Cuzick 2011a.

Study characteristics
Methods	Nested case‐control study from within a multicentre, international randomised controlled trial (First International Breast Intervention Study, IBIS‐I). Recruitment April 1992 to March 2001, diagnosis before 1 October 2007. Prognostic and predictive biomarker study. Prevention setting.
Participants	123 cases from the UK and Finland, 942 controls from the UK. Age 35 to 70 years at recruitment to IBIS‐I trial. Premenopausal and postmenopausal women. Approximately twice population risk of developing breast cancer.
Comparisons	Tamoxifen 20 mg daily (n = 507), placebo daily (n = 558), 5 years of treatment. Visually assessed per cent density by a single reader in 5% increments. Density reduction 10% or more vs no change at 12‐ to 18‐month follow‐up mammogram in tamoxifen arm (prognostic biomarker). Density reduction 10% or more vs less than 10% at 12‐ to 18‐month follow‐up mammogram in tamoxifen arm compared with placebo arm (interaction, predictive biomarker).
	Outcome: incidence of invasive breast cancer and DCIS.
Notes	ClinicalTrials.gov Identifier: NCT00002644; ISRCTN number ISRCTN91879928; EudraCT number 2005‐003091‐38 Study chair: Jack Cuzick (author) Sponsor: QMUL Additional data provided for this review. Funding: Cancer Research UK (UK) and the National Health and Medical Research Council (Australia).
Item	Authors' judgement	Support for judgement
Study participation	Yes	The source population broadly matched our review target population; likewise the study population. The case‐control study was a subset of the trial and was reported to be similar to those not included in terms of age, background risk, and demographic factors; and tumour characteristics for cases.
Study attrition	Yes	The analysis population only included women who complied with randomised treatment allocation and were followed up in the main trial. There was little loss to follow‐up in the main trial. 44 of 7154 women (0.6%) withdrew and were not included in this case‐control study (referenced Cuzick 2015).
Prognostic factor measurement	Unclear	The method to measure mammographic density was valid according to review criteria. However, the definition of cutpoint for density change was not made before analysis.
Outcome measurement	Yes	Breast cancer incidence was ascertained from a clinical trial database.
Study confounding	Yes	Confounding variables from trial questionnaire. Results were adjusted for age at entry, breast density at entry, history of LCIS or atypical hyperplasia, and BMI. There was no adjustment for co‐interventions or HRT use, but this had no material impact on the estimate of risk reduction associated with a reduction in breast density. There was no difference in reported compliance between cases on tamoxifen with at least 10% reduction and cases on tamoxifen with less than 10% reduction.
Statistical analysis and reporting	Yes	Sufficient presentation of data to assess adequacy of analysis. Confounding variables used in the model were based on prior knowledge and biological reasoning and selected based on a step‐wise procedure and statistical significance (P < 0.05). A limitation of the reported results is that no interaction effect was provided in the paper; however, this was determined from data provided by the study authors.