Breast density and risk factors for interval and screen-detected breast cancers: a case–case analysis of the Breast Cancer Now Generations Study, UK

Abstract Background Interval breast cancers (IBC), diagnosed between routine screening rounds, tend to have a worse prognosis than screen-detected breast cancers (SDBC). Identifying risk factors for IBCs is critical for improving early detection and developing risk-stratified screening strategies to reduce their incidence. We evaluated associations of breast density, reproductive, hormonal, lifestyle and medical factors with IBC compared to SDBC in a large UK cohort. Methods Analyses included 1,940 women diagnosed with breast cancer between 2004 and 2018 after enrolment in the Breast Cancer Now Generations Study, a prospective UK cohort linked to the National Health Service Breast Screening Programme. Pre-diagnostic risk factors were collected at enrolment, and breast density was estimated from pre-diagnostic mammograms using Cumulus in a subset of 1,191 cases. Risk factor associations with density were estimated using linear regression models. We identified 1,185 SDBCs and 755 IBCs included in logistic regression models to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between risk factors and IBC, adjusting for age at diagnosis, time since recruitment and year of diagnosis, breast density and tumour characteristics. Results Higher breast density was associated with later age at menarche, nulliparity, breastfeeding, history of benign breast disease (BBD), alcohol consumption, lower body mass index (BMI) at recruitment and at age 20, and current use of menopausal hormone therapy (MHT). In a fully-adjusted model, IBC risk was lower for overweight women (OR (95% CI ) = 0.74 (0.58–0.93) vs. normal weight), and higher for high breast density (2.13 (1.44–3.17) for Q4 vs. Q1), later age at menopause (1.60 (1.02–2.50) 55 + vs. < 50), current MHT use (1.41 (1.04–1.91) vs. never users), history of BBD (1.36 (1.11–1.68)), being underweight at age 20 (1.65 (1.14–2.38) vs. normal weight), family history of breast cancer (1.26 (1.00–1.58)) and ever using oral contraceptives (1.25 (0.93–1.69) vs. never). These risk factor associations were independent of tumour characteristics. Conclusions Breast density and several risk factors independently increase the likelihood of IBC, highlighting opportunities for tailored screening strategies to enhance early detection and reduce IBCs incidence.