Focal Irradiation And Systemic Transforming Growth Factor {beta} Blockade in Metastatic Breast Cancer

PURPOSE: This study examined the feasibility, efficacy (abscopal effect) and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients.EXPERIMENTAL DESIGN: 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.RESULTS: 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. CONCLUSIONS: 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.

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