Anastrozole in Preventing Breast Cancer in Postmenopausal Women at Increased Risk of Breast Cancer (IBIS II)

International Breast Cancer Intervention Study

RATIONALE: Chemoprevention therapy is the use of certain drugs to try to prevent the development of cancer. Anastrozole may be effective in preventing breast cancer.

PURPOSE: This randomized clinical trial is studying how well anastrozole works in preventing breast cancer in postmenopausal women who are at increased risk for the disease.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: anastrozole; Drug: placebo

Detailed Description

OBJECTIVES:

Primary

• Determine the effectiveness of anastrozole in preventing breast cancer in postmenopausal women at increased risk for the disease.

Secondary

• Determine the role of this drug in preventing estrogen receptor-positive breast cancer in these participants.
• Determine the effect of this drug on breast cancer mortality in these participants.
• Determine the effect of this drug on other cancers, cardiovascular disease, fracture rates, and non-breast cancer deaths in these participants.
• Determine the tolerability and acceptability of side effects of this drug in these participants.

OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Participants are stratified according to participating center. Participants are randomized to 1 of 2 treatment arms.

• Arm I: Participants receive oral anastrozole daily for 5 years.
• Arm II: Participants receive an oral placebo daily for 5 years. In both arms, treatment continues in the absence of the development of breast cancer (including ductal carcinoma in situ), a drop in the T-score below minus 4, or the occurrence of a new fragility fracture.

Participants are followed for at least a further 5 years.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

ACCRUAL: A total of 3,864 participants were recruited for this study over 10 years.

• Study Type: Interventional
• Enrollment (Actual): 3864
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Newcastle, New South Wales, Australia, 2310
      • Newcastle Mater Hospital
• Belgium
  • Leuven, Belgium, B-3000
    • University Hospitals
• Chile
  • Santiago, Chile
    • Corporacion Nacional del Cancer
• Denmark
  • Horsholm, Denmark, Dk- 2730 Herlev
    • Herlev University Hospital
• Finland
  • Tampere, Finland, 33100
    • Pirkanmaa Cancer Society
• Germany
  • Frankfurt, Germany, 63263
    • GBG Forschungs GmbH
• Hungary
  • Szeged, Hungary, 6720
    • Department of Oncotherapy, University of Szeged
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Cork, Ireland
    • South Infirmary Victoria Hospital
  • Dublin, Ireland, 4
    • St. Vincent's University Hospital
  • Dublin, Ireland, 8
    • St. James's Hospital
  • Galway, Ireland
    • University College Hospital
  • Limerick, Ireland, 0009
    • Mid-Western Cancer Centre at Mid-Western Regional Hospital
  • Sligo, Ireland
    • Sligo General Hospital
  • Beaumont
    • Dublin, Beaumont, Ireland, 9
      • Beaumont Hospital
  • Tallaght
    • Dublin, Tallaght, Ireland, 24
      • Adelaide and Meath Hospital, Dublin Incorporating the National Children's Hospital
• Italy
  • Milan, Italy, 20141
    • Division of Chemoprevention
• Malta
  • Floriana, Malta, VLT 14
    • Sir Paul Boffa Hospital, Harper Lane
• Portugal
  • Lisbon, Portugal, 1099-023
    • Instituto Portugues De Oncologia, Gabinete De Estudos Clinicos
• Switzerland
  • Bern, Switzerland, CH-3010
    • Inselspital Bern
  • Bern, Switzerland, CH-3012
    • Oncocare Sonnenhof-Klinik Engeriedspital
  • Geneva, Switzerland, CH-1211
    • Hopital Cantonal Universitaire de Geneve
  • Mendrisio, Switzerland, CH-6850
    • Ospedale Beata Vergine
  • St. Gallen, Switzerland, CH-9006
    • Tumor Zentrum ZeTup St. Gallen und Chur
  • Thun, Switzerland, 3600
    • Regionalspital
• Turkey
  • Istanbul, Turkey
    • Ortaklar cad Pehlivan sok, Basak koviah ap.
• United Kingdom
  • Aberdeen, United Kingdom, AB25 2ZA
    • Aberdeen Royal Infirmary
  • Grantham, United Kingdom, LN2 5QY
    • Lincoln County Hospital
  • Huddersfield, United Kingdom, HX3 0PW
    • Calderdale Royal Hospital
  • London, United Kingdom, N19 5LW
    • Royal Free and UCL Medical School
  • Manchester, United Kingdom, M20 4BX
    • Paterson Institute for Cancer Research
  • Middlesex, United Kingdom, HA1 3UJ
    • Northwick Park Hospital
  • Newcastle, United Kingdom, NE2 4HH
    • School of Surgical & Reproductive Sciences
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham University Hospitals NHS Trust
  • Oldham, United Kingdom, OL1 2JH
    • Department of General Surgery Pennine Acute Hospitals NHS Trust
  • Plymouth, United Kingdom, PL6 8DH
    • Derriford Hospital
  • Sheffield, United Kingdom, S10 2SJ
    • Cancer Clinical Trials Centre
  • Sheffield, United Kingdom, S10 2SJ
    • Weston Park Hospital, Cancer Clinical Trials Centre, Department of Clinical Oncology
  • Southampton, United Kingdom, SO16 5YA
    • Princess Anne Hospital
  • Stafford, United Kingdom, ST16 3SA
    • Mid Staffordshire NHS Foundation Trust
  • Truro, United Kingdom, TR1 3LJ
    • Treliske Royal Cornwall Hospital
  • Wishaw, United Kingdom, ML2 0DP
    • Wishaw General Hospital
  • Yeovil, United Kingdom, BA21 4AT
    • Yeovil District Hospital
  • England
    • Ashton-Under-Lyne, England, United Kingdom, OL6 9RW
      • Tameside General Hospital
    • Bolton, England, United Kingdom, BL4 0JR
      • Royal Bolton Hospital
    • Bournemouth, England, United Kingdom, BH7 7DW
      • Royal Bournemouth Hospital
    • Bradford, England, United Kingdom, BD5 0NA
      • St. Luke's Hospital
    • Brighton, England, United Kingdom, BN2 5BE
      • Sussex Cancer Centre at Royal Sussex County Hospital
    • Bristol, England, United Kingdom, BS2 8HW
      • Bristol Royal Infirmary
    • Bristol, England, United Kingdom, BS16 1LE
      • Frenchay Hospital
    • Burton-upon-Trent, England, United Kingdom, DE13 0RB
      • Queen's Hospital
    • Chelmsford, England, United Kingdom, CM1 7ET
      • Broomfield Hospital
    • Cheltenham, England, United Kingdom, GL53 7AN
      • Gloucestershire Oncology Centre at Cheltenham General Hospital
    • Chester, England, United Kingdom, CH2 1UL
      • Countess of Chester Hospital
    • Colchester, England, United Kingdom, C03 3NB
      • Essex County Hospital
    • Derby, England, United Kingdom, DE1 2QY
      • Royal Derby Hospital
    • Epping, England, United Kingdom, CM16 6TN
      • Saint Margaret's Hospital,
    • Exeter, England, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Frimley, England, United Kingdom, GU16 7UJ
      • Frimley Park Hospital
    • Hastings, England, United Kingdom, TN37 7RD
      • Conquest Hospital
    • Hull, England, United Kingdom, HU16 5JQ
      • Castle Hill Hospital
    • Keighley, England, United Kingdom, BD20 6TD
      • Airedale General Hospital
    • Leeds, England, United Kingdom, LS9 7TF
      • Leeds Cancer Centre at St. James's University Hospital
    • Lincoln, England, United Kingdom, LN2 5QY
      • Lincoln County Hospital
    • Liverpool, England, United Kingdom, L7 8XP
      • Royal Liverpool University Hospital
    • London, England, United Kingdom, EC1A 7BE
      • Saint Bartholomew's Hospital
    • London, England, United Kingdom, SW3 6JJ
      • Royal Marsden - London
    • London, England, United Kingdom, SE1 9RT
      • Guy's Hospital
    • Macclesfield, England, United Kingdom, SK10 3BL
      • Macclesfield District General Hospital
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT9 7AB
      • Centre for Cancer Research and Cell Biology at Queen's University Belfast
  • Scotland
    • Dundee, Scotland, United Kingdom, DD1 9SY
      • Ninewells Hospital
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Edinburgh Cancer Centre at Western General Hospital
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 4XW
      • University Hospital of Wales
    • Swansea, Wales, United Kingdom, SA2 8QA
      • Singleton Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• Meets at least 1 of the relative risk factors based on age as follows:

