{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:00:55Z","timestamp":1791644455597,"version":"4.3.4"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T00:00:00Z","timestamp":1780876800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"St. Joseph\u2019s Health Care Foundation"},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"crossref","award":["DoD BC180595"],"award-info":[{"award-number":["DoD BC180595"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"crossref","award":["DoD BC201085P3"],"award-info":[{"award-number":["DoD BC201085P3"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"award":["DoD BC180595"],"award-info":[{"award-number":["DoD BC180595"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DoD BC201085P3"],"award-info":[{"award-number":["DoD BC201085P3"]}],"id":[{"id":"https:\/\/ror.org\/0447fe631","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/0348ff195","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Neoadjuvant partial breast irradiation using stereotactic body radiotherapy (SBRT) has emerged as a strategy to induce tumor and immune responses in early-stage, low-risk breast cancer. While prior studies have demonstrated encouraging response rates and evidence of immune modulation, the optimal radiotherapy regimen for immune priming remains unclear. SIGNAL 2.0 is a randomized phase II trial designed to compare the biological and immunological impact of a single-fraction versus three-fraction neoadjuvant SBRT. Materials and Methods: Sixty-one postmenopausal patients \u2265 50 years with unifocal, hormone positive, node-negative invasive ductal carcinoma &lt; 3 cm were randomized 1:1 to receive either 21 Gy in one fraction or 30 Gy in three fractions, delivered to the tumor in the prone position. Core biopsies were collected pre-SBRT and 14\u201320 days post-SBRT at the time of surgery. Immune markers were assessed using tumor-infiltrating lymphocyte (TIL) scoring, NanoString nCounter PanCancer Immune Profiling, and NanoString GeoMx Digital Spatial Profiling (DSP). Results: Available tumor samples from 47 patients underwent paired tissue analysis. Three-fraction SBRT induced 200 differentially expressed genes, including enrichment of pathways related to adaptive immune activation, with significant increases in expression levels of macrophages, dendritic cells, neutrophils and CD8 T-cells. Proteomic profiling also identified a significant increase in the expression levels of neutrophils, Treg cells, macrophages, and NK cells in the tumor microenvironment of the samples from patients receiving the three-fraction regimen. Conclusions: Neoadjuvant SBRT induces measurable immune activation, with three-fraction regimens generating more extensive transcriptional, proteomic, and cellular immune changes than a single fraction. Three-fraction neoadjuvant SBRT may provide superior immune priming, providing a foundation for future trials integrating neoadjuvant radiotherapy with immunomodulatory therapies.<\/jats:p>","DOI":"10.3390\/cancers18121867","type":"journal-article","created":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T10:04:14Z","timestamp":1780913054000},"page":"1867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Determining Optimal Fractionation of Neoadjuvant Radiation in Low-Risk, Early-Stage Breast Cancer\u2014Randomized SIGNAL Clinical Trial"],"prefix":"10.3390","volume":"18","author":[{"given":"Melanie","family":"Spears","sequence":"first","affiliation":[{"name":"Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON M5G 1M1, Canada"},{"name":"Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON M5S 1A8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3782-4463","authenticated-orcid":false,"given":"Michael","family":"Lock","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"Division of Radiation Oncology, Western University, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5055-9027","authenticated-orcid":false,"given":"Brian","family":"Yaremko","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"Division of Radiation Oncology, Western University, London, ON N6A 5W9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vida","family":"Talebian","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON M5G 1M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoe","family":"Kerhoulas","sequence":"additional","affiliation":[{"name":"Medical Biophysics, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalan S.","family":"Lynn","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"St. Joseph\u2019s Health Care Centre, London, ON N6A 4V2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0733-7234","authenticated-orcid":false,"given":"William T.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada"},{"name":"Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Gelman","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"Medical Biophysics, Western University, London, ON N6A 5C1, Canada"},{"name":"Department of Medical Imaging, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Mouawad","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"Division of Radiation Oncology, Western University, London, ON N6A 5W9, Canada"},{"name":"Department of Medical Imaging, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stewart","family":"Gaede","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"Division of Radiation Oncology, Western University, London, ON N6A 5W9, Canada"},{"name":"Medical Biophysics, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3799-9630","authenticated-orcid":false,"given":"Allison","family":"Maciver","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"St. Joseph\u2019s Health Care Centre, London, ON N6A 4V2, Canada"},{"name":"Department of Surgery, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON M5G 1M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Liao","sequence":"additional","affiliation":[{"name":"Ontario Institute for Cancer Research, MaRS Centre, Toronto, ON M5G 1M1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang-I","family":"Lu","sequence":"additional","affiliation":[{"name":"Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6098-2091","authenticated-orcid":false,"given":"Anat","family":"Kornecki","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"St. Joseph\u2019s Health Care Centre, London, ON N6A 4V2, Canada"},{"name":"Department of Medical Imaging, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8227-8924","authenticated-orcid":false,"given":"Silvia C.","family":"Formenti","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Weill Cornell Medicine, New York City, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4426-0499","authenticated-orcid":false,"given":"Sandra","family":"Demaria","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Weill Cornell Medicine, New York City, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7741-2199","authenticated-orcid":false,"given":"Muriel","family":"Brackstone","sequence":"additional","affiliation":[{"name":"Lawson Health Sciences Research Institute, London, ON N6A 5W9, Canada"},{"name":"St. Joseph\u2019s Health Care Centre, London, ON N6A 4V2, Canada"},{"name":"Department of Surgery, Western University, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,8]]},"reference":[{"key":"ref_1","unstructured":"National Guideline Alliance (UK) (2018). 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