Focal Irradiation and Systemic TGFβ Blockade in Metastatic Breast Cancer.
Focal Irradiation and Systemic TGFβ Blockade in Metastatic Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-17-3322
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发表时间：
2018-06-01
期刊：
影响因子：
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通讯作者：
McBride WH
中科院分区：
文献类型：
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作者：
Formenti SC;Lee P;Adams S;Goldberg JD;Li X;Xie MW;Ratikan JA;Felix C;Hwang L;Faull KF;Sayre JW;Hurvitz S;Glaspy JA;Comin-Anduix B;Demaria S;Schaue D;McBride WH
本研究探讨了转移性乳腺癌患者放疗期间 TGFβ 阻断的可行性、有效性（远隔效应）和免疫效应。比较两种剂量的 TGFβ 阻断抗体 fresolimumab 的前瞻性随机试验。具有至少三个不同转移部位且肿瘤在至少一种治疗后出现进展的转移性乳腺癌患者被随机接受 1 或 10 mg/kg 的 fresolimumab，每 3 周一次，共 5 个周期，在第 1 周对转移部位进行局部放疗（3 剂 7.5 Gy），可在第 7 周对第二个病灶重复治疗。在基线、第 2 周、第 5 周和第 15 周抽取研究血液以进行分离PBMC、血浆和血清。 23 名患者被随机分组，中位年龄 57 岁（范围 35 至 77 岁）。 1mg/kg 组中有 5/11 名患者发生了 7 例 3/4 级不良事件，10mg/kg 组中有 2/12 名患者发生了 7 例 3/4 级不良事件。反应仅限于 3 种稳定的疾病。中位随访 12 个月后，20/23 的患者死亡。接受 10mg/kg 剂量的患者的中位总生存期显着高于接受 1mg/kg fresolimumab 剂量的患者（风险比：2.73，95% CI：1.02、7.30；p=0.039）。较高的剂量与外周血单核细胞计数的改善和 CD8 中央记忆池的显着增强相关。放射治疗期间的 TGFβ 阻断是可行的且耐受性良好。接受较高剂量fresolimumab的患者具有良好的全身免疫反应，并且比较低剂量组的中位总生存期更长。
This study examined the feasibility, efficacy (abscopal effect) and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients. Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, with focal radiotherapy to a metastatic site at week 1, (3 doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5 and 15 to isolate PBMCs, plasma and serum. Twenty-three patients were randomized, median age 57 (range 35 to 77). Seven grade 3/4 adverse events occurred in 5/11 patients in the 1mg/kg arm and in 2/12 patients in the 10mg/kg arm, respectively. Response was limited to 3 stable disease. At a median follow up of 12 months, 20/23 patients are deceased. Patients receiving the 10mg/kg had a significantly higher median overall survival than those receiving 1mg/kg fresolimumab dose (hazard ratio: 2.73 with 95% CI: 1.02, 7.30; p=0.039). The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group.