportional Hazards Models; D011960:Receptors, Estrogen / Q000032:analysis; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D011347:Procollagen; D011960:Receptors, Estrogen; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D000469:Alkaline Phosphatase; C056516:exemestane; D020123:Sirolimus