  • 45 to 70 years of age:

    • First-degree relative who developed breast cancer at ≤ 50 years of age
    • First-degree relative who developed bilateral breast cancer

    • Two or more first- or second-degree relatives who developed breast cancer or ovarian cancer

      • Participants having both relatives who are second degree and on the opposite sides of the family must have at least one that was diagnosed at ≤ 50 years of age
    • Nulliparous (or first birth at ≥ 30 years of age) and a first-degree relative who developed breast cancer
    • Benign biopsy with proliferative disease and a first-degree relative who developed breast cancer
    • Mammographic opacity covering at least 50% of the breast in the absence of hormone replacement therapy within the past 3 months

  • 60 to 70 years of age:

    • First-degree relative with breast cancer at any age
    • Age at menopause ≥ 55 years
    • Nulliparous or age at first birth ≥ 30 years

  • 40 to 44 years of age:

    • Two or more first- or second-degree relatives who developed breast cancer or ovarian cancer at ≤ 50 years of age
    • First-degree relative with bilateral breast cancer who developed the first breast cancer at ≤ 50 years of age
    • Nulliparous (or first birth at ≥ 30 years of age) and a first-degree relative who developed breast cancer at ≤ 40 years of age
    • Benign biopsy with proliferative disease and a first-degree relative who developed breast cancer at ≤ 40 years of age

• All age groups (40 to 70 ears of age) with a 10-year risk > 5% who do not fit into the above categories are allowed

  • Clearly apparent family history AND/OR other risk factors indicating appropriate increased risk of breast cancer for age

• The following prior breast conditions are allowed (for all age groups):

