Nyante 2015.

Study characteristics
Methods	Case‐control study. Controls matched to cases on age at diagnosis, diagnosis year, and disease stage. Non‐randomised allocation of endocrine therapy. Initial ER+ breast cancer diagnosis 1990 to 2008, recruitment 1 January 1991 to 31 December 2010 (also end of follow‐up). Prognostic biomarker. Treatment setting.
Participants	Kaiser Permanente Northwest, USA. 97 cases and 252 controls. Age 32 to 87 years at first diagnosis. Premenopausal and postmenopausal women. All invasive at first diagnosis.
Comparisons	Tamoxifen (all women), at least 1 tamoxifen prescription started within 1 year of diagnosis. Cumulus per cent density. Density reduction more than 8.7% vs less than 0.5% at 3‐ to 26‐month follow‐up mammogram.
	Outcome: breast cancer mortality (time to death caused by breast cancer).
Notes
Item	Authors' judgement	Support for judgement
Study participation	Unclear	The source population is women enrolled in a US health plan and diagnosed with early‐stage (no distant metastasis) ER‐positive unilateral primary breast cancer and treated with adjuvant tamoxifen, which is similar to the review target population. 2141 women met the eligibility criteria for the source population including 134 cases of whom 97 (72%) had mammograms available. 252 controls with mammograms available were matched. No information was provided on the characteristics of those cases included based on mammogram availability vs those not included.
Study attrition	Yes	"Follow‐up time was calculated as the time between the first tamoxifen prescription and the earliest of the following: breast cancer death, death from another cause, last tumor registry follow‐up, or December 31, 2010."
Prognostic factor measurement	Yes	Valid and reliable density and density change measures according to review protocol criteria.
Outcome measurement	Yes	From population registry, clear definitions of start of follow‐up and reasons for censoring
Study confounding	Yes	Several confounding measures were recorded, but not all kept in the final adjusted model (including chemotherapy, although this was considered). The adjusted model included tumour differentiation, duration of tamoxifen use, smoking status. Study used prescription records to test whether tamoxifen non‐adherence (compliance) affected the relationship between density change and breast cancer death.
Statistical analysis and reporting	Yes	Overall analysis well reported and adequate. Adjustment was based on "statistical significance" (P < 0.05) in a forward step‐wise variable selection procedure. This did not include selection of chemotherapy, resulting in a small risk of bias in the reported estimate. Chemotherapy affects breast density and prognosis and is expected to influence the adjusted effect size of density change, even if not selected in the step‐wise procedure.