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Optimal breast cancer screening approaches for women with ATM, CHEK2, and PALB2 PVs

Recently, a group of non-BRCA1/2, moderate- to high-risk breast cancer susceptibility genes, have been observed. Among them, the most prevalent ones are ATM, CHEK2 and PALB2.1-3 These pathogenic variants (PVs) can increase the risk of breast cancer by at least 2-fold, thus indicating an obvious and urgent need for screening them.1,3 However, optimal strategies for screening in women carrying these PVs have yet to be well established.1 In a recent study published in the Journal of the American Medical Association (JAMA), Lowry K P and his colleagues conducted a comparative simulation modeling analysis to determine whether screening using mammography and magnetic resonance imaging (MRI) could benefit breast cancer patients with ATM, CHEK2 and PALB2 PVs at various age intervals, which may increase the survival rate in these female patients.1

In this study, 2 simulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) for women with ATM, CHEK2 and PALB2 PVs utilizing risk estimates from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium, which included 32,247 cases and 32,544 controls in 12 population-based studies were used.1,3,4 The population profiles of the models included women from the United States with ATM, CHEK2 and PALB2 who were born in 1985 and were observed from the age of 25 years for their entire lifetimes.1

The results for mean model-estimated projections for the cumulative lifetime breast cancer risk was 20.9% (range across models=18.1%-23.7%) for women with ATM PVs, 27.6% (range=23.4%-31.7%) for women with CHEK2 PVs, and 39.5% (range=35.6%-43.3%) for women with PALB2 PVs.1

As per 1,000 women screened with yearly mammography alone starting at the age of 40-74 years, the breast cancer mortality was estimated to be reduced by a mean of 36.4% (range=34.6%-38.2%) to 38.5% (range=37.8%-39.2%), compared with the absence of screening.1,4

As per 1,000 women screened with yearly MRI beginning at the age of 35 years followed by yearly mammography + MRI at 40 years of age, the breast cancer mortality was estimated to be reduced by 54.4% (range=54.2%-54.7%) to 57.6% (range=57.2%-58.0%), in addition to 4,661 (range=4,635-4,688) to 5,001 (range=4,979-5,023) false-positive screening, and 1,280 (range=1,272-1,287) to 1,368 (range=1,362-1,374) benign biopsies.1,4

As per 1,000 women screened with yearly MRI beginning at the age of 30 years followed by mammography + MRI at 40 years of age, the breast cancer mortality was estimated to be reduced by 55.4% (range=55.3%-55.4%) to 59.5% (range=58.5%-60.4%), in addition to 5,075 (range=5,057-5,093) to 5,415 (range=5,393-5,437) false-positive screening, and 1,439 (range=1,429-1,449) to 1,528 (range=1,517-1,538) benign biopsies.1,4

As per 1,000 women, if yearly MRI was to begin at the age of 30 years and yearly mammography began at 30 years vs. 40 years of age, the estimated mean mortality rate would reduce by only 0.1% (range=0.1%-0.2%) to 0.3% (range=0.2%-0.3%). Also, it was estimated to add 649 (range=602-695) to 650 (range=603-696) false-positive screening, and 58 (range=41-76) to 59 (range=41-76) benign biopsies.1,4

In conclusion, this was the first study to use comparative modeling analysis to assess breast cancer screening strategies for patients with ATM, CHEK2 and PALB2 PVs.1 The findings ascertained that yearly MRI screening starting at 30-35 years of age, followed by yearly MRI in combination with mammography at 40 years of age in modeled women with the aforementioned PVs, had an estimated decrease in breast cancer mortality by 54% to 60% for all evaluated strategies.1 However, when MRI screening was conducted, beginning mammography before 40 years of age did not have a significant impact on the decrease of mortality rates, increased false-positive screening and benign biopsies.1 This newly observed knowledge will aid in screening guideline recommendations for women carrying these moderate- to high-risk PVs.1

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