What question did this study set out to answer?

The study aims to evaluate the effectiveness of FLASH radiotherapy in maintaining tumor control while reducing normal tissue toxicity in breast cancer models.

April 5, 2026

Abstract 5266: FLASH radiotherapy maintains tumor control and enables safe re-irradiation while preserving normal tissue in breast cancer PDX models

Key Points

The study aims to evaluate the effectiveness of FLASH radiotherapy in maintaining tumor control while reducing normal tissue toxicity in breast cancer models.
Utilized a triple-negative breast cancer patient-derived xenograft model for comparison of FLASH-RT with conventional radiotherapy (CONV-RT).
Administered a single 30Gy electron irradiation dose to TNBC-bearing mice using specialized jigs to target mammary and hemithoracic fields.
Assessed cumulative tolerance to re-irradiation in non-tumor-bearing mice with a second 25Gy FLASH dose and monitored for clinical decline.
Evaluated multiple endpoints including tumor regression, recurrence, survival, and skin toxicity scores.
FLASH-RT achieved similar tumor control to CONV-RT, with both methods resulting in complete tumor regression by day 16.
FLASH-RT significantly reduced acute skin toxicity (median score 0 vs. 5; p<0.0001) and eliminated ulceration in tumor-bearing mice.
Mice receiving FLASH-RT had increased survival (120 vs. 90 days) compared to those receiving CONV-RT.
Non-tumor-bearing mice showed better tolerance to re-irradiation with FLASH-RT, experiencing no clinical decline compared to adverse effects seen with CONV-RT.

Abstract

Abstract Background: Radiotherapy is central to breast cancer treatment but is limited by acute and cumulative skin toxicity, especially in large-field treatments and re-irradiation. Ultra-high-dose-rate FLASH radiotherapy (FLASH-RT, ≥ 40 Gy/s) may widen the therapeutic window by reducing normal-tissue injury without compromising tumor control. However, breast-directed and patient-derived models remain underexplored, including the effects of FLASH under repeated-irradiation conditions. Methods: We integrated an orthotopic triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) model and hemithoracic normal-tissue models to compare FLASH-RT (180 Gy/s) with CONV-RT (0.03 Gy/s). TNBC-bearing NRG mice received single-fraction of 30Gy electron irradiation via a custom stereotactic jig enabling mammary-targeted or hemithoracic fields. A separate cohort of non-tumor-bearing NRG mice underwent left-chest re-irradiation to assess cumulative tolerance. Endpoints included tumor regression, recurrence, survival, and graded skin toxicity; ongoing analyses incorporate histopathology and single-cell/spatial transcriptomics to elucidate FLASH-mediated tissue responses and mechanisms of normal-tissue sparing. Results: FLASH-RT achieved equivalent tumor control to CONV-RT in TNBC-PDX models, with both modalities inducing complete regression by day 16 and maintaining clearance for two weeks before recurrence at day 32 post-RT. In contrast, normal-tissue responses diverged markedly: FLASH-RT significantly reduced acute skin toxicity (median score 0 vs. 5; p0.0001), eliminated ulceration, and extended survival (120 vs. 90 days post-implantation) in tumor bearing mice. In non-tumor-bearing NRG mice, FLASH-RT also improved tolerance to cumulative thoracic irradiation; mice receiving a second 25Gy left-chest FLASH irradiation dose showed no clinical decline, whereas CONV-RT animals developed progressive toxicity requiring euthanasia within three months of re-irradiation. Multi-omics analyses are underway to define mechanisms of early tissue sparing and improved re-irradiation response. Conclusions: FLASH-RT maintains tumor-control efficacy equivalent to CONV-RT while significantly reducing skin toxicity in TNBC-PDX models and improving normal-tissue tolerance to re-irradiation in non-tumor-bearing NRG mice. These findings support FLASH-RT as a clinically promising strategy that may expand safe re-treatment options and broaden curative radiotherapy opportunities in breast cancer. Mechanistic studies are ongoing to elucidate the biological basis of early tissue sparing and guide translation into breast-conserving and post-mastectomy treatment settings. Citation Format: Adel Zaid I Mutahar, Banita Verma, Stavros Melemenidis, Suparna Dutt, Kerriann M. Casey, Zhen Qi, Angera Hsiao-Chi Kuo, Kathleen C. Horst, Edward Elliot Graves, Michael F. Clarke, Billy W. Loo, Frederick M. Dirbas. FLASH radiotherapy maintains tumor control and enables safe re-irradiation while preserving normal tissue in breast cancer PDX models abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5266.

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