Background: Screening guidelines for women at familial risk of breast cancer without a known causative gene mutation differ internationally. To our knowledge, no randomised controlled MRI-screening trial has been performed. The FaMRIsc-study aims to assess the efficacy of MRI versus mammography screening for familial risk and furthermore assesses the influence of breast density. Methods: In 12 Dutch hospitals, 1355 women aged 30-55 years with a cumulative lifetime risk of ≥20% without a BRCA1/2 mutation were randomised with a web-based computer generated hospital sequence, concealed for participants, physicians and researchers, in either the MRI-group with yearly MRI, clinical breast examination and mammography biennially, or the Mammography-group with yearly mammography and clinical breast examination. Breastfeeding, pregnancy, previous screening and previous ductal carcinoma in situ were permitted, but no previous invasive cancer. Primary outcomes were number, size and nodal-stage of breast cancers. Secondary outcomes were sensitivity, specificity and positive predictive value. Results were also stratified by mammographic density (BI-RADS AD). Intention to screen analyses were performed. This trial was registered with the Netherlands Trial Register, NTR2789. Findings: Between Jan 1 2011, and Dec 31 2017 in the MRI-group (674 women) compared to the Mammographygroup (680 women) with a median follow-up of 5.2 years for both groups, more breast cancers were detected (40 versus 15, p<0•001), invasive cancers were smaller (median size 9 versus 17 mm, p=0•010) and less frequently node positive (4/24, 17% versus 5/8, 63%, p=0•023). In the MRI-group, specificity was significantly lower compared to the Mammography-group (83•8% versus 91•0%, p<0•001), while sensitivity hardly differed (97•5% versus 86.7%, p=0.18). Clinical breast examination contributed hardly to detection (1/55). In incident cancers, tumour stage was better in the MRI-group (p=0•035), with lower numbers of node positive and ≥T2 tumours, while specificity improved in both arms (MRI-group: 87•4%, Mammography-group: 92•6%, p<0•001). All tumours ≥T2 were in the two highest density categories. In BI-RADS density A-C MRI was most effective. Interpretation: The earlier detection by MRI screening and especially the fewer late-stage cancers in incident rounds, may reduce adjuvant chemotherapy and mortality. However, especially for women with the highest breast density at the cost of more false positive results.

Background Extremely dense breast tissue is associated with increased breast cancer risk and limited sensitivity of mammography. The DENSE trial showed that additional magnetic resonance imaging (MRI) screening in women with extremely dense breasts resulted in a substantial reduction in interval cancers. The cost-effectiveness of MRI screening for these women is unknown. Methods We used the MISCAN-breast microsimulation model to simulate several screening protocols containing mammography and/or MRI to estimate long-term effects and costs. The model was calibrated using results of the DENSE trial and adjusted to incorporate decreases in breast density with increasing age. Screening strategies varied in the number of MRIs and mammograms offered to women ages 50-75 years. Outcomes were numbers of breast cancers, life-years, quality-adjusted life-years (QALYs), breast cancer deaths, and overdiagnosis. Incremental cost-effectiveness ratios (ICERs) were calculated (3% discounting), with a willingness-to-pay threshold of €22 000. Results Calibration resulted in a conservative fit of the model regarding MRI detection. Both strategies of the DENSE trial were dominated (biennial mammography; biennial mammography plus MRI). MRI alone every 4 years was cost-effective with €15 620 per QALY. Screening every 3 years with MRI alone resulted in an incremental cost-effectiveness ratio of €37 181 per QALY. All strategies with mammography and/or a 2-year interval were dominated because other strategies resulted in more additional QALYs per additional euro. Alternating mammography and MRI every 2 years was close to the efficiency frontier. Conclusions MRI screening is cost-effective for women with extremely dense breasts, when applied at a 4-year interval. For a willingness to pay more than €22 000 per QALY gained, MRI at a 3-year interval is cost-effective as well.

for the Familial MRI Screening (FaMRIsc) Study group IMPORTANCE For women with a 20% or more familial risk of breast cancer without a known BRCA1/2 (BRCA1, OMIM 113705; and BRCA2, OMIM 114480) or TP53 (OMIM 151623) variant, screening guidelines vary substantially, and cost-effectiveness analyses are scarce.OBJECTIVE To assess the cost-effectiveness of magnetic resonance imaging (MRI) screening strategies for women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant. DESIGN, SETTING, AND PARTICIPANTSIn this economic evaluation, conducted from February 1, 2019, to May 25, 2020, microsimulation modeling was used to estimate costs and effectiveness on a lifetime horizon from age 25 years until death of MRI screening among a cohort of 10 million Dutch women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant. A Dutch screening setting was modeled. Most data were obtained from the randomized Familial MRI Screening (FaMRIsc) trial, which included Dutch women aged 30 to 55 years. A health care payer perspective was applied.INTERVENTIONS Several screening protocols with varying ages and intervals including those of the randomized FaMRIsc trial, consisting of the mammography (Mx) protocol (annual mammography and clinical breast examination) and the MRI protocol (annual MRI and clinical breast examination plus biennial mammography). MAIN OUTCOMES AND MEASURESCosts, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated and discounted by 3%. A threshold of €22 000 (US $24 795.87) per QALY was applied.RESULTS This economic evaluation modeling study estimated that, on a lifetime horizon per 1000 women with the Mx protocol of the FaMRIsc trial, 346 breast cancers would be detected, and 49 women were estimated to die from breast cancer, resulting in 22 885 QALYs and total costs of €7 084 767 (US $7 985 134.61). The MRI protocol resulted in 79 additional QALYs and additional €2 657 266 (US $2 994 964.65). Magnetic resonance imaging performed only every 18 months between the ages of 35 and 60 years followed by the national screening program was considered optimal, with an ICER of €21 380 (US $24 097.08) compared with the previous nondominated strategy in the ranking, when applying the National Institute for Health and Care Excellence threshold. Annual screening alternating MRI and mammography between the ages of 35 and 60 years, followed by the national screening program, gave similar outcomes. Higher thresholds would favor annual MRI screening. The ICER was most sensitive to the unit cost of MRI and the utility value for ductal carcinoma in situ and localized breast cancer.CONCLUSIONS AND RELEVANCE This study suggests that MRI screening every 18 months between the ages of 35 and 60 years for women with a family history of breast cancer is cost-effective within the National Institute for Health and Care Excellence threshold for all densities. Higher thresholds would favor annual MRI screening. T...

IMPORTANCE Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women.OBJECTIVE To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants. DESIGN, SETTING, AND PARTICIPANTSThis comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985. INTERVENTIONS Screening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years. MAIN OUTCOMES AND MEASURES Estimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges. RESULTSThe mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women.CONCLUSIONS AND RELEVANCE This analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mort...

, on behalf of the FaMRIsc study group