Development and evaluation of a method to assess breast cancer risk using a longitudinal history of mammographic density: a cohort study.

BACKGROUND: Women with dense breasts have an increased risk of breast cancer. However, breast density is measured with variability, which may reduce the reliability and accuracy of its association with breast cancer risk. This is particularly relevant when visually assessing breast density due to variation in inter- and intra-reader assessments. To address this issue, we developed a longitudinal breast density measure which uses an individual woman's entire history of mammographic density, and we evaluated its association with breast cancer risk as well as its predictive ability. METHODS: In total, 132,439 women, aged 40-73 yr, who were enrolled in Kaiser Permanente Washington and had multiple screening mammograms taken between 1996 and 2013 were followed up for invasive breast cancer through 2014. Breast Imaging Reporting and Data System (BI-RADS) density was assessed at each screen. Continuous and derived categorical longitudinal density measures were developed using a linear mixed model that allowed for longitudinal density to be updated at each screen. Predictive ability was assessed using (1) age and body mass index-adjusted hazard ratios (HR) for breast density (time-varying covariate), (2) likelihood-ratio statistics (ΔLR-χ2) and (3) concordance indices. RESULTS: In total, 2704 invasive breast cancers were diagnosed during follow-up (median = 5.2 yr; median mammograms per woman = 3). When compared with an age- and body mass index-only model, the gain in statistical information provided by the continuous longitudinal density measure was 23% greater than that provided by BI-RADS density (follow-up after baseline mammogram: ΔLR-χ2 = 379.6 (degrees of freedom (df) = 2) vs. 307.7 (df = 3)), which increased to 35% (ΔLR-χ2 = 251.2 vs. 186.7) for follow-up after three mammograms (n = 76,313, 2169 cancers). There was a sixfold difference in observed risk between densest and fattiest eight-category longitudinal density (HR = 6.3, 95% CI 4.7-8.7), versus a fourfold difference with BI-RADS density (HR = 4.3, 95% CI 3.4-5.5). Discriminatory accuracy was marginally greater for longitudinal versus BI-RADS density (c-index = 0.64 vs. 0.63, mean difference = 0.008, 95% CI 0.003-0.012). CONCLUSIONS: Estimating mammographic density using a woman's history of breast density is likely to be more reliable than using the most recent observation only, which may lead to more reliable and accurate estimates of individual breast cancer risk. Longitudinal breast density has the potential to improve personal breast cancer risk estimation in women attending mammography screening.

An optimization framework to guide the choice of thresholds for risk-based cancer screening.

It is uncommon for risk groups defined by statistical or artificial intelligence (AI) models to be chosen by jointly considering model performance and potential interventions available. We develop a framework to rapidly guide choice of risk groups in this manner, and apply it to guide breast cancer screening intervals using an AI model. Linear programming is used to define risk groups that minimize expected advanced cancer incidence subject to resource constraints. In the application risk stratification performance is estimated from a case-control study (2044 cases, 1:1 matching), and other parameters are taken from screening trials and the screening programme in England. Under the model, re-screening in 1 year for the highest 4% AI model risk, in 3 years for the middle 64%, and in 4 years for 32% of the population at lowest risk, was expected to reduce the number of advanced cancers diagnosed by approximately 18 advanced cancers per 1000 diagnosed with triennial screening, for the same average number of screens in the population as triennial screening for all. Sensitivity analyses found the choice of thresholds was robust to model parameters, but the estimated reduction in advanced cancers was not precise and requires further evaluation. Our framework helps define thresholds with the greatest chance of success for reducing the population health burden of cancer when used in risk-adapted screening, which should be further evaluated such as in health-economic modelling based on computer simulation models, and real-world evaluations.

Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review.

