title: Specific adverse events predict survival benefit in patients treated with tamoxifen or aromatase inhibitors: an international tamoxifen exemestane adjuvant multinational trial analysis.
abstract: OBJECTIVE
  Specific adverse events (AEs) associated with endocrine therapy and related to depletion or blocking of circulating estrogens may be related to treatment efficacy. We investigated the relationship between survival outcomes and specific AEs including vasomotor symptoms (VMSs), musculoskeletal adverse events (MSAEs), and vulvovaginal symptoms (VVSs) in postmenopausal patients with breast cancer participating in the international Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial.
  
  
  METHODS
  Primary efficacy end points were disease-free survival (DFS), overall survival (OS), and distant metastases (DM). VMSs, MSAEs, and VVSs arising in the first year of endocrine treatment were considered. Patients who did not start or who discontinued their allocated therapy and/or had an event (recurrence/death) within 1 year after randomization were excluded. Landmark analyses and time-dependent multivariate Cox proportional hazards models assessed survival differences up to 5 years from the start of treatment.
  
  
  RESULTS
  A total of 9,325 patients were included. Patients with specific AEs (v nonspecific or no AEs) had better DFS and OS (multivariate hazard ratio [HR] for DFS: VMSs, 0.731 [95% CI, 0.618 to 0.866]; MSAEs, 0.826 [95% CI, 0.694 to 0.982]; VVSs, 0.769 [95% CI, 0.585 to 1.01]; multivariate HR for OS: VMSs, 0.583 [95% CI, 0.424 to 0.803]; MSAEs, 0.811 [95% CI, 0.654 to 1.005]; VVSs, 0.570 [95% CI, 0.391 to 0.831]) and fewer DM (VMSs, 0.813 [95% CI, 0.664 to 0.996]; MSAEs, 0.749 [95% CI, 0.601 to 0.934]; VVSs, 0.687 [95% CI, 0.436 to 1.085]) than patients not reporting these symptoms. Increasing numbers of specific AEs were also associated with better survival outcomes. Outcomes were unrelated to treatment allocation.
  
  
  CONCLUSIONS
  Certain specific AEs are associated with superior survival outcomes and may therefore be useful in predicting treatment responses in patients with breast cancer treated with endocrine therapy.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Duveken B Y
authors.initials: DB
authors.lastname: Fontein
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.forename: Peyman
authors.initials: P
authors.lastname: Hadji
authors.forename: Elysée T M
authors.initials: ET
authors.lastname: Hille
authors.forename: Willemien
authors.initials: W
authors.lastname: van de Water
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: Elma Meershoek-Klein
authors.initials: EM
authors.lastname: Kranenbarg
authors.forename: Annette
authors.initials: A
authors.lastname: Hasenburg
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Paridaens
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vannetzel
authors.forename: Christos
authors.initials: C
authors.lastname: Markopoulos
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hozumi
authors.forename: John M S
authors.initials: JM
authors.lastname: Bartlett
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Jones
authors.forename: Daniel William
authors.initials: DW
authors.lastname: Rea
authors.forename: Johan W R
authors.initials: JW
authors.lastname: Nortier
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000009:adverse effects* / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects* / Q000627:therapeutic use; D047072:Aromatase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005831:Genital Diseases, Female / Q000139:chemically induced; D006801:Humans; D007391:International Cooperation; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009140:Musculoskeletal Diseases / Q000139:chemically induced; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data*; D011379:Prognosis; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D013629:Tamoxifen / Q000009:adverse effects* / Q000627:therapeutic use; D014666:Vasomotor System / Q000187:drug effects / Q000473:pathology
chemical_list: D000730:Androstadienes; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D013629:Tamoxifen; C056516:exemestane