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Additional file 1. Risk of second primary cancer among women in the Kaiser Permanente Breast Cancer Survivors Cohort: Tables S1–S9 and Figures S1–S2.

IMPORTANCE: Digital breast tomosynthesis (DBT) was developed with the expectation of improving cancer detection in women with dense breasts. Studies are needed to evaluate interval invasive and advanced breast cancer rates, intermediary outcomes related to breast cancer mortality, by breast density and breast cancer risk. OBJECTIVE: To evaluate whether DBT screening is associated with a lower likelihood of interval invasive cancer and advanced breast cancer compared with digital mammography by extent of breast density and breast cancer risk. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of 504 427 women aged 40 to 79 years who underwent 1 003 900 screening digital mammography and 375 189 screening DBT examinations from 2011 through 2018 at 44 US Breast Cancer Surveillance Consortium (BCSC) facilities with follow-up for cancer diagnoses through 2019 by linkage to state or regional cancer registries. EXPOSURES: Breast Imaging Reporting and Data System (BI-RADS) breast density; BCSC 5-year breast cancer risk. MAIN OUTCOMES AND MEASURES: Rates per 1000 examinations of interval invasive cancer within 12 months of screening mammography and advanced breast cancer (prognostic pathologic stage II or higher) within 12 months of screening mammography, both estimated with inverse probability weighting. RESULTS: Among 504 427 women in the study population, the median age at time of mammography was 58 years (IQR, 50-65 years). Interval invasive cancer rates per 1000 examinations were not significantly different for DBT vs digital mammography (overall, 0.57 vs 0.61, respectively; difference, −0.04; 95% CI, −0.14 to 0.06; P = .43) or among all the 836 250 examinations with BCSC 5-year risk less than 1.67% (low to average-risk) or all the 413 061 examinations with BCSC 5-year risk of 1.67% or higher (high risk) across breast density categories. Advanced cancer rates were not significantly different for DBT vs digital mammography among women at low to average risk or at high risk with almost entirely fatty, scattered fibroglandular densities, or heterogeneously dense breasts. Advanced cancer rates per 1000 examinations were significantly lower for DBT vs digital mammography for the 3.6% of women with extremely dense breasts and at high risk of breast cancer (13 291 examinations in the DBT group and 31 300 in the digital mammography group; 0.27 vs 0.80 per 1000 examinations; difference, −0.53; 95% CI, −0.97 to −0.10) but not for women at low to average risk (10 611 examinations in the DBT group and 37 796 in the digital mammography group; 0.54 vs 0.42 per 1000 examinations; difference, 0.12; 95% CI, −0.09 to 0.32). CONCLUSIONS AND RELEVANCE: Screening with DBT vs digital mammography was not associated with a significant difference in risk of interval invasive cancer and was associated with a significantly lower risk of advanced breast cancer among the 3.6% of women with extremely dense breasts and at high risk of breast cancer. No significant difference was observed in the 96.4% of women with nondense breasts, heterogeneously dense breasts, or with extremely dense breasts not at high risk.

Importance: Moving to multigene testing for ‘all’ women with breast cancer (BC) could identify many more mutation carriers who can benefit from precision prevention. However, cost-effectiveness of this approach remains unaddressed. Objectives: To estimate incremental lifetime-effects, costs, and cost-effectiveness of multigene-testing all BC-patients compared with current practice of family-history/clinical-criteria based genetic (BRCA)-testing. Design: Cost-effectiveness microsimulation modelling study comparing lifetime costs-&-effects of high-risk BRCA1/BRCA2/PALB2 (multigene) testing all unselected BC-cases (Strategy-A) with family-history/clinical-criteria based BRCA1/BRCA2-testing (Strategy-B) in both UK-&-US populations. The time-horizon is lifetime and both payer and societal perspectives are presented. Probabilistic and one-way sensitivity-analyses evaluate model uncertainty. Setting: Population of UK-&-US women with BC and their relatives Participants: Data obtained from 11,836 population-based BC-patients (regardless of family-history) recruited to four large research studies in the UK (Predicting-Risk-of-Breast-Cancer-at-Screening (PROCAS: 1389 out of 57,000 women) & Prospective-Outcomes-in-Sporadic-versus-Hereditary-breast-cancer (POSH:2885) studies); US (Kaiser-Permanente Washington Breast-Cancer-Surveillance-Consortium (BCSC) registry: 5892 out of 132,139 women) and Australia (Population-based BC-cases of the Australian-Breast-Cancer-Family-Study (ABCFS:1670 women)). Interventions: Strategy-A: All BC-women undergo BRCA1/BRCA2/PALB2 testing. Strategy-B: Only BC-women fulfilling family-history/clinical-criteria (10% BRCA-probability) undergo BRCA-testing. Affected BRCA/PALB2-carriers can undertake contralateral preventive-mastectomy. BRCA-carriers can choose risk-reducing salpingo-oophorectomy (RRSO). Relatives of mutation-carriers undergo cascade-testing. Unaffected relative-carriers can undergo MRI/mammography, chemoprevention or risk-reducing-mastectomy for BC-risk and RRSO for ovarian-cancer (OC)-risk. Main Outcomes & Measures: Incremental-cost-effectiveness-ratio (ICER): incremental-cost per quality-adjusted-life-year (QALY) gained, is compared to standard £30,000/QALY(UK) and $100,000/QALY(US) thresholds. OC-incidence, BC-incidence, excess heart-disease deaths and overall population-impact are estimated. Results: Compared with current clinical-criteria/family-history-based BRCA-testing, (BRCA1/BRCA2/PALB2) multigene-testing for all BC-patients would cost £10,464/QALY (payer-perspective) or £7,216/QALY (societal-perspective) in UK or $65,661/QALY (payer-perspective) or $61,618/QALY (societal-perspective) in US women, well below UK/NICE and US cost-effectiveness thresholds. Probabilistic sensitivity-analysis shows unselected multigene-testing remains cost-effective for 98-99% UK/ 64-68% US health-system simulations. One year’s unselected multi-gene testing could prevent 2,101 BC/OC-cases and 633 deaths in the UK; and 9,733 BC/OC-cases and 2,406 deaths in the US. Correspondingly, 8 UK/35 US excess heart-disease deaths occur annually. Conclusions: Unselected high-risk multigene-testing for all BC-patients is extremely cost-effective compared with family-history/clinical-criteria testing for UK and US health-systems. This supports changing current policy to expand genetic-testing to all women with BC.