BACKGROUND: Endocrine therapy is effective at preventing or treating breast cancer. Some forms of endocrine therapy have been shown to reduce mammographic density. Reduced mammographic density for women receiving endocrine therapy could be used to estimate the chance of breast cancer returning or developing breast cancer in the first instance (a prognostic biomarker). In addition, changes in mammographic density might be able to predict how well a woman responds to endocrine therapy (a predictive biomarker). The role of breast density as a prognostic or predictive biomarker could help improve the management of breast cancer. OBJECTIVES: To assess the evidence that a reduction in mammographic density following endocrine therapy for breast cancer prevention in women without previous breast cancer, or for treatment in women with early-stage hormone receptor-positive breast cancer, is a prognostic or predictive biomarker. SEARCH METHODS: We searched the Cochrane Breast Cancer Group Specialised Register, CENTRAL, MEDLINE, Embase, and two trials registers on 3 August 2020 along with reference checking, bibliographic searching, and contact with study authors to obtain further data. SELECTION CRITERIA: We included randomised, cohort and case-control studies of adult women with or without breast cancer receiving endocrine therapy. Endocrine therapy agents included were selective oestrogen receptor modulators and aromatase inhibitors. We required breast density before start of endocrine therapy and at follow-up. We included studies published in English. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently extracted data and assessed risk of bias using adapted Quality in Prognostic Studies (QUIPS) and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tools. We used the GRADE approach to evaluate the certainty of the evidence. We did not perform a quantitative meta-analysis due to substantial heterogeneity across studies. MAIN RESULTS: Eight studies met our inclusion criteria, of which seven provided data on outcomes listed in the protocol (5786 women). There was substantial heterogeneity across studies in design, sample size (349 to 1066 women), participant characteristics, follow-up (5 to 14 years), and endocrine therapy agent. There were five breast density measures and six density change definitions. All studies had at least one domain as at moderate or high risk of bias. Common concerns were whether the study sample reflected the review target population, and likely post hoc definitions of breast density change. Most studies on prognosis for women receiving endocrine therapy reported a reduced risk associated with breast density reduction. Across endpoints, settings, and agents, risk ratio point estimates (most likely value) were between 0.1 and 1.5, but with substantial uncertainty. There was greatest consistency in the direction and magnitude of the effect for tamoxifen (across endpoints and settings, risk ratio point estimates were between 0.3 and 0.7). The findings are summarised as follows. Prognostic biomarker findings: Treatment Breast cancer mortality Two studies of 823 women on tamoxifen (172 breast cancer deaths) reported risk ratio point estimates of ~0.4 and ~0.5 associated with a density reduction. The certainty of the evidence was low. Recurrence Two studies of 1956 women on tamoxifen reported risk ratio point estimates of ~0.4 and ~0.7 associated with a density reduction. There was risk of bias in methodology for design and analysis of the studies and considerable uncertainty over the size of the effect. One study of 175 women receiving an aromatase inhibitor reported a risk ratio point estimate of ~0.1 associated with a density reduction. There was considerable uncertainty about the effect size and a moderate or high risk of bias in all domains. One study of 284 women receiving exemestane or tamoxifen as part of a randomised controlled trial reported risk ratio point estimates of ~1.5 (loco-regional recurrence) and ~1.3 (distance recurrence) associated with a density reduction. There was risk of bias in reporting and study confounding, and uncertainty over the size of the effects. The certainty of the evidence for all recurrence endpoints was very low. Incidence of a secondary primary breast cancer Two studies of 451 women on exemestane, tamoxifen, or unknown endocrine therapy reported risk ratio point estimates of ~0.5 and ~0.6 associated with a density reduction. There was risk of bias in reporting and study confounding, and uncertainty over the effect size. The certainty of the evidence was very low. We were unable to find data regarding the remaining nine outcomes prespecified in the review protocol. Prevention Incidence of invasive breast cancer and ductal carcinoma in situ (DCIS) One study of 507 women without breast cancer who were receiving preventive tamoxifen as part of a randomised controlled trial (51 subsequent breast cancers) reported a risk ratio point estimate of ~0.3 associated with a density reduction. The certainty of the evidence was low. Predictive biomarker findings: One study of a subset of 1065 women from a randomised controlled trial assessed how much the effect of endocrine therapy could be explained by breast density declines in those receiving endocrine therapy. This study evaluated the prevention of invasive breast cancer and DCIS. We found some evidence to support the hypothesis, with a risk ratio interaction point estimate ~0.5. However, the 95% confidence interval included unity, and data were based on 51 women with subsequent breast cancer in the tamoxifen group. The certainty of the evidence was low. AUTHORS' CONCLUSIONS: There is low-/very low-certainty evidence to support the hypothesis that breast density change following endocrine therapy is a prognostic biomarker for treatment or prevention. Studies suggested a potentially large effect size with tamoxifen, but the evidence was limited. There was less evidence that breast density change following tamoxifen preventive therapy is a predictive biomarker than prognostic biomarker. Evidence for breast density change as a prognostic treatment biomarker was stronger for tamoxifen than aromatase inhibitors. There were no studies reporting mammographic density change following endocrine therapy as a predictive biomarker in the treatment setting, nor aromatase inhibitor therapy as a prognostic or predictive biomarker in the preventive setting. Further research is warranted to assess mammographic density as a biomarker for all classes of endocrine therapy and review endpoints.

The Relationship between Body Mass Index and Mammographic Density during a Premenopausal Weight Loss Intervention Study.

We evaluated the association between short-term change in body mass index (BMI) and breast density during a 1 year weight-loss intervention (Manchester, UK). We included 65 premenopausal women (35-45 years, ≥7 kg adult weight gain, family history of breast cancer). BMI and breast density (semi-automated area-based, automated volume-based) were measured at baseline, 1 year, and 2 years after study entry (1 year post intervention). Cross-sectional (between-women) and short-term change (within-women) associations between BMI and breast density were measured using repeated-measures correlation coefficients and multivariable linear mixed models. BMI was positively correlated with dense volume between-women (r = 0.41, 95%CI: 0.17, 0.61), but less so within-women (r = 0.08, 95%CI: -0.16, 0.28). There was little association with dense area (between-women r = -0.12, 95%CI: -0.38, 0.16; within-women r = 0.01, 95%CI: -0.24, 0.25). BMI and breast fat were positively correlated (volume: between r = 0.77, 95%CI: 0.69, 0.84, within r = 0.58, 95%CI: 0.36, 0.75; area: between r = 0.74, 95%CI: 0.63, 0.82, within r = 0.45, 95%CI: 0.23, 0.63). Multivariable models reported similar associations. Exploratory analysis suggested associations between BMI gain from 20 years and density measures (standard deviation change per +5 kg/m2 BMI: dense area: +0.61 (95%CI: 0.12, 1.09); fat volume: -0.31 (95%CI: -0.62, 0.00)). Short-term BMI change is likely to be positively associated with breast fat, but we found little association with dense tissue, although power was limited by small sample size.