Abstract 4687: Clonal hematopoiesis of indeterminate potential may protect against radiation-induced toxicities in breast cancer patients

Abstract Introduction: Radiation therapy (RT) is administered to ∼50% of all cancer patients yet can lead to toxicities such as radiation-induced fibrosis and/or lymphedema. Detailed understanding of the underlying pathogenesis of these post-RT complications remains to be elucidated. One potential factor might relate to clonal hematopoiesis of indeterminate potential (CHIP); an age-related clonal expansion of hematopoietic stem cells (HSCs) harboring characteristic somatic mutations (e.g., Tet2). CHIP is implicated in cardiovascular disease and leukemia progression, as well as several chronic fibrosis states. The current hypothesis is that breast cancer patients with CHIP at the time of radiation therapy (RT) are at higher risk of radiation-induced toxicities. To investigate this hypothesis, we utilized patient samples and mouse models with Tet2 mutations. Methods: Blood samples were collected from breast cancer patients undergoing adjuvant RT prior to treatment. DNA was extracted, and CHIP mutations were identified using next-generation sequencing. We then examined the association between CHIP status and clinical data related to radiation-induced fibrosis and/or lymphedema. In addition, a CHIP mouse model was generated by transplanting myelo-ablated mice with HSCs heterozygous for Tet2 null mutations. Mouse hindlimbs were irradiated at 20 Gy to induce fibrosis, evaluated through joint angle contracture (measured weekly), dermal thickness, and collagen. Smaller joint angles indicated increasing contracture/fibrosis. At 16 weeks post-RT, skin samples were collected to assay dermal thickness and collagen deposition. Results: Amongst 138 breast cancer patients, 28 had CHIP mutations at baseline, of which only 1 patient developed radiation-induced fibrosis/lymphedema. Amongst the remaining 110 patients without CHIP, 24 developed fibrosis/lymphedema, demonstrating a significant association between toxicity outcomes with no-CHIP patients (Fisher’s exact test, p<0.05). This was reflected in the in vivo model, wherein CHIP-positive mice (carrying Tet2 mutant HSCs, n=9) exhibited reduced fibrosis, thinner skin (27% decrease), and less collagen (51% decrease) post-RT, compared to control mice with wild-type Tet2 HSCs (n=9). Conclusion: Our findings disproved the null hypothesis and unexpectedly demonstrated that breast cancer patients with CHIP displayed a lower risk of fibrosis/lymphedema compared to patients without CHIP. These findings need to be validated in other clinical cohorts and additional pre-clinical models to further understand the apparent protective effects of CHIP with development of radiation fibrosis. Citation Format: Tirthankar Ray, Madison Hossack, Pierre-Antoine Bissey, Justin Williams, Wei Shi, Sagi Abelson, Steven Chan, Kenneth W. Yip, Fei-Fei Liu. Clonal hematopoiesis of indeterminate potential may protect against radiation-induced toxicities in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4687.