Breast Cancer Screening Strategies for Women with ATM, CHEK2, and PALB2 Pathogenic Variants: A Comparative Modeling Analysis

Kathryn P. Lowry*, H. Amarens Geuzinge, Natasha K. Stout, Oguzhan Alagoz, John Hampton, Karla Kerlikowske, Harry J. De Koning, Diana L. Miglioretti, Nicolien T. Van Ravesteyn, Clyde Schechter, Brian L. Sprague, Anna N.A. Tosteson, Amy Trentham-Dietz, Donald Weaver, Martin J. Yaffe, Jennifer M. Yeh, Fergus J. Couch, Chunling Hu, Peter Kraft, Eric C. PolleyJeanne S. Mandelblatt, Allison W. Kurian, Mark E. Robson

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

36 Citations (Scopus)

Abstract

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 Participants: This 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 32247 cases and 32544 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. Results: The 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 mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit..

Original languageEnglish
Pages (from-to)587-596
Number of pages10
JournalJAMA Oncology
Volume8
Issue number4
Early online date17 Feb 2022
DOIs
Publication statusPublished - 2022

Bibliographical note

Funding/Support: This research was funded by the NIH/NCI (grants U01CA199218 and
U01CA253911 to Drs Lowry, Stout, Alagoz, de Koning, van Ravesteyn, Schechter,
Trentham-Dietz, and Mandelblatt) and the Breast Cancer Research Foundation (grant 17-137 to Dr Robson).
This research was also supported in part by the NIH/NCI (grant R35CA197289 to Dr Mandelblatt, and grant P30 CA014520 to
Dr Trentham-Dietz), the American Cancer Society (grant RSG-16-018-01–CPHPS to Dr Yeh), and NIH/NCI Cancer Center Support Grant P30
CQA0008748 to Dr Robson. The CARRIERS Consortium study was supported in part by NIH grants R35CA253187, R01CA192393,
R01CA225662; an NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer (grant P01CA116201), and the Breast Cancer
Research Foundation. See the eAppendix in Supplement 1 for complete funding information for the CARRIERS Consortium study. Data collection
for model inputs from the Breast Cancer Surveillance Consortium (BCSC) was supported by the NIH/NCI (grants P01 CA154292, U54 CA163303,
and R01 HS018366-01A1) and PCORI (grant PCS-1504-30370).

Publisher Copyright: © 2022 American Medical Association. All rights reserved.

Fingerprint

Dive into the research topics of 'Breast Cancer Screening Strategies for Women with ATM, CHEK2, and PALB2 Pathogenic Variants: A Comparative Modeling Analysis'. Together they form a unique fingerprint.

Cite this