PO.CL08.02 · 临床研究
FLASH放疗在乳腺癌PDX模型中维持肿瘤控制并实现安全的再照射，同时保护正常组织
FLASH radiotherapy maintains tumor control and enables safe re-irradiation while preserving normal tissue in breast cancer PDX models
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摘要 Abstract
中文摘要
背景：放疗是乳腺癌治疗的核心，但受到急性和累积性皮肤毒性的限制，尤其是在大野治疗和再照射中。超高剂量率FLASH放疗（FLASH-RT，≥40 Gy/s）可能通过减少正常组织损伤而不影响肿瘤控制来拓宽治疗窗。然而，针对乳腺的模型和患者来源的模型仍未被充分探索，包括FLASH在重复照射条件下的效应。
方法：我们整合了一个原位三阴性乳腺癌（TNBC）患者来源异种移植（PDX）模型和半胸正常组织模型，以比较FLASH-RT（180 Gy/s）与CONV-RT（0.03 Gy/s）。荷TNBC的NRG小鼠通过一个可实现乳腺靶向或半胸野的定制立体定向夹具接受单次30 Gy电子照射。另设一组非荷瘤NRG小鼠接受左胸再照射以评估累积耐受性。终点包括肿瘤消退、复发、生存和分级皮肤毒性；正在进行的分析纳入了组织病理学和单细胞/空间转录组学，以阐明FLASH介导的组织反应和正常组织保护的机制。
结果：在TNBC-PDX模型中，FLASH-RT实现了与CONV-RT相当的肿瘤控制，两种模式均在第16天诱导完全消退，并在复发（放疗后第32天）前维持清除达两周。相比之下，正常组织反应则明显不同：FLASH-RT显著减少了急性皮肤毒性（中位评分0对5；p<0.0001），消除了溃疡，并延长了荷瘤小鼠的生存期（植入后120天对90天）。在非荷瘤NRG小鼠中，FLASH-RT还改善了对累积胸部照射的耐受性；接受第二次25 Gy左胸FLASH照射剂量的小鼠未表现出临床恶化，而CONV-RT动物则出现进行性毒性，需要在再照射后三个月内实施安乐死。多组学分析正在进行中，以确定早期组织保护和改善再照射反应的机制。
结论：FLASH-RT维持了与CONV-RT相当的肿瘤控制疗效，同时在TNBC-PDX模型中显著减少了皮肤毒性，并在非荷瘤NRG小鼠中改善了正常组织对再照射的耐受性。这些发现支持FLASH-RT作为一种具有临床前景的策略，可能扩大安全再治疗的选择，并拓宽乳腺癌根治性放疗的机会。机制研究正在进行中，以阐明早期组织保护的生物学基础，并指导向保乳和乳房切除术后治疗场景的转化。
查看英文原文 English 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; p<0.0001), 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.
利益披露 Disclosure
A. Mutahar, None..
S. Melemenidis, None..
K. M. Casey, None..
K. C. Horst, None.