title: Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.
abstract: BACKGROUND
  In the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study.
  
  
  METHODS
  Patients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations.
  
  
  RESULTS
  The safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%).
  
  
  CONCLUSIONS
  Most EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education.
  
  
  BACKGROUND
  NCT00863655.
authors.affiliation: University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, UCSF, San Francisco, USA. Electronic address: hrugo@medicine.ucsf.edu.
authors.forename: H S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, Canada.
authors.forename: K I
authors.initials: KI
authors.lastname: Pritchard
authors.affiliation: Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Gnant
authors.affiliation: Department of Breast and Endocrine Surgery, Osaka University, Osaka, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Institut Jules Bordet, Brussels, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Piccart
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: G
authors.initials: G
authors.lastname: Hortobagyi
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York.
authors.forename: J
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Memorial Cancer Institute, Hollywood, USA.
authors.forename: A
authors.initials: A
authors.lastname: Perez
authors.affiliation: Praxisklinic am Rosengarten Mannheim, Schwerpunktpraxis für Gynaekologische Onkologie, Mannheim, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Geberth
authors.affiliation: Department of Medical Oncology, Jasz-Nagykun-Szolnok Megyei Hetenyi Geza Korhaz-Rendelointezet, Szolnok, Hungary.
authors.forename: T
authors.initials: T
authors.lastname: Csoszi
authors.affiliation: Cambridge Memorial Hospital, Cambridge, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Chouinard
authors.affiliation: Siriraj Hospital, Mahidol University, Bangkok.
authors.forename: V
authors.initials: V
authors.lastname: Srimuninnimit
authors.affiliation: Songklanagarind Hospital, Faculty of Medicine, Prince of Songkla University, Songkla, Thailand.
authors.forename: P
authors.initials: P
authors.lastname: Puttawibul
authors.affiliation: Florida Cancer Specialists, Ft Myers.
authors.forename: J
authors.initials: J
authors.lastname: Eakle
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, USA.
authors.forename: W
authors.initials: W
authors.lastname: Feng
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Bauly
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, USA.
authors.forename: M
authors.initials: M
authors.lastname: El-Hashimy
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, USA.
authors.forename: T
authors.initials: T
authors.lastname: Taran
authors.affiliation: Sarah Cannon Research Institute, Nashville, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D000068338:Everolimus; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D017698:Postmenopause; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
chemical_list: D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: advanced breast cancer; everolimus; mammalian target of rapamycin (mTOR); safety