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Here, we illustrate the use of collaborative breast cancer multilevel systems modeling in CISNET to demonstrate the flexibility of systems modeling to address important clinical and policy-relevant questions. Challenges and opportunities of future systems modeling are also summarized. The 6 CISNET breast cancer models embody the key features of systems modeling by incorporating numerous data sources and reflecting tumor, person, and health system factors that change over time and interact to affect the burden of breast cancer. Multidisciplinary modeling teams have explored alternative representations of breast cancer to reveal insights into breast cancer natural history, including the role of overdiagnosis and race differences in tumor characteristics. The models have been used to compare strategies for improving the balance of benefits and harms of breast cancer screening based on personal risk factors, including age, breast density, polygenic risk, and history of Down syndrome or a history of childhood cancer. The models have also provided evidence to support the delivery of care by simulating outcomes following clinical decisions about breast cancer treatment and estimating the relative impact of screening and treatment on the United States population. The insights provided by the CISNET breast cancer multilevel modeling efforts have informed policy and clinical guidelines. The 20 years of CISNET modeling experience has highlighted opportunities and challenges to expanding the impact of systems modeling. Moving forward, CISNET research will continue to use systems modeling to address cancer control issues, including modeling structural inequities affecting racial disparities in the burden of breast cancer. Future work will also leverage the lessons from team science, expand resource sharing, and foster the careers of early stage modeling scientists to ensure the sustainability of these efforts.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009020","type":"journal-article","created":{"date-parts":[[2021,6,17]],"date-time":"2021-06-17T17:24:45Z","timestamp":1623950685000},"page":"e1009020","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Reflecting on 20 years of breast cancer modeling in CISNET: Recommendations for future cancer systems modeling efforts"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5971-4660","authenticated-orcid":true,"given":"Amy","family":"Trentham-Dietz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5133-1382","authenticated-orcid":true,"given":"Oguzhan","family":"Alagoz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8513-5398","authenticated-orcid":true,"given":"Christina","family":"Chapman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1192-9336","authenticated-orcid":true,"given":"Xuelin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9212-7225","authenticated-orcid":true,"given":"Jinani","family":"Jayasekera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3531-466X","authenticated-orcid":true,"given":"Nicolien T.","family":"van Ravesteyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra J.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0010-2827","authenticated-orcid":true,"given":"Clyde B.","family":"Schechter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2724-7404","authenticated-orcid":true,"given":"Jennifer M.","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2796-9180","authenticated-orcid":true,"given":"Sylvia K.","family":"Plevritis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeanne S.","family":"Mandelblatt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the Breast Working Group of the Cancer Intervention and Surveillance Modeling Network (CISNET)","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,6,17]]},"reference":[{"issue":"4","key":"pcbi.1009020.ref001","doi-asserted-by":"crossref","DOI":"10.1007\/s13668-013-0052-4","article-title":"Systems Epidemiology: A New Direction in Nutrition and Metabolic Disease Research.","volume":"2","author":"MC Cornelis","year":"2013","journal-title":"Curr Nutr Rep"},{"issue":"3","key":"pcbi.1009020.ref002","first-page":"A97","article-title":"Complex systems modeling for obesity research","volume":"6","author":"RA Hammond","year":"2009","journal-title":"Prev Chronic Dis"},{"issue":"3","key":"pcbi.1009020.ref003","doi-asserted-by":"crossref","first-page":"e198","DOI":"10.5210\/ojphi.v6i3.5571","article-title":"Systems Epidemiology: What\u2019s in a Name?","volume":"6","author":"O Dammann","year":"2014","journal-title":"Online J Public Health Inform"},{"key":"pcbi.1009020.ref004","unstructured":"Cancer Intervention and Surveillance Modeling Network, National Cancer Institute. 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