title: Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial.
abstract: Despite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy.
  
  
  
  This randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed ≥4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] ≥1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety.
  
  
  
  Between 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1-4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole.
  
  
  
  These results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy.
  
  
  
  Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), ACTRN12607000137493.
authors: Australia and New Zealand Breast Cancer Trials Group, Waratah School of Medicine and Public Health, University of Newcastle, Callaghan, Australia nicholas.zdenkowski@anzbctg.org.
authors: N
authors: N
authors: Zdenkowski
authors: Australia and New Zealand Breast Cancer Trials Group, Waratah School of Medicine and Public Health, University of Newcastle, Callaghan, Australia.
authors: J F
authors: JF
authors: Forbes
authors: Australia and New Zealand Breast Cancer Trials Group, Waratah School of Medicine and Public Health, University of Newcastle, Callaghan, Australia Patricia Ritchie Centre for Cancer Care and Research, North Sydney.
authors: F M
authors: FM
authors: Boyle
authors: Ballarat Oncology and Haematology, Wendouree.
authors: G
authors: G
authors: Kannourakis
authors: Department of Surgery, Royal Adelaide Hospital, Adelaide.
authors: P G
authors: PG
authors: Gill
authors: Department of Medical Oncology, Royal Perth Hospital, Perth.
authors: E
authors: E
authors: Bayliss
authors: School of Surgery, University of Western Australia, Crawley.
authors: C
authors: C
authors: Saunders
authors: Southern Highlands Cancer Centre, Bowral.
authors: S
authors: S
authors: Della-Fiorentina
authors: Department of Surgery, St John of God Hospital, Bunbury, Australia.
authors: N
authors: N
authors: Kling
authors: Breast Care Centre, Waikato Hospital, Hamilton, New Zealand.
authors: I
authors: I
authors: Campbell
authors: Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville.
authors: G B
authors: GB
authors: Mann
authors: Australia and New Zealand Breast Cancer Trials Group, Waratah National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, Australia.
authors: A S
authors: AS
authors: Coates
authors: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, Australia.
authors: V
authors: V
authors: Gebski
authors: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, Australia.
authors: L
authors: L
authors: Davies
authors: Australia and New Zealand Breast Cancer Trials Group, Waratah.
authors: R
authors: R
authors: Thornton
authors: Australia and New Zealand Breast Cancer Trials Group, Waratah.
authors: L
authors: L
authors: Reaby
authors: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
authors: J
authors: J
authors: Cuzick
authors: Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville.
authors: M
authors: M
authors: Green
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D001315:Australia; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage*; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole
keywords: adjuvant; breast neoplasms; drug therapy; letrozole; postmenopausal