title: Prognostic and predictive effects of diabetes, hypertension, and coronary artery disease among women on extended adjuvant letrozole: NCIC CTG MA.17.
abstract: BACKGROUND
  Women with breast cancer and diabetes mellitus (DM) have poorer survival. Mechanisms include insulin dysregulation and/or DM related co-morbidities (CM). In MA.17 adjuvant letrozole (LET) after 5 years of tamoxifen (TAM) reduced the risk of recurrence and improved survival. We evaluated DM, hypertension (HTN), and coronary artery disease (CAD) as prognostic and predictive factors in MA.17.
  
  
  METHODS
  Disease free survival, distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: in women treated by placebo (PLAC) based on the presence or absence of baseline DM (n = 462), HTN (n = 1627), CAD (n = 604) or any one of these CM (n = 2049), and between LET and PLAC groups in each CM. Analyses based on nodal status were performed.
  
  
  RESULTS
  DM was neither prognostic nor predictive for women on extended LET. Women with one CM had similar outcomes on LET compared to women free of CM. For node positive women, the difference between LET and PLAC in DDFS was greater among women with one CM (hazard ratio [HR] = 0.30 [0.15-0.60], p = 0.001) compared to those without CM (HR = 0.72 [0.45-1.16], p = 0.17, p interaction = 0.04). Women on PLAC with HTN trended towards lower DDFS (HR = 1.50 [0.98-2.3], p = 0.06) and OS (HR = 1.61 [0.95-2.72], p = 0.08) than non-HTN women. HTN women had better DDFS on LET than non-HTN women. Women with one CM on PLAC had lower OS (HR = 2.10 [1.26-3.51], p = 0.004) than those free of CM.
  
  
  CONCLUSIONS
  DM was not prognostic or predictive of outcomes. Women with CM who remain disease free after 5 years of TAM should be offered LET. HTN trended towards a negative prognosticator and outcomes among this group were improved on LET. More studies are needed to assess impact of adrenergic stimulation as a possible link to poorer breast cancer outcomes.
authors.affiliation: The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Canada. Electronic address: rgoodwin@ottawahospital.on.ca.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Goodwin
authors.affiliation: Notre-Dame Hospital, CHUM, Montreal, Quebec, Canada.
authors.forename: Rahima
authors.initials: R
authors.lastname: Jamal
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, Canada.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Booth
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Goss
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, Canada.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eisenhauer
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, Canada.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.affiliation: NCIC Clinical Trials Group, Queen's University, Kingston, Canada.
authors.forename: Lois E
authors.initials: LE
authors.lastname: Shepherd
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects; D047072:Aromatase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D015897:Comorbidity; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D003920:Diabetes Mellitus / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D000077289:Letrozole; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole
keywords: Adjuvant letrozole; Coronary artery disease; Diabetes; Hypertension; Predictive; Prognostic