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Radiation-induced lymphocyte apoptosis (RILA) has recently been associated with the risk of fibrosis more than 10 years post-RT. Here, we show that a combination of five independent factors, RILA, two SNPs in the CTGF and NBS1 genes, and two clinical variables (body-mass index and hypertension) exhibits several important interactions. Partition analysis identified six partly nested subgroups, which could be consolidated into three clinically meaningful risk groups. Machine-learning modelling verified and refined these groups, demonstrating a five-fold variation (17\u201383%) in BF risk with an AUC\u2009=\u20090.735 in ROC analysis using only these five features. Our study provides proof-of-concept that a biologically realistic subgroup-based approach sharpens predictive performance and may enable clinical identification of a subgroup of breast cancer patients highly susceptible to BF.<\/jats:p>","DOI":"10.1038\/s41523-026-00980-7","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T19:53:01Z","timestamp":1781293981000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel method for risk stratification of radiation-induced breast fibrosis: subgroup hypothesis verified by machine learning"],"prefix":"10.1038","volume":"12","author":[{"given":"Ahmad","family":"Sami","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Seibold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Sticht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank A.","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlon R.","family":"Veldwijk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten","family":"Herskind","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"980_CR1","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/S0360-3016(01)02690-6","volume":"52","author":"A Safwat","year":"2002","unstructured":"Safwat, A., Bentzen, S. 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All other authors declare no conflicting financial interests relating to this work. MRV reports stocks from TME Pharma AG and honoraria from Carl Zeiss Meditec AG. F.A.G. reports travel expenses, stocks and honoraria from TME Pharma AG; research grants and travel expenses from ELEKTA AB; grants, research grants, travel expenses and honoraria from Carl Zeiss Meditec AG; grants, research grants, travel expenses and honoraria from OncoMANGETx, Inc.; travel expenses and research grants from Varian Medical Systems, Inc.; travel expenses and\/or honoraria from Bristol- Myers Squibb, Cureteq AG, Roche Pharma AG, MSD Sharp and Dohme GmbH, Siemens Healthineers AG, Varian Medical Systems, and AstraZeneca GmbH; non-financial support from Oncare GmbH and Opasca GmbH and patent US10857388B2 together with Carl Zeiss Meditec AG and patent EP4119191A1.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"84"}}