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Impact of radiation therapy dose, fractionation, and immunotherapeutic partner in a mouse model of hormone receptor-positive mammary carcinogenesis

A. Buqué, N. Bloy, G. Petroni, C. Jiménez-Cortegana, A. Sato, C. Iribarren, T. Yamazaki, C. Galassi, M. Hensler, B. Bhinder, A. Guarracino, B. Rippon, M. Beltran-Visiedo, R. Soler-Agesta, T. Pannellini, J. Fucikova, S. Demaria, XK. Zhou, O....

. 2025 ; 117 (5) : 934-947. [pub] 20250501

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25015987

Grant support
Breakthrough Level 2
Department of Defense
BC180476/BC180476P1 Breast Cancer Research
NIH HHS - United States
CA271915 NCI NIH HHS - United States
BC210945 DoD Breast Cancer Research Program
I16-0064 Starr Cancer Consortium
Transformative Breast Cancer Consortium
W81XWH2120034 DoD Breast Cancer Research Program
NIH HHS - United States
CA274291 NCI NIH HHS - United States
Mantle Cell Lymphoma Research Initiative
Leukemia and Lymphoma Society
Functional Genomics Initiative
Clinical Trials Innovation
Sandra and Edward Meyer Cancer Center
Department of Radiation Oncology
Weill Cornell Medicine
Luke Heller TECPR2 Foundation
Lytix Biopharma
Noxopharm

BACKGROUND: Hormone receptor-positive (HR+) breast cancer responds poorly to immune checkpoint inhibitors (ICIs). In some settings, radiation therapy (RT) has been shown to mediate immunostimulatory effects and promote ICI sensitivity. METHODS: We investigated whether hypofractionated RT may be successfully combined with ICIs in a mouse model of multifocal, metachronous HR+ mammary carcinogenesis. We hypothesized that focal RT targeting the first detectable (primary) tumor combined with ICIs may generate effective immunity, delaying the development of new lesions. RESULTS: Focal RT in various doses and fractionations limited primary tumor growth, with an optimum for a 20-Gy × 2 regimen (ablative in approximately 90% of mice). The degree of primary disease control, however, did not necessarily correlate with overall survival extension because of changes in the development of new neoplastic lesions contributing to global tumor burden. Adding a PD-1 blocker to focal RT delivered in a 10-Gy × 3, 20-Gy × 2, or 8-Gy × 6 regimen failed to alter overall survival extension enabled by RT alone. Similar results were obtained with a CTLA4 blocker, an IL-1β inhibitor, and a PD-1 blocker plus recombinant FLT3LG when combined with the 10-Gy × 3 regimen. CONCLUSIONS: In this model of HR+ mammary carcinogenesis, RT to the primary tumor ameliorates overall survival (to an extent based on dose and fractionation). Increasing local control through RT alone or RT plus immunotherapy beyond a hitherto undefined threshold, however, does not necessarily inhibit the development of subsequent nonirradiated neoplasms and hence does not necessarily provide extra overall survival benefits.

References provided by Crossref.org

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$a BACKGROUND: Hormone receptor-positive (HR+) breast cancer responds poorly to immune checkpoint inhibitors (ICIs). In some settings, radiation therapy (RT) has been shown to mediate immunostimulatory effects and promote ICI sensitivity. METHODS: We investigated whether hypofractionated RT may be successfully combined with ICIs in a mouse model of multifocal, metachronous HR+ mammary carcinogenesis. We hypothesized that focal RT targeting the first detectable (primary) tumor combined with ICIs may generate effective immunity, delaying the development of new lesions. RESULTS: Focal RT in various doses and fractionations limited primary tumor growth, with an optimum for a 20-Gy × 2 regimen (ablative in approximately 90% of mice). The degree of primary disease control, however, did not necessarily correlate with overall survival extension because of changes in the development of new neoplastic lesions contributing to global tumor burden. Adding a PD-1 blocker to focal RT delivered in a 10-Gy × 3, 20-Gy × 2, or 8-Gy × 6 regimen failed to alter overall survival extension enabled by RT alone. Similar results were obtained with a CTLA4 blocker, an IL-1β inhibitor, and a PD-1 blocker plus recombinant FLT3LG when combined with the 10-Gy × 3 regimen. CONCLUSIONS: In this model of HR+ mammary carcinogenesis, RT to the primary tumor ameliorates overall survival (to an extent based on dose and fractionation). Increasing local control through RT alone or RT plus immunotherapy beyond a hitherto undefined threshold, however, does not necessarily inhibit the development of subsequent nonirradiated neoplasms and hence does not necessarily provide extra overall survival benefits.
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