Op-jnci200131 434..442

Background: We assessed the clinical utility of a first-degree breast cancer family history and polygenic risk score (PRS) to inform screening decisions among women aged 30-50 years. Methods: Two established breast cancer models evaluated digital mammography screening strategies in the 1985 US birth cohort by risk groups defined by family history and PRS based on 313 single nucleotide polymorphisms. Strategies varied in initiation age (30, 35, 40, 45, and 50 years) and interval (annual, hybrid, biennial, triennial). The benefits (breast cancer deaths averted, life-years gained) and harms (false-positive mammograms, overdiagnoses) were compared with those seen with 3 established screening guidelines. Results: Women with a breast cancer family history who initiated biennial screening at age 40 years (vs 50 years) had a 36% (model range1⁄4 29%-40%) increase in life-years gained and 20% (model range1⁄4 16%-24%) more breast cancer deaths averted, but 21% (model range 1⁄4 17%-23%) more overdiagnoses and 63% (model range1⁄4 62%-64%) more false positives. Screening tailored to PRS vs biennial screening from 50 to 74 years had smaller positive effects on life-years gained (20%) and breast cancer deaths averted (11%) but also smaller increases in overdiagnoses (10%) and false positives (26%). Combined use of family history and PRS vs biennial screening from 50 to 74 years had the greatest increase in life-years gained (29%) and breast cancer deaths averted (18%). Conclusions: Our results suggest that breast cancer family history and PRS could guide screening decisions before age 50 years among women at increased risk for breast cancer but expected increases in overdiagnoses and false positives should be expected. Routine mammography screening starting at age 45 or 50 years has been shown to reduce population breast cancer mortality for women at average risk (1). It remains uncertain whether the current screening guidelines (2-4) are optimal for individual women considering the variability in breast cancer risk at any given age. The American Cancer Society (ACS) and the United States Preventive Services Task Force (USPSTF) recommend that women discuss their individual risk and screening options with their healthcare providers before the age of 45 or 50 years, yet there are limited data to inform such discussions. Risk-based screening has been proposed as a way to inform decisions about the starting age and frequency of screening for women at different levels of risk. Recent discoveries in the field of breast cancer genetics may hold the potential to guide risk-based screening strategies. The risk of developing breast cancer approximately doubles for women with a first-degree family member with A R T IC LE Received: December 12, 2019; Revised: August 10, 2020; Accepted: August 18, 2020 © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 434 JNCI J Natl Cancer Inst (2021) 113(4): djaa127 doi: 10.1093/jnci/djaa127 First published online August 27, 2020