Summary of findings 1. Prognostic biomarker ‐ treatment studies.

Women receiving endocrine therapy: mammographic density reduction versus no mammographic density reduction
Patient or population: women receiving endocrine therapy (selective oestrogen receptor modulator or aromatase inhibitor) Setting: treatment of early‐stage breast cancer Intervention: mammographic density reduction Comparison: no mammographic density reduction
Outcomes	Impact	№ of participants (studies)	Certainty of the evidence (GRADE)
Breast cancer mortality ‐ tamoxifen	OR 0.44 (95% CI 0.22 to 0.88) for per cent density reduction > 8.7% compared with < 0.5% (Cumulus density from mammograms 3 to 26 months apart; Nyante 2015). HR 0.50 (95% CI 0.27 to 0.93) for relative reduction in dense area > 20% compared with ≤ 9% increase to ≤ 10% reduction (automated machine‐learning measure on mammograms 6 to 36 months apart; Li 2013).	97 cases/252 controls (1 study) 217 exposed (26 events)/257 unexposed (49 events) (1 study)	⊕⊕⊝⊝ LOW 1
Recurrence ‐ tamoxifen	HR 0.66 (95% CI 0.40 to 1.09) for per cent density reduction ≥ 5% compared with < 5% (Cumulus density from mammograms 8 to 20 months apart; Kim 2012). HR 0.35 (95% CI 0.17 to 0.68) for reduction in BI‐RADS density categories compared with no reduction (BI‐RADS density on mammograms approximately 10 to 34 months apart; Ko 2013).	1956 (2 studies)	⊕⊝⊝⊝ VERY LOW 1 2 3
Recurrence ‐ AIs	HR 0.14 (95% CI 0.02 to 1.11) for per cent density reduction ≥ 5% compared with < 5% (Cumulus density from mammograms 8 to 20 months apart; Kim 2012).	175 (1 study)	⊕⊝⊝⊝ VERY LOW1 4 5
Recurrence (loco‐regional) ‐ endocrine therapies not separated (exemestane (AI)/tamoxifen (SERM))	HR 1.48 (95% CI 0.38 to 5.81) per Boyd category reduction (visual assessment of Boyd categories from mammograms 18 to 30 months apart; van Nes 2015).	284 (1 study)	⊕⊝⊝⊝ VERY LOW6 7
Recurrence (distance) ‐ endocrine therapies not separated (exemestane (AI)/tamoxifen (SERM))	HR 1.32 (95% CI 0.64 to 2.71) per Boyd category reduction (visual assessment of Boyd categories from mammograms 18 to 30 months apart; van Nes 2015).	284 (1 study)	⊕⊝⊝⊝ VERY LOW 6 7
Incidence of a secondary primary breast cancer (e.g. in the contralateral breast) ‐ endocrine therapies not separated (exemestane (AI)/tamoxifen (SERM)/unknown)	OR 0.52 (95% CI 0.18 to 1.51) for per cent density reduction ≥ 10% compared with < 10% increase to < 10% reduction (automated machine‐learning measure on mammograms 12 to 60 months apart; unknown endocrine therapy; Sandberg 2013). HR 0.58 (95% CI 0.08 to 4.44) per Boyd category reduction (visual assessment of Boyd categories from mammograms 18 to 30 months apart; exemestane or tamoxifen; van Nes 2015).	87 cases/87 controls (1 study) 277 (1 study)	⊕⊝⊝⊝ VERY LOW 8 9
AI: aromatase inhibitor; BI‐RADS: Breast Imaging Reporting and Data System; CI: confidence interval; DCIS: ductal carcinoma in situ; HR: hazard ratio; OR: odds ratio; SERM: selective oestrogen receptor modulator
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Certainty of evidence was initially graded low due to the observational, non‐randomised design of the contributing studies. No downgrading was applied.
²We downgraded the certainty of the evidence from low to very low (GRADE downgrading factor ‐ risk of bias): moderate risk of bias due to study participation, attrition, prognostic factor measurement, and outcome measurement in both studies; it is unclear if there were adjustments made in one study and no adjustment for important confounding factors such as chemotherapy made in another study; high risk of bias in statistical analysis for both studies due to potential difference in immortal time included in analysis (greater for those with larger density reductions).
³We downgraded the certainty of the evidence from low to very low (GRADE downgrading factor ‐ imprecision): confidence interval includes the null effect for the first study; in total, the evidence includes no more than 147 events (first study did not report the number of events in the tamoxifen subgroup (80 events in the study overall); 67 events in the second study).
⁴We downgraded the certainty of the evidence from low to very low (GRADE downgrading factor ‐ risk of bias): moderate risk of bias due to study participation, attrition, prognostic factor measurement, and outcome measurement; unclear if adjustments were made, and unclear if some women were treated with tamoxifen between baseline and follow‐up mammogram; high risk of bias in statistical analysis due to potential difference in immortal time included in analysis (greater for those with larger density reductions).
⁵We downgraded the certainty of the evidence from low to very low (GRADE downgrading factor ‐ imprecision): confidence interval includes the null effect; no more than 80 events (study does not provide the number of events in the AI subgroup, but there were 80 events in the study overall).
⁶Certainty of evidence was initially graded moderate because data for these outcomes were from a randomised controlled trial. We downgraded the certainty of the evidence from moderate to very low (GRADE downgrading factor ‐ risk of bias): the analysis of interest was a secondary objective and included only a subgroup of participants (women still at risk after two years of therapy), therefore data on women included in the subgroup analysis are not reported; results by individual endocrine therapy are not reported; there was no adjustment for important confounding factors such as age, body mass index, baseline density, time between mammograms, and chemotherapy.
⁷Certainty of evidence was initially graded moderate because data for these outcomes were from a randomised controlled trial. We downgraded the certainty of the evidence from moderate to very low (GRADE downgrading factor ‐ imprecision): confidence interval includes the null effect; no more than 284 events (study does not provide the number of events, but there were 284 women overall in the subgroup of women still at risk after 2 years of therapy).
⁸Certainty of evidence was initially graded low due to the observational, non‐randomised design of one of the contributing studies. We downgraded the certainty of the evidence from low to very low (GRADE downgrading factor ‐ risk of bias): in both studies, the analysis of interest was a secondary objective and included only a subgroup of participants (women on endocrine therapy and women still at risk after two years of therapy), therefore data on women included in the subgroup analyses are not reported; results by individual endocrine therapy are not reported (endocrine therapy was unknown in one study, and women were on either exemestane or tamoxifen between mammograms in the other study); one study matched for some confounding factors, but it was unclear if further adjustments were made, and no adjustments were made for important confounding factors such as age, body mass index, baseline density, time between mammograms, and chemotherapy in the other study.
⁹Certainty of evidence was initially graded low due to the observational, non‐randomised design of one of the contributing studies. We downgraded the certainty of the evidence from low to very low (GRADE downgrading factor ‐ imprecision): confidence intervals include the null effect; no more than 364 events (one study does not provide the number of events by density change category, but there were 87 cases overall on endocrine therapy; the other study does not provide the number of events, but there were 277 women overall in the subgroup of women still at risk after 2 years of therapy).