  • Lobular carcinoma in situ
  • Atypical ductal or lobular hyperplasia in a benign lesion
  • Ductal carcinoma in-situ (DCIS), diagnosed within the past 6 months, and treated by mastectomy
• No evidence of breast cancer on mammogram within the past year

• Hormone receptor status:

  • For patients with prior DCIS, estrogen- or progesterone-receptor status must have been positive

    • Must have had greater than or equal to 5% positive cells

PATIENT CHARACTERISTICS:

Age

• 40 to 70

Sex

• Female

Menopausal status

• Postmenopausal, defined as at least 1 of the following:

  • Over 60 years of age
  • Bilateral oophorectomy
  • ≤ 60 years of age with a uterus and amenorrhea for at least 12 months
  • ≤ 60 years of age without a uterus and with follicle-stimulating hormone levels > 30 IU/L

Performance status

• Not specified

Life expectancy

• At least 10 years

Hematopoietic

• Not specified

Hepatic

• Not specified

Renal

• Not specified

Other

• Psychologically and physically suitable to receive 5 years of anti-estrogen therapy
• No cancer within the past 5 years except non-melanoma skin cancer or carcinoma in situ of the cervix

• No evidence of osteoporosis or fragility fractures within the spine

  • Participants with a T-score > minus 4 and no more than 2 fragility fractures are allowed
• No concurrent severe disease that would place the participant at unusual risk or confound the results of the study
• No other medical condition that would preclude the ability to receive the study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• No prior tamoxifen, raloxifene, or other selective estrogen receptor modulator (SERM) use for more than 6 months in duration unless an IBIS-I participant (must have been off trial therapy for at least 5 years.
• No concurrent tamoxifen, raloxifene, or other SERM
• No concurrent estrogen-based hormone replacement therapy
• No concurrent systemic estrogen replacement therapy, including vaginal estrogen preparations

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics
• No prior prophylactic mastectomy
• No concurrent prophylactic mastectomy

Other

• More than 6 months since prior investigational drugs

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: anastrozole; anastrozole 1mg	Drug: anastrozole; aromatase inhibitor; Other Names: Arimidex
Placebo Comparator: placebo; anastrozole 1mg PLACEBO	Drug: placebo; Arimidex placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Development of histologically confirmed breast cancer, both invasive and non-invasive with median follow-up at 5 years	Dec 2013

Secondary Outcome Measures

Outcome Measure	Time Frame
Breast cancer mortality with median follow-up at 10 years	Dec 2018

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Investigators: Study Chair: Jack Cuzick, PhD, Queen Mary University of London; Study Chair: Anthony Howell, University of Manchester

Publications and helpful links

General Publications

• Sestak I, Singh S, Cuzick J, Blake GM, Patel R, Gossiel F, Coleman R, Dowsett M, Forbes JF, Howell A, Eastell R. Changes in bone mineral density at 3 years in postmenopausal women receiving anastrozole and risedronate in the IBIS-II bone substudy: an international, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2014 Dec;15(13):1460-1468. doi: 10.1016/S1470-2045(14)71035-6. Epub 2014 Nov 11. Erratum In: Lancet Oncol. 2014 Dec;15(13):e587. Lancet Oncol. 2014 Dec;15(13):e587.
• Cuzick J, Sestak I, Forbes JF, Dowsett M, Knox J, Cawthorn S, Saunders C, Roche N, Mansel RE, von Minckwitz G, Bonanni B, Palva T, Howell A; IBIS-II investigators. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet. 2014 Mar 22;383(9922):1041-8. doi: 10.1016/S0140-6736(13)62292-8. Epub 2013 Dec 12. Erratum In: Lancet. 2014 Mar 22;383(9922):1040. Lancet. 2017 Mar 11;389(10073):1010.
• Sestak I, Smith SG, Howell A, Forbes JF, Cuzick J. Early participant-reported symptoms as predictors of adherence to anastrozole in the International Breast Cancer Intervention Studies II. Ann Oncol. 2018 Feb 1;29(2):504-509. doi: 10.1093/annonc/mdx713.
• Jenkins VA, Ambroisine LM, Atkins L, Cuzick J, Howell A, Fallowfield LJ. Effects of anastrozole on cognitive performance in postmenopausal women: a randomised, double-blind chemoprevention trial (IBIS II). Lancet Oncol. 2008 Oct;9(10):953-61. doi: 10.1016/S1470-2045(08)70207-9. Epub 2008 Sep 1.

Helpful Links

• Clinical trial summary from Cancer Research UK Website
• IBIS-II website

Study record dates

Study Major Dates

• Study Start: September 1, 2003
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): May 31, 2021

Study Registration Dates

• First Submitted: March 8, 2004
• First Submitted That Met QC Criteria: March 8, 2004
• First Posted (Estimate): March 9, 2004

Study Record Updates

• Last Update Posted (Actual): October 6, 2021
• Last Update Submitted That Met QC Criteria: October 5, 2021
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: breast cancer, chemoprevention
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Anastrozole
• Other Study ID Numbers: ISRCTN31488319; EU-20227; EUDRACT-2004-003991-12