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In particular, patients with oestrogen receptor\u2010positive (ER+) tumours are treated with hormonal therapy. In Sweden, the recommended treatment duration is five years, with current guidelines advising an additional five years for women at high risk of disease recurrence. However, the impact of extended therapy on metastatic progression has not been thoroughly quantified at the population level. In this article, we use a modelling approach to estimate the time\u2010varying effect of hormonal treatment on time to metastasis. The model is then used to compare 5\u2010 and 10\u2010year treatment durations at different tumour sizes. Rather than using a common statistical modelling approach, we incorporate the effect of endocrine therapy within a biologically inspired natural history model of breast cancer to accommodate key features of the expected treatment\u2010outcome relationship. We fitted the model using maximum likelihood and data from a cohort of 9,716 incident cases diagnosed with invasive ER+ breast cancer between 2005 and 2020. Based on our main model estimates, the 10\u2010year metastasis\u2010free survival would improve from 92.8% to 96.1% for a symptomatic patient with a 20 mm tumour with ten years (instead of five) of hormonal treatment. Our natural history model quantifies the impact of prolonged hormonal treatment on metastatic events in ER+ breast cancer patients, including features that are not captured by traditional statistical approaches. Results suggest a significant reduction in metastatic tumour growth rates during treatment, supporting the extension of endocrine therapy to 10 years for people with large tumours.<\/jats:p>","DOI":"10.1002\/sim.70504","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T07:11:03Z","timestamp":1775113863000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Time\u2010Varying Hormonal Treatment and Metastasis\u2010Free Survival Among ER+ Breast Cancer Patients: A Natural History Modelling Approach"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6075-6668","authenticated-orcid":false,"given":"Letizia","family":"Orsini","sequence":"first","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics Karolinska Institutet  Stockholm Sweden"},{"name":"Swedish e\u2010Science Research Centre Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8319-7624","authenticated-orcid":false,"given":"Alessandro","family":"Gasparini","sequence":"additional","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics Karolinska Institutet  Stockholm Sweden"},{"name":"Red Door Analytics AB  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0066-0677","authenticated-orcid":false,"given":"Kamila","family":"Czene","sequence":"additional","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7458-8252","authenticated-orcid":false,"given":"Keith","family":"Humphreys","sequence":"additional","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics Karolinska Institutet  Stockholm Sweden"},{"name":"Swedish e\u2010Science Research Centre Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61963-1"},{"key":"e_1_2_11_3_1","doi-asserted-by":"crossref","unstructured":"R. G.Gray D.Rea andK.Handley \u201cATTOM: Long\u2010Term Effects of Continuing Adjuvant Tamoxifen to 10\u2009Years Versus Stopping at 5\u2009Years in 6 953 Women With Early Breast Cancer \u201d (2013).","DOI":"10.1200\/jco.2013.31.18_suppl.5"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1604700"},{"key":"e_1_2_11_5_1","unstructured":"Institute SNC \u201cNationellt V\u00e5rdprogram f\u00f6r Br\u00f6stcancer \u201d (2025)."},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2017-0423"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2023.100704"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2012.03.004"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.11.5451"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2011.140"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.19.2419"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-22-0900"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.publhealth.20.1.145"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12874-022-01773-9"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/0962280218811837"},{"key":"e_1_2_11_16_1","doi-asserted-by":"crossref","unstructured":"J. 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